CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today positive topline results from the interim analysis of the ENVISION Phase 3 Study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP). The pre-specified interim analysis was based on lowering of urinary ALA levels as a surrogate biomarker that is reasonably likely to predict clinical benefit.
Results of the interim analysis showed that givosiran treatment was associated with a statistically significant reduction in urinary ALA levels in acute intermittent porphyria (AIP) patients, relative to placebo (p less than 0.001). The Company plans to discuss these data and the regulatory path forward with the FDA, and, pending the outcome of those discussions, intends to file a New Drug Application (NDA) at or around year-end 2018 in support of a potential Accelerated Approval. The interim analysis had a data cut-off date of August 22, 2018 and included 43 patients with AHPs (41 patients with AIP, one with variegate porphyria [VP], and one with hereditary coproporphyria [HCP]) who were on study for at least three months. As of the data cut-off date, there were no deaths, and serious adverse events (SAEs) were reported in 22 percent (5/23) of givosiran patients and 10 percent (2/20) of placebo patients. One patient (4 percent) on givosiran discontinued treatment due to an increase in liver transaminase – which resolved – that was greater than eight times the upper limit of normal (ULN), a protocol-defined stopping rule. There were no treatment discontinuations in the placebo group.
“The AHPs are devastating diseases in which patients suffer from both debilitating neurovisceral attacks as well as chronic pain and fatigue. We are pleased and encouraged that the interim analysis of the ENVISION Phase 3 study demonstrated that givosiran treatment was associated with statistically significant lowering of ALA, a disease biomarker reasonably likely to predict clinical benefit,” said Akshay Vaishnaw, M.D., Ph.D., President of Research and Development at Alnylam. “With these interim results in hand, we plan to meet with the FDA to discuss the results and the overall benefit-risk profile for a potential NDA submission at or around year-end in support of an Accelerated Approval. In the meantime, with enrollment in ENVISION completed ahead of schedule, we look forward to reporting topline results for the full study early next year. If clinical efficacy and acceptable safety are confirmed in the full study, we believe givosiran has the potential to transform the lives of patients living with an AHP.”
Alnylam continues to dose patients in the ongoing ENVISION study, where enrollment was completed ahead of schedule with 94 AHP patients. The Company expects to report topline full study results of the primary endpoint – the annualized attack rate after six months of treatment – in early 2019.
Conference Call Details
Alnylam management will discuss the ENVISION interim analysis results via conference call today, September 27, 2018, at 8:00 am ET. A webcast presentation will also be available on the Investors page of the Company’s website, www.alnylam.com. To access the call, please dial (800) 682-0995 (domestic) or (334) 323-0505 (international) five minutes prior to the start time and refer to conference ID 9024965. A replay of the call will be available beginning at 11:00 am ET on September 27, 2018. To access the replay, please dial (888) 203-1112 (domestic) or (719) 457-0820 (international) and refer to conference ID 9024965.
About the ENVISION Phase 3 Study
The 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 AHPs. Patients were randomized on a 1:1 basis
to receive 2.5 mg/kg of givosiran or placebo subcutaneously administered
monthly, over a 6-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 6-month
treatment period. The interim analysis included 43 AHP patients who were
on study for at least three months and evaluated reduction of a urinary
biomarker – ALA – in 41 patients with AIP, as a surrogate endpoint
reasonably likely to predict clinical benefit. Key secondary and
exploratory endpoints will evaluate reductions in the hallmark symptoms
of AHPs, such as pain, nausea, and fatigue, as well as impact on quality
of life.
About Acute Hepatic Porphyrias
Acute 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 Givosira
Givosiran 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 RNAi
RNAi (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 Pharmaceuticals
Alnylam (Nasdaq: ALNY) is
leading the translation of RNA interference (RNAi) into a new class of
innovative medicines with the potential to improve 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. ONPATTRO™ (patisiran) lipid complex injection, available in
the U.S. for the treatment of the polyneuropathy of hereditary
transthyretin-mediated (hATTR) amyloidosis in adults, is Alnylam’s first
U.S. FDA-approved RNAi therapeutic. 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 three 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 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 Statements
Various 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 discuss the results
from the ENVISION interim analysis and overall benefit-risk profile of
givosiran and the regulatory path forward with the FDA, the timing for a
potential filing of an NDA in support of a possible Accelerated
Approval, the expected timing of the report of topline 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.
