– Revusiran Found to be Generally Well
Tolerated in Patients with Advanced Cardiac Disease –
– After Five Weeks of Treatment, No Significant
Changes in Exploratory Clinical Measurements Observed –
–Data Support Advancement of Revusiran to Phase
3 Clinical Trial;On Track to Start by Year End –
– Company to Host Conference Call at 8:00 a.m.
ET Today to Discuss Data –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today positive initial Phase 2 data
with revusiran (ALN-TTRsc), an investigational RNAi therapeutic
targeting transthyretin (TTR) for the treatment of TTR cardiac
amyloidosis. Initial results are being presented this weekend to
clinicians convening during the American Heart Association meeting
held in Chicago, including a meeting of the Association of Black
Cardiologists. In the pilot Phase 2 study, revusiran was found to
be generally well tolerated in TTR cardiac amyloidosis patients.
Revusiran demonstrated clinical activity with an up to 98.2%
knockdown of serum TTR – the disease causing protein. This included
similar knockdown effects toward wild type and mutant TTR protein
within V122I patients, who represent the most common genotype
associated with inherited forms of TTR cardiac amyloidosis. In the
five week course of treatment, there were no significant changes
observed in a number of exploratory clinical measurements.
Revusiran utilizes Alnylam’s proprietary GalNAc-conjugate delivery
platform that enables subcutaneous delivery of RNAi therapeutics
with a wide therapeutic index.
“Our pilot Phase 2 study was designed to evaluate the
tolerability and initial clinical activity of revusiran in patients
with TTR cardiac amyloidosis. These initial results demonstrate
that revusiran is generally well tolerated in patients with
significant disease burden. In addition, we continue to be
impressed with the level of knockdown – up to 98.2% – achieved with
revusiran toward both mutant and wild-type TTR. In fact, this level
of knockdown is the greatest ever reported for an RNAi therapeutic
in clinical studies. As would be expected with the short treatment
duration of five weeks, there were no significant changes in the
exploratory clinical measurements performed,” said Akshay Vaishnaw,
M.D., Ph.D., Executive Vice President and Chief Medical Officer of
Alnylam. “We look forward to further evaluation of revusiran in our
Phase 2 open-label extension (OLE) study that is now enrolling
patients who participated in the Phase 2 study. We believe
long-term dosing with revusiran could provide us with important
data on tolerability, in addition to the potential for activity
toward clinical endpoints. We plan on sharing data from the OLE
study about once annually, beginning in 2015. In addition, having
now concluded favorable regulatory discussions in the U.S. and
Europe, we expect to begin our Phase 3 trial in TTR cardiac
amyloidosis before year’s end.”
TTR-mediated amyloidosis (ATTR) is an inherited, progressively
debilitating, and often fatal disease caused by mutations in the
TTR gene. These mutations cause misfolding of the protein and the
formation of amyloid fibrils that deposit in tissues. One of the
clinical manifestations of ATTR is familial amyloidotic
cardiomyopathy (FAC), in which TTR amyloid deposition in the heart
leads to cardiac wall thickening and heart failure. In addition,
wild-type TTR can accumulate as amyloid deposits in the heart of
elderly people in a disease known as senile systemic amyloidosis
(SSA). FAC is fatal within 2.5 to 5 years of diagnosis and
treatment is currently limited to supportive care. Senile systemic
amyloidosis (SSA) is a non-hereditary form of TTR cardiac
amyloidosis caused by idiopathic deposition of wild-type TTR; its
prevalence is generally unknown, but is associated with advanced
age.
The revusiran pilot Phase 2 study was aimed at evaluating the
safety, tolerability, pharmacodynamic, and preliminary clinical
activity of revusiran in patients with FAC and SSA. This trial was
conducted as an open-label, multi-dose study. Revusiran was
administered initially as daily subcutaneous doses for five days
and then once weekly for five weeks at doses of 5.0 mg/kg or 7.5
mg/kg, for a total of 10 doses. The primary objective of the study
was to evaluate the safety and tolerability of revusiran. The
secondary objectives were to assess the clinical activity of
revusiran toward serum levels of TTR and characterize the drug’s
pharmacokinetic profile. In addition, a number of exploratory
clinical measurements were performed at baseline and days 42 and 90
after start of dosing.
