− Porphyria Attack Reductions Observed in
ENVISION Phase 3 Study Maintained with Ongoing Givosiran Dosing in
Open-Label Extension (OLE) Study –
− In ENVISION Phase 3 Study, Patients Receiving
Givosiran Reported Reduced Daily Worst Pain, a Cardinal Porphyria
Symptom, and Givosiran Was Associated with Improvements in
Patient-Reported Quality of Life Measures, Compared to Placebo
–
− In Phase 1/2 OLE, Givosiran Treatment of up
to 30 Months Demonstrated Sustained Clinical Activity with an Over
90 Percent Decrease in Mean Annualized Porphyria Attack Rate,
Relative to Baseline –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today that the Company and its
collaborators presented new clinical results at the 2019
International Congress on Porphyrins and Porphyrias (ICPP), held
September 8-11, 2019 in Milan, Italy. Presentations included
additional results from the ENVISION Phase 3 study and the Phase
1/2 open-label extension (OLE) study of givosiran, an
investigational RNAi therapeutic targeting aminolevulinic acid
synthase 1 (ALAS1) in development for the treatment of acute
hepatic porphyria (AHP).
“The new results that we and our collaborators presented this
week at ICPP reinforce our belief in the potential of givosiran to
reduce the disease burden associated with AHP and to improve
quality of life for patients,” said Akin Akinc, Ph.D., Vice
President and General Manager, Givosiran Program at Alnylam. “Of
note, patients in our open-label extension studies have continued
to experience sustained reduction of both porphyria attacks and
levels of toxic intermediates known to be causative of disease
manifestations. Accordingly, we are hopeful that givosiran will
continue to provide the potential for long term benefit for AHP
patients.”
“AHP is a tremendously burdensome condition accompanied by
disabling symptoms that have a profound impact on quality of life.
To that end, the patient reported outcomes in response to givosiran
treatment are highly encouraging, with patients reporting
significantly less pain – a primary manifestation of this condition
– less reliance on analgesic medication, improvements in their
daily functioning, and ability to lead a more normal life,” said
Laurent Gouya, M.D., Ph.D., Paris Diderot University, Head of
Centre Français des Porphyries, investigator in ENVISION Phase 3
study. “With patients reporting a positive treatment experience and
data suggesting an improved quality of life based on exploratory
endpoints, I am hopeful for the AHP patient community and look
forward to the continued evaluation of givosiran.”
ENVISION Phase 3 OLE Results As of the data cut-off date
of January 31, 2019, all eligible patients (N=93) from the ENVISION
Phase 3 study of givosiran rolled over into the OLE phase of the
study. Reduction in the composite porphyria attack rate with
givosiran treatment, which had been observed in the ENVISION Phase
3 study as early as one month after dosing, was shown to be
sustained with continued dosing in the OLE phase of the study.
Sustained reduction in levels of aminolevulinic acid (ALA), an
intermediate in the heme biosynthesis pathway believed to be the
primary neurotoxic intermediate responsible for causing both
porphyria attacks and ongoing symptoms in between attacks, was also
observed with continued dosing. Rapid and sustained lowering of
attack rate and ALA levels was also observed in placebo patients
who crossed over after the six-month double blind phase of the
ENVISION Phase 3 study to receive givosiran in the OLE phase of the
study. Givosiran’s safety profile in the OLE phase has remained
consistent with the profile observed in the double blind phase of
the ENVISION study.
ENVISION Results of Select Patient Reported Outcomes A
number of patient reported outcomes were collected as secondary and
exploratory measures in the ENVISION study. Daily worst pain did
not achieve statistical significance based on the prespecified
ANCOVA analysis (p equals 0.0530), however, the data were found to
not be normally distributed. A post-hoc analysis of daily worst
pain was therefore performed using the non-parametric stratified
Wilcoxon test. Based on the non-parametric test, patients on
givosiran had a significant reduction in daily worst pain (nominal
p equals 0.0455). In exploratory analyses, the reductions in pain
were accompanied by fewer days of use of both opioid and non-opioid
analgesics. Givosiran did not impact daily worst fatigue or daily
worst nausea at six months, although these assessments will be
repeated at twelve months to explore the effects of longer term
dosing.
