During the FDA’s review
of the BLA, the FDA suggested, and we agreed, to revise our proposed indication to remove the term “prevention,” as the term
“delay” more accurately reflects the results of the TN-10 trial.
In
October 2021, the FDA sent a second deficiency letter for our application for Rare
Pediatric Disease
designation for teplizumab. In its letter, the FDA’s Office of Orphan Drug Development (“OOPD”), noted that
they believe the At-Risk Stage 2 population is greater than 200,000 subjects in the United States and we have one
year from the date of the deficiency letter (or any approved extension thereof) to provide arguments otherwise, or
our request for Rare Pediatric Disease designation will be considered voluntarily withdrawn. We currently do not have plans
to take any additional steps to address OOPD’s positions. We previously applied for orphan drug designation of teplizumab for
the use in at-risk individuals which was denied by the OOPD in February 2021.
An Innovation Passport
in the United Kingdom was granted on July 12, 2021 in recognition of the significant patient or public need of teplizumab. Grant
of the Innovation Passport paves the way for enhanced engagement with the MHRA and health technology agencies such as the National Institute
for Health and Care Excellence (“NICE”) in the Innovative Licensing and Access Pathway (“ILAP”). ILAP is a new
pathway created in the United Kingdom to accelerate the time to market, thus facilitating patient access to innovative medicines. We
are targeting a potential filing of a MAA in the first half of 2023, assuming favorable regulatory interactions. We plan to continue
to evaluate the regulatory path forward in the United Kingdom and in the European Union based on our further engagement with the MHRA,
EMA and other European stakeholders in 2022.
Based
on our analysis of literature, we believe the following represent the approximate estimated prevalence of At-Risk individuals.
Familial direct relatives have 10x greater incidence of T1D autoimmunity than the general population:
We are currently exploring and
supporting research and lifecycle management programs for T1D beyond our current pipeline. Within T1D, we are exploring programs
which include repeat dosing and age expansion for both at-risk individuals and newly diagnosed patients, as well as subcutaneous
formulations and combination therapies potentially with antigens, regulatory T cells, metabolic drugs, immune modulators and islet or
beta cell transplants. We are evaluating other potential indications for teplizumab including, gastrointestinal (“GI”)
immunology disorders such as Crohn’s disease, celiac disease and autoimmune hepatitis or rheumatology disorders such
as rheumatoid arthritis. These initiatives may result in or include new clinical studies sponsored by us or investigator-initiated
studies, which are clinical studies initiated and sponsored by physicians or research institutions with funding from us.
T1D
Background Information
T1D
is the end result of immune-mediated destruction of the insulin-producing beta cells of the pancreas and is one of the most common and
serious chronic conditions occurring in childhood. T1D patients require life-long dependence on insulin products delivered through multiple
daily injections or continuous infusion pumps. While the disease presents in children and adults, the vast majority of T1D is diagnosed
in children, with more than half of T1D patients diagnosed before the age of 14 years. The life-expectancy of individuals with younger-onset
disease is on average 16 years shorter than non-diabetic individuals. Individuals diagnosed before the age of 10 years have a 30-times
greater risk of serious cardiovascular outcomes than the general population resulting in decreased life expectancy, compared to healthy
individuals. It is believed the loss of beta cells, which is more severe and rapid in younger individuals leading to increased glycemic
load, is the cause of increased cardiovascular-related deaths. The disease is believed to occur in genetically susceptible individuals
upon exposure to environmental triggers. In addition, because of a similar genetic predisposition, patients with T1D are at high risk
of developing celiac disease. Celiac disease is characterized by autoimmunity in the gut and other organs triggered by consumption of
gluten and can lead to malnutrition and other complications including a form of cancer called lymphoma. There is no approved therapy
for celiac disease.
Lack
of insulin secretory capacity has serious consequences, even when patients receive insulin replacement therapy. The complications of
T1D include eye disease, nerve damage, kidney disease and heart disease. Diabetic retinopathy has a prevalence of approximately 80% among
patients with T1D and is the leading cause of vision impairment and blindness among adults. Moreover, about 60% to 70% of people with
diabetes present some form of neuropathy that can induce numbness, weakness and blood pressure dysregulation. In addition, diabetic nephropathy
is the leading cause of chronic kidney disease and affects about 30% of T1D patients. Diabetes can also cause severe heart complications
and adults with diabetes are two to four times more likely to die from heart disease than adults without diabetes.
In
summary, people with T1D experience substantial morbidity and mortality owing to chronic complications.
Current
T1D Treatment Options and Their Limitations
So
far, no disease-modifying or curative treatment exists for T1D. Patients with T1D still need to use daily insulin injections to manage
blood sugar to within a normal range. However, it is estimated that fewer than one-third of people with T1D in the United States achieve
target blood glucose levels and insulin injections often cause hypoglycemia (low blood sugar). While insulin injections or infusion allow
a person with T1D to stay alive, they do not cure the disease, nor do they necessarily reduce the risk of serious effects and long-term
complications of T1D.
While
pancreatic and islet cell transplantation offer the ability to normalize glucose levels and remove the dependence on insulin products,
there are significant risks, resulting in a modest number of such transplants being conducted every year. There is risk associated with
mandatory immunosuppression, which commonly results in the development of infections that may be life-threatening. Furthermore, pancreas
transplantation may be associated with technical complications (vascular thrombosis, pancreatitis, infection, fistulas) as well as acute
and chronic organ rejection. Islet cell transplantation can provide better glycemic control and protect patients from hypoglycemic episodes,
but only approximately 50% of patients are insulin-free after three years of follow-up. In a small, published study, Bellin 2012, the
addition of teplizumab to the conditioning regimen has improved those figures to approximately 70% insulin-free at 5 years, providing
a rationale for the continued study of teplizumab in this context.
New
approaches are still required and could significantly enhance patient care. In particular, there is a strong need for new preventive
or curative treatments. Among the different possible strategies, primary prevention through vaccination, which we are investigating with
PRV-101, and secondary prevention (interception) with a disease-modifying non-chronic immune modulator, which we are investigating with
teplizumab.
Overview
of T1D Biology and teplizumab Mechanism of Action
T1D
is an autoimmune disease which occurs in genetically-predisposed individuals. Specialized white blood cells of our immune system, known
as self-reactive T cells (also called auto-reactive), are triggered, presumably by CVB viral infection of the beta cells in at least
50% of cases, to attack and destroy beta cells of the pancreas, thus causing a decline in the natural production of insulin. Simultaneously,
another type of T cell, Tregs, which normally suppress the activity of self-reactive T cells, fail to do so effectively.
The
clinical progression of T1D is relatively well understood and predictable, as it is a continuum marked by clinically-relevant biomarkers
which identify stages of the disease. In an individual with genetic risk (primarily driven by human leukocyte antigen (“HLA”)
haplotypes), the natural evolution of T1D has been described in stages (see figure below).
| |
● |
Stage
1: emergence of T1D-related autoantibodies which reflect the initiation of the autoimmune process; this stage is associated with
normoglycemia. |
| |
● |
Stage
2: persistence T1D-related autoantibodies, but with further loss of beta cell function and development of dysglycemia. |
| |
● |
Stage
3: symptomatic or clinical T1D, when remaining beta cell capacity is insufficient to maintain glucose metabolism. |
Stages
of Type 1 Diabetes
It
is important to note that once subjects develop two or more T1D-related autoantibodies (Stage 1), the progression to clinical T1D (Stage
3) is not a matter of “if” but “when” as greater than 95 percent of the Stage 1 subjects and virtually all of
the Stage 2 subjects will progress to Stage 3 necessitating insulin dependence. The progression of Stage 1 to Stage 3 is 44% in five
years, and of Stage 2 to Stage 3 is 75% in four to five years.
Current
Clinical Development Program
Newly-Diagnosed
Patients (Stage 3)
Phase
3 Clinical Trial of teplizumab in Pediatric Patients Newly-Diagnosed T1D (PROTECT Study)
The
PROTECT study (PROvention T1D trial Evaluating C-peptide with Teplizumab) is a randomized, double-blind,
placebo-controlled, multicenter Phase 3 clinical trial in pediatric and adolescent patients (aged eight to 17 years) that are newly-diagnosed
with clinical T1D. Patients with minimum beta-cell cell function (C-peptide >0.2 pmol/mL) and within six weeks of T1D diagnosis will
receive two courses of teplizumab, six months apart. Each course will consist of 12 days of teplizumab administered intravenously, with
a cumulative dose of ~9.0 mg/m2. The primary endpoint is the change in C-peptide at 18 months. Secondary endpoints including insulin
use, HbA1C levels, hypoglycemic events and safety will also be evaluated. The study is expected to enroll approximately 300 patients
with 2:1 randomization (200 active: 100 placebo) and enrollment commenced in the second quarter of 2019. We reached the target enrollment
of 300 patients during the third quarter of 2021. Given the challenges the COVID-19 pandemic has presented to clinical trials across
the industry, we ultimately exceeded the enrollment target by approximately ten percent to ensure there were a sufficient number of evaluable
patients. We expect to report top line data from the PROTECT Phase 3 study in the second half of 2023.
In
March 2020, we announced a temporary pause in the randomization of patients with newly diagnosed T1D into our global Phase 3 PROTECT
study of teplizumab. This pause was taken to protect patients, caregivers, clinical site staff, company employees and contractors as
part of the collective global efforts to combat the COVID-19 pandemic. Patients that were undergoing study therapy were allowed to complete
their course, as recommended by the PROTECT study’s Data Safety Monitoring Board, which was expanded to include infectious disease
expertise. In June 2020, we resumed enrollment on a country by country, site by site basis based upon review of local COVID-19 infection
rates and the site’s ability to maintain the safety of participants.
We
are also conducting an extension study of the PROTECT trial, PROTECT Extension. The purpose of this study is to evaluate the long-term
safety profile of PROTECT study patients who received a 12-day course of teplizumab treatment upon T1D diagnosis and a second 12-day
course of teplizumab treatment approximately six months later. The extension study will provide a total of 5-year safety data from the
initiation of treatment for the participants in the PROTECT Study.
Prior
Clinical Evaluation of teplizumab
To
date, clinical development of teplizumab has included both academic and biopharmaceutical sponsors. Approximately 1,100 subjects have
been enrolled in teplizumab clinical trials, with over 800 subjects receiving teplizumab. These studies represent various doses, formulations,
and indications and includes earlier smaller investigator-sponsored studies. The majority of patients were enrolled in T1D studies (>1,000),
and the rest in renal or renal-pancreatic allograft rejection, pancreatic islet transplant, psoriatic arthritis or plaque psoriasis trials.
In
T1D patients, ten studies have been conducted, of which nine involved intravenous dosing (two Phase 1, three Phase 2, two Phase 3 and
a Phase 3 extension study) and one subcutaneous dosing (Phase 1).
Among
the T1D studies of teplizumab:
| |
● |
In
Stage 2, the At-Risk study enrolled Stage 2 individuals who were characterized as having at least two T1D autoantibodies and evidence
of hyperglycemia. |
| |
● |
In
Stage 3, five studies (Study 1, Study 2, Study 3, Study 4 “AbATE”, and Study 5 “Delay”) were completed under
the direction of Dr. Kevan Herold (currently at Yale University) and collaborators. Studies 2, 3 and 4 were sponsored by the Immune
Tolerance Network. Four additional studies were conducted by MacroGenics: three with intravenous administration (“Protégé”,
“Protégé Extension”, and “Protégé Encore”) and one with subcutaneous administration
(SUBCUE) of teplizumab. Among these studies, “Protégé” and “Protégé Encore” were
Phase 3 studies. Protégé was the largest completed study for treatment of T1D, which enrolled 516 patients (aged eight
to 35 years and T1D diagnosis within 12 weeks of study entry) and randomized into three teplizumab dosing regimens compared to placebo.
Teplizumab showed promising immunological and clinical activities in these studies and was well tolerated. In particular, teplizumab
treatment showed promising data on the preservation of C-peptide levels and the reduction of exogenous insulin use. |
Stage
2 Programs
Phase 2 Clinical
Trial of teplizumab in At-Risk Relatives who develop T1D (At-Risk TN-10 Study)
The
“At-Risk” TN-10 Study, a pivotal Phase 2 clinical trial, conducted at TrialNet sites and sponsored by National Institute
of Diabetes and Digestive and Kidney Diseases (“NIDDK”), part of the National Institute of Health (“NIH”), evaluated
teplizumab for the delay of clinical T1D in at-risk individuals. At-risk was defined by the presence of two or more T1D-related autoantibodies
and dysglycemia (abnormal glucose metabolism). 76 subjects were enrolled, ages eight to 49 years, with 72 percent under the
age of 18, and randomized to receive a single 14-day course of either teplizumab (cumulative dose of ~9.0 mg/m2) or placebo. Subjects
were followed in a blinded fashion until a minimum 40 subjects developed clinical T1D which triggered the analysis of the primary endpoint.
Thereafter, subjects were followed indefinitely in other TrialNet studies. Those who developed clinical T1D after the primary analysis
was completed are eligible to enroll in a Provention trial, PRV-031-002, which we initiated in March 2020, described below.
Participants
over eight years of age with Stage 2 T1D (presence of at least two T1D autoantibodies and dysglycemia, who were non-diabetic relatives
of T1D individuals) were randomized 1:1 to receive teplizumab or placebo. Dysglycemia was defined on oral glucose tolerance test (“OGTT”)
as: (a) Fasting plasma glucose ≥ 110mg/dL, and <126mgdL, or (b) 2-hour plasma glucose ≥140mg/dL, and <200mg/dL, or (c) 30,
60, or 90-minute value on OGTT ≥200mg/dL.
The
primary endpoint was the time from randomization to the clinical diagnosis of diabetes, using ADA criteria. Criteria for clinical T1D
diagnosis are based on glucose testing, or the presence of unequivocal hyperglycemia with acute metabolic decompensation (diabetic ketoacidosis).
One of the following criteria must be met on two occasions as soon as possible but no less than one day apart for diabetes to be defined:
| |
● |
Symptoms
of diabetes plus casual plasma glucose concentration > 200 mg/dL (11.1 mmol/l). Casual is defined as any time of day without regard
to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. |
| |
● |
Fasting
plasma glucose ≥ 126 mg/dL (7 mmol/l). Fasting is defined as no caloric intake for at least eight hours. |
| |
● |
2-hour
plasma glucose ≥ 200 mg/dL (11.1 mmol/l). The test should be performed using a glucose load containing the equivalent of 1.75g/kg
body weight to a maximum of 75 g anhydrous glucose dissolved in water. |
Teplizumab
was administered over a 14-day course: 51 μg/m2, 103 μg/m2, 207 μg/m2, and 413 μg/m2 on study days 0–3, respectively,
and 826 μg/m2 on each of study days four through 13. A total of 112 participants were screened and 76 were randomized, 44 to teplizumab
and 32 to placebo. The baseline characteristics were balanced for age (median ~13-14 years of age), relationship to the relative with
T1D, type of T1D autoantibodies and HbA1c.
At-Risk
TN-10 Study– Primary Data Readout in June 2019
Treatment
with a single course of teplizumab delayed the time to T1D (see figure below): 19 of the 44 (43%) teplizumab-treated and 23 of the 32
(72%) placebo-treated participants were diagnosed with T1D. The annualized rates of T1D development were 14.9% and 35.9% per year, for
the teplizumab and placebo groups, respectively. The median time to T1D was 24.4 months in the placebo and 48.4 months in the teplizumab
groups (hazard ratio = 0.412 (95% CI: 0.216, 0.783) p=0.006 (2-sided)).
Time
to T1D
In
pre-specified analyses, the effects of teplizumab on the primary outcome based on baseline characteristics were evaluated. Although subgroup
analyses had small sample sizes and need to be taken with caution, participants without anti-ZnT8 antibodies showed a greater effect
size compared to those who did not have the antibody. The presence of HLA-DR4 and absence of HLA-DR3 were also associated with greater
effect size, as was a below median C-peptide response to the OGTT at baseline (1.75 nmol/L). These larger effect sizes are attributed
to more rapid progression of the disease in these subgroups, rather than clinically-actionable baseline characteristics able to predict
response to teplizumab. We believe all patients with Stage 2 T1D can benefit from teplizumab as long as they have beta cells to be protected.
With regard to adverse events,
similar to previous studies with teplizumab in newly-diagnosed T1D patients, the most common adverse events were transient lymphopenia
and transient rash. Regarding lymphopenia, lymphocyte count declined to a nadir on day five by 72.3% (IQR 82.1, 68.4%) (p<0.0001)
and then returned to baseline levels. This transient lymphopenia is believed to be the mechanistic consequence of margination (adhesion
to the blood vessel wall) rather than depletion. Fifteen (34.1%) of the grade 3 events in the teplizumab group involved lymphopenia during
the first 30 days after study drug administration. The lymphocyte counts recovered quickly: Lymphopenia resolved in all participants
by day 45 except in one, whose counts returned on day 105. A spontaneously resolving rash, as previously noted, occurred in 36% of drug
treated participants. The rates of clinical infection were similar in the two treatment arms.
Other
anti-CD3 mAb experimental treatments, such as otelixizumab, have been associated with Epstein Barr virus (“EBV”), clinical
reactivation in patients with latent infection. At entry, 30 participants (39%) (16 teplizumab and 14 placebo) had antibodies against
EBV in TN-10. At weeks 3-6 after study drug treatment, there was quantifiable EBV DNA in whole blood in eight of the seropositive participants
– all in the teplizumab group, one of whom had symptoms of pharyngitis, rhinorrhea, and cough on day 38. In these participants,
the EBV DNA levels were below the level of quantification between day 43 and 134 (average 77 days). At entry, 17 participants (ten teplizumab
and seven placebo) had antibodies against cytomegalovirus (“CMV”). One teplizumab participant, who was CMV seropositive,
had detectable levels of CMV DNA at day 20 that was undetectable by day 42. These results show that, while viral reactivation may be
observed during the first weeks post-teplizumab administration, these are typically asymptomatic and that immune competence is maintained
that results in the resolution of viremia.
