Market Overview

Alnylam Presents New Analyses of Clinical Results from APOLLO Phase 3 Study of Patisiran at 2018 Peripheral Nerve Society Annual Meeting


− Patisiran-Treated Patients Showed Improvements in Overall Health
Status Compared to Placebo −

− Indirect Analysis Shows Patisiran's Impact on Measures of
Neuropathy and Quality of Life in APOLLO Study Relative to those
Measured in Randomized Study of Tafamidis −

− Improvements in Neuropathy Impairment with Patisiran Treatment
Associated with Ambulatory Status −

Pharmaceuticals, Inc.
 (NASDAQ:ALNY), the leading RNAi therapeutics
company, announced today that the Company presented new analyses from
the APOLLO Phase 3 study of patisiran, an investigational RNAi
therapeutic for the treatment of hereditary ATTR (hATTR) amyloidosis, in
six presentations at the 2018 Peripheral Nerve Society (PNS) Annual
Meeting being held July 22-25, in Baltimore, MD.

"We are pleased to continue to share new analyses from the APOLLO Phase
3 study with six presentations at the PNS annual meeting. We believe the
new data presented underscore the potential clinical benefit of
patisiran for patients with hATTR amyloidosis. First, the results of the
exploratory EQ-5D-5L and EQ-VAS assessments show that patisiran
treatment, relative to placebo, may help patients maintain or improve
mobility and independence, reduce anxiety and depression, and favorably
impact overall health status," said Eric Green, Vice President and
General Manager, TTR Program at Alnylam. "Further, we believe the
results of an indirect analysis between patisiran and tafamidis
highlight the therapeutic potential of patisiran, if approved. Finally,
with patients on placebo experiencing substantial worsening in
neuropathy in as little as nine months and irrespective of baseline
disease severity, our new analyses show a clear need to intervene early
in the course of this disease."

Results on Overall Health Status Endpoints

Overall health status was an exploratory endpoint assessed in APOLLO
using EuroQOL-5-dimension 5-level (EQ-5D-5L), a standardized measure of
health status based on five dimensions: mobility, self-care, usual
activities, pain/discomfort, and anxiety/depression, and the EuroQOL
visual analogue scale (EQ-VAS), a measure of a patient's global
impression of their overall health as evaluated on a scale of zero
(worst possible health) to 100 (best possible health). At 18 months, a
larger proportion of patients on patisiran than placebo, respectively,
showed preservation (defined as no change in score) or improvement
relative to baseline in each EQ-5D-5L domain: mobility, 70 versus 22
percent; self-care, 66 versus 21 percent; usual activities, 72 versus 25
percent; pain/discomfort, 73 versus 31 percent; anxiety/depression, 81
versus 45 percent. Overall health, as measured by EQ-VAS, improved by an
average of 2.4 points in patients on patisiran, while declining by an
average of 7.1 points in placebo patients, indicating a 9.5 point
difference (nominal p value less than 0.001).

Results from an Indirect Treatment Comparison (ITC) of Tafamidis and

We also presented results from an ITC of patisiran and tafamidis (a
transthyretin tetramer stabilizer) using the standard pairwise Bucher
method. The analysis was based on publicly available randomized trial
efficacy data for tafamidis in hATTR amyloidosis with polyneuropathy1-2.
Importantly, there are limitations to this approach, and there have been
no head-to-head studies comparing the safety and effectiveness of
patisiran and tafamidis. With those caveats, indirect comparisons were
conducted for endpoints or components of endpoints measured in both
trials: change from baseline in NIS-LL (Neuropathy Impairment Score of
the Lower Limbs), NIS-LL response (less than two point increase in
NIS-LL from baseline), Norfolk QoL-DN, and mBMI (modified body mass
index). Safety was not compared as part of this analysis. The base case
analysis indirectly compared these results in patients with Stage 1
polyneuropathy after 18 months of treatment. In the base case ITC,
statistically significant differences in mean change from baseline for
NIS-LL (-5.5 [95% CI -10.0, -1.0]) and Norfolk QoL-DN (-13.1 [95% CI
-23.6, -2.7]) at 18 months were observed favoring patisiran treatment as
compared to tafamidis, and the differences were corroborated by
sensitivity analyses. Favorable trends were also seen for NIS-LL
response rate and mBMI.

