− Givosiran Associated with Substantial and
Sustained Lowering of Neurotoxic Heme Synthesis Intermediates
Implicated in Acute Intermittent Porphyria –
− Givosiran also Associated with Reduced Rate
of Porphyria Attacks and Hemin Use –
− Topline Phase 3 Readout Expected in Early
2019, with a Rolling NDA Submission Initiated –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading
RNAi therapeutics company, announced today that results from the
Phase 1 study of givosiran, an investigational, subcutaneous RNAi
therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for
the treatment of acute hepatic porphyria (AHP), were published
online today in The New England Journal of Medicine (NEJM). The
full manuscript, titled “Phase 1 Trial of an RNA Interference
Therapy for Acute Intermittent Porphyria,” will appear in the
February 7, 2019 issue of NEJM.
In the Phase 1 study, the proportion of patients reporting
adverse events (AEs) was similar across treatment groups with no
clear relationship with givosiran dose. The majority of AEs were
mild or moderate; the most common AEs included nasopharyngitis,
abdominal pain, and diarrhea. Serious AEs (SAEs) were reported in
six patients treated with givosiran (N=33), including – as
previously reported – one fatal SAE of hemorrhagic pancreatitis,
assessed as unlikely related to study drug by the study
investigator. Additional unrelated SAEs included influenza
infection, opioid bowel dysfunction, miscarriage, and two patients
with abdominal pain. No SAEs were reported in the placebo group
(N=10).
Results showed that basal ALAS1 messenger RNA (mRNA),
aminolevulinic acid (ALA), and porphobilinogen (PBG) levels were
associated with disease activity, with higher levels noted in those
with recurrent attacks, confirming the central importance of liver
ALAS1 induction and ALA and PBG in the pathophysiology of acute
intermittent porphyria (AIP). Monthly givosiran administration
resulted in sustained reductions of ALAS1 mRNA, urinary ALA, and
PBG to near normal levels. In exploratory analyses, these
reductions were associated with a 79 percent decrease in mean
annualized attack rate and an 83 percent decrease in mean
annualized hemin usage, compared with placebo.
“We are pleased to have our givosiran Phase 1 findings published
in such a highly esteemed, peer-reviewed journal. Indeed, we are
encouraged by the emerging safety and tolerability profile for
givosiran, as well as the results of exploratory analyses
suggesting favorable effects on porphyria attack rate and hemin use
for acute attacks,” said Akin Akinc, Ph.D., Vice President and
General Manager, Givosiran Program at Alnylam. “With no treatment
options currently approved for the prevention of porphyria attacks,
we believe givosiran has the potential to make a meaningful
difference in the lives of AHP patients.”
“Acute intermittent porphyria is the most common subtype of AHP
where patients experience recurrent, incapacitating, neurovisceral
attacks requiring hospitalization or urgent medical attention. The
Phase 1 results not only advance our understanding of the
pathologic basis of AIP but they also signal hope to patients and
their caregivers living with the tremendous burden of this disease
and its current management,” said Dr. Eliane Sardh, Karolinska
Institutet, Karolinska University Hospital, Porphyria Centre
Sweden, the lead author of the NEJM paper. “I look forward to
continued evaluation of the safety and efficacy of givosiran in the
ongoing OLE and Phase 3 studies.”
Dosing of eligible patients is ongoing in the Phase 1/2
open-label extension (OLE) study. In addition, safety and efficacy
of givosiran are being evaluated in the ongoing ENVISION Phase 3
trial, a randomized, double-blind, placebo-controlled pivotal
study. The Company recently announced positive topline interim
analysis results based on reduction of urinary ALA in 43 patients
with AHP. Topline results from the complete 6-month double-blind
portion of ENVISION, including annualized porphyria attack rate –
the primary endpoint of the study – are expected in early 2019.
Rolling submission for a new drug application (NDA) has been
recently initiated, with full clinical sections planned to be
submitted in mid-2019, assuming positive results.
About Givosiran Phase 1 Study
The Phase 1 study of givosiran was conducted in three parts.
Parts A and B were randomized, single-blind, single-dose (Part A)
and multi-dose (Part B), dose-escalation studies that enrolled 23
subjects who were “chronic high excreters” (CHE). Per protocol, CHE
subjects in the study had a defined mutation in the porphobilinogen
deaminase (PBGD) gene and elevated urinary levels of ALA and PBG,
but did not have a recent history of porphyria attacks or disease
activity. 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 of the Phase 1 study, all patients
were eligible to receive givosiran in an open-label extension
study.
About Acute Hepatic Porphyria
Acute hepatic porphyria (AHP) refers to a family of rare,
genetic diseases characterized by potentially life-threatening
attacks and for some patients chronic debilitating symptoms that
negatively impact daily functioning and quality of life. AHP is
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
AHP include severe, diffuse abdominal pain, weakness, nausea, and
fatigue. The nonspecific nature of AHP signs and symptoms can often
lead to misdiagnoses of other more common conditions such as
irritable bowel syndrome, appendicitis, fibromyalgia, and
endometriosis, and consequently, patients afflicted by AHP often
remain without a proper diagnosis for up to 15 years. In addition,
long-term complications of AHP and its treatment can include
chronic neuropathic pain, hypertension, chronic kidney disease and
liver disease, including iron overload, fibrosis, cirrhosis and
hepatocellular carcinoma. Currently, there are no treatments
approved to prevent debilitating attacks or to treat the chronic
manifestations of the disease.
About Givosiran
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 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)/ocular 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 five 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 1,000 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 complete an NDA submission and pursue a full
approval in 2019, assuming positive final 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/20190206005759/en/
Alnylam Pharmaceuticals, Inc.Christine Regan
Lindenboom(Investors and Media)617-682-4340Josh
Brodsky(Investors)617-551-8276
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