The
TN-10 trial results demonstrate that a single course of teplizumab significantly delayed the progression to clinical T1D in high-risk
Stage 2 relatives who had at least two autoantibodies and dysglycemia. The median delay in the diagnosis of diabetes was approximately
two years, and at the conclusion of the trial, the frequency of diabetes-free subjects was double in the drug (57%) vs placebo-treated
subjects (28%). The relatively rapid rate of progression to clinical diabetes in the placebo group, consistent with the previously reported
natural history, reflects the very high risk of these individuals and reflects the inevitability of progression from Stage 2 to Stage
3 disease, consistent with observations of high rates of beta cell killing in these subjects. The rapid development of clinical T1D may
also reflect the enrichment of pediatric participants (72.4%) in whom the rate of progression is rapid. The safety profile was consistent
with previous experience and teplizumab was well-tolerated.
At-Risk
TN-10 Study - Extended Data Readout in June 2020
After the primary readout in
the TN-10 study, patients were followed indefinitely in other TrialNet observational studies. On June 15, 2020, we announced that new
data from the TN-10 study was presented on that date by TrialNet at the 2020 American Diabetes Association Annual meeting. These follow-up
data demonstrated that the single 14-day course of teplizumab had delayed the onset of clinical T1D, as compared to placebo, by a median
of approximately three years in at-risk individuals. In other words, the follow-up data from the TN-10 added approximately one year to
the two-year median delay that was previously observed and reported in the primary analysis. The median time to clinical diagnosis of
T1D after one course of teplizumab was approximately five years (59.6 months) compared to approximately two years (27.1 months)
for the placebo group (unchanged from previously published data). Nearly half of those treated with teplizumab are estimated to be
free of clinical T1D at five years. The hazard ratio was 0.457 or a 54 percent reduction in risk of developing clinical T1D (p=0.01).
On
March 3, 2021, we announced the peer reviewed publication of the extended follow-up results from the TN-10 study showing that a single
teplizumab 14-day course delayed the onset of insulin dependence in T1D patients by approximately 32.5 months compared to placebo.
In
addition, teplizumab treatment was associated with a greater on-study C-peptide (p=0.009), a measure of a persons’ own insulin
production, compared to placebo. For both groups, C-peptide AUC mean slopes preceding study entry were similar and declining. In the
placebo group, this decline continued over the six months after study entry. By contrast, the teplizumab-treated group showed an increased
C-peptide AUC over this period (p=0.02 relative to study entry).
Note:
Adapted from presentation 277-OR at ADA 2020 (Sims et al, June 15, 2020).
Mechanistically,
the association between the expansion of partially exhausted CD8 T cells and the delay of clinical T1D conferred by teplizumab, previously
described in newly diagnosed T1D patients, was also confirmed in subjects at-risk. C-peptide levels at three, six and 18 months post-teplizumab
administration correlated with the levels of exhausted CD8+ T cells in the circulation (p=0.01 vs placebo). Subjects with the highest
increase (top quartile) in exhausted CD8 T cells at 3 months post-teplizumab had no progression to clinical T1D in the period of observation
of the study (p=0.005 vs placebo). Finally, inflammatory cytokines IFN-gamma and TNF-alpha were lower in the exhausted CD8 T cells in
teplizumab vs placebo-treated subjects (p<0.0001).
In
summary, the follow-up results showed that teplizumab’s effect on delaying the onset of clinical T1D was not only consistent from
previous analyses, but was durable and now extended the median delay to approximately three years, without any additional safety signals
noted.
Stage
3 Programs
Protégé
Study
Protégé
was a randomized, controlled Phase 3 clinical trial conducted in 83 centers in North America (United States, Canada, Mexico),
India, Israel, and Europe (Czech Republic, Estonia, Germany, Latvia, Poland, Romania, Spain, Sweden, Ukraine) completed between 2007
and 2011. Patients aged eight to 35 years with recently diagnosed T1D (≤12 weeks) were followed for 12 months (Protégé)
and continued to 24 months (Protégé Extension). Three dose regimens of teplizumab were administered to 417 patients as
intravenous infusions for six to 14 days; 99 patients received placebo. At 12 months, the primary efficacy endpoint, the proportion of
patients with insulin use <0.5 U/kg per day and HbA1c <6.5%, ranged from 13.7% to 20.8% patients in the teplizumab groups, depending
on dosing regimen, and 20.4% in the placebo group. The difference between teplizumab-treated patients and placebo-treated patients was
not significant. The change in HbA1c from baseline also did not show a significant difference between teplizumab and placebo. However,
subgroup analyses indicated the following findings:
| |
● |
We
believe that the primary endpoint could have been achieved if cut-offs were changed to insulin use of <0.25 U/kg per day and HbA1c
<7.0%, not only at 12 months but also at 24 months (figure below). |
| |
● |
C-peptide
levels significantly improved in the teplizumab group compared with placebo group in all patients, and further analyses indicated
that this difference was more pronounced in younger patients (aged eight to 11 years) and patients enrolled in United States sites.
These findings are consistent with other clinical trials, showing a stronger effect in T1D patients who are younger (<17 years),
more recently diagnosed (<10 weeks), and with higher C-peptide levels at baseline. |
Protégé
Encore Study
Protégé
Encore was a randomized, controlled Phase 3 clinical trial conducted in 125 centers in 16 countries completed between 2009 and 2012.
Patients aged eight to 35 years with recently diagnosed T1D were to be followed for 24 months. Three dose regimens of teplizumab, given
as intravenous infusions for six to 14 days, were compared with placebo. The primary endpoint, the proportion of patients with insulin
use <0.5 U/kg per day and HbA1c <6.5% at 12 months, was not met. Study enrollment was stopped at 254 patients (400 planned) when
the Protégé study showed that the primary endpoint was not met. Efficacy analyses were not conducted in this study.
A
summary of the C-peptide data in the completed Phase 2 clinical trials and Phase 3 Protégé study are shown in the table
below. All these studies have shown consistent and significant C-peptide benefit. Furthermore, subgroup analysis of the Protégé
data indicated that younger patients (aged eight to 17 years) with minimum baseline beta cell function (C-peptide >0.2 pmol/mL) along
with even more robust data in T1D patients with diagnosis under six weeks (Study 1), informed the inclusion criteria applied in our Phase 3 study, PROTECT.
| * |
Full
9.0 mg/m2/course 14-Day regimen was explored in 205 treated patients and 98 placebos; |
| ** |
Delay
study based on 12-month time-point. All other studies based on 24-month time-points |
SUBCUE
Study
SUBCUE
was a randomized, controlled Phase 1 clinical trial to evaluate the safety and tolerability, PK, and PD of subcutaneously injected teplizumab
conducted between 2010 and 2011. Patients aged 18 to 35 years who were diagnosed with T1D within 12 months were to be given three dosing
regimens of teplizumab or placebo. Patients were to be followed for 91 days. However, the study was stopped after one subject was enrolled,
upon the Protégé study results.
Safety
Data
Teplizumab
safety data in T1D subjects have been analyzed from five clinical studies with similar study characteristics including a randomized controlled
design and testing the proposed cumulative dose of 9034 µg/m2 (~9.0 mg/m2) per treatment course. Four of
these studies enrolled subjects with newly diagnosed Stage 3 clinical T1D (two Phase 2 studies, AbATE and Delay, and two Phase 3 studies,
Protégé and Encore). One of these trials enrolled Stage 2 subjects in the At-risk (TN-10) study. The safety summary provided
below pools data from the four Stage 3 clinical studies and a separate summary for the Stage 2, At-risk study (TN-10).
In
Stage 3 teplizumab and placebo subjects, there were no major differences in the overall adverse events (“AEs”) (99.6% and
99.1%), and serious adverse events (“SAEs”) (12.2% (91 of 729 subjects), and 8.9% (19 out of 213 subjects), although there
were more severe AEs in teplizumab subjects (59% and 25%). In At-risk Stage 2 subjects, there was a higher incidence of AEs, SAEs, and
severe AEs in the teplizumab subjects compared with placebo (AEs: 97.7% and 68.8%, SAEs: 15.9% (7 of 44 subjects) and 3.1% (1 of 32 subjects),
and severe AEs: 59.1% and 9.4%).
The
most common AEs were related to decreases in white blood cells (lymphopenia, leukopenia and neutropenia) as well as rash.
Lymphopenia was expected based on the mechanism of action of teplizumab and was observed in approximately 80% of Stage 3 and 73% of
Stage 2 T1D subjects who received teplizumab compared with approximately 18% of Stage 3 and 6% of Stage 2 subjects who received
placebo. Lymphopenia was commonly mild to moderate and resolved within 14 days. In Stage 3 T1D subjects, approximately 36% and 12%
of teplizumab - and placebo-treated subjects, respectively, reported rash. In Stage 2 TID subjects, approximately 14% and 0% of
teplizumab - and placebo-treated subjects, respectively, reported rash. In teplizumab-treated patients, the rash was predominantly
mild to moderate and usually resolved within one to two weeks. Laboratory abnormalities were also reported as AEs. The main
differences in incidence in teplizumab and placebo subjects were related to liver function tests. For example, increased alanine
aminotransferase occurred in 27.8% and 12.7% of Stage 3 teplizumab and placebo subjects and 4.5% and 3.1% of Stage 2 teplizumab and
placebo subjects. These transaminase elevations were likely due to cytokine effects on the liver, usually resolved within 14 days of
dose completion, and did not cause significant or lasting clinical concern. Cytokine release syndrome, which may include symptoms of
rash, headache, nausea, vomiting, and chills/fever, occurred in 6% and 1.4% of teplizumab- and placebo-treated Stage 3 subjects and
2.3% and 0% of teplizumab- and placebo-treated Stage 2 subjects. Cytokine release syndrome was predominantly mild to moderate in
severity, and in the majority of subjects (~80%), the treatment course was completed.
In
both Stage 3 and Stage 2 subjects, a total of 118 subjects (98 teplizumab (12.4%), 20 control (8.2%)) experienced one or more
SAEs for a total of 167 SAEs. The majority, 76.7%, (128 out of 167) of SAEs were not considered treatment-related, while 23.4% (39 out
of 167) were deemed related.
| |
● |
In
Stage 3 subjects, 110 of 729 total participants (91 teplizumab (12.2%), 19 control (8.8%)) reported at total of 158 SAEs. The most
common SAEs were related to diabetes control including diabetic ketoacidosis, hypoglycemic seizures/unconsciousness, hyperglycemia,
hypoglycemia (consistent with the underlying disorder) and were reported in 4.9% and 2.3% of Stage 3 teplizumab and placebo subjects,
respectively. These events did not occur in any Stage 2 subjects. |
| |
● |
In
Stage 2 subjects, 8 of 76 total participants (7 of 44 teplizumab (15.9%), 1 of 32 controls (3.1%)) reported a total of 9 SAEs during
the study. Of the 8 SAEs reported in teplizumab subjects, 4 were infections (pneumonia, cellulitis, wound infection, and gastroenteritis).
Two of the 8 SAEs reported in teplizumab subjects were considered by the investigators to be related to study treatment and included
serum sickness and pneumonia. |
Three
deaths were observed in Stage 3 subjects and categorized by the principal investigator (in accordance with International Conference on
Harmonisation/Good Clinical Practice guidelines) and included in the Investigator Brochure for teplizumab filed with the FDA. The relationship
between each death and teplizumab is listed in the Investigator Brochure as follows: one death, “none”; one death “not
related”; and one death “unlikely.” The specific causes of deaths were (1) unknown for subject with gastrointestinal
symptoms which the relationship was listed as “none” in the Investigator Brochure, (2) anterior myocardial infarction with
ventricular tachycardia and cardio-respiratory arrest for which the relationship was listed as “not related” in the Investigator
Brochure and (3) diabetic ketoacidosis for which the relationship was listed as “unlikely” in the Investigator Brochure.
No deaths were reported in Stage 2 subjects.
The
most common severe AE occurring in at least 10% of Stage 3 subjects was lymphopenia observed in 43.6% (326 out of 729 subjects) and 5.2%
(11 out of 213 subjects) of teplizumab and placebo subjects, respectively. In Stage 2 subjects, lymphopenia was also the most frequently
observed severe AE, occurring in 47.5% (21of 44 subjects) teplizumab-treated subjects but none of the placebo subjects. This AE is consistent
with the mechanism of action of teplizumab.
Overall,
in both Stage 3 and Stage 2 subjects, infections were reported in comparable rates between teplizumab and controls (53.0% vs 52.7%) with
the most common infections reported involving upper respiratory infections (19.0% vs 17.6%), nasopharyngitis (11.1% vs 9.4%) and pharyngitis
(5.1% vs 4.5%). The rate of primary EBV infections does not appear to be increased with teplizumab (1.9% vs 3.6%). While there were more
cases of EBV reactivation with teplizumab (3.9% vs 1.2%), they were asymptomatic in the majority of subjects and were associated with
transient viremia.
The
safety profile of teplizumab in the at-risk population (Stage 2 T1D), appeared to be comparable with those of newly diagnosed patients
(Stage 3 T1D). No new safety signals were identified. The majority of the adverse events were mild to moderate and were transient and
manageable.
Phase
2 Clinical Trial of teplizumab in combination with AG019 in newly diagnosed T1D patients
We
believe that combination therapy may enhance the potential therapeutic benefit of teplizumab by increasing efficacy, enhancing the durability
of response, or restoring insulin production by beta cells. Combination therapies may include islet or beta-cell transplant, regulatory
T cells, beta cell antigens, tolerogenic cytokines and other immune modulators, which could enhance the removal of self-reactive lymphocytes
or increase the function of Tregs, or metabolic agents that could further improve or preserve beta cell function or mass.
We
are collaborating with Precigen and its subsidiary, Precigen ActoBio, to explore the combination of teplizumab and the orally
administered AG019, a Lactococcus lactis (“L. lactis”) strain genetically engineered to secrete human proinsulin
and human interleukin-10, an anti-inflammatory cytokine. Precigen reported positive interim results from the Phase 1b/2a clinical
trial, in June 2021 and October 2021, for the combination of AG019 and teplizumab, with a 79% response (C-peptide
preservation) in newly diagnosed T1D. In addition to this collaboration, we plan to explore other combination therapies in the future.
AG019
is an oral-capsule consisting of engineered L. lactis specifically modified to deliver autoantigen
human proinsulin and the tolerance-enhancing cytokine human interleukin-10 to the mucosal lining of the gastro-intestinal tissues. The
primary objective of the study was to assess the safety and tolerability of different doses of AG019 alone as well as AG019 in
association with teplizumab. The secondary objectives of this study are: to obtain PD data of AG019 as monotherapy as well as
AG019 in combination with teplizumab; and PK data to determine the potential presence of AG019 in systemic circulation (safety
- systemic exposure) and the presence of L. lactis bacteria in fecal excretion (local exposure). The study has been completed
and was conducted in two phases:
| |
● |
Phase 1b
(27 participants enrolled): open-label part of the study which investigated the safety and tolerability of two different
doses of AG019 in two age groups (18 to 40 years of age and 12 to 17 years of age). |
| |
● |
Phase 2a
(18 participants enrolled): randomized, double-blind part of the study which investigated the safety and tolerability of
AG019, in association with teplizumab, in two age groups (18 to 40 years of age and 12 to 17 years of age). Patients receive a daily
dose of oral AG019 monotherapy for 8 weeks in combination with daily intravenous infusions of teplizumab for 12 days. |
The
study commenced in October 2018 and enrollment is completed. Precigen presented updates in June and October 2021, on their interim
data from the Phase 1b (monotherapy) and Phase 2a (combination) arms of the study:
| |
● |
AG019
was well tolerated as a monotherapy and in combination with teplizumab with no serious SAEs reported. |
| |
● |
In
the AG019 monotherapy arm, 56% of adult patients (5 of 9) showed stabilization or increase of C-peptide levels during the first 6
months post treatment initiation. |
| |
● |
In
the teplizumab combination arm, 79% of all patients (11 of 14) showed stabilization of C-peptide levels at 6 months post treatment
initiation. |
| |
● |
Exhaustion
of autoreactive T cells, only seen in the teplizumab combination arm, correlated with response. |
| |
● |
There
was an increase in pre-proinsulin (“PPI”) - specific Type 1 regulatory (“Tr1”) cells in both monotherapy
and combination arms. |
| |
● |
There
was a significant decrease in PPI-specific CD8+ T cells in both monotherapy and combination arms. |
PRV-3279
(Humanized CD32B x CD79B Dual Affinity Biologic for SLE and Other Autoimmune Diseases)
PRV-3279
is a humanized CD32B x CD79B dual affinity biologic in a new class of bispecific scaffold antibody-like molecules called DARTs. It is
designed to simultaneously bind to CD32B and CD79B on B cells. The simultaneous binding of both CD32B and CD79B triggers CD32B-coupled
immunoreceptor tyrosine-based inhibitory motif signaling, which leads to the suppression of B cells activated to produce auto-antibodies,
while not causing broad B cell depletion.
We believe PRV-3279 may intercept
the pathophysiology of SLE by preventing the production of auto-antibodies by abnormally active B cells. Additionally, based on our
published clinical (hepatitis A vaccination) and pre-clinical (Pompe disease gene therapy model) studies, we believe PRV-3279 may
prevent the detrimental immunogenicity of biotherapeutic products, such as gene therapy products, though, we will need to conduct additional
clinical studies to confirm and support our belief.
Current
Clinical Development Program in SLE
Preclinical
Studies for the SLE
In
support of the clinical evaluation of PRV-3279 in lupus, we and our partner, MacroGenics, studied the effect of PRV-3279 on B cells from
lupus patients ex vivo. PRV-3279 reduced the activation of these B cells similarly to its effects on healthy volunteer B cells,
regardless of the activity level of the lupus patients. These data were presented at the American College of Rheumatology (“ACR”)
conference in November 2020.
Phase
1b/2a clinical trial of PRV-3279 in Healthy Volunteers and Patients with Lupus
We
are conducting a two-part study in SLE, the PREVAIL (PRV-3279 EVAluation In Lupus) study. PREVAIL is a randomized,
double-blind, placebo-controlled Phase 1b/2a clinical trial to evaluate the safety, tolerability, PK, PD, and immunogenicity of multiple
ascending doses of PRV-3279 in 16 healthy adult volunteers (Part 1) and the efficacy of PRV-3279 in patients with lupus (Part 2). Our
ultimate goal is to determine if PRV-3279 can intercept the pathophysiology of SLE by preventing the production of auto-antibodies by
abnormally active B cells.
