− In Randomized, Double-Blind,
Placebo-Controlled Phase 1 Study, Monthly Givosiran Demonstrated an
Over 80 Percent Lowering of Urinary Aminolevulinic Acid (ALA), a
Disease Biomarker, and an Over 75 Percent Decrease in Mean
Annualized Porphyria Attack Rate, Relative to Placebo −
− Evidence of Enhanced Clinical Activity with
Long-Term Treatment of up to 22 Months in Ongoing Phase 1/2
Open-Label Extension (OLE) Study, with an Over 90 Percent Decrease
in Mean Annualized Porphyria Attack Rate, Relative to Baseline
Run-in Attack Rate −
− Clinical Activity and Safety Results Support
Accelerated Efforts to Bring Givosiran to Patients with Acute
Hepatic Porphyrias –
− Management to Discuss Results in Webcast
Conference Call Today, Saturday, April 14 at 8:00 am
ET −
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading
RNAi therapeutics company, today announced new results from the
Phase 1 and Phase 1/2 open-label extension (OLE) studies of
givosiran, an investigational RNAi therapeutic targeting
aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute
hepatic porphyrias (AHPs). These results were presented at the
European Association for the Study of the Liver (EASL) 53rd Annual
International Liver Congress™, being held April 11-15, 2018 in
Paris, France. New data from the ongoing EXPLORE natural history
study were also presented.
“We view these new results with givosiran as very encouraging,
since they demonstrate robust and what we believe to be clinically
meaningful reductions in urinary ALA, porphyria attack rate, and
hemin administration with continued dosing for up to nearly two
years. We also believe our new data support use of a monthly dosing
regimen for sustained reductions in ALAS1 mRNA and urinary ALA,
with improved clinical activity. In sum, we believe the clinical
activity and overall safety profile for givosiran continue to
support an accelerated Phase 3 development plan,” said Akin Akinc,
Vice President and General Manager, Givosiran Program at Alnylam.
“In the meanwhile, we continue to enroll patients in the ENVISION
Phase 3 pivotal study, which was initiated at the end of 2017.
Further, we are pleased to announce today that we expect to enroll
the thirtieth patient into ENVISION in the coming weeks in support
of the planned interim analysis in mid-2018, which, if positive,
would support a potential NDA filing for givosiran by end of this
year.”
“People afflicted with acute hepatic porphyrias – a family of
ultra-rare inherited disorders – suffer from potentially
life-threatening neurovisceral attacks, accompanied by frequent
need for urgent care and hospitalization, and often endure
debilitating chronic symptoms. This is a disease with overwhelming
burden and an arduous journey to diagnosis, with patients having a
severely diminished quality of life,” said Karl Anderson, M.D.,
FACP, University of Texas Medical Branch. “There is no question
that there is an urgent need for novel therapies that can offer new
hope to these patients by preventing attacks, addressing the
chronic manifestations of this condition, and reducing disease
burden overall. I believe that the new results presented for
givosiran are encouraging, and the medical community looks forward
to the results of the pivotal Phase 3 study underway.”
Phase 1 Part C Study ResultsGivosiran treatment led to
rapid, dose-dependent, and durable lowering of induced ALAS1 mRNA
in patients with recurrent attacks. Lowering of ALAS1 resulted in
corresponding reductions in both aminolevulinic acid (ALA),
believed to be the primary neurotoxic intermediate responsible for
disease manifestations, and porphobilinogen (PBG). Compared with a
once quarterly dose regimen, monthly dosing led to consistent and
sustained lowering of ALA and PBG of greater than 80 percent,
relative to baseline; increasing the monthly dose from 2.5 mg/kg to
5.0 mg/kg did not lead to further lowering of ALA and PBG levels.
Monthly givosiran dosing at 2.5 mg/kg led to mean reductions in
annualized attack rate (AAR)* of 83 percent and annualized hemin
use of 88 percent, relative to placebo. Monthly dosing regimens led
to enhanced clinical activity as compared to quarterly dosing. A
continuous relationship between greater ALA lowering and AAR
reduction was also observed.