The initial Phase 2 results presented were from 26 patients,
including 14 diagnosed with FAC and 12 with SSA. Results being
presented are from a data cutoff date of October 3, 2014. Revusiran
was found to be generally well tolerated in both FAC and SSA
patients. The most common adverse event was injection site
reactions (ISR) that occurred in 23% of patients. These were all
mild in severity and were similar to the ISRs observed and
previously reported in the revusiran Phase 1 study. The next most
common adverse event was a low incidence of transient mild liver
function test (LFT) changes (15%) that, in all cases, resolved
without discontinuing therapy. In 3 of 4 patients, these elevations
appeared to be clinically insignificant and were less than 1.5
times the upper limit of normal (ULN). One patient had an
approximate 4-fold elevation in liver transaminases that was deemed
a serious adverse event (SAE) and mild in severity; this event
resolved during continued dosing. There was also a low incidence
(15%) of mild, transient, and clinically insignificant monocytosis
(increase in percentage monocyte count), which occurred in 4
individuals with elevated baseline monocytosis. There were no
discontinuations and no significant changes in renal function or
any other laboratory chemistry or hematologic parameters.
Revusiran demonstrated clinical activity in TTR cardiac
amyloidosis patients as measured by knockdown of serum TTR, the
disease-causing protein. Specifically, administration of revusiran
resulted in potent, rapid, and durable knockdown of serum TTR of up
to 98.2%, with a mean maximum knockdown of 87.2% +/- 9.1%. Using a
mass spectrometric assay capable of measuring the V122I mutant TTR,
a similar level of knockdown was observed for wild-type and mutant
TTR in V122I patients. In particular, there was a strong
correlation of knockdown of the wild-type protein and the V122I
mutant protein (r2=0.79, p less than 0.0001). Further, a similar
degree of TTR knockdown was observed in both FAC and SSA patients.
After five weeks of treatment in this small study population, there
were no significant changes observed in the exploratory clinical
measurements performed, including 6-minute walk distance (6-MWD),
modified body mass index (mBMI), echocardiogram and cardiac MRI,
circulating cardiac biomarkers including NT-proBNP and troponin,
and questionnaires to assess cardiomyopathy symptoms and quality of
life. Alnylam expects to present the full data set from this Phase
2 trial in early 2015.
“TTR cardiac amyloidosis represents a significant unmet medical
need with no approved therapies, and I believe that revusiran holds
promise as a potential new treatment option for patients. I am very
encouraged by these initial Phase 2 results, showing a favorable
tolerability profile, in addition to potent and rapid knockdown of
circulating levels of serum TTR, the disease-causing protein,” said
Julian Gillmore, M.D., Ph.D., of the National Amyloidosis Centre,
University College London. “I look forward to continuing to work
with Alnylam as they advance this investigational agent in clinical
development.”
Alnylam has also initiated its Phase 2 open-label extension
(OLE) study of revusiran. All patients who completed dosing in the
Phase 2 trial are eligible to be enrolled in the OLE study.
Revusiran will be administered at a fixed subcutaneous dose of 500
mg, with once-daily dosing for the first five days followed by
weekly dosing thereafter. The study is designed to evaluate the
tolerability and clinical activity of revusiran with long-term
dosing for up to two years. In addition to data on mortality,
hospitalization, general tolerability, and knockdown of serum TTR,
the study will assess a number of clinical endpoints every six
months. These include the same exploratory clinical measures used
in the pilot Phase 2 trial noted above, as well as additional
measures of amyloid burden including technetium imaging of the
heart and quantitation of amyloid in abdominal fat pad aspirates.
