Alnylam Announces Publication of Phase 1 Givosiran Data in The New England Journal of Medicine

− Givosiran Associated with Substantial and Sustained Lowering of
Neurotoxic Heme Synthesis Intermediates Implicated in Acute Intermittent
Porphyria –

− Givosiran also Associated with Reduced Rate of Porphyria Attacks
and Hemin Use –

− Topline Phase 3 Readout Expected in Early 2019, with a Rolling NDA
Submission Initiated –

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Alnylam
Pharmaceuticals, Inc.
 (Nasdaq: ALNY), the leading RNAi therapeutics
company, announced today that results from the Phase 1 study of
givosiran, an investigational, subcutaneous RNAi therapeutic targeting
aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute
hepatic porphyria (AHP), were published online
today
in The New England Journal of Medicine (NEJM). The full
manuscript, titled “Phase 1 Trial of an RNA Interference Therapy for
Acute Intermittent Porphyria,” will appear in the February 7, 2019 issue
of NEJM.

In the Phase 1 study, the proportion of patients reporting adverse
events (AEs) was similar across treatment groups with no clear
relationship with givosiran dose. The majority of AEs were mild or
moderate; the most common AEs included nasopharyngitis, abdominal pain,
and diarrhea. Serious AEs (SAEs) were reported in six patients treated
with givosiran (N=33), including – as previously reported – one fatal
SAE of hemorrhagic pancreatitis, assessed as unlikely related to study
drug by the study investigator. Additional unrelated SAEs included
influenza infection, opioid bowel dysfunction, miscarriage, and two
patients with abdominal pain. No SAEs were reported in the placebo group
(N=10).

Results showed that basal ALAS1 messenger RNA (mRNA), aminolevulinic
acid (ALA), and porphobilinogen (PBG) levels were associated with
disease activity, with higher levels noted in those with recurrent
attacks, confirming the central importance of liver ALAS1 induction and
ALA and PBG in the pathophysiology of acute intermittent porphyria
(AIP). Monthly givosiran administration resulted in sustained reductions
of ALAS1 mRNA, urinary ALA, and PBG to near normal levels. In
exploratory analyses, these reductions were associated with a 79 percent
decrease in mean annualized attack rate and an 83 percent decrease in
mean annualized hemin usage, compared with placebo.

“We are pleased to have our givosiran Phase 1 findings published in such
a highly esteemed, peer-reviewed journal. Indeed, we are encouraged by
the emerging safety and tolerability profile for givosiran, as well as
the results of exploratory analyses suggesting favorable effects on
porphyria attack rate and hemin use for acute attacks,” said Akin Akinc,
Ph.D., Vice President and General Manager, Givosiran Program at Alnylam.
“With no treatment options currently approved for the prevention of
porphyria attacks, we believe givosiran has the potential to make a
meaningful difference in the lives of AHP patients.”

“Acute intermittent porphyria is the most common subtype of AHP where
patients experience recurrent, incapacitating, neurovisceral attacks
requiring hospitalization or urgent medical attention. The Phase 1
results not only advance our understanding of the pathologic basis of
AIP but they also signal hope to patients and their caregivers living
with the tremendous burden of this disease and its current management,”
said Dr. Eliane Sardh, Karolinska Institutet, Karolinska University
Hospital, Porphyria Centre Sweden, the lead author of the NEJM paper. “I
look forward to continued evaluation of the safety and efficacy of
givosiran in the ongoing OLE and Phase 3 studies.”

Dosing of eligible patients is ongoing in the Phase 1/2 open-label
extension (OLE) study. In addition, safety and efficacy of givosiran are
being evaluated in the ongoing ENVISION Phase 3 trial, a randomized,
double-blind, placebo-controlled pivotal study. The Company recently
announced positive topline interim analysis results based on reduction
of urinary ALA in 43 patients with AHP. Topline results from the
complete 6-month double-blind portion of ENVISION, including annualized
porphyria attack rate – the primary endpoint of the study – are expected
in early 2019.

Rolling submission for a new drug application (NDA) has been recently
initiated, with full clinical sections planned to be submitted in
mid-2019, assuming positive results.