On
March 12, 2020, we announced positive top-line results from the Phase 1b portion of the PREVAIL study. PRV-3279 was well-tolerated, with
no serious adverse events, and as expected, did not deplete B cells and demonstrated profound and sustained binding to circulating B
lymphocytes, with reduction of circulating immunoglobulin M levels in a dose-proportional manner. While anti-drug antibody production
was observed at both dose levels tested, immunogenicity was found not to affect exposure, safety or pharmacodynamic parameters. Data
from PREVAIL-1 was presented at the ACR conference in November 2020.
On
January 20, 2022, we announced the initiation of the Phase 2a PREVAIL-2 study. The PREVAIL-2 study is a Phase 2a POC study in moderate-to-severe
SLE patients induced into response with a short course of corticosteroids, and then monitored for relapse, after randomization to either
PRV-3279 or placebo treatment. This design enables the withdrawal of most concomitant medications and clear POC evaluation. The study
will be conducted in the United States and Hong Kong. Screening has commenced in the United States with the goal of identifying and enrolling
approximately 100 patients to 6 monthly infusions of PRV-3279 or placebo, with primary efficacy readout at 24 weeks. Stratification and
pre-defined subset analysis in PREVAIL-2 of a potentially highly responsive SLE population using a B cell gene signature may identify
patients most likely to benefit from PRV-3279 therapy in the future
Clinical
endpoints for the PREVAIL-2 Study will include the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the British
Isles Lupus Assessment Group score, urine protein to creatinine ratio, and daily glucocorticoid use. Additional biomarkers will include
urinary/renal markers (e.g., serum creatinine, estimated glomerular filtration rate) and blood/circulating markers (e.g., auto-antibodies,
complement (C3 and C4), B cell function/phenotype, including CD32B expression/response relationship).
Current
Preclinical Development Program in Gene Therapy
Preclinical
Studies for the Prevention of the Immunogenicity of Biotherapeutics Including Gene Therapy
We
believe that PRV-3279 has the potential to prevent or reduce the immunogenicity of biotherapeutics, including but not limited to gene
therapy vectors and transgenes (new proteins expressed as a result of the gene therapy).
As
the field of gene therapy advances, patients’ immune responses to the viral vectors and the transgene products remain a key challenge
negatively impacting the safety, efficacy and ability to deliver additional courses systemically. One of the current mitigation strategies
to overcome these immune responses is pharmacological modulation of the patients’ antibody immune responses with the B cell depleting
agent rituximab in combination with the immune-suppressive agent sirolimus. The use of rituximab has been associated with certain adverse
events. The use of PRV-3279, as a non-depleting B cell inhibitor, is a potential strategy to address this unmet need in serious genetic
diseases.
PRV-3279
reduced B cell responses to viral antigens using an experimental vaccine challenge in a Phase 1 study. In addition, In January 2021,
we announced positive results of pre-clinical proof-of-concept experiments in support of the prevention of immunogenicity indication.
A PRV-3279 mouse surrogate was tested in mice transgenic for human CD32B, which received gene therapy with an adeno-associated virus
(“AAV”) vector AAV9 encoding for the enzyme acid-alpha-glucosidase (“GAA”) gene. Errors in the GAA gene cause
the serious human glycogen storage disease type II known as Pompe disease. In the study, the PRV-3279 surrogate reduced anti-AAV9 vector
antibody levels in a dose-dependent fashion. Anti-AAV9 antibodies have been linked to reduced efficacy, safety concerns and the inability
to re-dose patients based on these and other study data, we believe PRV-3279 co-administration with gene therapy products has the potential
to improve the safety and efficacy of this therapeutic modality. The PRV-3279 surrogate in combination with sirolimus increased skeletal
muscle levels of GAA enzyme expression. Consistent with prior results from clinical trials in healthy human subjects, the PRV-3279 surrogate
decreased Immunoglobulin M (“IgM”) production and was well tolerated. These results have been presented at the 2021 American
Society for Gene and Cell Therapy conference.
Based
on these data, we plan to look for opportunities to work with academic and industry experts to combine PRV-3279 with gene therapy and
other biotherapeutic products to further our mission of preventing and intercepting devastating immune-mediated conditions.
SLE
Market and Other Opportunities for PRV-3279
Sales
of therapies to treat SLE are expected to climb to nearly $3.0 billion by 2025-2027, approximately 7-8% annual growth from 2019. This
growth is driven primarily by treatments that target B cells, such as belimumab, with a new indication in lupus nephritis in 2020, off-label
use of rituximab, and the approval of new mechanisms (voclosporin for lupus nephritis, approved in January 2021, and the type I interferon
inhibitor, anifrolumab, approved in July 2021 for systemic lupus). Despite these available medications, substantial unmet need remains,
for novel and safe non-depleting B cell therapy with greater efficacy than belimumab.
In
addition to SLE, PRV-3279 has the potential to treat other B cell- and auto-antibody-driven autoimmune diseases. Such diseases include
multiple sclerosis and RA, where B cell therapies rituximab and ocrelizumab have sales in excess of $1 billion. Several niche/orphan
indications may also be explored, including T1D (potentially in combination with teplizumab), Sjogren’s syndrome, vasculitis (e.g.,
polymyalgia rheumatica, giant cell arteritis, Behçets disease), myasthenia gravis, pemphigus, neuromyelitis optica, anti-NMDA
receptor encephalitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Grave’s ophthalmopathy,
IgG4-related disease, and idiopathic thrombocytopenic purpura.
SLE
Background Information
SLE
is a chronic autoimmune disorder that can affect nearly every major organ system, causing inflammation, tissue injury, organ damage,
and in some patients, organ failure. The prognosis of SLE is highly variable in individual patients, often waxing and waning throughout
their lifetime. The natural history of SLE ranges from relatively benign disease to rapidly progressive and even fatal disease. Comorbidities,
such as infections, malignancies, hypertension, lipid disorders and diabetes increase the risk of disability and death in patients with
SLE. Organ systems commonly affected by SLE include the central nervous system, kidneys, gastrointestinal system, mucous membranes, heart,
skin, hematologic system, musculoskeletal system and lungs, with specific organ involvement defining subsets of the disease (e.g., lupus
nephritis). According to the Lupus Foundation of America, at least 1.5 million Americans are afflicted by SLE and more than 16,000 new
cases of lupus are reported annually. It is estimated that five million people throughout the world suffer from some form of lupus. Lupus
affects primarily women of childbearing age (15 to 44 years). However, men, children, and teenagers can also develop lupus.
The
pathogenesis of SLE is characterized by an abnormal overactivation of B cells and subsequent pathologic production of auto-antibodies
(antibodies that attack one’s own cells and tissues). Uncontrolled activation of B cells is normally terminated when the activating
stimulus is exhausted and when a negative feedback loop is triggered by the engagement of an inhibitory Fc receptor (“FcR”),
known as FcgammaRIIb (“CD32B”). Mutations in the CD32B gene in humans are associated with an increased likelihood of SLE,
and reduced expression of CD32B is apparent in B cells from SLE patients. It is thought that activation of this inhibitory pathway could
ameliorate the overactive B cell-driven pathology of SLE and other autoimmune diseases. In addition, the excess auto-antibodies produced
bind to target antigens and form immune complexes.
When
the B cell receptor (“BCR”) (which is the “Y” shaped molecule, resembling an antibody in the figure below) is
bound and activated by an antigen, it initiates a cascade of biochemical changes necessary for the activation of the CD32B inhibitory
pathway, thus triggering the negative feedback loop. CD79B is a subunit of the BCR that plays a key role in this process when it is close
to CD32B. Therefore, if a pharmacologic treatment is to activate the CD32B inhibitory pathway, it also has to simultaneously bind to
CD79B. PRV-3279 (formerly MGD010), is a humanized CD32B x CD79B DART protein developed originally by MacroGenics as a bi-specific therapy
with these properties, and thus a potential treatment for SLE and other similar diseases. It is designed to simultaneously bind to CD32B
and CD79B on B cells.
PRV-3279
and related molecules have shown inhibitory effects on BCR-induced B cell proliferation and antibody secretion (including B cells obtained
from SLE patients) as well as beneficial effects in mouse models of autoimmunity. PRV-3279 is expected to boost the negative feedback
loop on B cells by robustly engaging the available CD32B and CD79B.
PRV-3279
has been studied in humans and was shown to be well tolerated. Proof of mechanism and PRV-3279’s inhibitory effect on antibody
immune responses were demonstrated in a Phase 1a single ascending dose study in healthy volunteers, including a cohort demonstrating
inhibition of the immunogenicity of the hepatitis A vaccine. Immunogenicity of PRV-3279 was also observed, but had no impact on mechanistic
effects, safety or pharmacokinetics, and decreased with increasing doses of PRV-3279, possibly a reflection of its mechanism of action.
Our
ultimate goal is to determine if PRV-3279 can intercept the pathophysiology of SLE by preventing the production of auto-antibodies by
abnormally active B cells.
Current
Treatment Options for SLE and Their Limitations
The
treatment and management of SLE depends on disease severity and disease manifestations. Hydroxychloroquine plays a central role in the
long-term treatment of SLE and is the cornerstone of SLE therapy. Corticosteroids, nonsteroidal anti-inflammatory drugs (“NSAIDs”),
and immunosuppressive agents (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate, and mycophenolate mofetil) have also
been used in the treatment and management of SLE. These treatments are only modestly effective and present safety and/or immune suppression
concerns with prolonged use. The B cell-depleting antibody rituximab (Rituxan), while not approved for treatment of SLE, appears to be
beneficial in certain subsets of patients.
In
2011, the FDA approved belimumab (Benlysta), an antibody that targets B lymphocyte stimulator, for the treatment of mild to moderate
SLE in combination with standard therapy, providing additional clinical validation of the therapeutic benefit of B cell-targeted therapy
for autoimmune diseases. However, the modest therapeutic benefit of belimumab and delayed onset of disease intervention indicate the
need for additional therapeutic strategies to inhibit overactive B cells. We believe PRV-3279 can fulfill that requirement and is uniquely
differentiated to allow for rapid inhibition of activated B cells (potentially more effective than belimumab), while sparing non-activated
B cells from depletion or inactivation (potentially safer than rituximab).
In
December 2020, January 2021, and July 2021, the FDA approved belimumab, voclosporin and anifrolumab, respectively, for the treatment
of lupus (lupus nephritis, in the case of voclosporin). We are focused on development of PRV-3279 in SLE.
Overview
of CD32B Biology and Relevance in Lupus
CD32B
is expressed widely on the surface of human B cells. In addition to its expression on B cells, CD32B is also expressed on other immune
cells such as dendritic cells, macrophages, neutrophils, and mast cells. It is a single-chain protein with a portion that sits outside
of the cell membrane, which can be bound by chemical signals.
CD32B
is the only known inhibitory FcR in the immune system. It plays an important role not only for innate and adaptive immune responses,
but also in the maintenance of immune tolerance and controlling autoimmunity. Mice deficient in CD32B have increased antibody responses
due in part to chronic B cell activation, and as a result, develop autoimmune disease similar to human SLE. In contrast, B cell-specific
overexpression of CD32B and cross-linking of CD32B with antibodies ameliorate the incidence and severity of lupus in mouse lupus models.
In humans, mutations and decreased expression of the CD32B gene are associated with an increased likelihood of SLE. These results underscore
the important role of CD32B in regulating the antibody immune response and suggest that drug-mediated engagement of CD32B could provide
therapeutic benefit in autoimmune diseases by dampening the effects of chronically activated B cells and reducing the production of auto-antibodies.
In particular, preventing the production of auto-antibodies could intercept the disease course in lupus nephritis, a subtype of lupus
driven by accumulation of auto-antibodies and immune complexes (a mass of antibodies and other molecules) in the kidneys.
Consistently,
a monoclonal antibody anti-CD19 which binds CD32B with high affinity, XmAb5871 (Xencor), was shown in 2018 to be efficacious -albeit
missing the primary endpoint- in a Phase 2 lupus trial, particularly in patients with B cell biomarker signatures, providing indirect
validation for the potential of PRV-3279 in lupus. XmAb5871, which has shown thrombocytopenia (unlike PRV-3279, XmAb5871 appears to bind
to CD32A, which is expressed on platelets), has not moved forward in development to date. In November 2021, Xencor announced the licensing
of XmAb5871 (obexelimab) to Zenas BioPharma.
Mechanism
of Action of PRV-3279
PRV-3279
is in a new class of bispecific scaffold antibody-like molecules called DARTs. It is designed to simultaneously bind to CD32B and CD79B
on B cells. The simultaneous binding of both CD32B and CD79B triggers CD32B-coupled immunoreceptor tyrosine-based inhibitory motif signaling,
which leads to the suppression of B cells activated to produce auto-antibodies, while not causing broad B cell depletion.
To
prolong its half-life in the body, PRV-3279 contains a human IgG1 Fc region (a specific antibody fragment) that is manipulated to eliminate
its effector function. As a molecule designed to inhibit immune responses, PRV-3279 does not activate any part of the immune system either
in the body or in laboratory tests. PRV-3279 also does not bind to platelets, a unique feature compared to competing molecules targeting
CD32B that are associated with toxicity due to binding to platelets (e.g., XmAb5871, an anti-CD19 mAb which binds to CD32 via the Fc
fragment).
Prior
Preclinical Evaluation of PRV-3279
The
only nonhuman species that PRV-3279 binds to is chimpanzees. An initial non-GLP study with PRV-3279 in chimpanzees demonstrated it to
be well tolerated at all doses, with an assigned no observed-adverse-effect level (“NOAEL”), of 10 mg/kg.
Due
to the lack of target binding, chronic four-week and three-month repeat-dose GLP toxicology studies were performed using a surrogate
DART molecule similar to PRV-3279 that was designed to target human CD32B and mouse CD79B in a transgenic mouse line that expresses human
CD32B. A NOAEL at the highest dose of 50 mg/kg was assigned in the three-month study. We believe these studies, and our regulatory interactions,
support the advancement of PRV-3279 in long-term efficacy studies in humans, such as PREVAIL-2.
Prior
Clinical Evaluation and Proof of Mechanism for PRV-3279
To
date, there have been two clinical trials completed with PRV-3279. The first study was conducted at a single site in the United States,
from February 2015 to February 2017 and was a first-in-human (“FIH”), double-blind, placebo-controlled Phase 1a
clinical trial to evaluate the safety, tolerability, PK, PD, and immunogenicity of PRV-3279 in healthy adult volunteers.
A
total of 49 subjects were randomized; 12 received placebo and 37 received PRV-3279 intravenously at escalating doses from 0.1 mg/kg to
10 mg/kg in six cohorts. PRV-3279 was well tolerated over the range of doses, with only mild adverse events that resolved quickly, including
headache, somnolence (sleepiness), upper respiratory tract infection, folliculitis and night sweats. Target binding and proof of mechanism
were demonstrated by measuring functional B cell inhibition at doses of 1 mg/kg or higher, without broader B cell activation or depletion
observed.
Subsequently,
proof of mechanism was further confirmed in a dose escalation extension of the study in which single doses of PRV-3279 at 3 mg/kg and
10 mg/kg (16 subjects) were compared with placebo (eight subjects) for the ability to affect B cell responses to a hepatitis A vaccine,
which was administered to participants who had no previous hepatitis A immunity, on day two of the study. At both doses, PRV-3279 reduced
the proportion of volunteers who generated an immune response against the vaccine, as well as the amount of antibody they produced, in
both cases as compared to placebo.
PRV-3279
exhibited an approximate half-life of seven days after a single dose. A majority (~86%) of study participants developed antibodies against
PRV-3279 (i.e., immunogenicity) after receiving the 3 mg/kg dose, but no detrimental effect was observed on the pharmacokinetics of PRV-3279.
The proportion of participants developing antibodies against PRV-3279 decreased with increasing dose (29% in the 10 mg/kg dose) and such
antibodies did not occur in the multiple dose chimpanzee study, suggesting that PRV-3279 may limit its own immunogenicity at therapeutic
doses, which is consistent with its mechanism of action.
The
second study was the Phase 1b portion of the PREVAIL study, which was a double-blind, placebo-controlled, multiple ascending dose study
in 16 health volunteers described above.
PRV-015
(ordesekimab, human anti-interleukin 15 mAb) for Non-Responsive Celiac Disease (NCRD)
PRV-015
(ordesekimab) is a fully human immunoglobulin (“IgG1”) mAb that binds to and inhibits pro-inflammatory cytokine interleukin
(“IL-15”), which has been identified as a major mediator in the pathophysiology of celiac disease. PRV-015 has emerged as
a leading candidate for the treatment of nonresponsive celiac disease, in which patients continue to have disease activity despite ongoing
gluten free diet (“GFD”).
PRV-015
has undergone clinical testing in approximately 250 subjects who have received PRV-015 across two Phase 1 (healthy volunteers and psoriasis,
rheumatoid arthritis (“RA”)) and three Phase 2 clinical trials (celiac disease, RCD-II, RA). No serious adverse events
deemed related to PRV-015 were observed that would preclude further clinical development. Proof of mechanism and/or proof of concept
was demonstrated in RA, celiac disease and refractory celiac disease Type II. The effect of PRV-015 in celiac disease was evidenced by
reduction in inflammation and symptoms after a controlled gluten challenge in a Phase 2a clinical trials with 63 celiac patients.
Celiac
Disease Market
There
is no approved drug for CD. The annual healthcare utilization by NRCD patients in 2013 was $18,206, for $4,796 in matched controls due
to the extra costs of uncontrolled CD investigations and treatment of complications. Given the large prevalence (15 to 20 million patients
world-wide, 1% of the population in the Western world and 0.5% in Asia), and the unmet need (50% of patients on GFD continue to suffer
from disease activity due to contaminating gluten in the diet), NRCD is considered a substantial opportunity for pharmaceutical development
of an effective and well-tolerated adjunctive treatment to the GFD.
