Alnylam Announces Publication in Circulation of Exploratory Cardiac Endpoint Data from APOLLO Phase 3 Study of Patisiran

− Published Data From the APOLLO Study Show That Patisiran Improved
Markers of Cardiomyopathy in Patients with Hereditary ATTR Amyloidosis
with Polyneuropathy –

− In Exploratory Post-Hoc Analysis, Reduction of All-Cause Mortality
and Hospitalization Was Observed in Patients Treated with Patisiran –

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Alnylam
Pharmaceuticals, Inc.
 (Nasdaq: ALNY), the leading RNAi therapeutics
company, announced today publication of data from exploratory cardiac
assessments in the APOLLO Phase 3 study of patisiran, an RNAi
therapeutic for the treatment of the polyneuropathy of hereditary
transthyretin-mediated (hATTR) amyloidosis in adults. The results were
published online
today
in the journal Circulation, and showed that patisiran
improved markers of cardiomyopathy in patients with hATTR amyloidosis
with polyneuropathy.

“We are encouraged by these data from the APOLLO study on the effects of
patisiran on measures of cardiac disease in hATTR amyloidosis patients
with polyneuropathy,” said Pushkal Garg, M.D., Chief Medical Officer at
Alnylam. “These data support the hypothesis that patisiran may favorably
impact certain cardiac manifestations of hATTR amyloidosis. Accordingly,
we believe these results support further study of the effects of
patisiran on cardiac features of hATTR amyloidosis.”

“Our publication highlights the potential for patisiran to favorably
impact certain cardiac manifestations of hATTR amyloidosis,” said Scott
D. Solomon M.D., Professor of Medicine, Brigham and Women’s Hospital,
Harvard Medical School, lead author of the paper. “The results on
exploratory endpoints of NT-proBNP – an independent predictor of
survival in patients with ATTR amyloidosis – and certain
echocardiographic measures of cardiac structure and function are
encouraging. Together, these data support the therapeutic potential of
patisiran in patients with cardiac involvement due to hATTR amyloidosis,
where there is a substantially reduced lifespan and limited treatment
options.”

The publication presents data on the treatment effects of patisiran
relative to placebo on certain measures of cardiac structure and
function in patients with echocardiographic evidence of cardiac amyloid
involvement at study entry with no confounding medical history (APOLLO
cardiac subpopulation*: n=126; 56 percent of total study population). In
pre-specified analyses, left ventricular (LV) wall thickness was reduced
by a mean of 0.9 mm (p=0.017) in patisiran-treated patients, compared to
those receiving placebo. Global longitudinal strain was also
significantly improved by an absolute value of -1.4 percent (p=0.015),
suggesting improved systolic, or contractile, function. Differences in
global longitudinal strain of this magnitude have been shown in other
studies to be an independent predictor of survival in patients with ATTR
and light-chain (AL) amyloidosis.1 In addition to the
favorable impact on echocardiographic measures of cardiac structure and
function, a treatment effect on NT-proBNP – a cardiac biomarker released
in response to ventricular wall stress – was also observed in the
cardiac subpopulation, with a significant 55 percent relative reduction
in NT-proBNP levels compared to placebo. This effect was noted as early
as 9 months of treatment, the first assessment time point in APOLLO. In
post-hoc categorical analyses, a greater proportion of patients treated
with patisiran versus placebo experienced reductions in LV wall
thickness, decreases in global longitudinal strain and reductions in
NT-proBNP relative to baseline, providing evidence for potential
improvement in markers of cardiomyopathy.

In the overall study population, the proportions of patients with
cardiac adverse events (AEs) and cardiac serious AEs (SAEs) were similar
in the patisiran and placebo groups. The incidence of cardiac arrhythmia
AEs was lower in the patisiran group compared with placebo (18.9 versus
28.6 percent). Deaths occurred in 4.7 percent of patients treated with
patisiran (3.2 per 100 patient-years) and 7.8 percent of patients
treated with placebo (6.2 per 100 patient-years). In a post-hoc
analysis, the exposure-adjusted rates of all-cause death and/or
hospitalization were 71.8 and 34.7 per 100 patient-years in the placebo
and patisiran groups, respectively, representing an approximately 50
percent reduction in event rate. A similar trend was seen for reduction
of all-cause death and/or cardiac hospitalizations.

As described in U.S. prescribing information for ONPATTRO™(patisiran),
four serious adverse reactions of atrioventricular (AV) heart block (2.7
percent) occurred in ONPATTRO-treated patients, including three cases of
complete AV block. No serious adverse reactions of AV block were
reported in placebo-treated patients.

The full manuscript titled, “Effects of Patisiran, an RNA Interference
Therapeutic, on Cardiac Parameters in Patients with Hereditary
Transthyretin-Mediated Amyloidosis: an Analysis of the APOLLO Study,”
will appear in an upcoming issue of Circulation.

*Patients with baseline left ventricular wall thickness ≥ 13 mm and no
medical history of aortic valve disease or hypertension.

1. Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M,
Gagliardi C, Milandri A, Rapezzi C, Falk RH. Left ventricular structure
and function in transthyretin-related versus light-chain cardiac
amyloidosis. Circulation. 2014;129:1840–1849.

About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial was
a randomized, double-blind, placebo-controlled, global study designed to
evaluate the efficacy and safety of patisiran in hATTR amyloidosis
patients with polyneuropathy. The primary endpoint of the study was the
change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7)
relative to placebo at 18 months. Secondary endpoints included: the
Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness
(NIS-W); Rasch-built Overall Disability Scale (R-ODS); timed 10-meter
walk (10-MWT); modified BMI (mBMI); and the composite autonomic symptom
score-31 (COMPASS-31). In addition, exploratory cardiac assessments
included measurement of N-terminal pro-brain natriuretic peptide
(NT-ProBNP) levels and echocardiographic assessments. The trial enrolled
225 hATTR amyloidosis patients from 19 countries with 39 genotypes who
were randomized 2:1, patisiran:placebo, with patisiran administered at
0.3 mg/kg once every three weeks for 18 months. All patients who
completed the APOLLO Phase 3 study were eligible to screen for the
Global open-label extension or OLE study, which is ongoing.

About ONPATTRO™ (patisiran) lipid complex injection
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 approval
from the U.S. Food and Drug Administration (FDA) 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.
ONPATTRO (patisiran) is indicated 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. In the EU, ONPATTRO
(patisiran) was approved by the European Commission in August 2018 for
the treatment of hATTR amyloidosis in adults with stage 1 or stage 2
polyneuropathy. 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.
Additional regulatory filings in other markets, including Japan, are
planned in 2018. 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, 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.

IMPORTANT SAFETY INFORMATION

Infusion-related reactions
Infusion-related reactions (IRRs)
have been observed in patients treated with ONPATTRO. In a controlled
clinical study, 19 percent of ONPATTRO-treated patients experienced
IRRs, compared to 9 percent 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 percent) and infusion-related reactions (19 percent). For
additional information about ONPATTRO, please see the full Prescribing
Information
.

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 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 data and results from its APOLLO Phase 3 clinical trial for
patisiran, including its views with respect to the potential of
patisiran to impact certain cardiac manifestations of hATTR amyloidosis,
the expected timing for additional regulatory filings for approval of
ONPATTRO in global markets, 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)