NEWARK, Calif., Nov. 15, 2021 /PRNewswire/
-- Protagonist Therapeutics (Nasdaq: PTGX)
("Protagonist" or "the Company") today announced results from a
Phase 2a study in which rusfertide, an investigational new drug, is
being evaluated for the treatment of hereditary hemochromatosis
(HH). HH is a genetic disorder arising from a deficiency or
dysregulation of the natural hormone hepcidin, a condition
which causes the body to absorb too much iron. The clinical data
from the study were presented in an oral presentation at The Liver
Meeting® of the American Association for the Study of Liver
Diseases (AASLD).
"Despite its prevalence, no drug therapies have been developed
to date for the treatment of hereditary hemochromatosis," said
Kris V. Kowdley, M.D., Director of
Liver Institute Northwest, Professor at the Elson S. Floyd College of Medicine at Washington State University, an author of the ACG
Guidelines for HH, and the study's principal investigator. "I'm
encouraged by the efforts Protagonist has undertaken in this area
of iron overload diseases, and specifically by the Phase 2 data
that demonstrates rusfertide's therapeutic effect by several
different measures, including pharmacodynamic effects, reduction in
phlebotomy requirements, stabilization of liver iron content, and
possible improvements in quality-of-life measures. Hereditary
hemochromatosis is characterized by low levels of hepcidin, with
variability of severity in clinical manifestations across different
patient sub-populations. Rusfertide has the potential to offer a
treatment option for patients in whom phlebotomy may be difficult
or contraindicated."
"Rusfertide has the potential to be the first-in-class drug
therapy for an HH indication," said Dinesh
Patel, Ph.D., President and Chief Executive Officer of
Protagonist. "After polycythemia vera, this marks a second
indication where rusfertide has demonstrated a positive clinical
proof-of-concept, thereby signaling a broader potential utility to
address unmet needs of patients in these diseases. The study
results announced at AASLD will serve as an important foundation
for the next steps that we will determine in consultation with key
clinical investigators and regulatory agencies. Going forward, our
focus will be on proving rusfertide's potential to address unmet
medical needs in specific subpopulations of HH."
Study Design and Summary of Results:
- The study was an open-label multicenter Phase 2 study in 16
patients that was designed to evaluate the safety and efficacy of
rusfertide as a treatment for patients with HH. The requirement
for, and frequency of, therapeutic phlebotomies, a key endpoint of
the study, was statistically significant: rusfertide-treated
patients had 0.009 phlebotomies per month during the study compared
to 0.28 phlebotomies per month pre-study (p<0.0001).
- The average TSAT during treatment with rusfertide was 31.4%
compared to 45.0% pre-study (p=0.0051) and the serum iron during
treatment with rusfertide was 101 mcg/dl compared to 137 mcg/dl
pre-study (p=0.0106). Eighty percent of patients who came into the
study with baseline TSAT values above 45% (N=10) achieved average
TSAT values that were normalized (<45%) during rusfertide
treatment. All the subjects with elevated serum iron above 170
mcg/dl at baseline (N=5) were able to maintain an average serum
iron within a normal range of <170 mcg/dl during rusfertide
treatment. While ferritin levels varied during treatment with
rusfertide, average ferritin levels were below 200 ng/mL in 15 of
the 16 patients.
- Patients underwent MRI to measure Liver Iron Content (LIC) at
the beginning and end of the study. Rusfertide treatment maintained
or reduced average LIC, despite fewer phlebotomies over the
duration of the study.
- Patients reported trends of qualitative improvements in Quality
of Life measures through the duration of the study.
- Rusfertide was well tolerated in this study population. Adverse
events (AEs) were generally of Grade 1 or 2 except for one report
of an adenocarcinoma of the pancreas that was pre-existing and
therefore considered not related to drug. Treatment-emergent
injection site reactions, all of which were mild or moderate and
transient in nature, occurred in 50% of patients. Other
treatment-emergent AEs reported in two or more patients included
headache, diarrhea, dizziness, hypertension, and fatigue all of
which were mild or moderate.
About Hereditary Hemochromatosis
Hereditary hemochromatosis (HH) is a genetic disorder
characterized by excessive iron absorption due to a deficiency or
dysregulation in hepcidin. The disorder results in the accumulation
of excess iron in the body's organs. Approximately one million
people in the United States have
HFE mutations consistent with type 1 HH; out of these, 10 to 15
percent develop clinical manifestations of the disease. The
clinical symptoms of hemochromatosis usually appear after
significant iron accumulation—generally after the age of 40. Early
signs are nonspecific and can include weakness, lethargy, increased
skin pigmentation, hair loss, impotence, joint pains, vertigo, and
loss of memory.
In HH types 1-3, mutations in genes encoding hepcidin regulators
or hepcidin itself lead to diminished production of hepcidin, thus
decreasing the inhibitory effect of hepcidin on duodenal iron
absorption and causing clinical iron overload (Brissot 2011).
