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.
Copyright Business Wire 2014