Current
Clinical Development Program
Phase
2b Clinical Trial of PRV-015 (ordesekimab) in Celiac Disease (PROACTIVE Study)
We
and our partner Amgen conducted chronic toxicology studies in 2019 and early 2020. In August 2020, we initiated the PROACTIVE study (PROvention
Amgen Celiac ProtecTIVE Study), a randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 2 clinical trial in
adult patients with NRCD. PRV-015 will be administered every two weeks via subcutaneous route for six months. The hypothesis of this
study is that PRV-015 will be superior to the GFD at intercepting the effects of contaminating gluten exposure in celiac patients following
a GFD, as measured by symptoms and objective signs of intestinal inflammation after 24 weeks of treatment. Approximately 220 subjects
are planned to be enrolled. Due to the impacts of the COVID-19 pandemic on certain aspects of medical care during the pandemic, such
as a temporary halting of elective endoscopy procedures, lack of prioritization of chronic life-threatening conditions and reduced exposure
to gluten due to reductions of travel and dining out, we are experiencing enrollment delays that have extended the enrollment target.
We now expect to report top line results from the Phase 2b PROACTIVE study by the end of 2023.
Celiac
Disease Background Information
Celiac
disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals. Approximately 1% of
the western population is affected by celiac disease. This prevalence has been reported to be doubling every 20 years. Gluten is ubiquitous
in food and elicits autoimmune responses in celiac patients, with damage to the mucosal lining of the small intestine. Celiac disease
causes debilitating symptoms and serious medical complications, as the small bowel damage can lead to nutrient malabsorption and results
in a range of subsequent intestinal and extra-intestinal clinical manifestations. The stimulation of intestinal lymphocytes for decades
can lead to the development of lymphoma, with increased mortality.
Gluten
is the main protein present in some of the most common cereals (wheat, barley, rye). Modern diets are increasingly enriched with gluten
and it is also used as an additive in processed foods, cosmetics and oral medications. Gluten is also present in trace amounts in foods
labeled as “gluten-free”, as a tableting excipient, and in products such as toothpaste and lipstick. As little as 50mg/day
of gluten triggers the disease. A normal diet contains >10 g/day, 200 times the amount that causes damage and intestinal histological
abnormalities. As such, celiac patients face enormous challenges to follow a strict GFD.
The
pathophysiology of celiac disease is characterized by an abnormal immune response to gluten. Humans lack enzymes to fully digest gluten,
which against the right genetic background triggers inflammation and autoimmunity in the intestine and in other organs. An adaptive immune
response is triggered when gluten peptides are deamidated in the extracellular space, by the enzyme tissue transglutaminase, normally
an intracellular enzyme that is released by damaged cells. This deamidation renders gluten peptides high-avidity binders to HLA-DQ2 and
HLA-DQ8, which present these peptides to intestinal CD4+ T cells, thereby activating these T cells and initiating the inflammatory cascade.
The innate immune system’s intraepithelial lymphocytes (“IELs”), primarily CD8+, are able to directly lyse and destroy
intestinal epithelial cells, damaging the mucosal lining of the small intestine, in response to IL-15 release stimulated by gluten peptides.
In healthy individuals, the activated T cells are controlled by Tregs, but this does not happen in celiac disease as IL-15 confers the
effector CD4+ T cells resistance to suppression by Tregs.
Celiac
disease causes debilitating symptoms and serious medical complications. In many patients, gastrointestinal symptoms derived from intestinal
mucosal damage dominate the patient reported symptoms at diagnosis. The normal villi (absorptive finger-like prolongations) present in
the gut of healthy individuals are lost in active celiac disease as a result of mucosal atrophy and crypt enlargement. Small bowel damage
often leads to nutrient malabsorption that can result in a range of further clinical manifestations (anemia, osteopenia, failure to thrive
in children). In addition, extra-intestinal symptoms and systemic manifestations are often present, such as dermatitis, infertility,
or neurological and skeletal disorders. Mortality is increased in subjects with persistent intestinal mucosal damage.
The
most serious complication of celiac disease is the development of an in situ small bowel T cell lymphoma after many years of exposure,
voluntary or inadvertent, to gluten. This malignant complication of celiac disease, which appears to be independent of gluten and unresponsive
to a strict GFD, is termed RCD-II when the percentage of aberrant IELs is >20% and Type I refractory celiac disease when the percentage
is <20%. In RCD-II, aberrant IELs proliferate in what represents a slow-growing non-Hodgkin lymphoma localized (in situ) in the small
bowel, primarily in the epithelial compartment. RCD-II affects approximately 0.5% of celiac patients and can lead to overt and systemic
enteropathy-associated T cell lymphoma, with very poor prognosis and >80% mortality in five years.
Current
Treatment Options and Their Limitations
Celiac
disease is the only common autoimmune disorder with no approved medication. The only current available strategy for the management of
celiac disease is a lifelong total avoidance of gluten. While simple in theory, the ubiquity of gluten in foodstuffs, medications, household
substances, cosmetics, and gluten-free items makes total avoidance of gluten difficult, if not impossible.
The
main challenge to the successful maintenance of a GFD is that cereal flours are widely used in the food industry and are present in numerous
food products either naturally or as additives. Although gluten-free products can be purchased, commercially manufactured gluten-free
products may be difficult to find, tend to be less flavorful and are more expensive than regular gluten containing foods. In addition,
labeling of food products is deficient in many countries. Even in countries with superior labeling guidelines foods labeled “gluten-free”
may nevertheless contain gluten. For example, in northern European countries amounts of up to 100 parts per million are permitted in
gluten-free products designated apt for celiac sufferers.
For
these reasons, celiac sufferers are regularly exposed to gluten contamination in the food and beverages they consume. This exposure to
gluten contamination and the associated physiological and psychological consequences results in a self-limitation of social activities
and/or a reduction in the variety of foods consumed. Thus, the only currently available management option of a GFD presents both a considerable
challenge and substantial burden for patients. A study by Shah and collaborators (2014) found the burden of celiac disease and GFD on
patient quality of life to be very high, second only to end-stage renal disease – a condition that requires multiple, weekly dialysis
treatments.
As
a result of the difficulty in maintaining total avoidance of gluten while on a GFD, gluten contamination causes 50% or more of all diagnosed
celiac patients on a GFD to continue to experience disease activity. Patients who continue to have symptoms despite attempting to maintain
a GFD are deemed to have NRCD. NRCD has been defined as “persistent symptoms, signs or laboratory
abnormalities typical of celiac disease despite 6–12 months of dietary gluten avoidance”. As requested by patient
support groups and experts, alternative treatment options that can be administered independently or in combination with a GFD, as well
as treatments for refractory celiac disease, are required in order to improve the quality of life for celiac patients.
Overview
of IL-15 Biology and PRV-015 Mechanism of Action
IL-15
is a pro-inflammatory cytokine that serves as a potent growth, survival, and activation factor for T cells, particularly IELs, and for
natural killer (“NK”), cells. Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions,
including celiac disease, RA, and psoriasis. IL-15 is considered a central regulator of celiac disease immunopathology and a non-redundant
driver of lymphomagenesis in RCD-II.
Substantial
evidence suggests a pathophysiological role for IL-15 in celiac disease:
Innate
immunity:
| |
● |
IL-15
is an essential, non-redundant growth and activation factor for the IELs which destroy the intestinal mucosa; |
| |
● |
The
expression of IL-15 in the intestinal epithelium is necessary for villous atrophy; and |
| |
● |
In
some patients, IL-15 drives progression towards lymphomagenesis and potentially fatal RCD-II. |
Adaptive
immunity:
| |
● |
IL-15
enhances the presentation of deamidated gluten peptides by APCs; |
| |
● |
IL-15
renders the activated CD4+ T cells resistant to inhibition by Tregs; and |
| |
● |
IL-15
has been proven to be a key factor in the loss of tolerance to food antigens.
|
By
activating the IELs, IL-15 is believed to be the main mediator in the mucosal damage that ensues in response to gluten exposure in celiac
disease. The expression of IL-15 in the intestinal epithelium is necessary for villous atrophy in animal models of celiac disease and
circumstantial evidence suggests this to be the case in humans, as well. In addition, IL-15 renders effector T cells resistant to inhibition
by Tregs, promoting loss of tolerance to food antigens.
One
of the studied mouse models of celiac disease is an IL-15-transgenic mouse, in which IL-15 overexpression by gut epithelial cells leads
to celiac-like disease, including T and B cell-mediated pathology. IEL apoptosis has been observed in this animal model after treatment
with anti-IL-15 or anti-IL-15-receptor monoclonal antibodies.
Figure
1. Multiple actions of IL-15 in the pathophysiology of celiac and refractory celiac disease
PRV-015
(ordesekimab, also known as AMG 714, and formerly HuMax-IL15), is a fully human immunoglobulin (IgG1κ) mAb which binds
to and inhibits the function of IL-15 in all its forms (cis, trans, soluble IL-15 bound to IL-15Rα). PRV-015 inhibits IL-15-induced T
cell proliferation and shows a dose-dependent inhibition of IL-15-induced TNF-α production. PRV-015 underwent preclinical testing and
was subsequently evaluated in a Phase 1 and Phase 2 study in subjects with RA, in a Phase 1 study in healthy volunteers and in patients
with psoriasis, and in two Phase 2a studies in celiac disease and refractory celiac disease Type-II.
Pre-clinical
Evaluation of PRV-015
The
nonclinical development of PRV-015 consisted of a series of in vitro studies demonstrating the binding properties of PRV-015 against
human IL-15; in vitro and in vivo studies providing proof-of-concept for the benefit of blocking the IL-15 pathway in celiac
disease; and a series of GLP studies evaluating the nonclinical safety profile of Hu714MuXHu, the PRV-015 surrogate molecule which is
active in macaques.
Pharmacology
PRV-015
was found to be efficacious in a mouse model of celiac disease triggered by the transgenic expression of human IL-15 in the gut epithelium.
In this model, PRV-015 prevented IEL activation and proliferation, as well as histological abnormalities. In addition, PRV-015 was able
to induce apoptosis of human IELs in ex vivo culture of small intestinal explants from active celiac disease and RCD-II patients.
In this culture experiment, PRV-015 resulted in a suppression of IL-15-driven anti-apoptotic signaling via JAK3 and STAT5.
Toxicology
In
vitro studies demonstrated that PRV-015 had high binding affinity for human IL-15, but lower affinity for macaque IL-15. Additionally,
PRV-015 neutralized human IL-15 but did not efficiently neutralize macaque IL-15. To enable preclinical and toxicology studies in macaques,
a surrogate antibody, Hu714MuXHu, was developed by Amgen by fusing the F(ab) portion of a mouse anti-human IL-15 mAb known to neutralize
macaque IL-15, M111, with human IgG1 Fc. Hu714MuXHu was shown to neutralize macaque IL-15 with approximately the same potency as PRV-015
neutralizes human IL-15.
There
was a decrease in NK cell counts and NK cell activity following administration of Hu714MuXHu to monkeys, reflecting a PD response to
IL-15 blockade in this species, given the known role of IL-15 in NK cell biology in animal models (rodents and non-human primates). Of
note, no changes in absolute or relative numbers of NK cells were observed in any of the human studies. This difference between observations
in preclinical studies and clinical trials appears related to a differential sensitivity of human versus cynomolgus monkey NK cells to
IL-15 deprivation. Human NK cells are not dependent on IL-15 for their survival, possibly due to the redundant role of IL-2 on human
NK cells.
Pharmacokinetics
of PRV-015
The
PK of PRV-015 was consistent with a typical human immunoglobulin G1 antibody with no apparent target-mediated disposition within the
investigated dosing range. The mean half-life in human studies has been 20 to 22 days, potentially enabling monthly dosing.
There
was no development of anti-drug antibodies to PRV-015 in healthy volunteers, patients with psoriasis or patients with refractory celiac
disease. Only one RA patient in the phase 2b study was positive for anti-drug antibodies. Approximately 14% of patients with celiac disease
developed anti-drug antibodies in the Phase 2a clinical trial, with an additional 10% presenting pre-existing anti-drug antibodies, a
reflection of the abnormal antibody responses which characterize celiac disease. The anti-drug antibodies were not associated with injection
reactions or adverse events, and they were non-neutralizing, with no impact on PK.
Proof
of Mechanism for PRV-015 and Prior Clinical Evaluation
PRV-015
was initially developed for RA in two small Phase 1 and 2 studies with approximately 200 patients with moderate-to-severe disease. Although
PRV-015 missed the primary endpoint in the Phase 2 study at week 14, the results were significant at weeks 12 and 16, establishing proof-of-concept.
Approximately 60% of patients with active RA in both Phase 1 and Phase 2 studies versus approximately 30% of patients in the placebo
groups demonstrated a response to treatment as measured by the American College of Rheumatology 20% improvement score (ACR 20) at 8 and
12 weeks, respectively. PRV-015 also led to decreases in RA inflammatory biomarkers such as C-reactive protein and erythrocyte sedimentation
rate. PRV-015 was not effective in psoriasis in a small Phase 1 study, suggesting PRV-015’s action is selective, unlike that of
broad systemic immune suppressants.
Upon
gluten challenge in a Phase 2 clinical trial in celiac disease (CELIM-NRCD-001), PRV-015 did not prevent gluten-induced architectural
mucosal injury, and thus missed the primary endpoint, yet the high dose of PRV-015, 300 mg, showed statistically significant attenuation
of gluten’s effects on the change from baseline in intestinal inflammation, in patient-reported symptom questionnaires (the Celiac
Disease Patient Reported Endpoint, CeD PRO, a registrational endpoint in NRCD) and in diarrhea, compared with placebo. The totality of
the results from the patients who had gluten challenge indicate that 300 mg PRV-015 (formerly AMG 714) given every two weeks can ameliorate
the inflammation and symptoms caused by substantial gluten exposure, the first demonstration of such dual benefit in intestinal inflammation
and symptoms for any experimental medication for celiac disease. The results suggest that PRV-015 can be a potential adjunctive treatment
for NRCD to the GFD to ameliorate or resolve persistent inflammation seen in the majority of celiac patients already on GFD.
In
the Phase 2a clinical trial in RCD-II (CELIM-RCD-002), the primary endpoint (reduction in intestinal IELs) was not achieved, yet PRV-015
showed statistically significant benefit over placebo in reducing T cell receptor clonality (no increase in clonality with PRV-015) and
symptoms (diarrhea). Other endpoints, such as histology, did not reach statistically significant differences between groups, but the
results consistently favored PRV-015 numerically. PRV-015 was generally well tolerated, with no observed immunogenicity.
Summary
data of the Phase 2a clinical trial as presented at Digestive Disease Week in June 2018 is shown below:
The
CELIM-NRCD-001 study included 62 randomized celiac patients on a gluten-free diet, of which 49 patients underwent a substantial gluten
challenge of 2.5 grams per day for 10 weeks in order to assess the ability of PRV-015 to ameliorate the effects of gluten. Upon gluten
challenge, PRV-015 did not prevent gluten-induced architectural mucosal changes, the primary endpoint in the study. However, in secondary
efficacy assessments, the PRV-015 300 mg dose consistently attenuated the effects of gluten in intestinal inflammation (intraepithelial
lymphocyte density, p=0.03), and in gastrointestinal symptoms as measured by three independent endpoints: the Celiac Disease Patient
Reported Endpoint (CeD-PRO, p=0.02), the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD-GSRS, p=0.07) and the Bristol Stool
Form Scale (BSFS/diarrhea, p=0.0002). The CeD-PRO is a validated endpoint acceptable for registrational trials. In addition, patients
in the PRV-015 300 mg arm had a significantly improved Physician Global Assessment of disease (PGA, p=0.03). The totality of the
results demonstrated proof-of-concept for PRV-015 300 mg given subcutaneously every two weeks in the amelioration of inflammation and
symptoms caused by the consumption of gluten by celiac patients. Importantly, PRV-015 was well tolerated, and only 14% of patients developed
anti-drug antibodies, which were non-neutralizing and not correlated with impact of efficacy or safety. The PK profile was consistent
with a monoclonal antibody, and potentially enables future monthly dosing.
Summary
of clinical trials
| Study
Number (Phase; Sponsor) |
|
Key
Design Features |
|
Dose
Route, Duration |
|
Study
Population |
Hx-IL15-001
(Phase
1;
Genmab) |
|
Double-blind,
placebo-controlled, single SC infusion, dose escalation, study with open-label, repeat-dose (4 weekly doses) follow-up |
|
Initial
single dose: 0 or 0.15 to 8 mg/kg SC infusion
Repeated
dose: 0.5 to 4 mg/kg SC infusion once weekly for four weeks. five doses over eight weeks |
|
30
subjects with RA |
| |
|
|
|
|
|
|
20030210
(Phase
2;
Genmab/
Amgen) |
|
Double-blind,
placebo-controlled, multiple SC infusion, parallel-group, multicenter study |
|
0
or 40 to 280 mg SC infusion dose every two weeks for 12 weeks with initial 200% loading dose |
|
180
subjects with RA |
| |
|
|
|
|
|
|
20050193
(Phase
1;
Amgen) |
|
Double-blind,
placebo-controlled, single SC or IV doses, dose-escalation study |
|
SC
doses: 0, 30, 100, 300 or 700 mg (cohorts 1 to 4) IV dose: 0 or 100 mg (cohort 5) |
|
40
healthy subjects
|
| |
|
|
|
|
|
|
20060349
(Phase
1b/2a; Amgen) |
|
Double-blind,
placebo-controlled, multiple SC doses, dose-escalating study |
|
0
or 150 mg SC (cohort 1)
0
or 300 mg SC (cohort 2)
Every
two weeks for 12 weeks |
|
22
subjects with moderate to severe psoriasis |
| |
|
|
|
|
|
|
| CELIM-NRCD-001
(Phase 2a; Celimmune) |
|
Double-blind,
placebo- controlled, SC, parallel group, multicenter study |
|
0,
150 mg or 300 mg PRV-015 once every two weeks for six consecutive doses over ten weeks |
|
63
subjects with NRCD |
| |
|
|
|
|
|
|
| CELIM-RCD-002
(Phase 2a; Celimmune) |
|
Double-blind,
placebo controlled IV infusion, parallel group, multicenter study |
|
0
or 8 mg/kg IV, a total of seven times over ten weeks |
|
24
subjects with Type II refractory celiac disease |
Safety
of PRV-015
Approximately
250 subjects have been exposed to PRV-015 to date, including approximately 200 subjects for 12 weeks of biweekly dosing. In all studies
to date, PRV-015 was generally well tolerated by healthy volunteers, patients with active RA, and patients with celiac disease or RCD-II.
