− Givosiran Demonstrated Sustained Clinical
Activity, with an Over 90 Percent Decrease in Mean Annualized
Porphyria Attack Rate, Relative to Baseline –
− Safety Profile Encouraging with up to 25
Months of Treatment –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading
RNAi therapeutics company, announced today that the Company
presented updated results from the ongoing Phase 1/2 open-label
extension (OLE) study of givosiran, an investigational RNAi
therapeutic, targeting aminolevulinic acid synthase 1 (ALAS1) for
the treatment of acute hepatic porphyria (AHP). The new data were
presented at The Liver Meeting® 2018 of the American Association
for the Study of Liver Diseases (AASLD) being held November 9-13 in
San Francisco, CA.
“We are encouraged by the sustained clinical activity and safety
profile of givosiran in the ongoing Phase 1/2 OLE study, now with
up to over two years of dosing. We believe these results
demonstrate clinically meaningful reductions in neurotoxic
biomarkers, porphyria attack rate, and hemin usage, supporting the
potential of givosiran to be an important treatment option for AHP
patients,” said Akin Akinc, Vice President and General Manager,
Givosiran Program at Alnylam. “We remain committed to bringing
givosiran to patients as rapidly as possible, and are on course to
initiate a rolling submission for an NDA by the end of 2018, and
report topline results from the ENVISION Phase 3 pivotal study in
early 2019.”
“Patients with acute hepatic porphyria not only endure
potentially life-threatening neurovisceral attacks but often
present with debilitating chronic symptoms and a severely
diminished quality of life, highlighting the profound unmet need in
this disease setting for both patients and their caregivers,” said
Karl Anderson, M.D., FACP, University of Texas Medical Branch and
an investigator in the ENVISION Phase 3 trial. “I am encouraged by
the sustained clinical activity of givosiran and look forward to
results of the ENVISION Phase 3 trial, evaluating the potential of
this investigational RNAi therapeutic as a treatment option for
AHP.”
Updated Phase 1/2 OLE ResultsAs of the data cut-off date
of June 7, 2018, a robust treatment effect was maintained in
givosiran-treated patients with continued dosing in the Phase 1/2
OLE study (N=16), with a mean time on treatment of 13.6 months and
total time on treatment across the Phase 1 and OLE studies of up to
25 months. Monthly dosing at 2.5 mg/kg led to sustained lowering of
aminolevulinic acid (ALA) and porphobilinogen (PBG) toward normal
levels, with a mean reduction from baseline of 87 and 83 percent,
respectively, at 12 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 annualized attack rate (AAR)*
of 93 percent and annualized hemin use of 94 percent were observed,
relative to pre-treatment results (measured in the Phase 1 blinded,
prospective run-in period). Similarly, patients in the placebo arm
of the Phase 1 study crossing over to givosiran treatment in the
OLE study (N=4) experienced mean reductions in AAR of 95 percent
and annualized hemin use of 98 percent. Seven of sixteen patients
(44 percent) achieved an AAR of zero with a mean of 11.3 months on
treatment; the average AAR during the run-in period for these seven
patients was 15.2.
Serious adverse events (SAEs) were reported in four patients.
Previously reported SAEs included: a patient with an upper
extremity deep vein thrombosis, assessed as unlikely related to
study drug by the investigator; and one patient who had an
anaphylactic reaction after the third dose of givosiran, assessed
as definitely related to study drug, which resolved with medical
management. New SAEs included: a patient with two episodes of
pyrexia related to a suspected Port-a-Cath infection and chlamydia
bronchitis, assessed as unlikely related to study drug; and one
patient with a change in mental status due to a possible
glucocorticoid toxicity from an acute bacterial sinusitis, both of
which were assessed as unlikely related to study drug. Adverse
events (AEs) occurring in three or more patients included abdominal
pain, fatigue, injection site erythema, nausea, myalgia, diarrhea,
headache, and nasopharyngitis. Six patients had injection site
reactions, all mild to moderate. No clinically significant
increases in liver function tests or lipase levels were noted with
continued dosing in the OLE study.
Results presented at AASLD can be viewed on
the Capella section of the Alnylam website.
*Attacks requiring hospitalization, urgent health care visit or
hemin administration, which is the attack rate definition used in
the ENVISION Phase 3 trial.
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 the ENVISION Phase 3 StudyThe ENVISION Phase 3
trial is a randomized, double-blind, placebo-controlled, global,
multicenter study to evaluate the efficacy and safety of givosiran
in patients with a documented diagnosis of an AHP. Patients were
randomized on a 1:1 basis to receive 2.5 mg/kg of givosiran or
placebo subcutaneously administered monthly, over a six-month
treatment period. The primary endpoint is the annualized rate of
porphyria attacks requiring hospitalization, urgent healthcare
visit or hemin administration at home over the six-month treatment
period. Key secondary and exploratory endpoints will evaluate
reductions in the hallmark symptoms of AHP, such as pain, nausea,
and fatigue, as well as impact on quality of life.
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. 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 an AHP are often misdiagnosed
or remain undiagnosed for an average of 15 years. Currently, there
are no treatments approved to prevent debilitating attacks and
treat the chronic symptoms of the disease.
About GivosiranGivosiran is an investigational,
subcutaneously administered RNAi therapeutic targeting
aminolevulinic acid synthase 1 (ALAS1) in development for the
treatment of acute hepatic porphyria (AHP). 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 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 AHP. 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 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 new class of medicines, known as RNAi
therapeutics, is now a reality. 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,
hepatic infectious, and central nervous system (CNS) 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. Alnylam’s first U.S.
FDA-approved RNAi therapeutic is ONPATTRO™ (patisiran) lipid
complex injection available in the U.S. for the treatment of the
polyneuropathy of hereditary transthyretin-mediated (hATTR)
amyloidosis in adults. In the EU, ONPATTRO is approved for the
treatment of hATTR amyloidosis in adults with stage 1 or stage 2
polyneuropathy. Alnylam has a 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 1000 people worldwide 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 the potential benefits of givosiran, plans to initiate a
rolling NDA submission in 2018 and pursue a full approval in 2019
based on the complete results of the ENVISION Phase 3 study of
givosiran, the expected timing of the report of topline full
results from the ENVISION study, 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, successfully launching, marketing and
selling its approved products globally, Alnylam’s ability to
successfully expand the indication for ONPATTRO in the future,
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 Quarterly Report on Form 10-Q 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20181109005087/en/
Alnylam Pharmaceuticals, Inc.(Investors and
Media)Christine Regan Lindenboom, 617-682-4340or(Investors)Josh
Brodsky, 617-551-8276
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