The company expects to present results from the revusiran Phase 2
OLE study at least once annually starting in 2015. Finally, Alnylam
has now completed its meetings with regulatory authorities from the
U.S. and EU regarding the design of a Phase 3 trial for revusiran
in TTR cardiac amyloidosis, and expects to initiate the study by
the end of the year. The company will provide details on the design
of this study when it announces the start of the Phase 3 trial.
In January 2014, Alnylam and Genzyme, a Sanofi company, formed
an alliance to accelerate and expand the development and
commercialization of RNAi therapeutics across the world. The
alliance is structured as a multi-product geographic alliance in
the field of rare diseases. In the case of revusiran, Alnylam and
Genzyme are co-developing and co-commercializing the
investigational RNAi therapeutic in North America and Western
Europe, while Genzyme is developing and commercializing revusiran
in the rest of world.
Conference Call Information
Alnylam management will discuss these initial Phase 2 results
with revusiran (ALN-TTRsc), for the treatment of TTR cardiac
amyloidosis in a webcast conference call on Friday, November 14 at
8:00 a.m. ET. A slide presentation will also be available on the
News & Investors page of the company's website,
www.alnylam.com, to accompany the conference call. To access the
call, please dial 877-312-7507 (domestic) or 631-813-4828
(international) five minutes prior to the start time and refer to
conference ID 35351048. A replay of the call will be available
beginning at 11:00 a.m. ET. To access the replay, please dial
855-859-2056 (domestic) or 404-537-3406 (international), and refer
to conference ID 35351048.
About ATTR
Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited,
progressively debilitating, and often fatal disease caused by
mutations in the TTR gene. TTR protein is produced primarily in the
liver and is normally a carrier of vitamin A. Mutations in TTR
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. ATTR represents a major unmet
medical need with significant morbidity and mortality; familial
amyloidotic polyneuropathy (FAP) affects approximately 10,000
people worldwide and familial amyloidotic cardiomyopathy (FAC) is
estimated to affect at least 40,000 people worldwide. FAP patients
have a life expectancy of 5 to 15 years from symptom onset, and the
only approved treatment options for early stage disease are liver
transplantation, and tafamidis (approved in Europe). FAC is fatal
within 2.5 to 5 years of diagnosis and treatment is currently
limited to supportive care. Senile systemic amyloidosis (SSA) is a
non-hereditary form of TTR cardiac amyloidosis caused by idiopathic
deposition of wild-type TTR; its prevalence is generally unknown,
but is associated with advanced age. There is a significant need
for novel therapeutics to treat patients with TTR amyloid
polyneuropathy and/or cardiomyopathy.
About RNAi
RNAi (RNA interference) is a revolution in biology, representing
a breakthrough in understanding how genes are turned on and off in
cells, and a completely new approach to drug discovery and
development. Its discovery has been heralded as “a major scientific
breakthrough that happens once every decade or so,” and represents
one of the most promising and rapidly advancing frontiers in
biology and drug discovery today which was awarded the 2006 Nobel
Prize for Physiology or Medicine. RNAi is a natural process of gene
silencing that occurs in organisms ranging from plants to mammals.
By harnessing the natural biological process of RNAi occurring in
our cells, the creation of 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, target the cause of diseases by potently
silencing specific mRNAs, thereby preventing disease-causing
proteins from being made. RNAi therapeutics have the potential to
treat disease and help patients in a fundamentally new way.