Serious adverse events (SAEs) were reported in six patients
receiving givosiran in the Phase 1 study; none were assessed as
related to study drug. SAEs consisted of two patients with
abdominal pain leading to hospitalization, and one patient each
with miscarriage, opioid bowel dysfunction, and influenza
infection. As previously reported, the remaining SAE occurred in a
recurrent attack patient who died due to hemorrhagic pancreatitis
complicated by a pulmonary embolism and following a recent
hospitalization for bacteremia. There were no other
discontinuations due to adverse events (AEs) and no clinically
significant changes in clinical laboratory assessments.
Interim Phase 1/2 OLE ResultsAs of February 26, 2018, a
robust treatment effect was maintained in givosiran-treated
patients with extended dosing in the OLE study, with a total time
on treatment across the Phase 1 and OLE studies of up to 22 months.
In patients who received givosiran during the Phase 1 study and
continued with givosiran dosing in the OLE study (N=12), mean
reductions in AAR of 93 percent and annualized hemin use of 94
percent were observed, relative to the AAR and annualized hemin use
recorded for these patients in the Phase 1 run-in period. The
extent of these reductions in the OLE study exceeded that observed
in response to givosiran treatment during the Phase 1 study,
suggesting that extended dosing at 2.5 mg/kg monthly potentially
leads to enhanced clinical activity. Patients in the placebo arm of
the Phase 1 study crossing over to givosiran treatment in the OLE
study (N=4) experienced mean reductions of greater than 90 percent
in AAR and annualized hemin use, relative to the Phase 1 run-in and
placebo treatment periods. For patients in the OLE study, seven of
sixteen, or 44 percent, achieved an AAR of zero with a mean of 8.5
months on treatment; during the prospectively monitored run-in
period, these same patients experienced a median AAR of 15.1 (range
from 6.3 to 34.0).
SAEs were reported in two patients. One patient presented with
upper extremity deep vein thrombosis, assessed as unlikely related
to study drug due to the presence of an indwelling central venous
catheter and a prior history of venous damage from chronic hemin
use. One patient had an anaphylactic reaction after the third dose
of givosiran (first dose in the OLE study), assessed as definitely
related to study drug. The patient had a past history of asthma,
oral allergy syndrome, and allergic reactions to acne cream and
possibly latex gloves. The event resolved with medical management,
and the patient discontinued from the study. AEs occurring in three
or more patients included abdominal pain, nausea, injection site
erythema, headache, injection site pruritus, fatigue, and
nasopharyngitis. No clinically significant increases in liver
function tests or lipase levels were noted with ongoing dosing.
EXPLORE Natural History Study ResultsData as of November
21, 2017 from the EXPLORE natural history study were also presented
at the conference. EXPLORE is the first observational,
multinational, prospective study designed to characterize the
natural history, clinical management and quality of life of AHP
patients (N=112) with recurrent attacks (three or more
attacks/year) or who receive hemin or gonadotropin-releasing
hormone analogue prophylaxis to prevent attacks. Updated data from
EXPLORE demonstrate that patients suffer from both acute attacks
and chronic symptoms (in 65 percent of patients) in between
attacks, that together result in a diminished quality of life.
Patients in the EXPLORE study had an AAR of 3.7, inclusive of 46
percent of patients taking hemin prophylaxis, with a mean attack
duration of 7.3 days. The majority of attacks (76 percent) were
treated in a healthcare facility or with hemin.
All results presented at EASL can be viewed on
the Capella section of the Alnylam website.
*Attacks requiring hospitalization, urgent health care visit or
hemin, which is the attack rate definition used in the ENVISION
Phase 3 trial.
Conference CallAlnylam management will discuss these
results via conference call today, April 14, 2018 at 8:00 am ET. A
slide presentation will also be available on the Investors page of
the Company’s website, www.alnylam.com, to accompany the conference
call. To access the call, please dial 866-548-4713 (domestic) or
323-794-2093 (international) five minutes prior to the start time
and refer to conference ID 6810175. A replay of the call will be
available beginning at 11:00 am ET on April 14,
2018. To access the replay, please dial 888-203-1112 (domestic) or
719-457-0820 (international) and refer to conference ID
6810175.
About Givosiran Phase 1 StudyThe Phase 1 study of
givosiran (Part C) was conducted as a randomized, double-blind,
placebo-controlled study in 17 patients with acute intermittent
porphyria (AIP) who experienced recurrent porphyria attacks.
