Market Overview

Alnylam Receives Approval of ONPATTRO™ (patisiran) in Europe


– ONPATTRO Indicated for the Treatment of Hereditary
Transthyretin-Mediated (hATTR) Amyloidosis (hATTR amyloidosis) in Adults
with Stage 1 or Stage 2 Polyneuropathy –

– First-Ever RNAi Therapeutic Approved in the European Union (EU) –

Pharmaceuticals, Inc.
(NASDAQ:ALNY), the leading RNAi therapeutics
company, announced today that the European Commission (EC) has granted
marketing authorization for ONPATTRO (patisiran) for the
treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in
adults with stage 1 or stage 2 polyneuropathy. ONPATTRO is based on
Nobel Prize-winning science and is the first-ever RNA interference
(RNAi) therapeutic to be approved in the European Union.

"Today's approval is the result of many years of dedicated effort and
marks the next step towards bringing a potentially life-changing
treatment to patients with hATTR amyloidosis and their families.
Patisiran has been shown to improve polyneuropathy, quality of life and
activities of daily living," said Theresa Heggie, Head of Europe,
Alnylam Pharmaceuticals. "This is the start of a new chapter in the
treatment of this rare, rapidly progressive, fatal disease. We want to
express our profound gratitude to the patients who participated in the
patisiran clinical trials and their families and caregivers who
supported them, as well as the investigators and study staff, without
whom this important milestone would not have been achieved. We look
forward to applying our innovative therapeutic approach to help patients
with other rare diseases in the future."

"Until recently, patients diagnosed with hereditary ATTR amyloidosis
faced an uncertain future. A lack of treatments to halt or reverse the
progression of disease resulted in a gradual and inescapable decline in
their day-to-day functioning, placing a heavy burden not just on the
patient themselves but on their partners and families, many of whom end
up being full time carers," said Professor Philip N. Hawkins, Ph.D,
FRCP, FRCPath, FMedSci, National Amyloidosis Centre, Division of
Medicine, and University College London Medical School, Royal Free
Hospital, UK. "Patisiran has the potential not only to transform these
patients' lives but to change the way in which we think about and treat
hereditary ATTR amyloidosis."

Many serious, chronic and life-threatening diseases, such as hATTR
amyloidosis, are caused by a fault or mutation that interferes with the
way the body manufactures proteins. RNAi is a completely new approach to
the treatment of these diseases; targeting the faulty protein that is
causing the disease rather than treating the symptoms. RNAi therapeutics
are an entirely new class of medicines.

The EC decision was based on the evaluation of the effects of patisiran
in hATTR amyloidosis patients with polyneuropathy and its safety profile
as demonstrated in the APOLLO Phase 3 study. The Summary of Product
Characteristics (SmPC) includes data from APOLLO on primary and
secondary endpoints, as well as exploratory cardiac endpoints. The
European Medicines Agency reviewed patisiran under the accelerated
assessment procedure that is granted to medicines judged to be of major
interest for public health and therapeutic innovation.

The marketing authorization for patisiran 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 patisiran 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 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
    at 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 oedema and infusion-related reactions. To reduce the risk
    of infusion-related reactions, patients received premedications prior
    to infusion.

For ONPATTRO™ prescribing information in the EU, please visit the EMA
Summary of Opinion

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. Regulatory filings in other markets, including Japan, are
planned in 2018.

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. In Europe, treatment options that can
modify the course of the disease are limited and there remains a
pressing need for novel medicines to help treat patients with hATTR

About RNAi
RNAi (RNA interference) is a natural cellular
process of gene silencing that represents one of the most promising and
rapidly advancing frontier 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

Important Safety Information (ISI) for ONPATTRO™

Infusion-Related Reactions

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

To reduce the risk of IRRs, patients should receive premedication with a
corticosteroid, paracetamol, and antihistamines (H1 and H2 blockers) at
least 60 minutes prior to patisiran 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

Patisiran treatment leads to a decrease in serum vitamin A levels.
Patients receiving patisiran should take oral supplementation of
approximately 2500 IU vitamin A per day to reduce the potential risk of
ocular toxicity due to vitamin A deficiency. Doses higher than 2500 IU
vitamin A per day should not be given to try to achieve normal serum
vitamin A levels during treatment with patisiran, 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. including reduced night vision or night blindness,
persistent dry eyes, eye inflammation, corneal inflammation or
ulceration, corneal thickening or corneal perforation).

Adverse Reactions

The most common adverse reactions that occurred in patients treated with
patisiran were peripheral oedema (30%) and infusion-related reactions

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 transform 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 and deep pipeline of
investigational medicines, including four 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.

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 data supporting the EC Decision and the potential implications of
such data for patients, plans for regulatory filings in other markets,
including Japan, in 2018, and expectations regarding the company's
"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 patisiran 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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