Hepcidin deficiency leads to increased circulating transferrin
saturation, and ultimately, iron accumulation in organs such as the
liver, pancreas, heart, and bone. Iron in excess may induce or
favor the development of complications such as cirrhosis, liver
cancer, diabetes, heart failure, hypogonadism, but also, complaints
such as asthenia and disabling arthritis.
The goal of treatment in HH patients is to reduce the
development of such complications. Per ACG Guidelines, patients
with elevated serum ferritin above 200 ng/mL in females and 300
ng/mL in males along with a transferrin saturation (TSAT) at or
above 45 percent will require treatment to reduce serum ferritin to
the range of 50-100 ng/mL and subsequently decrease TSAT levels to
below 45 percent.
There is no approved medicine for treatment of HH, and
phlebotomy continues to be the main treatment option. Patients
living with clinical manifestations of HH require continued
phlebotomies for their entire lives to limit end-organ damage.
While therapeutic phlebotomy is effective in removing excess iron
and preventing most of the complications associated with excess
iron in the body, this treatment does not target the biological
mechanisms leading to iron metabolism disturbance. Approximately
25% of patients in maintenance felt that receiving phlebotomies was
"inconvenient" or "very inconvenient" (Brissot 2011), and patient
compliance with phlebotomies generally declines over time (Hicken
et al, 2003).
In hepcidin-deficient mouse models of hemochromatosis, a
mini-hepcidin and rusfertide were found to be effective in
decreasing iron loading in the liver compared to vehicle treated
control mice that were iron overloaded (Ramos 2012, Taranath 2019).
These pre-clinical observations along with our clinical findings in
the current study suggest that a hepcidin mimetic such as
rusfertide may be effective for preventing iron overload in
patients with hemochromatosis.
About Protagonist
Protagonist Therapeutics is a biopharmaceutical company with
multiple peptide-based investigational new chemical entities in
different stages of development, all derived from the Company's
proprietary technology platform.
Protagonist's pipeline includes rusfertide (PTG-300), an
investigational, injectable hepcidin mimetic currently in a Phase 2
proof-of-concept clinical trial for polycythemia vera (PV), a Phase
2 study in PV subjects with high hematocrit levels, and a Phase 2a
study for hereditary hemochromatosis. The Company plans to initiate
a single, global Phase 3 randomized, placebo-controlled trial
evaluating the efficacy and safety of a once weekly, subcutaneously
self-administered dose of rusfertide.
The Company is also evaluating an orally delivered,
gut-restricted alpha-4-beta-7 integrin specific antagonist peptide
(PN-943) currently in a Phase 2 study in adults with moderate to
severe active ulcerative colitis (UC). The Company is targeting
ulcerative colitis as the initial indication.
The Company has a worldwide license and collaboration agreement
with Janssen Biotech, Inc., for the development of oral peptide
IL-23 receptor antagonists. Compounds in development include PN-235
and PN-232, both second-generation oral interleukin-23 receptor
antagonist candidates. The Phase 1 study of PN-235 is
completed, and Janssen is expected to initiate a Phase 2 study in
psoriasis in early 2022. The Phase 1 study with PN-232 is in
progress, with study completion expected by mid-2022. Additional
clinical development in IBD is expected to initiate in
2022.
Cautionary Note on Forward-Looking Statements
This press release contains forward-looking statements for
purposes of the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995. Forward-looking statements include
statements regarding our intentions or current expectations
concerning, among other things, the Company's clinical development
program for rusfertide in HH, and the potential benefits of
rusfertide in HH patients. In some cases, you can identify these
statements by forward-looking words such as "anticipate,"
"believe," "may," "will," "expect," or the negative or plural of
these words or similar expressions. Forward-looking statements are
not guarantees of future performance and are subject to risks and
uncertainties that could cause actual results and events to differ
materially from those anticipated, including, but not limited to,
our ability to develop and commercialize our product candidates,
our ability to earn milestone payments under our collaboration
agreements, the impact of the current COVID-19 pandemic on our
discovery and development efforts, our ability to use and expand
our programs to build a pipeline of product candidates, our ability
to obtain and maintain regulatory approval of our product
candidates, our ability to operate in a competitive industry and
compete successfully against competitors that have greater
resources than we do, and our ability to obtain and adequately
protect intellectual property rights for our product
candidates. Additional information concerning these and other
risk factors affecting our business can be found in our periodic
filings with the Securities and Exchange Commission, including
under the heading "Risk Factors" contained in our most recently
filed periodic reports on Form 10-K and Form 10-Q filed with
the Securities and Exchange Commission. Forward-looking
statements are not guarantees of future performance, and our actual
results of operations, financial condition and liquidity, and the
development of the industry in which we operate, may differ
materially from the forward-looking statements contained in this
press release. Any forward-looking statements that we make in
this press release speak only as of the date of this press release.
We assume no obligation to update our forward-looking statements,
whether as a result of new information, future events or otherwise,
after the date of this press release.
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