About Givosiran Phase 1 Study

The Phase 1 study of givosiran was conducted in three parts. Parts A and
B were randomized, single-blind, single-dose (Part A) and multi-dose
(Part B), dose-escalation studies that enrolled 23 subjects who were
“chronic high excreters” (CHE). Per protocol, CHE subjects in the study
had a defined mutation in the porphobilinogen deaminase (PBGD) gene and
elevated urinary levels of ALA and PBG, but did not have a recent
history of porphyria attacks or disease activity. Part C was conducted
as a randomized, double-blind, placebo-controlled study in 17 patients
with acute intermittent porphyria (AIP) who experienced recurrent
porphyria attacks. Patients were initially followed in a 3-month run-in
phase, where the number and frequency of porphyria attacks and levels of
ALA and PBG were measured prospectively. Patients who experienced at
least one porphyria attack during the run-in phase were then eligible to
enter the 6-month treatment phase of the study, where they were
randomized to receive 2 once-quarterly doses or 4 once-monthly doses of
placebo or givosiran at doses of 2.5 or 5.0 mg/kg. During the treatment
phase, the effects of placebo or givosiran on the number and frequency
of porphyria attacks, as well as on the levels of ALA and PBG, were
measured prospectively in a blinded manner and then compared to run-in
phase results. Additional measures included safety, tolerability,
hospitalizations, use of hemin, levels of ALAS1 mRNA, and givosiran
pharmacokinetics. Hemin is an FDA-approved agent used to treat porphyria
attacks when they occur. Following the treatment phase of the Phase 1
study, all patients were eligible to receive givosiran in an open-label
extension study.

About Acute Hepatic Porphyria

Acute hepatic porphyria (AHP) refers to a family of rare, genetic
diseases characterized by potentially life-threatening attacks and for
some patients chronic debilitating symptoms that negatively impact daily
functioning and quality of life. AHP is comprised of four subtypes, each
resulting from a genetic defect leading to deficiency in one of the
enzymes of the heme biosynthesis pathway in the liver: acute
intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate
porphyria (VP), and ALAD-deficiency porphyria (ADP). These defects cause
the accumulation of neurotoxic heme intermediates aminolevulinic acid
(ALA) and porphobilinogen (PBG), with ALA believed to be the primary
neurotoxic intermediate responsible for causing both attacks and ongoing
symptoms between attacks. Common symptoms of AHP include severe, diffuse
abdominal pain, weakness, nausea, and fatigue. The nonspecific nature of
AHP signs and symptoms can often lead to misdiagnoses of other more
common conditions such as irritable bowel syndrome, appendicitis,
fibromyalgia, and endometriosis, and consequently, patients afflicted by
AHP often remain without a proper diagnosis for up to 15 years. In
addition, long-term complications of AHP and its treatment can include
chronic neuropathic pain, hypertension, chronic kidney disease and liver
disease, including iron overload, fibrosis, cirrhosis and hepatocellular
carcinoma. Currently, there are no treatments approved to prevent
debilitating attacks or to treat the chronic manifestations of the
disease.

About Givosiran

Givosiran is an investigational, subcutaneously administered RNAi
therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in
development for the treatment of acute hepatic porphyria (AHP). Monthly
administration of givosiran has the potential to significantly lower
induced liver ALAS1 levels in a sustained manner and thereby decrease
neurotoxic heme intermediates, aminolevulinic acid (ALA) and
porphobilinogen (PBG), to near normal levels. By reducing accumulation
of these intermediates, givosiran has the potential to prevent or reduce
the occurrence of severe and life-threatening attacks, control chronic
symptoms, and decrease the burden of the disease. Givosiran utilizes
Alnylam’s Enhanced Stabilization Chemistry ESC-GalNAc conjugate
technology, which enables subcutaneous dosing with increased potency and
durability and a wide therapeutic index. Givosiran has been granted
Breakthrough Therapy designation by the U.S. Food and Drug
Administration (FDA) and PRIME designation by the European Medicines
Agency (EMA). Givosiran has also been granted orphan drug designations
in both the U.S. and the EU for the treatment of AHP. The safety and
efficacy of givosiran are currently being investigated in the ENVISION
Phase 3 clinical trial and ongoing Phase 1/2 OLE study and have not been
evaluated by the FDA, the EMA or any other health authority.

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 new class of medicines, known as RNAi
therapeutics, is now a reality. 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, hepatic infectious, and central nervous system
(CNS)/ocular 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. Alnylam’s
first U.S. FDA-approved RNAi therapeutic is ONPATTRO®
(patisiran) lipid complex injection available in the U.S. for the
treatment of the polyneuropathy of hereditary transthyretin-mediated
(hATTR) amyloidosis in adults. 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 five 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 1,000 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 potential benefits of givosiran,
plans to complete an NDA submission and pursue a full approval in 2019,
assuming positive final results of the ENVISION Phase 3 study of
givosiran, the expected timing of the report of topline full results
from the ENVISION study, 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.

Givosiran has not been evaluated 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.

Contacts

Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom
(Investors
and Media)
617-682-4340

Josh Brodsky
(Investors)
617-551-8276

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