− Givosiran Achieved a 74 Percent Mean
Reduction in Composite Annualized Attack Rate (AAR) Relative to
Placebo, with Consistent Reductions Across all Components of
Composite Endpoint and Subgroups –
− Treatment Effect Includes a 90 Percent Median
Decrease in Composite AAR Relative to Placebo, with 50 Percent of
Givosiran Patients Attack-Free –
− Ninety-Nine Percent of Patients Enrolled in
Open-Label Extension Study –
− Alnylam to Host Conference Call Saturday,
April 13th at 8:00 am ET –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading
RNAi therapeutics company, announced today positive complete
results from the ENVISION Phase 3 study of givosiran, an
investigational RNAi therapeutic targeting aminolevulinic acid
synthase 1 (ALAS1) in development for the treatment of acute
hepatic porphyria (AHP). The clinical data are being presented in
an oral presentation at the European Association for the Study of
the Liver (EASL) International Liver Congress™ being held April
10-14 in Vienna, Austria.
The full ENVISION results demonstrated a 74 percent mean and 90
percent median reduction in the primary endpoint measure of
annualized rate of composite attacks in patients on givosiran
relative to placebo during the six-month double-blind period. In
addition, givosiran achieved statistically significant positive
results for five of nine secondary endpoints, with an overall
safety and tolerability profile that the Company believes is
encouraging, especially in this high unmet need disease. Adverse
events (AEs) were reported in 89.6 percent of givosiran patients
and 80.4 percent of placebo patients; serious adverse events (SAEs)
were reported in 20.8 percent of givosiran patients and 8.7 percent
of placebo patients. Ninety-three of 94 patients, or 99 percent,
enrolled in the open-label extension (OLE) period of the study.
Based on the ENVISION results, the Company plans to complete its
rolling submission of a New Drug Application (NDA) and file a
Marketing Authorisation Application (MAA) in mid-2019.
“Given the high unmet need in this disease setting, we are very
pleased for the patients and families living with acute hepatic
porphyria for whom these results signal hope for a potential new
therapeutic option,” said Akshay Vaishnaw, M.D., Ph.D., President
of R&D at Alnylam. “Givosiran substantially reduced the
frequency of attacks, providing strong support for a treatment
benefit, with a consistent effect across all components of the
primary endpoint and all subgroups analyzed. In this disease with
high burden and associated comorbidities, we’re encouraged by the
overall tolerability profile. We firmly believe givosiran has the
potential to be a transformative medicine for patients living with
AHP.”
“Currently, there are no approved therapies aimed at preventing
the painful, often incapacitating attacks and chronic symptoms
associated with AHP,” said Manisha Balwani, M.D., M.S, Associate
Professor of the Department of Genetics and Genomic Sciences and
Department of Medicine at the Icahn School of Medicine at Mount
Sinai and principal investigator of the ENVISION study. “The
results from ENVISION are promising and demonstrate a strong
treatment effect for givosiran, with reduction of attacks and
improvement in patient-reported measures of overall health status
and quality of life. Thus, givosiran represents a novel and
targeted treatment approach that has the potential to make a
significant impact on the lives of patients who are struggling with
the disabling symptoms of this disease.”
Efficacy ResultsGivosiran met the primary efficacy
endpoint with a 74 percent mean reduction relative to placebo in
the annualized rate of composite porphyria attacks, defined as
those requiring hospitalization, urgent healthcare visit, or hemin
administration, in patients with acute intermittent porphyria (AIP)
over six months (p equal to 6.04x10-9). There was a corresponding
90 percent median reduction in composite annualized attack rate
(AAR), with a median AAR of 1.0 in givosiran patients compared with
a median AAR of 10.7 in placebo patients. Fifty percent of
givosiran-treated patients were attack-free during the six-month
treatment period as compared to 16.3 percent of placebo-treated
patients. The reductions in attack rates were observed across all
components of the primary endpoint. The treatment benefit for
givosiran compared to placebo was maintained across all
pre-specified patient subgroups, including age, race, geography,
historical attack rates, prior hemin prophylaxis status, disease
severity, and other baseline characteristics.
Givosiran also demonstrated statistically significant
differences in five of nine hierarchically tested secondary
endpoints relative to placebo. These included mean reductions
of:
- 91 percent in urinary aminolevulinic
acid (ALA) in patients with AIP at three months (p equal to
8.74x10-14).
- 83 percent in urinary ALA in patients
with AIP at six months (p equal to 6.24x10-7).
- 73 percent in urinary levels of
porphobilinogen (PBG) in patients with AIP at six months (p equal
to 8.80x10-7).
- 77 percent in the number of annualized
days on hemin in patients with AIP (p equal to 2.35x10-5).
- 73 percent in composite AAR for
patients with any AHP (p equal to 1.35x10-8).
The remaining four secondary endpoints did not meet the
prespecified criteria for statistical significance in hierarchical
testing.