While PRV-015 has the potential, to increase susceptibility to infections as is the case with immune modulators, PRV-015 has not demonstrated
this effect in the six clinical trials completed to date. No deaths or clinically significant changes in laboratory parameters were observed,
including no NK cell depletion.
The
only adverse events clearly increased in PRV-015-treated patients have been injection site reactions, which were more commonly reported
in subjects exposed to PRV-015, in a dose-dependent fashion (up to ~52% on PRV-015 vs ~26% in placebo in the celiac Phase 2a clinical
trial), and nasopharyngitis (most cases with suspected allergic origin at a single site in RCD-II). In the population which will be studied
in Phase 2b, celiac disease, there were no SAEs in the Phase 2a clinical trial, while there were six SAEs (five on PRV-015 and one on
placebo) in the RCD-II, a much sicker patient population with immune suppression at baseline. Of the five SAE on PRV-015 in RCD-II patients,
two were infections (both resolved while on PRV-015). There was one mild balance disorder (considered unlikely to be related to PRV-015
and resolved while on the drug). Another patient had mild cerebellar syndrome which led to discontinuation from the study.
PRV-101
(CVB Vaccine) for Acute Infection and T1D
PRV-101 is a polyvalent inactivated
prophylactic CVB vaccine candidate targeting all five key CVB serotypes associated the development of T1D, intended to prevent acute
CVB infection and the development of CVB-induced T1D and celiac autoimmunity. Based on epidemiological and pre-clinical study data to
date, we believe that, if successful, PRV-101 may prevent up to 50% of T1D cases and up to 20% of celiac cases. Preclinical studies completed
to date by Vactech and replicated independently by us demonstrate that CVB triggers diabetes in animal models of T1D and that vaccination
against CVB protects mice from acute infection as well as prevents the onset of diabetes triggered by CVB infection. Interim results
in normal adult healthy volunteers, which we disclosed in a press release in October 2021, showed that in this study PRV-101 was
well tolerated and elicited high titers of virus neutralizing antibodies, in a dose dependent fashion in healthy volunteers, against
all CVB serotypes included in the vaccine, thus supporting further development of this vaccine.
Current
Clinical Development Program
First
in Human Phase 1 Clinical Trial of PRV-101 (PROVENT Study)
In
December 2020, we initiated the PROVENT (PROtocol for coxsackievirus VaccinE in healthy voluNTeers) study, a first-in-human study of
PRV-101. PROVENT is a placebo-controlled, double-blind, randomized first-in-human study. The study’s primary endpoint is the safety
of two dose levels of PRV-101 in healthy adult volunteers provided three administrations with 4-week intervals. Tolerability and immunogenicity
were also evaluated. We completed enrollment in April 2021.
We
reported positive interim results from this first-in-human study in October 2021. The interim analysis was conducted after all trial
participants completed 4 weeks of follow-up after the 3rd dose (Week 12) to assess vaccine response and safety. In this interim analysis,
PRV-101 met the primary endpoint demonstrating that it was well tolerated in this study, with no treatment-emergent Serious Adverse Events,
Adverse Events of Special Interest, or Adverse Events that led to study drug discontinuation or study withdrawal. PRV-101 also met the
secondary efficacy endpoint as it induced high titers of viral-neutralizing antibodies against all CVB serotypes included in the vaccine
in a dose-dependent fashion. The percent of subjects who responded to all 5 serotypes (response defined as seroconversion if baseline-negative
or >= 4x increase in VNT if baseline-positive) was 0% in placebo, 67% in the low dose and 100% in the high dose arm of PRV-101.
An
additional 6-month safety and efficacy follow up will be conducted and final trial results from the trial are expected in the
first half of 2022.
CVB
Infection Market
Enteroviruses
are responsible for an estimated ten to 15 million symptomatic infections in the United States annually. CVB contributes to a major part
of the healthcare costs of enteroviruses as they cause the most serious complications and are among the most frequently reported enteroviral
infections according to the CDC. Acute CVB infection is usually asymptomatic or causes common cold-type symptoms. It often also leads
to a febrile illness associated by rash, hand-foot-mouth disease and/or mild GI distress. However, CVB infections also cause more severe
manifestations including pericarditis, myocarditis, meningitis and pancreatitis.
| |
● |
Myocarditis:
CVB is the most common etiologic agents for myocarditis in the Western world, responsible for up to 33% of cases of myocarditis.
Myocarditis is an important cause of sudden unexpected death: the prevalence of myocarditis in children and adolescents leading to
sudden unexpected death has been reported to be as high as 8% to 42%. In certain individuals, acute myocarditis progresses to chronic
myocarditis and dilated cardiomyopathy, which is a severe life-threatening condition. |
| |
● |
Otitis
media: otitis media (middle ear inflammation) may develop in patients with upper respiratory disease caused by enterovirus.
Otitis media constitutes 18% of physician visits in the United States (largest single reason in children). The costs of otitis media
treatment in the United States were estimated to be approximately $3 billion in 2014. |
| |
● |
Meningitis:
CVB is a common cause of enteroviral meningitis. Meningitis beyond the neonatal period is characterized by the sudden onset
of fever of 38-40°C. Headache and photophobia are almost universally reported in these patients. Reports on the incidence of
viral meningitis vary from approximately 50,000 hospitalized cases to over 2 million cases of aseptic meningitis per year. Based
on 300,000 annual cases of aseptic meningitis in the United States (of which enteroviruses, and coxsackie viruses in particular,
are the most common cause), the economic impact is estimated to be $1.5 billion in direct costs alone. |
Overview
of CVB Infection of the Pancreas, T1D and PRV-101’s Mechanism of Action
Longitudinal
studies of more than 200,000 children studied for up to two decades in Finland by our technology licensor, Vactech, and its collaborators
(“DIPP Study”), identified CVB infection as a likely environmental trigger in the onset of T1D autoimmunity and T1D-associated
celiac disease (“CD”) autoimmunity. Subsequent full-virome analysis of the TEDDY Study (400,000 children international study)
confirmed that CVB is the only virus whose persistent infection is associated with the development of T1D and celiac disease autoimmunity
(T1D-associated and also independent of T1D).
CVB
infection is very common and is responsible for various symptoms and complications ranging from mild respiratory disease, gastrointestinal
disturbances and hand-foot-mouth disease to life-threatening cardiomyopathy and meningitis. However, in patients with a certain genetic
background, CVB appears responsible for the development of autoimmunity. The T1D association with CVB infection has been observed in
independent cohorts in 15 countries, including in North America, Europe and Australasia. These epidemiological observations have been
substantiated by biological experimentation. Insulin-producing beta cells in the pancreas express specialized receptors associated with
the transport, storage and release of insulin. These receptors appear to be used by CVB to preferentially infect these cells and polymorphism
in these receptors are associated with development of T1D autoimmunity. Infection by enteroviruses can be detected in the pancreatic
beta cells of approximately 60% of T1D patients and in the gut of most patients with T1D-associated CD. Importantly, if mothers have
anti-CVB immunity at the time of the pregnancy, a 50% reduction in the onset of T1D autoimmunity (T1D-associated auto-antibodies) has
been observed in their offspring, presumably due to protection by maternal antibodies passed on to the fetus. This observation strongly
suggests the potential efficacy of CVB vaccination for children and/or mothers, resulting in the development of protective antibodies
potentially capable of preventing or delaying the onset of T1D.
An
analysis of stool samples collected from these individuals identified enterovirus infections prior to the first detection of T1D auto-antibodies.
Enterovirus RNA was also detected in stool samples. Examination of antibodies present in DIPP children who developed at least two islet
cell auto-antibodies (sign of early T1D) and/or progressed to clinical T1D confirmed that among all enteroviruses, only CVB was significantly
associated with initiation of beta cell autoimmunity.
Enterovirus
RNA in Blood is Linked to the Development of T1D
OR:
odd ratio; CI: confidence interval; EV: enterovirus
Preclinical
Evaluation PRV-101
Preclinical
Data for PRV-101
The
mechanism of action and efficacy of PRV-101 is supported by the results of several in vivo studies. Inactivated CVB-based viral vaccines
efficiently protect mice from CVB infections and from viral spread to the pancreas, as seen for CVB1 and CVB3 vaccines. Similar experiments
conducted with a vaccine covering all six CVB serotypes demonstrated that it can induce a strong neutralizing anti-CVB response in mice
and protect the animals against multiple CVB infections from the corresponding live viruses. Independent experiments confirm that CVB
infection can accelerate T1D onset in T1D susceptible NOD (Non-obese diabetic) or SOCS-1-Tg (suppressor of cytokine signaling 1 transgenic)
mice, suggesting that protection from CVB infection would therefore protect against T1D development. This hypothesis has been confirmed
in experiments conducted by the Karolinska Institute (Sweden) and the University of Tampere (Finland), demonstrating that CVB1 and CVB3
vaccines produced by Provention indeed protected SOCS-1-Tg mice against T1D induced by CVB1 and CVB3, respectively. These mice develop
T1D after CVB infection as a consequence of a direct infection of insulin-producing beta cells in the pancreas and the subsequent immune
response against the beta cells, mimicking human T1D. A three-injection vaccination course induced robust neutralizing antibody responses
against CVB1/CVB3 and protected mice from both CVB1/CVB3 infection and CVB1/CVB3-driven T1D. CVB1/CVB3 infection led to a loss of insulin-producing
cells in unvaccinated mice, which also was prevented by the vaccine. These data strongly supported the development of PRV-101 for the
prevention of T1D in humans.
Formalin-Inactivated
CVB1 Vaccine is effective against CVB1-Induced T1D in a Mouse Model.
As
seen in the left panel below, CVB1 infection led to loss of insulin-producing cells, and this pathology was completely prevented by the
CVB1 vaccine (right panel). In this experiment, while 50% of unvaccinated mice develop T1D as a consequence of CVB1 infection, all vaccinated
mice were protected (not shown).
Important
from a safety point of view, the formalin-inactivated CVB1 vaccines did not cause any undesirable effects in the pancreas. There was
no vaccine-induced pancreatic pathological change, islet autoimmunity or diabetes in the vaccinated mice. Similar results were obtained
for Provention-manufactured CVB1 and CVB3 vaccines (not shown).
Finally,
maternal CVB infection during gestation in mice protects the offspring from CVB infection and subsequent T1D development, presumably
through transfer of specific antibodies from the mother to the fetus, corroborating previous findings in humans in the DIPP study and
further supporting the use of a prophylactic vaccine to protect against CVB-associated-T1D.
CTA-Enabling
Program to Support FIH Study
The
CVB vaccine toxicology program to date has consisted of Good Laboratory Practices (“GLP”) and non-GLP safety and immunogenicity
studies conducted in mice. These studies were designed to identify and characterize potential toxicities associated with PRV-101 treatment,
including those arising from the immune responses induced by the product. They mirrored the administration regimen that is now used in
the PROVENT FIH study, and by the same route of administration.
Pharmacology
studies have also been conducted to determine the desired composition of the vaccine, leading to successful GMP manufacturing of the
final polyvalent vaccine for clinical trials.
Significant
Contracts and Agreements Related to Research and Development Activities
License
and Acquisition Agreements
MacroGenics
Asset Purchase Agreement
In
May 2018, we entered into an Asset Purchase Agreement (the “MacroGenics Asset Purchase Agreement”) with MacroGenics pursuant
to which we acquired MacroGenics’ interest in teplizumab (renamed PRV-031), a humanized mAb for the treatment of T1D. As partial
consideration for the MacroGenics Asset Purchase Agreement, we granted MacroGenics a warrant to purchase 2,162,389 shares of our common
stock at an exercise price of $2.50 per share. In July 2019, these warrants were exercised by MacroGenics on a cashless basis. We are
obligated to pay MacroGenics contingent milestone payments totaling $170.0 million upon the achievement of certain regulatory approval
milestones, including $60.0 million payable within 90 days of an approval of a BLA for a first indication in the United States. In addition,
we are obligated to make contingent milestone payments to MacroGenics totaling $225.0 million upon the achievement of certain sales milestones.
We have also agreed to pay MacroGenics a single-digit royalty on net sales of the product. We have also agreed to pay third-party obligations,
including low single-digit royalties, a portion of which is creditable against royalties payable to MacroGenics, aggregate milestone
payments of up to approximately $0.7 million and other consideration, for certain third-party intellectual property under agreements
we assumed pursuant to the MacroGenics Asset Purchase Agreement. Further, we are required to pay MacroGenics a low double-digit percentage
of certain consideration to the extent it is received in connection with a future grant of rights to teplizumab by us to a third party.
We are obligated to use reasonable commercial efforts to develop and seek regulatory approval for teplizumab.
MacroGenics
License Agreement
In
May 2018, we entered into a License Agreement with MacroGenics (the “MacroGenics License Agreement”), pursuant to which MacroGenics
granted us exclusive global rights for the purpose of developing and commercializing MGD010 (renamed PRV-3279), a humanized protein and
a potential treatment for SLE and other similar diseases. As partial consideration for the MacroGenics License Agreement, we granted
MacroGenics a warrant to purchase 270,299 shares of our common stock at an exercise price of $2.50 per share. In July 2019, these warrants
were exercised by MacroGenics on a cashless basis. We are obligated to make contingent milestone payments to MacroGenics totaling $42.5
million upon the achievement of certain developmental and approval milestones for the first indication and an additional $22.5 million
upon the achievement of certain regulatory approvals for a second indication. In addition, we are obligated to make contingent milestone
payments to MacroGenics totaling $225.0 million upon the achievement of certain sales milestones. We have also agreed to pay MacroGenics
a single-digit royalty on net sales of the product. Further, we are required to pay MacroGenics a low double-digit percentage of certain
consideration to the extent received in connection with a future grant of rights to PRV-3279 by us to a third party. In connection with
our grant of certain rights for PRV-3279 to Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd. (“Huadong”) under the Huadong
License Agreement (as defined below), in May 2021, we paid $1.1 million to MacroGenics related to “qualified” consideration,
as defined in the MacroGenics License Agreement, that we received from Huadong. See below for further description of the Huadong
License Agreement.
We
are obligated to use commercially reasonable efforts to develop and seek regulatory approval for PRV-3279. The license agreement may
be terminated by either party upon a material breach or bankruptcy of the other party, by us without cause upon prior notice to MacroGenics,
and by MacroGenics in the event that we challenge the validity of any licensed patent under the agreement.
Huadong
License Agreement
In
February 2021, we entered into a License Agreement with Huadong, a wholly-owned subsidiary of Huadong Medicine Co., Ltd. (the “Huadong
License Agreement”), pursuant to which we granted Huadong exclusive rights for the purpose of developing and commercializing PRV-3279,
a DART® (bispecific antibody-based molecule) targeting the B cell surface proteins CD32B and CD79B, in Greater China (mainland China,
Hong Kong, Macau and Taiwan). We will retain exclusive worldwide rights to develop PRV-3279 for combination uses to reduce the immunogenicity
of biotherapeutics, but Huadong will have the exclusive right to distribute PRV-3279 in that field in Greater China. In consideration
of the license and other rights granted as part of the Huadong License Agreement, we received an upfront payment of $6.0 million and
will receive up to $11.5 million in research, development and manufacturing funding over the next three years, of which $2.5 million
was received as of December 31, 2021. If Huadong successfully develops, obtains regulatory approval for, and commercializes PRV-3279
in Greater China, we are eligible to receive up to $37.0 million in regulatory milestones and up to $135.0 million in commercial milestones
based on aggregate net sales in a calendar year in Greater China. If commercialized, we would also be eligible to receive low double-digit
royalties on net sales of PRV-3279 by Huadong in Greater China. The License Agreement may be terminated by either party upon a material
breach or bankruptcy of the other party, by Huadong without cause upon at least 12 months prior notice to us, and by us in the event
Huadong challenges a licensed patent or in the event that our upstream license terminates. We may also terminate the License Agreement
if Huadong ceases commercialization of PRV-3279 for a consecutive period of six months after first commercial sale. We are generally
responsible for the manufacturing of PRV-3279 through regulatory approval in Greater China, and Huadong will exclusively purchase all
clinical and commercial supply requirements of PRV-3279 from us until Huadong exercises its option to assume manufacturing responsibilities,
which may be triggered after regulatory approval in China. We will retain all rights to PRV-3279 in the rest of the world. We recently
initiated a Phase 2a trial of PRV-3279 in systemic lupus erythematosus in January 2022 and are conducting a portion of this trial
in Hong Kong.
Vactech
License
In
April 2017, we entered into a License Agreement with Vactech (the “Vactech License Agreement”), pursuant to which Vactech
granted us exclusive global rights for the purpose of developing and commercializing the CVB vaccine platform technology. In consideration
of the licenses and other rights granted by Vactech, we issued two million shares of our common stock to Vactech. We recorded
the issuance of the shares at their estimated fair value of approximately $1.70 per share, for a total of $3.4 million as a license fee
expense included as part of research & development expense for the year ended December 31, 2017. We paid Vactech a total of approximately
$0.5 million for transition and advisory services during the first 18 months of the term of the agreement. Vactech is obligated to transition
its intellectual property, provide reference samples, assist with the technology transfer to a third-party contract manufacturer, and
participate on our scientific advisory board. In addition, we may be obligated to make a series of contingent milestone payments to Vactech
totaling up to an additional $24.5 million upon the achievement of certain clinical development and regulatory filing milestones, of
which we paid $0.5 million to Vactech in April 2021. This payment was triggered upon the dosing
of the first patient in the Phase 1 PROVENT study, which occurred in January 2021. In addition, we have agreed to pay Vactech
tiered single-digit royalties on net sales of any approved product based on the CVB platform technology and three additional payments
totaling $19.0 million upon the achievement of certain annual net sales levels. The Vactech License Agreement may be terminated by us
on a country by country basis without cause (in which case the exclusive global rights to the technology will transfer back to Vactech)
and by either party upon a material breach or insolvency of the other party. If we terminate the agreement with respect to two or more
specified European countries, the agreement will be deemed terminated with respect to all of the European Union, and if we terminate
the agreement with respect to the United States, the agreement will be deemed terminated with respect to all of North America. The agreement
expires upon the expiration of our last obligation to make royalty payments to Vactech.
