CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today the initiation of the ENVISION Phase 3 clinical study with givosiran, a subcutaneously administered, investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias (AHPs). The Company is also reiterating its previous guidance that it expects to report interim analysis data in mid-2018 and, assuming positive results and pending U.S. Food and Drug Administration (FDA) review of the program at the time of the interim analysis, it intends to file a New Drug Application (NDA) for givosiran at or around year-end 2018.
Alnylam has also reached alignment on the ENVISION Phase 3 study design with the European Medicines Agency (EMA). Givosiran previously received Breakthrough Therapy designation by the FDA and PRIME designation by the EMA.
“The acute hepatic porphyrias are a family of ultra-rare, often misdiagnosed genetic diseases characterized by acute, potentially life-threatening attacks and debilitating multi-system symptoms; nearly 65% of patients suffer from chronic symptoms that result in a significantly diminished quality of life. The disease burden for these patients is dire and can include frequent hospitalizations, severe abdominal pain, neuropsychiatric symptoms, and weakness. The diagnosis of AHPs are often delayed an average of 15 years, further negatively impacting patients’ lives. A once-monthly, subcutaneous injection with acceptable tolerability and the potential to prevent porphyria attacks could be transformational for patients,” said Jeff Miller, General Manager of the givosiran program. “Based on our Phase 1 and Phase 2 open-label extension study results, we believe that givosiran could meaningfully reduce the frequency of attacks requiring hospitalizations and the need for hemin, with an encouraging tolerability profile. As a global, wholly owned program, we are committed to rapidly advancing givosiran and most importantly, if approved, delivering this novel therapy to AHPs patients in need of new options.”
ENVISION Phase 3 study design
The ENVISION Phase 3 trial is
a randomized, double-blind, placebo-controlled, global, multicenter
study in more than 20 countries to evaluate the efficacy and safety of
givosiran in approximately 75 patients with a documented diagnosis of
AHPs. Patients will be 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
planned interim analysis will evaluate reduction of a urinary biomarker
– aminolevulinic acid (ALA) – in 30 patients after three months of
dosing, 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. All patients completing
the 6-month treatment period will be eligible to continue on an
open-label extension (OLE) study in which they will receive treatment
with givosiran for up to 30 months.
About Givosiran
Givosiran is an investigational,
subcutaneously administered RNAi therapeutic targeting ALAS1 for the
treatment of AHPs, including acute intermittent porphyria (AIP). AIP is
the most common of the hepatic porphyrias, an ultra-rare autosomal
dominant disease caused by increased ALAS1 in the presence of downstream
enzyme defects of the heme biosynthesis pathway resulting in
accumulation of neurotoxic intermediates, 5-aminolavulinic acid (ALA)
and porphobilinogen (PBG) that cause AHPs symptoms. Inhibition of ALAS1,
a liver-expressed enzyme upstream of PBGD in the heme biosynthesis
pathway, is known to reduce the accumulation of heme intermediates that
cause the clinical manifestations of AIP. Givosiran has the potential to
be the first novel treatment approach to effectively and consistently
prevent attacks, reduce chronic symptoms, and decrease burden of
disease. Givosiran has been granted Breakthrough Therapy designation by
the FDA and PRIME designation by the EMA. These regulatory designations
are intended to expedite the development and review of new drugs that
treat serious or life-threatening diseases. 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 have not been
evaluated by the FDA, the EMA or any other health authority.
Givosiran utilizes Alnylam’s ESC-GalNAc-siRNA conjugate technology, which enables subcutaneous dosing with increased potency and durability. The clinical significance of this technology is under investigation.
About Acute Hepatic Porphyrias
Porphyrias are a family of
rarely diagnosed diseases with mostly autosomal dominant inheritance
primarily caused by a genetic mutation in one of the eight enzymes
responsible for heme biosynthesis. AHPs constitute a subset where the
enzyme deficiency occurs within the liver and includes AIP, hereditary
coproporphyria (HCP), variegate porphyria (VP) and ALAD-deficiency
porphyria (ADP). AIP is the most prevalent form of hepatic porphyrias
with an estimated 5,000 patients in the U.S. and EU. Accumulation of
ALAS1, an enzyme in the heme biosynthesis pathway, can lead to
accumulation of neurotoxic heme intermediates that precipitate disease
signs and symptoms ranging from a severe and potentially
life-threatening event — most commonly characterized by severe abdominal
pain, vomiting, constipation, tachycardia, neurological symptoms, and
possibly paralysis and death if untreated or if there are delays in
treatment — to chronic symptoms involving peripheral and autonomic
neuropathy, neuropsychiatric manifestations, with frequent
hospitalizations. A recently published natural history study, EXPLORE,
demonstrated that nearly 2/3 of patients suffer from both acute attacks
and chronic symptoms. The commonality of these symptoms across a wide
range of diseases, as well as the low incidence of AHPs, can delay
proper diagnosis and thereby add to the disease burden. Current
treatment options do not prevent attacks, control chronic symptoms, or
decrease the burden of disease; the only approved treatment for attacks
is hemin, a preparation of heme derived from human blood. Hemin is used
on demand for attacks and off-label as prophylactic therapy; it does not
control chronic symptoms nor effectively and consistently prevent
attacks and requires IV administration through a large vein or a central
intravenous line and is associated with a number of complications
including thrombophlebitis or coagulation abnormalities. Chronic
administration of hemin may result in renal insufficiency, iron
overload, systemic infections (due to the requirement for central venous
access) and, in some instances, tachyphylaxis.
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 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 Pharmaceuticals
Alnylam (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 600 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 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 for givosiran for the treatment of patients with AHPs,
expectations regarding the timing for initial clinical data from the
interim analysis in the Phase 3 clinical study of givosiran and timing
of a potential filing with the FDA for regulatory approval should such
data be 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 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 approved by the U.S. Food and Drug Administration, European Medicines Agency, or any other regulatory authority and no conclusions can or should be drawn regarding the safety or effectiveness of this investigational therapeutic.