Change from baseline at six months of the Physical Component
Summary (PCS) of the Short Form 12 (SF-12) health and quality of
life questionnaire was a secondary endpoint that showed a trend
favoring givosiran compared to placebo (nominal p equals 0.0216).
There was consistent evidence of effect favoring givosiran compared
to placebo (nominal p less than 0.05 for each) in the SF-12 domains
of bodily pain, social functioning, and role physical (a domain
that assesses limitations in routine activity due to physical
impairment). The Patient Global Impression of Change (PGIC) at six
months was an exploratory endpoint. The majority (59 percent) of
givosiran treated patients reported their health status as “very
much improved” or “much improved” since the beginning of the study
compared to 18 percent of placebo patients reporting their status
as “much improved”. Similarly, the Porphyria Patient Experience
Questionnaire (PPEQ) at six months was assessed as an exploratory
endpoint. On all eight items of the PPEQ, a greater proportion of
patients on givosiran, relative to patients on placebo, reported
improvements. In particular, a higher proportion (67 percent versus
11 percent) of givosiran-treated patients versus those on placebo
reported “always” or “most of the time” in response to the question
about the role of the study drug in helping them return to a more
normal life over the prior four weeks.
Updated Phase 1/2 OLE Results As of the data cut-off date
of April 19, 2019, 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 22.8 months and
total time on treatment across the Phase 1 and OLE studies of up to
35 months. Substantial mean reductions in annualized attack rate
(AAR) and in annualized hemin use of greater than 90 percent were
observed, with evidence for sustained or potentially enhanced
clinical activity with continued dosing. Five out of twelve
patients (42 percent) who received givosiran during the Phase 1
study and continued with givosiran dosing in the OLE study and two
out of four patients (50 percent) who had been in the placebo arm
of the Phase 1 study and crossed over to givosiran treatment in the
OLE study achieved an AAR of zero for a mean of 18.1 and 24.9
months, respectively.
The overall safety profile of givosiran in the Phase 1/2 OLE as
of the data cut-off date remains consistent with that previously
reported. Serious adverse events (SAEs) were reported in six
patients. Those SAEs not previously reported at earlier data
cut-off dates included: one patient with synovitis, assessed as not
related to study drug, and one patient with abdominal pain,
assessed as unlikely related to study drug. No clinically
significant laboratory changes, including liver function tests,
were observed with ongoing dosing in the Phase 1/2 OLE study.
The Company and collaborators also presented additional results
on a drug-drug interaction study with givosiran, recent analyses
from the EXPLORE natural history study, data on patient journey to
diagnosis, real-world analysis of illness burden and management,
and an overview of AHP symptomology based on peer-reviewed
publications and patient narratives.
To view the results presented at ICPP, please visit
https://www.alnylam.com/capella.
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 were
evaluated in the ENVISION Phase 3 trial with positive results;
these results 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 transform the lives
of people afflicted with rare genetic, cardio-metabolic, hepatic
infectious, and central nervous system/ocular diseases. Based on
Nobel Prize-winning science, RNAi therapeutics represent a
powerful, clinically validated approach for the treatment of
diseases with high unmet need. Alnylam’s first commercial RNAi
therapeutic is ONPATTRO® (patisiran), approved in the U.S., EU,
Canada, and Japan. Alnylam has a deep pipeline of investigational
medicines, including five product candidates in Phase 3 studies and
one in registration. 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. Headquartered in
Cambridge, MA, Alnylam employs over 1,200 people worldwide. 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 implications of the additional data from the ongoing
Phase 3 and Phase 1/2 OLE studies of givosiran, including the
potential treatment benefits of givosiran, the safety profile of
givosiran, the potential for enhanced clinical activity with
continued dosing, and the potential for givosiran to improve the
quality of life of patients, Alnylam's 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20190910005090/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media)
617-682-4340
Josh Brodsky
(Investors) 617-551-8276
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