Relationship between Improvements in Neuropathy Impairment and
Ambulatory Status

The primary endpoint in APOLLO was the change from baseline in the
modified Neuropathy Impairment Score + 7 (mNIS+7) relative to placebo,
with patisiran demonstrating significant improvement in neuropathy.
Results were presented from an analysis conducted to interrogate whether
changes in mNIS+7 were associated with ambulatory status (as measured by
polyneuropathy disability [PND] score) at 18 months in patisiran-treated
patients. Predictive modeling analysis demonstrated that greater
reduction in mNIS+7 is consistently associated with a higher probability
that a patient will have improved or stabilized ambulatory status (p
value less than 0.0001). Modeling also showed that patients with an
mNIS+7 change of less than zero points after 18 months of patisiran
treatment were predicted to have substantially greater odds of improving
or stabilizing their ambulatory status compared to patients with an
mNIS+7 score of greater than or equal to zero (p value less than 0.0001).

FAP (familial amyloid polyneuropathy) Stage and PND score are commonly
used to indicate neuropathy severity in hATTR amyloidosis and are based
largely on ambulatory ability (e.g. whether, and how many, walking aids
are required). It was shown that following 18 months of treatment, a
greater proportion of patisiran patients compared to placebo showed
stable or improved FAP Stage (79 versus 44 percent) and PND score (73
versus 30 percent). Improvements in FAP Stage and PND score were only
seen with patisiran, and worsening occurred twice as frequently with
placebo compared to patisiran. The observed changes in FAP Stage and PND
score were statistically significant (p=9.5 x 10-8 and p=1.3
x 10-10, respectively), and further support the clinical
benefit of patisiran compared to placebo in improving or preserving

Finally, results highlighting neuropathy progression in the placebo arm
of the APOLLO study were presented. Patients randomized to placebo
experienced significant neuropathy progression as early as 9 months, the
first assessment time point in APOLLO. At 9 and 18 months, neuropathy
progression relative to baseline was observed with a least squares (LS)
mean increase in mNIS+7 of 14.0 and 28.0 points, respectively. Placebo
patients had substantial progression regardless of their baseline
disease severity. The rapid disease progression observed across multiple
endpoints underscores the need for early administration of an effective
therapy for patients with hATTR amyloidosis to prevent disability and
morbidity accumulation.

Results on Infusion-Related Reactions

Patisiran was generally well tolerated, and the common adverse events
(AEs) occurring more frequently with patisiran than placebo were
peripheral edema (29.7 versus 22.1 percent) and infusion-related
reactions (IRRs; 18.9 versus 9.1 percent). All patients in APOLLO
received premedications, consisting of corticosteroids, antihistamines
(H1 and H2 blockers), and acetaminophen, prior to each infusion. A new
analysis of IRRs was presented. In the patisiran-treated patients with
IRRs, the majority of patients had their first IRR within the first two
doses. IRR incidence rate and the number of associated symptoms
decreased over time. Only one patient (less than one percent)
discontinued treatment due to an IRR (moderate flushing). Thus, IRRs
associated with patisiran were manageable and rarely led to treatment

1. Study Fx-005; NCT00409175.
2. Coelho T., et al., J
Neurol. 2013; 260(11):2802-14.

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 echocardiography. The trial enrolled 225 hATTR
amyloidosis patients in 19 countries with 39 genotypes who were
randomized 2:1, patisiran:placebo, with patisiran administered at 0.3
mg/kg intravenously 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 (OLE) study, in which they receive patisiran
on an ongoing basis.

About Patisiran

Patisiran is an investigational, intravenously administered RNAi
therapeutic targeting transthyretin (TTR) in development 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. This may help to reduce the deposition
and facilitate the clearance of TTR amyloid in peripheral tissues and
potentially restore function to these tissues. Patisiran is currently
under Priority Review as a Breakthrough Therapy with the U.S. Food and
Drug Administration (FDA) and under accelerated assessment by the
European Medicines Agency (EMA) for the treatment of patients with hATTR
amyloidosis. The FDA has set a PDUFA date of August 11, 2018. The safety
and efficacy of patisiran have not been evaluated by the FDA or any
other health authority.

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. The only available treatment options for early stage
disease are liver transplantation and, in some countries, tafamidis
(approved in Europe, and certain countries in Asia and Latin America,
specific indication varies by region). As such, there is a significant
need for novel therapeutics 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
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 diseases.

About Alnylam Pharmaceuticals

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 in the
U.S. and Europe 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,
Alnylam's views with respect to the results from its APOLLO Phase 3
clinical trial for patisiran, including from new analyses of the data,
and the potential implications of such results for patients, its
expectations concerning the review of patisiran by regulatory
authorities in the United States and Europe, its expectations regarding
the potential for patisiran to improve the lives of hATTR amyloidosis
patients and their families, 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, 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.

Patisiran has not been approved by the FDA, EMA, or any other regulatory
authority and no conclusions can or should be drawn regarding the safety
or effectiveness of this investigational therapeutic.

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