Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

− First and Only FDA-approved Treatment Available in the United
States for this Indication –

− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with
Reversal of Neuropathy Impairment Compared to Baseline in Majority of
Patients –

− Improvement in Specified Measures of Quality of Life and Disease
Burden Demonstrated Across Diverse, Global Patient Population –

− Alnylam to Host Conference Call Today at 3:00 p.m. ET. −

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Alnylam
Pharmaceuticals, Inc.
 (Nasdaq: ALNY), the leading RNAi therapeutics
company, announced today that the United States Food and Drug
Administration (FDA) approved ONPATTRO™ (patisiran) lipid complex
injection, a first-of-its-kind RNA interference (RNAi) therapeutic, for
the treatment of the polyneuropathy of hereditary transthyretin-mediated
(hATTR) amyloidosis in adults. ONPATTRO is the first and only
FDA-approved treatment for this indication. hATTR amyloidosis is a rare,
inherited, rapidly progressive and life-threatening disease with a
constellation of manifestations. In addition to polyneuropathy, hATTR
amyloidosis can lead to other significant disabilities including
decreased ambulation with the loss of the ability to walk unaided, a
reduced quality of life, and a decline in cardiac functioning. In the
largest controlled study of hATTR amyloidosis, ONPATTRO was shown to
improve polyneuropathy – with reversal of neuropathy impairment in a
majority of patients – and to improve a composite quality of life
measure, reduce autonomic symptoms, and improve activities of daily
living.


“Alnylam was founded on the vision of harnessing the potential of RNAi
therapeutics to treat human disease, and this approval heralds the
arrival of an entirely new class of medicines. We believe today draws us
ever-closer to achieving our Alnylam 2020 goals of becoming a
fully integrated, multi-product biopharmaceutical company with a
sustainable pipeline,” said John Maraganore, Ph.D., Chief Executive
Officer of Alnylam. “With the potential for the sequential launches of
several new medicines in the coming years, we believe we have the
opportunity to meaningfully impact the lives of people around the world
in need of new approaches to address serious diseases with significant
unmet medical needs.”

“Today’s historic approval marks the arrival of a first-of-its kind
treatment option for a rare and devastating condition with limited
treatment options,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D
at Alnylam. “We extend our deepest gratitude to the patients who
participated in the ONPATTRO clinical trials and their families and
caregivers who supported them. We are also grateful for the tireless
efforts of the investigators and study staff, without whom this
important milestone would not have been possible. We also look forward
to working with the FDA to potentially expand the ONPATTRO indication in
the future.”

The FDA approval of ONPATTRO was based on positive results from the
randomized, double-blind, placebo-controlled, global Phase 3 APOLLO
study, the largest-ever study 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 ONPATTRO were evaluated in a
diverse, global population of hATTR amyloidosis patients in 19
countries, with a total of 39 TTR mutations. Patients were randomized in
a 2:1 ratio to receive intravenous ONPATTRO (0.3 mg per kg of body
weight) or placebo once every 3 weeks for 18 months. The study showed
that ONPATTRO 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
pressure.

  • Patients treated with ONPATTRO 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 ONPATTRO-treated patients experienced a treatment
    benefit relative to placebo, 56 percent of ONPATTRO-treated patients
    at 18 months of treatment experienced reversal 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 ONPATTRO 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
    ONPATTRO 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 ONPATTRO
    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.
  • The most common adverse events that occurred more frequently with
    ONPATTRO than with placebo were upper respiratory tract infections and
    infusion-related reactions. To reduce the risk of infusion-related
    reactions, patients received premedications prior to infusion.

“FDA approval of ONPATTRO represents an entirely new approach to
treating patients with polyneuropathy in hATTR amyloidosis and shows
promise as a new era in patient care,” said John Berk, M.D., Associate
Professor of Medicine at Boston University School of Medicine and
assistant director of the Amyloidosis Center at Boston University School
of Medicine. “Given the strength of the APOLLO data, including data
showing the possibility of halting or improving disease progression in
many patients, ONPATTRO holds tremendous promise for people living with
this disease.”

“For years I have witnessed the tragic impact of hATTR amyloidosis on
generations of families. Today, we celebrate the FDA approval of
ONPATTRO,” said Muriel Finkel, President of Amyloidosis Support Groups.
“It’s extremely gratifying to see promising science translate into a
treatment option that will allow patients to potentially experience an
improvement in their disease and an improvement in their overall quality
of life.”

“Today’s approval is significant in so many respects. It means the hATTR
amyloidosis community of patients, families, caregivers and healthcare
professionals in the United States now has a treatment option that
offers renewed hope,” said Isabelle Lousada, Founder and Chief Executive
Officer of the Amyloidosis Research Consortium. “With an FDA-approved
treatment now available, I am more optimistic than ever that we can
increase awareness of this rare disease and encourage more people to get
tested and receive the proper diagnosis.”

ONPATTRO is expected to be available for shipment to healthcare
providers in the U.S. within 48 hours.

Alnylam is committed to helping people access the medicines they are
prescribed and will be offering comprehensive support services for
people prescribed ONPATTRO through Alnylam Assist™. Visit AlnylamAssist.com
for more information or call 1-833-256-2748.

