Alnylam Announces Submission of New Drug Application in Japan for ONPATTRO™ (patisiran sodium) for Treatment of Hereditary ATTR Amyloidosis

Pharmaceuticals, Inc.
(Nasdaq: ALNY), the leading RNAi therapeutics
company, announced today that it has submitted a New Drug Application
(NDA) to Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) for
approval of patisiran for the treatment of hereditary
transthyretin-mediated (hATTR) amyloidosis. Patisiran has orphan drug
designation from the Ministry of Health, Labor and Welfare (MHLW), which
makes it eligible for priority review as well as 10 years of market
exclusivity, if approved. Based on the priority review timeline, Alnylam
expects a decision from the MHLW and PMDA in mid-2019.

Patisiran – which will be commercialized under the brand name ONPATTRO
– is Alnylam’s first drug submitted for regulatory review in
Japan, and if approved, will be the first product to be launched and
marketed by Alnylam in the country. The Company established operations
in Japan this summer.

“The NDA submission highlights Alnylam’s continued commitment to bring
RNAi therapeutics to patients in need with the potential to make a
meaningful impact on serious rare diseases that have devastating effects
on the lives of patients and their families,” said Masako Nakamura,
Senior Vice President, Head of Asia, Alnylam. “Hereditary ATTR
amyloidosis is endemic in Japan, with V30M being the most common
mutation. We look forward to working with the PMDA during the review
process so that we can make patisiran available to patients as
expeditiously as possible.”

The NDA submission is based on positive data from the APOLLO Phase 3
study, which evaluated the efficacy and safety of patisiran in hATTR
amyloidosis patients with polyneuropathy. Results from the APOLLO study
were published in the July 5, 2018, issue of The New
England Journal of Medicine

In APOLLO, the safety and efficacy of patisiran were evaluated in a
diverse, global population of hATTR amyloidosis patients in 19
countries, with a total of 39 TTR mutations. Of the 225 patients
enrolled, 16 patients were from Japan. Patients were randomized in a 2:1
ratio to receive intravenous patisiran (0.3 mg per kg of body weight) or
placebo once every 3 weeks for 18 months. The study showed that
patisiran improved measures of polyneuropathy, quality of life,
activities of daily living, ambulation, nutritional status and autonomic
symptoms relative to placebo in adult patients with hATTR amyloidosis
with polyneuropathy. The primary endpoint of the APOLLO study was the
modified Neuropathy Impairment Score +7 (mNIS+7), which assesses motor
strength, reflexes, sensation, nerve conduction and postural blood

  • Patients treated with patisiran had a mean 6.0-point decrease
    (improvement) in mNIS+7 score from baseline compared to a mean
    28.0-point increase (worsening) for patients in the placebo group,
    resulting in a mean 34.0-point difference relative to placebo, after
    18 months of treatment.
  • While nearly all patisiran-treated patients experienced a treatment
    benefit relative to placebo, 56 percent of patisiran-treated patients
    after 18 months of treatment experienced improvement of neuropathy
    impairment (as assessed by mNIS+7 score) relative to their own
    baseline, compared to four percent of patients who received placebo.
  • Patients treated with patisiran had a mean 6.7-point decrease
    (improvement) in Norfolk Quality of Life Diabetic Neuropathy (QoL-DN)
    score from baseline compared to a mean 14.4-point increase (worsening)
    for patients in the placebo group, resulting in a mean 21.1-point
    difference relative to placebo, after 18 months of treatment.
  • As measured by Norfolk QoL-DN, 51 percent of patients treated with
    patisiran experienced improvement in quality of life at 18 months
    relative to their own baseline, compared to 10 percent of the
    placebo-treated patients.
  • Over 18 months of treatment, patients treated with patisiran
    experienced significant benefit vs. placebo for all other secondary
    efficacy endpoints, including measures of activities of daily living,
    walking ability, nutritional status, and autonomic symptoms.
  • Patisiran was associated with favorable effects on exploratory
    endpoints related to cardiac structure and function in the
    prespecified subpopulation of patients with cardiac involvement.
  • The incidence and severity of adverse events were similar in patients
    receiving patisiran and placebo. The most common adverse events that
    occurred more frequently with patisiran than with placebo were
    peripheral edema and infusion-related reactions. To reduce the risk of
    infusion-related reactions, patients received premedications prior to

About ONPATTRO™ (patisiran)
Patisiran is an intravenously
administered RNAi therapeutic targeting transthyretin (TTR) for the
treatment of hereditary ATTR amyloidosis. It is designed to target and
silence specific messenger RNA, potentially blocking the production of
TTR protein before it is made. Patisiran blocks the production of
transthyretin in the liver, reducing its accumulation in the body’s
tissues in order to halt or slow down the progression of the disease. In
August 2018, patisiran received U.S. Food and Drug (FDA) approval for
the treatment of the polyneuropathy of hereditary transthyretin-mediated
amyloidosis in adults, having been reviewed by the FDA under Priority
Review and previously granted Breakthrough Therapy and Orphan Drug
Designations. Also, in August 2018, patisiran received European
Commission marketing authorization for the treatment of hATTR
amyloidosis in adults with stage 1 or stage 2 polyneuropathy. The
European Medicines Agency (EMA) reviewed patisiran under the accelerated
assessment procedure that is granted to medicines judged to be of major
interest for public health and therapeutic innovation. In Japan, the
non-proprietary adopted name (JAN) for patisiran is patisiran sodium.

About hATTR amyloidosis
Hereditary transthyretin
(TTR)-mediated amyloidosis (hATTR) is an inherited, progressively
debilitating, and often fatal disease caused by mutations in the TTR
gene. TTR protein is primarily produced in the liver and is normally a
carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid
proteins to accumulate and damage body organs and tissue, such as the
peripheral nerves and heart, resulting in intractable peripheral sensory
neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as
other disease manifestations. hATTR amyloidosis represents a major unmet
medical need with significant morbidity and mortality, affecting
approximately 50,000 people worldwide. The median survival is 4.7 years
following diagnosis, with a reduced survival (3.4 years) for patients
presenting with cardiomyopathy.

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

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
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, expectations regarding the
filing of its first regulatory application in Japan for ONPATTRO and the
expected timing of a decision from the PMDA on such application, the
potential impact of an approval for patients and their families,
expectations for the potential commercialization of ONPATTRO in Japan,
if approved, 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.


Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom,
(Investors and Media)
Josh Brodsky,