Patients were initially followed in a 3-month run-in phase, where
the number and frequency of porphyria attacks and levels of ALA and
PBG were measured prospectively. Patients who experienced at least
one porphyria attack during the run-in phase were then eligible to
enter the 6-month treatment phase of the study, where they were
randomized to receive 2 once-quarterly doses or 4 once-monthly
doses of placebo or givosiran at doses of 2.5 or 5.0 mg/kg. During
the treatment phase, the effects of placebo or givosiran on the
number and frequency of porphyria attacks, as well as on the levels
of ALA and PBG, were measured prospectively in a blinded manner and
then compared to run-in phase results. Additional measures included
safety, tolerability, hospitalizations, use of hemin, levels of
ALAS1 mRNA, and givosiran pharmacokinetics. Hemin is
an FDA-approved agent used to treat porphyria attacks when
they occur. Following the treatment phase, all patients were
eligible to receive givosiran in an open-label extension study.
About GivosiranGivosiran is an investigational,
subcutaneously administered RNAi therapeutic targeting
aminolevulinic acid synthase 1 (ALAS1) in development for the
treatment of acute hepatic porphyrias (AHPs). Monthly
administration of givosiran has the potential to significantly
lower induced liver ALAS1 levels in a sustained manner and thereby
decrease neurotoxic heme intermediates, aminolevulinic acid (ALA)
and porphobilinogen (PBG) to near normal levels. By reducing
accumulation of these intermediates, givosiran has the potential to
prevent or significantly reduce the occurrence of severe and
life-threatening attacks, control chronic symptoms, and decrease
the burden of the disease. Givosiran utilizes Alnylam’s Enhanced
Stabilization Chemistry ESC-GalNAc conjugate technology, which
enables subcutaneous dosing with increased potency and durability
and a wide therapeutic index. Givosiran has been granted
Breakthrough Therapy designation by the U.S. Food and Drug
Administration (FDA) and PRIME designation by the European
Medicines Agency (EMA). Givosiran has also been granted orphan drug
designations in both the U.S. and the EU for the treatment of AHPs.
The safety and efficacy of givosiran are currently being
investigated in the ENVISION Phase 3 clinical trial and ongoing
Phase 1/2 OLE study and have not been evaluated by the FDA, the EMA
or any other health authority.
About Acute Hepatic PorphyriasAcute hepatic porphyrias
(AHPs) are a family of rare, genetic diseases characterized by
potentially life-threatening attacks and for many patients chronic
debilitating symptoms that negatively impact daily functioning and
quality of life. AHPs are comprised of four subtypes, each
resulting from a genetic defect leading to deficiency in one of the
enzymes of the heme biosynthesis pathway in the liver: acute
intermittent porphyria (AIP), hereditary coproporphyria (HCP),
variegate porphyria (VP), and ALAD-deficiency porphyria (ADP).
These defects cause the accumulation of neurotoxic heme
intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG),
with ALA believed to be the primary neurotoxic intermediate
responsible for causing both attacks and ongoing symptoms between
attacks. Common symptoms of AHPs include severe, diffuse abdominal
pain, weakness, nausea, and fatigue. The symptoms of AHPs can often
resemble that of other more common conditions such as irritable
bowel syndrome, appendicitis, fibromyalgia, and endometriosis and
consequently, patients afflicted with AHPs are often misdiagnosed
or remain undiagnosed for up to 15 years. Currently, there are no
treatments approved to prevent debilitating attacks and treat the
chronic symptoms of the disease.
About RNAiRNAi (RNA interference) is a natural cellular
process of gene silencing that represents one of the most promising
and rapidly advancing frontiers in biology and drug development
today. Its discovery has been heralded as “a major scientific
breakthrough that happens once every decade or so,” and was
recognized with the award of the 2006 Nobel Prize for Physiology or
Medicine. By harnessing the natural biological process of RNAi
occurring in our cells, a major new class of medicines, known as
RNAi therapeutics, is on the horizon. Small interfering RNA
(siRNA), the molecules that mediate RNAi and comprise Alnylam's
RNAi therapeutic platform, function upstream of today’s medicines
by potently silencing messenger RNA (mRNA) – the genetic precursors
– that encode for disease-causing proteins, thus preventing them
from being made. This is a revolutionary approach with the
potential to transform the care of patients with genetic and other
diseases.