Amgen
License and Collaboration Agreement
In
November 2018, we entered into a License and Collaboration Agreement (the “Amgen Agreement”) with Amgen for PRV-015 (ordesekimab,
also known as AMG 714), a novel anti-IL-15 monoclonal antibody being developed for the treatment of gluten-free diet NRCD. Under
the terms of the agreement, we will conduct and fund a Phase 2b trial in NRCD and lead the development and regulatory activities for
the program. Amgen agreed to make an equity investment of up to $20.0 million in us, which was completed in September 2019 through the
purchase of 2,500,000 shares of our common stock. Amgen is also responsible for the manufacturing of PRV-015. Upon completion of the
Phase 2b trial, a $150.0 million milestone payment is due from Amgen to us, plus an additional regulatory milestone payment, and single
digit royalties on future sales; provided, however, that Amgen has the right to elect not to pay the $150.0 million milestone, in which
case we will have an option to negotiate for the transfer to us of rights to AMG 714 pursuant to a termination license agreement between
Amgen and us. The material terms of the termination license agreement have been negotiated and agreed and form part of the Amgen Agreement.
Under the terms of the termination license agreement, we would be obligated to make certain contingent milestone payments to Amgen and
other third parties totaling up to $70.0 million upon the achievement of certain clinical and regulatory milestones and a low double-digit
royalty on net sales of any approved product based on the IL-15 technology. The agreement may be terminated by either party upon a material
breach or upon an insolvency event and by Amgen if we are not able to fund our clinical development obligations (among other termination
triggers). The agreement expires upon the expiration of Amgen’s last obligation to make royalty payments to us.
AGC
Biologics Agreement
In
February 2019, we entered into services agreement with AGC Biologics (“AGC”), to manufacture and supply teplizumab for our
anticipated clinical and commercial supply needs. We may terminate the agreement or any stage of services thereunder with 90 days’
prior written notice. If we provide less than 12 months’ notice of termination for the termination of a scheduled batch, we may
incur a cancellation fee. The amount of the cancellation fee would depend on the timing of such notice. Each party also has the right
to terminate the agreement for other customary reasons such as material breach and bankruptcy. The agreement contains provisions relating
to compliance by AGC with current GMP, cooperation by AGC in connection with potential marketing applications for teplizumab, indemnification,
confidentiality, dispute resolution and other customary matters for an agreement of this kind.
Parexel
Services Agreement
In
February 2019, we entered into a services agreement with Parexel (the “Parexel Services Agreement”), pursuant to which we
retained Parexel to perform implementation and management services in connection with the PROTECT study of teplizumab. We may terminate
the services agreement or any work order for any reason and without cause with 90 days’ written notice. Either party may terminate
the agreement in the event of a material breach or, bankruptcy petition by the other party or, if any approval from a regulatory authority
is revoked, suspended or expires without renewal.
Intellectual
Property
We
believe that our current patent applications and any future patents and other proprietary rights that we own, or control through licensing,
are and will be essential to our business. We believe that these intellectual property rights will affect our ability to compete effectively
with others. We also rely and will rely on trade secrets, know-how, continuing technological innovations and licensing opportunities
to develop, maintain and strengthen our competitive position. We seek to protect these, in part, through confidentiality agreements with
certain employees, consultants, advisors and other parties. Our success will depend in part on our ability, and the ability of our licensor,
to obtain, maintain (including making periodic filings and payments) and enforce patent protection for our/their intellectual property,
including those patent applications to which we have secured exclusive rights.
We
plan to spend considerable resources and focus in the future on obtaining United States and foreign patents. We have and will continue
to actively protect our intellectual property. No assurances can be given that any of our patent applications will result in the issuance
of a patent or that the examination process will not require us to narrow our claims. In addition, any issued patents may be contested,
circumvented, found unenforceable or invalid, and we may not be able to successfully enforce our patent rights against third parties.
No assurance can be given that others will not independently develop a similar or competing technology or design around any patents that
may be issued to us. We intend to expand our international operations in the future and our patent portfolio, copyright, trademark and
trade secret protections may not be available or may be limited in foreign countries.
PRV-031
(teplizumab anti-CD3 antibody)
Through
our agreement with MacroGenics, we have acquired a patent portfolio that includes seven issued patents, including two United States patents
and five ex-United States patents in Australia, Israel, Mexico and Singapore. The issued patents are set to expire no earlier than dates
ranging from 2026 and 2028, subject to any disclaimers, patent term adjustments or extensions available under the law. These issued patents
cover use of certain humanized antibodies that bind to CD3 in the treatment of autoimmune disorders, including T1D and RA.
We
have additionally filed one PCT international patent application, three United States non-provisional patent application, four United
States provisional patent applications, and fourteen ex-United States patent applications directed to various new uses of anti-CD3
antibodies, including teplizumab for the prevention or delay of clinical T1D, as well as new dosing regimens. If issued, patents claiming
priority to these applications will expire no earlier than 2040, subject to any disclaimers, patent term adjustments or extensions available
under the law.
PRV-101
(CVB vaccine for the prevention of T1D and celiac disease)
Through
our agreement with Vactech, we have a licensed patent portfolio that includes three issued United States patents, two pending United
States patent applications, and 14 patents in various European countries (i.e., one granted European patent validated in 14 European
Patent Convention member states). We also have two pending provisional United States patent applications co-owned by Vactech and
Provention. The pending United States patent applications and the European country patents disclose use of a CVB vaccine composition
in the prevention or treatment of T1D.
The
patents issued in the United States and various European countries generally have terms of 20 years from their respective priority filing
dates, subject to available extensions, and are thus set to expire no earlier than 2032, subject to any disclaimers, patent term adjustments
or extensions available under the law.
PRV-3279
(CD32B/CD79B diabody)
Through
our agreement with MacroGenics, we have licensed a patent portfolio that includes: i) 191 issued patents, including 12 United States
patents, 110 patents in European countries, and 69 patents in other ex-United States jurisdictions; and ii) 35 pending patent applications,
including eight pending United States patent applications, four pending European patent applications, and 23 pending patent applications
in other ex-United States jurisdictions.
The
patents and patent applications disclose a platform technology for making diabodies, specific anti-CD32B antibodies, specific anti-CD79B
antibodies, specific diabodies that co-ligate both CD32B and CD79B, as well as use of these antibodies and diabodies in treating various
disorders, including cancer, autoimmune disorder, inflammatory disorder, and IgE-mediated allergic disorder.
The
issued patents in the United States and various ex-United States countries generally have terms of 20 years from their respective priority
filing dates, subject to available extensions, and are thus set to expire no earlier than dates ranging from 2032 and 2034, subject to
any disclaimers, patent term adjustments or extensions available under the law. In the event that the pending patent applications issue
as patents, although there can be no assurance that the patent applications will issue, the patents would be set to expire no earlier
than dates ranging from 2032 and 2037, subject to any disclaimers, patent term adjustments or extensions available under the law.
We
have additionally filed two PCT international patent applications, three United States non-provisional patent application, and one United
States provisional patent application directed to new uses of B cell inhibitors such as PRV-3279, including the prevention of immunogenicity
associated with gene therapy, and treatment of B cell driven autoimmune and/or allergic diseases, among other things. If issued, patents
claiming priority to these applications will expire no earlier than 2040, subject to any disclaimers, patent term adjustments or extensions
available under the law.
PRV-015
(ordesekimab anti-IL-15 antibody)
Through
our agreement with Amgen, we have licensed a patent portfolio that includes: i) 80 issued patents, including eight United States patents,
42 patents in European countries, and 30 patents in other ex-United States jurisdictions; and ii) 18 pending patent applications, including
two pending United States patent applications, one pending European patent application, and 15 pending patent applications in other ex-United
States jurisdictions.
The
patents and patent applications disclose anti-IL-15 antibodies, methods of using the same, manufacturing conditions and dosages of the
same.
The
issued patents are set to expire no earlier than dates ranging from 2022 and 2027, subject to any disclaimers or extensions under the
law. In the event that the pending patent applications issue as patents, although there can be no assurance that the patent applications
will issue, the patents would be set to expire no earlier than dates ranging from 2026 and 2037, subject to any disclaimers, patent term
adjustments of extensions available under the law.
PRV-6527
(CSF-1R small molecule inhibitor)
Through
our agreement with Janssen Pharmaceutica NV, we have licensed a patent portfolio that includes: i) 73 issued patents, including one United
States patent, one patent in European countries, and 71 patents in other ex-United States jurisdictions; and ii) three pending patent
applications, including one pending United States patent application, one pending European patent application, and one pending patent
applications in other ex-United States jurisdictions. The issued patents are set to expire no earlier than dates ranging from 2027 and
2030, subject to any disclaimers, patent term adjustments or extensions under the law. In the event that the pending patent applications
issue as patents, although there can be no assurance that the patent applications will issue, the patents would be set to expire no earlier
than dates ranging from 2027 and 2030, subject to any disclaimers, patent term adjustments or extensions under the law.
Sales
and Marketing
We
are a clinical stage company without a history of commercial revenue or marketing experience. We intend to commercialize teplizumab ourselves
in the United States, however, because commercialization is expensive and time consuming, we intend to explore multiple commercialization
strategies outside the United States, including:
| |
● |
exploring
strategic partners for commercialization in markets outside the United States; |
| |
● |
considering
launching in the U.K. ourselves, depending on ongoing discussions with potential partners ex-United States; |
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● |
developing
drug candidates through the earlier stages of clinical development with the objectives of rapid, cost effective risk reduction and
value creation and then establishing strategic partnership for late stage clinical development and subsequent commercialization; |
| |
● |
developing
a robust pipeline of promising drug candidates at various stages of the development process to establish optionality and regular
value inflection opportunities and revenue(s); |
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● |
strategically
entering into co-development partnership(s) to retain potential for commercialization rights on selected drug candidate(s) and market
opportunities; and |
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● |
partnering
with industry participants to incorporate our technology into new and existing drugs. |
We
expect that partnering with pharmaceutical or biotherapeutic companies may accelerate product acceptance into target market areas outside
the United States and gain the sales and marketing advantages of the partner’s distribution infrastructure. We intend to continue
to strengthen our market position and solidify our leadership position in immunotherapy by continuing to improve our technology, broadening
our clinical and therapeutic applications, identifying new clinical and therapeutic applications and forming strategic relationships
with our licensors.
Manufacturing
We
do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of any of our product
candidates. Although we rely and intend to continue to rely upon third–party contract manufacturers to produce our products and
product candidates, we have recruited personnel and consultants with experience to manage these third–party contract manufacturers.
In certain cases, our collaboration partners for each respective program are responsible for providing clinical drug supply or drug product
for those program’s clinical trials. In other cases, we have engaged third-party manufacturers to provide services related to process
development, non-GMP and GMP manufacturing and other related services.
The
table below lists the third-party responsible for manufacturing drug supply for each of our programs:
| Product
Candidate |
|
Supplier |
|
Party
Responsible for Costs |
| PRV-031
(teplizumab) |
|
AGC
Biologics |
|
Provention |
| PRV-101 |
|
Intravacc |
|
Provention |
| PRV-3279 |
|
Existing
drug supply – MacroGenics
Future
drug supply – vendors being evaluated |
|
MacroGenics
Provention |
| PRV-015
(ordesekimab) |
|
Amgen |
|
Amgen |
We
have historically relied upon an existing supply of teplizumab produced by MacroGenics for use in our clinical trials of teplizumab.
This existing supply is insufficient to fully supply the ongoing PROTECT study to completion or our potential commercialization need.
In February 2019, we entered into an agreement with AGC Biologics to manufacture teplizumab for our anticipated clinical trial needs
as well as for potential commercialization of teplizumab.
Supplies
of teplizumab sufficient to supply the PROTECT study have been manufactured by our CMOs and are currently being utilized in the study.
In
order to obtain regulatory approval for teplizumab, third-party manufacturers have been required to consistently produce teplizumab in
commercial quantities and of specified quality on a repeated basis and document their ability to do so. The required number of batches
of teplizumab have been manufactured at our CMOs by the processes we intend to use for commercialization. The quality and consistency
of these lots, along with their comparability to teplizumab manufactured for clinical studies, is now under review by the FDA.
If
the FDA concludes that the teplizumab manufactured by the current third-parties is not of sufficient quality, or is not comparable
to drug product used in the TN-10 study, delays in FDA acceptance of our BLA resubmission may occur. If the FDA applies a shorter
shelf life of teplizumab than we planned, this may negatively impact our commercial supply. Such impacts would, in turn, delay the
potential marketing and commercialization of teplizumab, which would materially and adversely affect our business.
Competition
We
face substantial competition from well-established large pharmaceutical companies, as well as innovative new entrants. Nevertheless,
we believe our strategic intent is sufficiently differentiated in that we are focusing on intercepting or potentially preventing the
onset and progression of immune-mediated and inflammatory diseases by selecting and developing product candidates that are aimed at relevant
and predominantly upstream pathophysiological targets.
The
symptomatic treatment of T1D is a highly competitive market with large incumbents such as Sanofi, Novo Nordisk and Eli Lilly providing
insulin and Medtronic, Abbott, and Dexcom providing blood glucose monitoring products and many working on new ways to manage the disease.
Our goal is to delay or prevent the onset of T1D and spare patients the need to live with blood glucose monitoring and daily insulin
injections and this therapy’s many complications and clinically relevant shortfalls. We believe our enteroviral vaccine approach
is unique in that it aims to prevent the onset of T1D prior to the rise of immune cells and auto-antibodies programmed to attack insulin
producing beta cells. We are aware of competitive vaccine technologies in development that are attempting to alter the autoimmune cycle
once these auto-antibodies have been detected. However, we believe our vaccine approach may intercept the process prior to this cycle
being initiated (primary prevention).
We
believe, our secondary prevention (i.e., interception) approach with teplizumab is more advanced and differentiated from other immunomodulation
therapies which have shown preservation of beta cell function in early phase studies of newly diagnosed onset T1D including anti-thymocyte
globulin (ATG), CTLA4-Ig (costimulatory blocker), anti-CD20 (Rituxan) and LFA3-Ig (alefacept). All of these Phase 2 studies were conducted
by the academic community or by T1D networks and do not appear to be in active Phase 3 development by industry sponsors. The most recent
data were reported with Thymoglobulin which is an approved anti-thymocyte globulin obtained by immunization of rabbits with human thymocytes
and is indicated for the treatment of renal transplant acute rejection in conjunction with concomitant immunosuppression and for induction
in adult renal transplant recipients. Low dose ATG was administered intravenously for 2 days in early onset T1D (within 100 days of diagnosis).
While C-peptide preservation was observed, due to the risk of serum sickness, ATG was administered during a 2-3 day hospitalization and
required pre-medication, including intravenous corticosteroids. In January 2020, a Phase 3 trial in newly diagnosed T1D patients with
ladarixin (Dompe) an interleukin-8 inhibitor, was announced on the basis of post-hoc results in a subset of patients after the drug failed
to improve C-peptide in Phase 2a. Importantly, teplizumab is the only experimental drug with positive data in Stage 2, in the prevention/delay
of clinical T1D, and no other pivotal studies are on-going in this indication.
PRV-015
has the potential to be the first drug ever approved for CD since it is the only medication which has shown simultaneous improvement
in gluten-induced symptoms and gut inflammation to date, and since most clinical-stage products are early in development and have not
established proof-of-concept. There is another anti-IL-15 mAb in clinical development, CALY002 by Calypso, currently in Phase 1. Potential
competition includes the recent initiation of a Phase 1b study with the marketed psoriasis anti-IL-23 mAb guselkumab (TREMFYA, Janssen),
and experimental medications in development by: 9 Meters (larazotide acetate, Phase 2b study completed in 2014; Phase 3 started in 2019
as a symptomatic relief, not disease-modifying agent), ImmunogenX (IMGX-003/latiglutenase, Phase 2b study completed in 2016 missed primary
endpoint, new phase 2a started in 2019), Zedira/Dr. Falk (ZED1227, positive phase 2a reported in 2021), Takeda (with TAK-101, formerly
NP-GLI, in Phase 1b/2a after Phase 1/2 completed in 2019; and TAK-062, formerly KumaMax, in Phase 1b after Phase 1 completed in 2019)
and Anokion (in Phase 1 with KAN-101).
The
market for lupus is currently led by large pharmaceutical companies commercializing older, off-patent products such as steroids, immunosuppressive
agents including azathioprine, cyclosphosphamide, cyclosporine and mycophenolate. In addition, Glaxo SmithKline (“GSK”)
and Roche offer recently approved B cell-targeted agents. GSK received approval for belimumab (Benlysta) in 2011, the first drug
approval in lupus in 50 years. Despite modest efficacy and slow onset of effect, belimumab’s annual sales are currently approximately
$800 million and are expected to grow with the December 2020 approval in lupus nephritis. Roche’s rituximab (Rituxan), a blockbuster
drug, is used off-label in lupus despite not having been approved in SLE. The calcineurin inhibitor voclosporin (Aurinia Pharmaceuticals)
was approved for lupus nephritis in January 2021. Anifrolumab (SAPHNELO, Astra Zeneca) is a type 1 interferon receptor mAb approved in
July 2021. The lupus field is competitive and new experimental drugs are being tested in late-stage trials by large pharmaceutical companies
and early to mid-stage biotech companies. We expect that PRV-3279 will be differentiated from the competition because of greater and
faster-onset efficacy, better safety (PRV-3279 does not deplete B cells and is not expected to be immune-suppressive), and less side
effects (since PRV-3279 is a highly specific mAb with likely minimal off-target side effects).
There
are no drugs approved for the prevention of the immunogenicity of biotherapeutics, and rituximab is occasionally used off-label in gene
therapy. Experimental medications are being tested in Phase 1-2 by Selecta Biosciences and Hansa Biopharma.
Government
Regulation
Our
business activities, including the manufacturing, research, development and marketing of our product candidates, are subject to extensive
regulation by numerous governmental authorities in the United States and other countries. Before marketing in the United States, any
new drug developed by us or our collaborators must undergo rigorous preclinical testing, clinical trials and an extensive regulatory
clearance process implemented by the FDA. The process for obtaining regulatory approval and compliance with applicable federal, state
and local laws and regulations requires the expenditure of substantial time and financial resources. Moreover, government coverage and
reimbursement policies will both directly and indirectly impact our ability to successfully commercialize any future approved products,
and such coverage and reimbursement policies will be impacted by enacted and any applicable future healthcare reform and drug pricing
measures. In addition, we are subject to state and federal laws, including, among others, anti-kickback laws, false claims laws, data
privacy and security laws, and transparency laws that restrict certain business practices in the pharmaceutical industry.