Safety and TolerabilityAEs were reported in 43/48 (89.6
percent) of givosiran patients and 37/46 (80.4 percent) of placebo
patients. SAEs were reported in 10/48 (20.8 percent) of givosiran
patients and 4/46 (8.7 percent) of placebo patients. SAEs in
givosiran patients consisted of two cases of chronic kidney disease
(CKD; 4.2 percent), and one case (2.1 percent) each of asthma,
device-related infection, gastroenteritis, hypoglycemia, abnormal
liver function test, major depression, pain management, and
pyrexia. Three SAEs in givosiran patients were reported as related
to study drug: pyrexia, abnormal liver function test, and CKD (one
case). The two SAEs of CKD noted above were considered serious due
to elective hospitalization for diagnostic evaluation. There were
no deaths in the study. One patient, described below, in the
givosiran arm (2.1 percent) discontinued treatment due to an AE.
AEs reported in greater than 10 percent of givosiran patients and
seen more frequently compared to placebo were nausea (27.1 versus
10.9 percent), injection site reactions (16.7 versus 0 percent),
CKD (10.4 versus 0 percent), and fatigue (10.4 versus 4.3 percent).
Four of five of the patients with AEs reported as CKD had a prior
history of CKD or a baseline estimated glomerular filtration rate
(eGFR) less than 60 mL/min/1.73m2; no patients had clinically
significant proteinuria and there were no treatment
discontinuations due to renal AEs.
Liver transaminase increases greater than three times the upper
limit of normal (ULN) or baseline were observed in 7/48 (14.6
percent) patients on givosiran and 1/46 (2.2 percent) patients on
placebo; all had evidence of iron overload or liver disease at
baseline. As previously reported and as noted above, one patient on
givosiran discontinued treatment due to an increase in alanine
aminotransferase (ALT) level greater than eight times ULN, a
protocol-defined stopping rule; this elevation did not meet Hy’s
Law and subsequently resolved. In the other six givosiran-treated
patients, peak ALT levels ranged from 3.0-5.4 times ULN and were
not accompanied by bilirubin increases; the ALT elevations were
asymptomatic and all events resolved with continued dosing (N=5) or
after a brief pause in dosing (N=1).
Patient PerspectivesIn exploratory measures of
patient-reported outcomes, a greater proportion of patients
reported an improvement in overall health status on givosiran (89
percent) than placebo (37 percent), as measured by the Patient
Global Impression of Change (PGIC) Questionnaire. Similarly,
patients on givosiran reported an overall higher level of treatment
satisfaction on givosiran (72 percent) than placebo (14 percent)
and an increased ability to perform activities of daily living, as
measured by the Porphyria Patient Experience Questionnaire (PPEQ).
Specifically, a greater proportion of patients on givosiran
reported improvements in traveling for work or pleasure (35.1
versus 13.2 percent), participating in social activities (35.1
versus 7.9 percent), planning for future events (35.1 versus 10.5
percent), doing household chores (35.1 versus 5.3 percent), and
exercising moderately (32.4 versus 5.3 percent), relative to
patients on placebo.
To view the results presented by Alnylam at EASL, please visit
https://www.alnylam.com/capella.
Conference Call InformationAlnylam management will
discuss these results via a conference call on Saturday, April 13,
2019 at 8:00 am ET (2:00 pm CET). A slide presentation will also be
available on the Investors page of the Company’s website,
www.alnylam.com, to accompany the conference call. To access the
call, please dial 866-548-4713 (domestic) or 323-794-2093
(international) five minutes prior to the start time and refer to
conference ID 3368636. A replay of the call will be available
beginning at 11:00 am ET on the day of the call. To access the
replay, please dial 888-203-1112 (domestic) or 719-457-0820
(international) and refer to conference ID 3368636.
About Acute Hepatic PorphyriaAcute 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 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 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 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)/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 StatementsVarious statements in
this release concerning Alnylam's future expectations, plans and
prospects, including, without limitation, Alnylam's views with
respect to the potential treatment benefits of givosiran and
potential for givosiran to impact the lives of patients, the safety
profile for givosiran, plans and expected timing for completion of
the rolling submission of an NDA and MAA, 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 Annual Report on Form 10-K 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.
Author DisclosuresDr. Manisha Balwani (Principal
Investigator in the ENVISION study) receives financial compensation
as an advisory board member for Alnylam (the study sponsor and
manufacturer of the study drug givosiran).
The Icahn School of Medicine at Mount Sinai (“ISMMS”) holds
issued and pending patents related to the study drug givosiran and
has licensed these patents to Alnylam. As part of the license to
Alnylam, ISMMS will receive payments from Alnylam, including a
payment when givosiran entered Phase 3 clinical studies, as well as
future payments if givosiran becomes a marketed treatment for acute
hepatic porphyria. ISMMS, as well as the ISMMS faculty that are
named inventors on the licensed patents, will benefit
financially.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20190412005455/en/
Alnylam Pharmaceuticals, Inc.Christine Regan
Lindenboom(Investors and Media)617-682-4340
Josh Brodsky(Investors)617-551-8276
Alnylam Pharmaceuticals (NASDAQ:ALNY)
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