About Alnylam PharmaceuticalsAlnylam (Nasdaq: ALNY) is
leading the translation of RNA interference (RNAi) into a whole new
class of innovative medicines with the potential to transform the
lives of people afflicted with rare genetic, cardio-metabolic, and
hepatic infectious diseases. Based on Nobel Prize-winning science,
RNAi therapeutics represent a powerful, clinically validated
approach for the treatment of a wide range of severe and
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust discovery platform and deep pipeline of investigational
medicines, including four product candidates that are in late-stage
development. Looking forward, Alnylam will continue to execute on
its "Alnylam 2020" strategy of building a multi-product,
commercial-stage biopharmaceutical company with a sustainable
pipeline of RNAi-based medicines to address the needs of patients
who have limited or inadequate treatment options. Alnylam employs
over 800 people in the U.S. and Europe and is headquartered in
Cambridge, MA. For more information about our people, science and
pipeline, please visit www.alnylam.com and engage with us on
Twitter at @Alnylam or on LinkedIn.
Alnylam Forward Looking StatementsVarious statements in
this release concerning Alnylam's future expectations, plans and
prospects, including, without limitation, Alnylam's views with
respect to data presented for givosiran, and the potential
implications of such data for patients, its expectations regarding
the timing of the enrollment of the thirtieth patient in the
ENVISION Phase 3 study, a planned interim analysis and potential
NDA filing for givosiran if such interim analysis is positive, and
expectations regarding its "Alnylam 2020" guidance for the
advancement and commercialization of RNAi therapeutics, constitute
forward-looking statements for the purposes of the safe harbor
provisions under The Private Securities Litigation Reform Act of
1995. Actual results and future plans may differ materially from
those indicated by these forward-looking statements as a result of
various important risks, uncertainties and other factors,
including, without limitation, Alnylam's ability to discover and
develop novel drug candidates and delivery approaches, successfully
demonstrate the efficacy and safety of its product candidates, the
pre-clinical and clinical results for its product candidates, which
may not be replicated or continue to occur in other subjects or in
additional studies or otherwise support further development of
product candidates for a specified indication or at all, actions or
advice of regulatory agencies, which may affect the design,
initiation, timing, continuation and/or progress of clinical trials
or result in the need for additional pre-clinical and/or clinical
testing, delays, interruptions or failures in the manufacture and
supply of its product candidates, obtaining, maintaining and
protecting intellectual property, Alnylam's ability to enforce its
intellectual property rights against third parties and defend its
patent portfolio against challenges from third parties, obtaining
and maintaining regulatory approval, pricing and reimbursement for
products, progress in establishing a commercial and ex-United
States infrastructure, competition from others using technology
similar to Alnylam's and others developing products for similar
uses, Alnylam's ability to manage its growth and operating
expenses, obtain additional funding to support its business
activities, and establish and maintain strategic business alliances
and new business initiatives, Alnylam's dependence on third parties
for development, manufacture and distribution of products, the
outcome of litigation, the risk of government investigations, and
unexpected expenditures, as well as those risks more fully
discussed in the "Risk Factors" filed with Alnylam's most recent
Annual Report on Form 10-K filed with the Securities and Exchange
Commission (SEC) and in other filings that Alnylam makes with the
SEC. In addition, any forward-looking statements represent
Alnylam's views only as of today and should not be relied upon as
representing its views as of any subsequent date. Alnylam
explicitly disclaims any obligation, except to the extent required
by law, to update any forward-looking statements.
Givosiran has not been evaluated by the FDA, EMA, or any other
regulatory authority and no conclusions can or should be drawn
regarding the safety or effectiveness of this investigational
therapeutic.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20180413005605/en/
Alnylam Pharmaceuticals, Inc.Christine Regan Lindenboom,
617-682-4340(Investors and Media)orJosh Brodsky,
617-551-8276(Investors)
Alnylam Pharmaceuticals (NASDAQ:ALNY)
Historical Stock Chart
From Aug 2024 to Sep 2024
Alnylam Pharmaceuticals (NASDAQ:ALNY)
Historical Stock Chart
From Sep 2023 to Sep 2024