About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel
therapeutics based on RNA interference, or RNAi. The company is
leading the translation of RNAi as a new class of innovative
medicines with a core focus on RNAi therapeutics as genetic
medicines, including programs as part of the company’s “Alnylam
5x15™” product strategy. Alnylam’s genetic medicine programs are
RNAi therapeutics directed toward genetically defined targets for
the treatment of serious, life-threatening diseases with limited
treatment options for patients and their caregivers. These include:
patisiran (ALN-TTR02) targeting transthyretin (TTR) for the
treatment of TTR-mediated amyloidosis (ATTR) in patients with
familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc)
targeting TTR for the treatment of ATTR in patients with TTR
cardiac amyloidosis, including familial amyloidotic cardiomyopathy
(FAC) and senile systemic amyloidosis (SSA); ALN-AT3 targeting
antithrombin (AT) for the treatment of hemophilia and rare bleeding
disorders (RBD); ALN-CC5 targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-AS1 targeting
aminolevulinic acid synthase-1 (ALAS-1) for the treatment of
hepatic porphyrias including acute intermittent porphyria (AIP);
ALN-PCS targeting PCSK9 for the treatment of hypercholesterolemia;
ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of
AAT deficiency-associated liver disease; ALN-HBV targeting the
hepatitis B virus (HBV) genome for the treatment of HBV infection;
ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and
iron-overload disorders; ALN-ANG targeting angiopoietin-like 3
(ANGPTL3) for the treatment of genetic forms of mixed
hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting
apolipoprotein C-III (apoCIII) for the treatment of
hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for
the treatment of hypertensive disorders of pregnancy (HDP),
including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO)
for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV
targeting the hepatitis delta virus (HDV) genome for the treatment
of HDV infection; ALN-PDL targeting programmed death ligand 1
(PD-L1) for the treatment of chronic liver infections; and other
programs yet to be disclosed. As part of its “Alnylam 5x15”
strategy, as updated in early 2014, the company expects to have six
to seven genetic medicine product candidates in clinical
development – including at least two programs in Phase 3 and five
to six programs with human proof of concept – by the end of 2015.
The company’s demonstrated commitment to RNAi therapeutics has
enabled it to form major alliances with leading companies including
Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko
Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, and The
Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi
company, formed a multi-product geographic alliance on Alnylam's
genetic medicine programs in the rare disease field. Specifically,
Alnylam will lead development and commercialization of programs in
North America and Europe, while Genzyme will develop and
commercialize products in the rest of world. In addition, Alnylam
and Genzyme will co-develop and co-commercialize revusiran in North
America and Europe. In March 2014, Alnylam acquired Sirna
Therapeutics, a wholly owned subsidiary of Merck. In addition,
Alnylam holds an equity position in Regulus Therapeutics Inc., a
company focused on discovery, development, and commercialization of
microRNA therapeutics. Alnylam scientists and collaborators have
published their research on RNAi therapeutics in over 200
peer-reviewed papers, including many in the world’s top scientific
journals such as Nature, Nature Medicine, Nature Biotechnology,
Cell, New England Journal of Medicine, and The Lancet. Founded in
2002, Alnylam maintains headquarters in Cambridge, Massachusetts.
For more information, please visit www.alnylam.com.
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 for RNAi
therapeutics, including revusiran (ALN-TTRsc) for the treatment of
FAC, its expectations with respect to timing of regulatory filings
and the reporting of initial data from its Phase 2 OLE clinical
trial for revusiran, the expected start of a Phase 3 trial for
revusiran, and, the potential therapeutic opportunities for
revusiran, as well as its expectations regarding its “Alnylam 5x15”
product strategy, and its plans regarding 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 may differ materially
from those indicated by these forward-looking statements as a
result of various important 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 drug candidates, the pre-clinical and clinical
results for its product candidates, which may not support further
development of product candidates, actions of regulatory agencies,
which may affect the initiation, timing and progress of clinical
trials, obtaining, maintaining and protecting intellectual
property, Alnylam’s ability to enforce its patents against
infringers and defend its patent portfolio against challenges from
third parties, obtaining regulatory approval for products,
competition from others using technology similar to Alnylam’s and
others developing products for similar uses, Alnylam’s ability to
manage operating expenses, Alnylam’s ability to 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,
marketing, sales and distribution of products, the outcome of
litigation, 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 to update any forward-looking
statements.
Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations andCorporate
CommunicationsorSpectrum (Media)Liz Bryan, 202-955-6222 x2526
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