ONPATTRO was reviewed by the FDA under Priority Review and had
previously been granted Breakthrough Therapy and Orphan Drug
Designations. On July 27, patisiran received a positive opinion from the
Committee for Medicinal Products for Human Use (CHMP) for the treatment
of hereditary transthyretin-mediated amyloidosis in adults with stage 1
or stage 2 polyneuropathy under accelerated assessment by the European
Medicines Agency. The recommended Summary of Product Characteristics
(SmPC) for the European Union (EU) includes data on secondary and
exploratory endpoints. Expected in September, the European Commission
will review the CHMP recommendation to make a final decision on
marketing authorization, applicable to all 28 EU member states, plus
Iceland, Liechtenstein and Norway. Regulatory filings in other markets,
including Japan, are planned beginning in mid-2018.

Visit ONPATTRO.com
for more information, including full Prescribing
Information
.

Conference Call Details

Alnylam management will discuss the FDA approval via conference call
today, August 10, 2018, at 3:00 p.m. ET. A webcast presentation will
also be available on the Investors page of the Company’s website, www.alnylam.com.
To access the call, please dial (800) 682-0995 (domestic) or (334)
323-0509 (international) five minutes prior to the start time and refer
to conference ID 7371935. A replay of the call will be available
beginning at 6:00 p.m. ET on August 10, 2018. To access the replay,
please dial (888) 203-1112 (domestic) or (719) 457-0820 (international)
and refer to conference ID 7371935.

IMPORTANT SAFETY INFORMATION

Infusion-Related Reactions
Infusion-related reactions (IRRs)
have been observed in patients treated with ONPATTRO. In a controlled
clinical study, 19% of ONPATTRO-treated patients experienced IRRs,
compared to 9% of placebo-treated patients. The most common symptoms of
IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain,
dyspnea, and headache.

To reduce the risk of IRRs, patients should receive premedication with a
corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers)
at least 60 minutes prior to ONPATTRO infusion. Monitor patients during
the infusion for signs and symptoms of IRRs. If an IRR occurs, consider
slowing or interrupting the infusion and instituting medical management
as clinically indicated. If the infusion is interrupted, consider
resuming at a slower infusion rate only if symptoms have resolved. In
the case of a serious or life-threatening IRR, the infusion should be
discontinued and not resumed.

Reduced Serum Vitamin A Levels and Recommended Supplementation
ONPATTRO
treatment leads to a decrease in serum vitamin A levels. Supplementation
at the recommended daily allowance (RDA) of vitamin A is advised for
patients taking ONPATTRO. Higher doses than the RDA should not be given
to try to achieve normal serum vitamin A levels during treatment with
ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular
symptoms suggestive of vitamin A deficiency (e.g. night blindness).

Adverse Reactions
The most common adverse reactions that
occurred in patients treated with ONPATTRO were upper respiratory tract
infections (29%) and infusion related reactions (19%).

For additional information about ONPATTRO, please see the full Prescribing
Information
.

About ONPATTRO™ (patisiran) lipid complex injection
ONPATTRO
was approved by the U.S. Food and Drug Administration (FDA) for the
treatment of the polyneuropathy of hereditary transthyretin-mediated
(hATTR) amyloidosis in adults. ONPATTRO is the first and only RNA
interference (RNAi) therapeutic approved by the FDA for this indication.
ONPATTRO utilizes a novel approach to target and reduce production of
the TTR protein in the liver via the RNAi pathway. Reducing the TTR
protein leads to a reduction in the amyloid deposits that accumulate in
tissues. ONPATTRO is administered through intravenous (IV) infusion once
every 3 weeks following required premedication and the dose is based on
actual body weight. Home infusion may be an option for some patients
after an evaluation and recommendation by the treating physician, and
may not be covered by all insurance plans. Regardless of the setting,
ONPATTRO infusions should be performed by a healthcare professional. For
more information about ONPATTRO, visit ONPATTRO.com.

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. The median
survival is 4.7 years following diagnosis. Until now, people living with
hATTR amyloidosis in the U.S. had no FDA-approved treatment options.

Alnylam Assist™
As part of Alnylam’s commitment to making
therapies available to those who may benefit from them, Alnylam Assist
will offer a wide range of services to guide patients through treatment
with ONPATTRO, including financial assistance options for eligible
patients, benefit verification and claims support, and ordering
assistance and facilitation of delivery via specialty distributor or
specialty pharmacy. Patients will have access to dedicated Case Managers
who can provide personalized support throughout the treatment process
and Patient Education Liaisons to help patients gain a better
understanding of the disease. Visit AlnylamAssist.com
for more information.

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. RNAi therapeutics are a
new class of medicines that harness the natural biological process of
RNAi. 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 in
developing medicines to improve the care of patients with genetic and
other diseases.

About Alnylam
Alnylam (Nasdaq: ALNY) is leading the
translation of RNA interference (RNAi) into a whole new class of
innovative medicines with the potential to improve 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. ONPATTRO, 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. 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 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 approval of ONPATTRO™ (patisiran) lipid complex injection,
including the approved indication, and the implications of such approval
for patients, the results from its APOLLO Phase 3 clinical trial for
patisiran, its expectations concerning when ONPATTRO will be available
for shipment to healthcare providers in the U.S., its plan to offer
comprehensive support services for people prescribed ONPATTRO through
Alnylam Assist™, the expected timing for additional regulatory filings
for approval in global markets, its expectations regarding the potential
for patisiran to improve the lives of hATTR amyloidosis patients with
polyneuropathy and their families, its plans to work with the FDA to
expand the indication for ONPATTRO in the future, 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.

Contacts

Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom,
617-682-4340
(Investors and Media)
or
Josh Brodsky,
617-551-8276
(Investors)