US
Regulation of Drugs and Biologics
In
the United States, FDA regulates human drugs under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and in the case of biologics,
also under the Public Health Service Act (“PHSA”) and their implementing regulations. The FDA regulates, among other things,
the development, testing, manufacture, safety, efficacy, record keeping, packaging, labeling, storage, approval, advertising, promotion,
import, export, sale and distribution of biopharmaceutical products.
The
process required by the FDA before a drug or biologic may be marketed in the United States generally involves the following:
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● |
completion
of preclinical laboratory tests, animal studies and formulation studies according to GLP regulations or other applicable regulations; |
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● |
submission
to the FDA of an Investigational New Drug Application (“IND”), which must become effective before human clinical trials
may begin; |
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● |
approval
by an independent institutional review board (“IRB”) or ethics committee at each clinical trial site before each clinical
trial may be initiated; |
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● |
performance
of adequate and well-controlled human clinical trials in accordance with applicable IND regulations, good clinical practices (“GCPs”),
and other clinical-trial related regulations to evaluate the safety and efficacy of the investigational product for each proposed
indication; |
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● |
preparation
and submission to the FDA of a New Drug Application (“NDA”) or BLA requesting marketing approval for one or more proposed
indications, including payment of application user fees; |
| |
● |
acceptance
of the NDA or BLA for filing and review by the FDA; |
| |
● |
review
of the NDA or BLA by an FDA advisory committee, where applicable; |
| |
● |
satisfactory
completion of one or more FDA inspections of the manufacturing facility or facilities at which the drug or biologic is produced to
assess compliance with GMP requirements to assure that the facilities, methods and controls are adequate to preserve the product’s
identity, strength, quality and purity; |
| |
● |
satisfactory
completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCPs and the integrity of the
clinical data submitted in support of the NDA or BLA; and |
| |
● |
FDA
review and approval of the NDA or BLA, which may be subject to additional post-approval requirements, including the potential requirement
to implement a Risk Evaluation and Mitigation Strategy (“REMS”), and any post-approval studies required by the FDA. |
Nonclinical
and Clinical Development
Before
testing any drug product candidates in humans, the product candidate intended for human use must undergo rigorous laboratory and animal
testing until adequate proof of safety is established. This preclinical testing generally involves laboratory evaluations of drug chemistry,
formulation and stability, as well as in vitro and animal studies, to assess the potential for adverse events and in some cases to establish
a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP
regulations for safety and toxicology studies. The sponsor must submit the results of the preclinical studies, together with manufacturing
information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND,
An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before
human clinical trials may begin. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time, the
FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold. In such a case,
the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an
IND may not result in the FDA allowing clinical trials to commence.
The
clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the
supervision of qualified investigators, in accordance with GCP requirements, which include the requirement that all patients provide
their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing the objectives
of the study, inclusion and exclusion criteria, the parameters to be used in monitoring the safety and effectiveness criteria to be evaluated.
Each protocol, as well as any subsequent amendments, must be submitted to the FDA as part of the IND. Additionally, each clinical trial
and its related documentation, including the trial protocol and informed consent form, must be reviewed and approved by an IRB for each
institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials
are minimized and are reasonable in relation to anticipated benefits. Some clinical trials are also overseen by an independent group
of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group may recommend
continuation of the study as planned, changes in study conduct, or cessation of the study at designated checkpoints based on access to
certain data from the study.
Clinical
trials for new product candidates are then typically conducted in humans in three sequential phases that may overlap. Phase 1 trials
involve the initial introduction of the product candidate into a small number of healthy human volunteers or disease-affected patients
who are initially exposed to a single dose and then multiple doses of the product candidate. The emphasis of Phase 1 trials is on testing
for safety or adverse events, dosage, tolerance, metabolism, distribution, excretion and clinical pharmacology. Phase 2 involves studies
in a limited patient population to determine the initial efficacy of the compound for specific targeted indications, to determine dosage
tolerance and optimal dosage, and to identify possible adverse side effects and safety risks. Once a compound shows evidence of effectiveness
and is found to have an acceptable safety profile in Phase 2 evaluations, Phase 3 trials are undertaken to more fully evaluate clinical
outcomes. Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data
necessary to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk
relationship of the product and provide an adequate basis for product labeling. Post-approval trials, sometimes referred to as Phase
4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment
of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials
as a condition of approval of an NDA or BLA. Failure to exhibit due diligence with regard to conducting mandatory Phase 4 clinical trials
could result in withdrawal of approval for products.
During
the development of a new drug or biological product, sponsors have the opportunity to meet with the FDA at certain points, including
prior to submission of an IND, at the end of phase 2, and before submission of an NDA or BLA. These meetings can provide an opportunity
for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA
to reach agreement on the next phase of development. Regulatory authorities, IRBs and Data Monitoring Committees may require additional
data before allowing clinical trials to commence, continue or proceed from one phase to another, and could demand that studies be discontinued
or suspended at any time if there are significant safety issues. Progress reports detailing the results of the clinical trials must be
submitted at least annually to the FDA and more frequently if serious adverse events occur. The FDA or the sponsor may suspend or terminate
a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable
health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not
being conducted in accordance with the clinical protocol, GCP, or other IRB requirements or if the drug has been associated with unexpected
serious harm to patients.
Information
about certain clinical trials, including details of the protocol and eventually study results, also must be submitted within specific
time frames to the National Institutes of Health for public dissemination on the Clinicaltrials.gov data registry.
Concurrent
with clinical trials, companies usually complete additional animal studies and must also develop additional information about the physical
characteristics of the drug or biologic and finalize a process for manufacturing the product in commercial quantities in accordance with
GMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among
other things, the manufacturer must develop methods for testing the identity, strength, quality, potency and purity of the final drug
or biological product. For biological products in particular, the PHSA emphasizes the importance of manufacturing control for products
whose attributes cannot be precisely defined in order to help reduce the risk of the introduction of adventitious agents. Additionally,
appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate
does not undergo unacceptable deterioration over its shelf life.
Generating
the required data and information for regulatory approval takes many years and requires the expenditure of substantial resources. Following
completion of the required testing, the results of the nonclinical studies and clinical trials, along with information relating to the
product’s chemistry, manufacturing, and controls and proposed labeling, are submitted to the FDA as part of an NDA or BLA requesting
approval to market the product for one or more indications. To support marketing approval, the data submitted must be sufficient in quality
and quantity to establish the safety and efficacy of the investigational product in the proposed patient population to the satisfaction
of the FDA. Under the PDUFA, each NDA or BLA must be accompanied by a user fee, which for federal fiscal year 2021 is $2,875,842
for an application requiring clinical data. The sponsor of an approved NDA or BLA is also subject to an annual program fee, which for
fiscal year 2021 is $336,432. The FDA adjusts the PDUFA user fees on an annual basis, but fee waivers or reductions are available
in certain circumstances.
Under
applicable laws and FDA regulations, each NDA or BLA submitted for FDA approval is given an internal administrative review within 60
days following submission of the NDA or BLA. If deemed sufficiently complete to permit a substantive review, the FDA will accept the
NDA or BLA for filing. The FDA can refuse to file any NDA and BLA that it deems incomplete or not properly reviewable. Once the submission
is accepted for filing, the FDA begins an in-depth review of the NDA or BLA. The FDA has established internal goals of eight months from
submission for priority review of NDAs or BLAs that cover product candidates that offer major advances in treatment or provide a treatment
where no adequate therapy exists, and 12 months from submission for the standard review of NDAs and BLAs. However, the FDA is not legally
required to complete its review within these periods, these performance goals may change over time and the review is often extended by
FDA requests for additional information or clarification.
Before
approving an NDA or BLA, the FDA will typically conduct pre-approval inspections of the facilities at which the product is manufactured
to determine whether the manufacturing processes and facilities are in compliance with GMP requirements and adequate to assure consistent
production of the product within required specifications. The FDA may also audit the clinical trial sponsor and one or more sites at
which clinical trials have been conducted to determine compliance with GCPs and data integrity. Additionally, the FDA may refer any NDA
or BLA, including applications for novel product candidates which present difficult questions of safety or efficacy, to an advisory committee.
Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts that reviews, evaluates
and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the
recommendation of an advisory committee, but it considers such recommendations when making final decisions on approval. The FDA likely
will re-analyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review
process.
Before
receiving FDA approval to market a potential product, we or our collaborators must demonstrate through adequate and well-controlled clinical
trials that the potential product is safe and effective in the patient population that will be treated. In addition, under the Pediatric
Research Equity Act (“PREA”), an NDA or BLA or supplement thereto must contain data to assess the safety and effectiveness
of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric
subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of pediatric data or full or partial
waivers of the requirement to provide data from pediatric studies.
After
the FDA evaluates an NDA or BLA, it will issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial
marketing of the drug or biologic with specific prescribing information for specific indications. A Complete Response Letter indicates
that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response
Letter usually describes all of the specific deficiencies in the NDA or BLA identified by the FDA. The Complete Response Letter may require
additional clinical data and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or
manufacturing. If a Complete Response Letter is issued, the applicant has one year to either resubmit the NDA or BLA, addressing all
of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may
decide that the NDA or BLA does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive and
the FDA may interpret data differently than we interpret the same data. In addition, delays or rejections may be encountered based upon
changes in regulatory policy, regulations or statutes governing product approval during the period of product development and regulatory
agency review.
If
regulatory approval of a potential product is granted, this approval will be limited to those disease states and conditions for which
the product is approved. Marketing or promoting a drug for an unapproved indication is generally prohibited. Furthermore, FDA approval
may require that contraindications, warnings, or precautions be included in the product labeling and entail ongoing requirements for
risk management, including post-marketing, or Phase 4, studies, testing and surveillance programs, and distribution restrictions. Following
approval, many types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling
claims, are subject to further testing requirements and FDA review and approval and may require the development of additional data or
preclinical studies and clinical trials.
Any
drug is likely to produce some toxicities or undesirable side effects in animals and in humans when administered at sufficiently high
doses and/or for sufficiently long periods of time. Unacceptable toxicities or side effects may occur at any dose level at any time in
the course of studies in animals designed to identify unacceptable effects of a product candidate, known as toxicological studies, or
during clinical trials of our potential products. The appearance of any unacceptable toxicity or side effect could cause us or regulatory
authorities to interrupt, limit, delay or abort the development of any of our product candidates. Further, such unacceptable toxicity
or side effects could ultimately prevent a potential product’s approval by the FDA or foreign regulatory authorities for any or
all targeted indications or limit any labeling claims and market acceptance, even if the product is approved.
In
addition, as a condition of approval, the FDA may require an applicant to develop a REMS. A REMS uses risk minimization strategies beyond
the professional labeling to ensure that the benefits of the product outweigh the potential risks. To determine whether a REMS is needed,
the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product,
expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a new molecular entity.
REMS can include medication guides, physician communication plans for healthcare professionals, and elements to assure safe use (“ETASU”).
ETASU may include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain
circumstances, special monitoring, and the use of patient registries. The FDA may require a REMS before approval or post-approval if
it becomes aware of a serious risk associated with use of the product. The requirement for a REMS can materially affect the potential
market and profitability of a product.
Any
trade name that we intend to use for a potential product must be approved by the FDA irrespective of whether we have secured a formal
trademark registration from the United States Patent and Trademark Office. The FDA conducts a rigorous review of proposed product names
and may reject a product name if it believes that the name inappropriately implies medical claims or if it poses the potential for confusion
with other product names. The FDA will not approve a trade name until the NDA or BLA for a product is approved. If the FDA determines
that the trade names of other products that are approved prior to the approval of our potential products may present a risk of confusion
with our proposed trade name, the FDA may elect to not approve our proposed trade name. If our trade name is rejected, we will lose the
benefit of any brand equity that may already have been developed for this trade name, as well as the benefit of our existing trademark
applications for this trade name.
We
and our collaborators and contract manufacturers also are required to comply with the applicable FDA GMP regulations. GMP regulations
include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and documentation.
Manufacturing facilities are subject to inspection by the FDA. These facilities must be approved before we can use them in commercial
manufacturing of our potential products and must maintain ongoing compliance for commercial product manufacture. Manufacturers and other
entities involved in the manufacture and distribution of approved drugs or biologics are required to register their establishments with
the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance
with GMPs and other laws. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality
control to maintain GMP compliance. Future inspections by the FDA and other regulatory agencies may identify compliance issues at the
facilities of our contract manufacturers that may disrupt production or distribution or require substantial resources to correct. In
addition, the discovery of conditions that violate these rules, including failure to conform to GMPs, could result in enforcement actions,
and the discovery of problems with a product after approval may result in restrictions on a product, manufacturer or holder of an approved
NDA or BLA, including voluntary recall and regulatory sanctions.
If
a product is approved, we must also comply with post-marketing requirements, including, but not limited to, compliance with advertising
and promotion requirements, which include restrictions on promoting products for unapproved uses or patient populations (known as “off-label
use”), monitoring and record-keeping activities, reporting of adverse events and other periodic reports, product sampling
and distribution restrictions, and limitations on industry sponsored scientific and educational activities. If there are any modifications
to the product, including changes in indications, labeling or manufacturing processes or facilities, we may be required to submit and
obtain FDA approval of a new NDA or BLA or an NDA or BLA supplement, which may require us to develop additional data or conduct additional
pre-clinical studies and clinical trials.
Although
physicians may prescribe legally available products for off-label uses, manufacturers may not market or promote such uses. The FDA and
other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to
have improperly promoted off-label uses may be subject to adverse publicity as well as significant liability. The federal government
has levied large civil and criminal fines against companies for alleged improper promotion and has also requested that companies enter
into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
The
FDA may withdraw approval of an NDA or BLA if compliance with regulatory requirements and standards is not maintained or if problems
occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of
unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in
mandatory revisions to the approved labeling to add new safety information; imposition of post-market or clinical trials to assess new
safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among other
things: restrictions on the marketing or manufacturing of the product; complete withdrawal of the product from the market or product
recalls; issuance of safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other
safety information about the product; fines, warning letters or other enforcement-related letters or clinical holds on post-approval
clinical trials; refusal of the FDA to approve pending NDAs or BLAs or supplements to approved NDAs or BLAs, or suspension or revocation
of product approvals; product seizure or detention, or refusal to permit the import or export of products; injunctions or the imposition
of civil or criminal penalties; and consent decrees, corporate integrity agreements, debarment, or exclusion from federal health care
programs; or mandated modification of promotional materials and labeling and the issuance of corrective information.
In
addition to FDA requirements, we must also comply with federal and state anti-fraud and abuse laws, including anti-kickback and false
claims laws, healthcare information privacy and security laws, post-marketing safety surveillance, and disclosure of payments or other
transfers of value to healthcare professionals and entities. In addition, we are subject to other federal and state regulation including,
for example, the implementation of corporate compliance programs.
If
we elect to distribute our products commercially, we must comply with state laws that require the registration of manufacturers and wholesale
distributors of pharmaceutical products in a state, including, in certain states, manufacturers and distributors who ship products into
the state even if such manufacturers or distributors have no place of business within the state. Some states also impose requirements
on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require
manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.
Outside
of the United States, our ability to market a product is contingent upon receiving a marketing authorization from the appropriate regulatory
authorities, including the EMA. The requirements governing the conduct of clinical trials, marketing authorization, pricing and reimbursement
vary widely from country to country. At present, foreign marketing authorizations are applied for at a national level, although within
the European Community, centralized registration procedures are available to companies wishing to market a product in more than one European
Community member state. If the regulatory authority is satisfied that adequate evidence of safety, quality and efficacy has been presented,
marketing authorization will be granted. This foreign regulatory development and approval process involves all of the risks associated
with achieving FDA marketing approval in the United States as discussed above. In addition, foreign regulations may include applicable
post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs
and reporting of payments or other transfers of value to healthcare professionals and entities.
Expedited
development and review programs
The
FDA is authorized to designate certain products for expedited development or review if they are intended to address an unmet medical
need in the treatment of a serious or life-threatening disease or condition. These programs include fast track designation, breakthrough
therapy designation, priority review designation, and accelerated approval pathway.
The
FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that meet certain
criteria. Specifically, new drugs and biologics are eligible for fast track designation if they are intended to treat a serious or life-threatening
condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition. Fast track designation
applies to both the product and the specific indication for which it is being studied. Fast track designation provides opportunities
for more frequent interactions with the FDA review team to expedite development and review of the product. The sponsor of a drug or biologic
can request the FDA to designate the product for fast track status any time before receiving NDA or BLA approval. Fast track designation
may be withdrawn by the sponsor or rescinded by the FDA if the designation is no longer supported by data emerging from the clinical
trial process.
Additionally,
a drug or biologic may be eligible for designation as a breakthrough therapy if the product is intended, alone or in combination with
one or more other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that
the product may demonstrate substantial improvement over existing currently approved therapies on one or more clinically significant
endpoints. The benefits of breakthrough therapy designation include the same benefits as fast track designation, plus intensive guidance
from the FDA to ensure an efficient drug development program. Drugs or biologics designated as breakthrough therapies are also eligible
for accelerated approval of their respective marketing applications.
A
product may also be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a meaningful
advantage over available therapies. In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict
clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (“IMM”)
that is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval, the FDA may require that
a sponsor of a drug or biologic receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials. If
the FDA concludes that a drug or biologic shown to be effective can be safely used only if distribution or use is restricted, it will
require such post-marketing restrictions as it deems necessary to assure safe use of the product. If the FDA determines that the conditions
of approval are not being met, such as the required post-marketing confirmatory trial does not demonstrate a clinical benefit, the FDA
can withdraw its accelerated approval for such drug or biologic. In addition, unless otherwise informed by the FDA, the FDA currently
requires, as a condition for accelerated approval, that all advertising and promotional materials that are intended for dissemination
or publication be submitted to the agency in advance for review.
Finally,
the FDA may designate a product for priority review if it is a drug or biologic that treats a serious condition and, if approved, would
provide a significant improvement in safety or effectiveness. The FDA determines at the time that the marketing application is submitted,
on a case-by-case basis, whether the proposed drug represents a significant improvement in treatment, prevention or diagnosis of disease
when compared with other available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the
treatment of a condition, elimination or substantial reduction of a treatment-limiting drug reaction, documented enhancement of patient
compliance that may lead to improvement in serious outcomes, or evidence of safety and effectiveness in a new subpopulation. A priority
review designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s
goal for taking action on a marketing application from ten months to six months for an original BLA or NDA from the date of filing.
Even
if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for
qualification or decide that the time period for FDA review or approval will not be shortened. Furthermore, fast track designation, priority
review, accelerated approval and breakthrough therapy designation, do not change the standards for approval and may not ultimately expedite
the development or approval process.
Orphan
drug designation and exclusivity
Orphan
drug designation in the United States is designed to encourage sponsors to develop products intended for the treatment of rare diseases
or conditions. In the United States, a rare disease or condition is statutorily defined as a condition that affects fewer than 200,000
individuals in the United States or that affects more than 200,000 individuals in the United States and for which there is no reasonable
expectation that the cost of developing and making the product available for the disease or condition will be recovered from sales of
the product in the United States.
Orphan
drug designation qualifies a company for certain tax credits. In addition, if a drug candidate that has orphan drug designation subsequently
receives the first FDA approval for that drug for the disease for which it has such designation, the product is entitled to orphan drug
exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven
years following product approval unless the subsequent product candidate is demonstrated to be clinically superior. Absent a showing
of clinical superiority, FDA cannot approve the same product made by another manufacturer for the same indication during the market exclusivity
period unless it has the consent of the sponsor or the sponsor is unable to provide sufficient quantities.
A
sponsor may request orphan drug designation of a previously unapproved product or new orphan indication for an already marketed product.
In addition, a sponsor of a product that is otherwise the same product as an already approved orphan drug may seek and obtain orphan
drug designation for the subsequent product for the same rare disease or condition if it can present a plausible hypothesis that its
product may be clinically superior to the first drug. More than one sponsor may receive orphan drug designation for the same product
for the same rare disease or condition, but each sponsor seeking orphan drug designation must file a complete request for designation.
To qualify for orphan exclusivity, however, the drug must be clinically superior to the previously approved product that is the same
drug for the same condition. If a product designated as an orphan drug ultimately receives marketing approval for an indication broader
than what was designated in its orphan drug application, it may not be entitled to exclusivity.
Rare
pediatric disease priority review voucher program
Under
the Rare Pediatric Disease Priority Review Voucher program, FDA may award a priority review voucher to the sponsor of an approved marketing
application for a product that treats or prevents a rare pediatric disease. The voucher entitles the sponsor to priority review of one
subsequent marketing application.
A
voucher may be awarded only for an approved rare pediatric disease product application. A rare pediatric disease product application
is an NDA or BLA for a product that treats or prevents a serious or life-threatening disease in which the serious or life-threatening
manifestations primarily affect individuals aged from birth to 18 years; in general, the disease must affect fewer than 200,000 such
individuals in the U.S.; the NDA or BLA must be deemed eligible for priority review; the NDA or BLA must not seek approval for a different
adult indication (i.e., for a different disease/condition); the product must not contain an active ingredient that has been previously
approved by FDA; and the NDA or BLA must rely on clinical data derived from studies examining a pediatric population such that the approved
product can be adequately labeled for the pediatric population. Before NDA or BLA approval, FDA may designate a product in development
as a product for a rare pediatric disease, but such designation is not required to receive a voucher.
To
receive a rare pediatric disease priority review voucher, a sponsor must notify FDA, upon submission of the NDA or BLA, of its intent
to request a voucher. If FDA determines that the NDA or BLA is a rare pediatric disease product application, and if the NDA or BLA is
approved, FDA will award the sponsor of the NDA or BLA a voucher upon approval of the NDA or BLA. FDA may revoke a rare pediatric disease
priority review voucher if the product for which it was awarded is not marketed in the U.S. within 365 days of the product’s approval.
The
voucher, which is transferable to another sponsor, may be submitted with a subsequent NDA or BLA and entitles the holder to priority
review of the accompanying NDA or BLA. The sponsor submitting the priority review voucher must notify FDA of its intent to submit the
voucher with the NDA or BLA at least 90 days prior to submission of the NDA or BLA and must pay a priority review user fee in addition
to any other required user fee. FDA must take action on an NDA or BLA under priority review within six months of receipt of the NDA or
BLA.
The
Rare Pediatric Disease Priority Review Voucher program was reauthorized in the Creating Hope Reauthorization Act in December 2020, allowing
a product that is designated as a product for a rare pediatric disease prior to October 1, 2020 to be eligible to receive a rare pediatric
disease priority review voucher upon approval of a qualifying NDA or BLA prior to October 1, 2026.
Pediatric
Exclusivity
Pediatric
exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of
an additional six months of marketing protection to the term of any existing regulatory exclusivity, including orphan exclusivity. This
six-month exclusivity may be granted if an NDA or BLA sponsor submits pediatric data that fairly respond to a written request from the
FDA for such data. The data do not need to show the product to be effective in the pediatric population studied; rather, if the clinical
trial is deemed to fairly respond to the FDA’s request, the additional protection is granted. If reports of requested pediatric
studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity
that cover the product are extended by six months.
United
States Patent Term Restoration and Extension
and Marketing Exclusivity
In
the United States, a patent claiming a new drug product, its method of use or its method of manufacture may be eligible for a limited
patent term extension under the Hatch-Waxman Act, which permits a patent extension of up to five years for patent term lost during product
development and FDA regulatory review. Assuming grant of the patent for which the extension is sought, the restoration period for a patent
covering a product is typically one-half the time between the effective date of the IND and the submission date of the NDA, plus the
time between the submission date of the NDA and the ultimate approval date, except that the review period is reduced by any time during
which the applicant failed to exercise due diligence. Patent term restoration cannot be used to extend the remaining term of a patent
past a total of 14 years from the product’s approval date in the United States. Only one patent applicable to an approved product
is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent for which
extension is sought. A patent that covers multiple products for which approval is sought can only be extended in connection with one
of the approvals. The USPTO reviews and approves the application for any patent term extension in consultation with the FDA.
Marketing
exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications. The FDCA provides a five-year
period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of an NDA for a new chemical
entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety,
which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept
for review an abbreviated new drug application (ANDA), or a 505(b)(2) NDA submitted by another company for another version of such drug
where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may
be submitted after four years if it contains a certification of patent invalidity or non-infringement. The FDCA also provides three years
of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability
studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application,
for example, new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the conditions of use
associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original
active agent. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting
a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled
clinical trials necessary to demonstrate safety and effectiveness.
Biosimilars
And Exclusivity
The
Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or, collectively,
the ACA, which was signed into law in March 2010, included a subtitle called the Biologics Price Competition and Innovation Act of 2009
(“BPCIA”). The BPCIA established a regulatory scheme authorizing the FDA to approve biosimilars and interchangeable biosimilars.
A biosimilar is a biological product that is highly similar to an existing FDA-licensed “reference product.” The FDA has
issued multiple guidance documents outlining an approach to review and approval of biosimilars. Under the BPCIA, a manufacturer may submit
an application for licensure of a biologic product that is “biosimilar to” or “interchangeable with” a previously
approved biological product or “reference product.” In order for the FDA to approve a biosimilar product, it must find that
there are no clinically meaningful differences between the reference product and proposed biosimilar product in terms of safety, purity
and potency. For the FDA to approve a biosimilar product as interchangeable with a reference product, the agency must find that the biosimilar
product can be expected to produce the same clinical results as the reference product, and (for products administered multiple times)
that the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks
or risks of diminished efficacy relative to exclusive use of the reference biologic.
Under
the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date of approval of
the reference product. The FDA may not approve a biosimilar product until 12 years from the date on which the reference product was approved.
Even if a product is considered to be a reference product eligible for exclusivity, another company could market a competing version
of that product if the FDA approves a full BLA for such product containing the sponsor’s own preclinical data and data from adequate
and well-controlled clinical trials to demonstrate the safety, purity and potency of their product. The BPCIA also created certain exclusivity
periods for biosimilars approved as interchangeable products. At this juncture, it is unclear whether products deemed “interchangeable”
by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law. Since the passage of the BPCIA,
many states have passed laws or amendments to laws, including laws governing pharmacy practices, which are state regulated, to regulate
the use of biosimilars.
Regulation
of companion diagnostic tests
Although
we do not believe that a companion diagnostic test will be required for the safe and effective use of our product candidates, FDA may
disagree and require use of a companion diagnostic to identify appropriate patient populations for our products. Under the FDCA, in vitro
diagnostics, including companion diagnostics, are regulated as medical devices. In the United States, the FDCA and its implementing regulations,
and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and
clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion,
sales and distribution, export and import, and post-market surveillance. Unless an exemption applies, diagnostic tests require marketing
clearance or approval from the FDA prior to commercial distribution. In August 2014, the FDA issued final guidance clarifying the requirements
that will apply to approval of therapeutic products and in vitro companion diagnostics. According to the guidance, for novel drugs, a
companion diagnostic device and its corresponding therapeutic should be approved or cleared contemporaneously by FDA for the use indicated
in the therapeutic product’s labeling. Approval or clearance of the companion diagnostic device will ensure that the device has
been adequately evaluated and has adequate performance characteristics in the intended population.
Reimbursement
Potential
sales of any of our product candidates, if approved, will depend, at least in part, on the extent to which such products will be covered
by third-party payors, such as government health care programs, commercial insurance and managed healthcare organizations. These third-party
payors are increasingly managing access and using restrictive measures to contain costs. If a third-party payor decides to provide coverage
for an approved drug product, patient access and reimbursement is not certain. Further, one payor’s determination to provide coverage
for a drug product does not assure that other payors will also provide coverage for the drug product. Decreases in third-party reimbursement
or a decision by a third-party payor to not cover a product candidate, if approved, could reduce utilization of our products, and have
a material adverse effect on our sales, results of operations and financial condition. Adequate third-party reimbursement may not be
available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.
In
addition, the United States government, state legislatures and foreign governments have continued implementing cost-containment programs,
including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption of price controls
and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could
further limit our future revenues and results of operations.
Within
the United States, if we obtain appropriate marketing approval in the future to market for any of our current product candidates, we
may be required to provide discounts or rebates under government healthcare programs or to certain government and private purchasers
in order to obtain coverage under federal health care programs such as Medicaid. Participation in such programs may require us to track
and report certain drug prices. We may be subject to fines and other penalties if we fail to report such prices accurately.
Healthcare
Laws and Regulations
Sales
of our product candidates, if approved, or any other future product candidate will be subject to healthcare regulation and enforcement
by the federal government and the states and foreign governments in which we might conduct our business. In the United States, our business
operations and any current or future arrangements with healthcare professionals (including principal investigators), third-party payors,
health care providers, patients and other customers may be subject to various federal and state fraud and abuse and other healthcare
laws and regulations that may affect our current or future manufacturing, sales, marketing, scientific, educational or other business
activities. The healthcare laws and regulations that may affect our ability to operate include the following:
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The
federal anti-kickback statute makes it illegal for any person or entity to knowingly and willfully, directly or indirectly, solicit,
receive, offer, or pay any remuneration that is in exchange for or to induce the referral of business, including the purchase, order,
lease of any good, facility, item or service for which payment may be made under a federal healthcare program, such as Medicare or
Medicaid. The term “remuneration” has been broadly interpreted to include anything of value. A person or entity need
not have actual knowledge of the federal anti-kickback statute or specific intent to violate it in order to have committed a violation. |
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Federal
false claims and false statement laws, including the federal civil False Claims Act (“FCA”),
prohibits, among other things, any person or entity from knowingly presenting, or causing
to be presented, for payment to, or approval by, federal programs, including Medicare and
Medicaid, claims for items or services, including drugs, that are false or fraudulent. Manufacturers
can be held liable under the FCA even when they do not submit claims directly to government
payors if they are deemed to “cause” the submission of false or fraudulent claims.
Actions under the FCA may be brought by the Attorney General or by private individuals in
the name of the federal government.
The
federal civil monetary penalties laws impose civil fines for, among other things, the offering or transfer or remuneration to a Medicare
or state healthcare program beneficiary, if the person knows or should know it is likely to influence the beneficiary’s selection
of a particular provider, practitioner, or supplier of services reimbursable by Medicare or a state health care program, unless an
exception applies. |
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The
United States federal Health Insurance Portability and Accountability Act of 1996, as amended (“HIPAA”), which prohibits
executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters and which
also imposes certain requirements relating to the privacy, security and transmission of individually identifiable health information
on certain types of entities, which include many healthcare providers and health plans with which we interact. |
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The
Federal Food, Drug, and Cosmetic Act, which among other things, strictly regulates drug product and medical device marketing, prohibits
manufacturers from marketing such products prior to approval or for unapproved indications and regulates the distribution of samples. |
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Federal
laws, including the Medicaid Drug Rebate Program, that require pharmaceutical manufacturers to report certain calculated product
prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition
of reimbursement under government healthcare programs. |
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The
so-called “federal sunshine” law, which requires pharmaceutical and medical device companies to monitor and report certain
financial interactions with physicians, teaching hospitals, and additional categories of healthcare practitioners to the federal
government for re-disclosure to the public. |
Also,
many states have similar laws and regulations, such as anti-kickback and false claims laws that may be broader in scope and may apply
to claims reimbursed by private payors as well as government programs or regardless of reimbursement. Additionally, we may be subject
to state laws that require pharmaceutical companies to comply with the federal government’s and/or pharmaceutical industry’s
voluntary compliance guidelines, impose specific restrictions on interactions between pharmaceutical companies and healthcare providers
or require pharmaceutical companies to report information related to payments and other transfers of value to physicians and other healthcare
providers or marketing expenditures, as well as state laws governing the privacy and security of health information, many of which differ
from each other in significant ways and often are not preempted by HIPAA. Many of these laws and regulations also contain ambiguous requirements
or require administrative guidance for implementation.
Our
current or future activities may also be subject to state and federal and state consumer protection and unfair competition laws and federal
and state licensing requirements and regulations that apply to the manufacture, sale, warehousing, and distribution of pharmaceutical
products.
The
scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform,
especially in light of the lack of applicable precedent and regulations. Federal and state enforcement bodies have recently increased
their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions,
convictions and settlements in the healthcare industry. Because of the breadth of these laws, the narrowness of available statutory exceptions
and safe harbors and the lack of clear guidance on the application of these laws to certain activities, it is possible that governmental
authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving
applicable fraud and abuse or other healthcare laws and regulations.
Violation
of these laws can subject us to significant civil, criminal and administrative penalties, damages, fines, imprisonment, disgorgement,
exclusion from government funded healthcare programs, such as Medicare and Medicaid, reputational harm, additional oversight and reporting
obligations if we become subject to a corporate integrity agreement or similar settlement to resolve allegations of non-compliance with
these laws and the curtailment or restructuring of our operations. If any of the physicians or other healthcare providers or entities
with whom we expect to do business is found not to be in compliance with applicable laws, they may be subject to similar actions, penalties
and sanctions. Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations
by government authorities, can be time- and resource-consuming and can divert a company’s attention from its business.
Additionally,
to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws.
Segments
and Geographic Information
Operating
segments are defined as components of an enterprise about which separate discrete information is available for evaluation by the chief
operating decision maker, or decision-making group, in deciding how to allocate resources and in assessing performance. We view our operations
and manage our business in one operating and reporting segment.
In
October 2021, we incorporated Provention Bio Limited, a wholly-owned private limited subsidiary, in the United Kingdom. We incorporated
this subsidiary to facilitate the potential future submission of an MAA for teplizumab, to the MHRA.
Human
Capital
Employees
As
of February 21, 2022, we had 82 full-time employees which are located throughout the United States. While we lease office
space for our principal executive offices in Red Bank, NJ, our employees work remotely. None of our employees are represented by a labor
union or covered by a collective bargaining agreement, and we believe our relationship with our employees is good. Additionally, we utilize
independent contractors and other third parties to assist with various aspects of our drug and product development.
We
provide salaries and benefits that are competitive based on compensation information from independent compensation consultants. A portion
of the compensation for almost all of our employees is performance-based. Performance-based compensation takes into account both individual
and Company-wide performance. In addition, a portion of performance-based compensation consists of equity incentives. The split between
base salary and performance-based compensation is tailored to each employee’s job function and level. In addition, we provide nationally
competitive benefits, including healthcare, a 401(k) program and a technology allowance.
We
are committed to the well-being of our employees and recognize that a remote workforce especially values the ability to balance work
with other aspects of their lives. As a virtual company, we embrace variable work schedules for our employees. We also allow part-time
arrangements and flexible work schedules.
We
provide professional development and advancement opportunities for our employees that include internal training, skills building and
opportunities for internal advancement.
Diversity
and Inclusion
We
seek to provide a collaborative and inclusive workplace where all employees feel empowered to do their best work and contribute to our
mission. We are an equal opportunity employer and strictly prohibit and do not tolerate discrimination against employees, including based
on race, creed, color, religion, national origin, citizenship status, age, gender, military and veteran status and sexual orientation.
We also prohibit any form of harassment or abuse in the workplace.
We
are focused on maintaining a diverse and inclusive work environment. Among other factors in hiring, we consider geographic, gender, age,
racial and ethnic diversity. Currently, women represent 38% of our C-suite team, and 17% of our board of directors. We expect to continue
implementing initiatives to enhance our workforce diversity, advance the development of diverse talent and ensure diverse succession
plans both in our employee workforce and on our board of directors.
Our
Corporate Information
We
are a Delaware corporation formed on October 4, 2016. Our principal executive offices are located at 55 Broad Street, 2nd Floor, Red
Bank, New Jersey 07701. Our phone number is (908) 336-0360 and our web address is http://www.proventionbio.com. Information contained
in or accessible through our web site is not, and should not be deemed to be, incorporated by reference in, or considered part of, this
Annual Report on Form 10-K.
Available
Information
We
make available free of charge through our website our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on
Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act. We make these reports
available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports
to, the SEC. You can review our electronically filed reports and other information that we file with the SEC on the SEC’s web site
at http://www.sec.gov. We also make available, free of charge on our website, the reports filed with the SEC by our executive officers,
directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those
filings are provided to us by those persons. The information contained on, or that can be accessed through, our website is not a part
of or incorporated by reference in this Annual Report on Form 10-K.