– Results Provide Continued Evidence Supporting
Potential for ALN-CC5 to Reduce Dose and Frequency of Eculizumab in
Patients with PNH –
Alnylam Pharmaceuticals, Inc.
(Nasdaq:ALNY), the leading RNAi therapeutics company, today
presented new results from Part C of its Phase 1/2 clinical trial
with ALN-CC5, a subcutaneously administered investigational RNAi
therapeutic targeting complement component 5 (C5) for the treatment
of complement-mediated diseases, in a poster presentation at the
58th Annual Meeting of the American Society of Hematology (ASH),
held December 3 – 6, 2016 in San Diego, California.
Part C evaluated the tolerability and clinical activity of
ALN-CC5 in patients (N=6) with paroxysmal nocturnal hemoglobinuria
(PNH), a rare hematologic disease where acquired mutations in the
PIG-A gene lead to complement-mediated destruction of red blood
cells (RBC). In an exploratory analysis, ALN-CC5 was evaluated in
combination with eculizumab, an approved anti-C5 monoclonal
antibody used for treatment of PNH. New results show that
ALN-CC5-mediated knockdown of serum C5 has the potential to enable
effective sparing of eculizumab in patients with PNH. These data
further support development of ALN-CC5 to potentially reduce the
dose level and frequency of eculizumab in patients with PNH, and to
improve disease control in patients with an inadequate response to
eculizumab.
The Company also announced today that Sanofi Genzyme has decided
not to exercise its opt-in right for the development of ALN-CC5 in
territories outside of the United States, Canada and Western
Europe, providing Alnylam with full global control of the program
for further development and potential commercialization.
“There remains significant unmet medical need for novel
medicines to treat complement-mediated diseases, including PNH. We
believe ALN-CC5, both as monotherapy and in combination with
anti-C5 monoclonal antibodies, represents an opportunity to change
disease management by achieving clamped inhibition of hepatic C5
synthesis,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice
President of R&D and Chief Medical Officer of Alnylam. “In our
Phase 1/2 study in PNH, we previously generated evidence that
ALN-CC5 may enable a reduced dose and frequency of anti-C5
monoclonal antibody therapy and may improve disease control in
patients with an inadequate response to therapy. We’re pleased to
now extend these findings showing initial evidence for effective
control of hemolysis in patients with PNH with a once-monthly
reduced dose eculizumab regimen during six months of ongoing
ALN-CC5 pharmacology. We look forward to further exploring the
therapeutic potential of ALN-CC5 through future studies in PNH and
other complement-mediated diseases.”
Clinical Activity Results
In the Phase 1/2 study, a total of 6 patients with PNH were
enrolled in Part C of the trial, including patients who were
eculizumab naive (N=3) and patients who were receiving background
eculizumab therapy (N=3). ALN-CC5 was administered at weekly doses
of 200 or 400 mg for 2 to 16 weeks and achieved C5 knockdown of up
to 98 percent and residual serum C5 levels less than 1 microgram
per milliliter (mcg/mL). Upon completion of ALN-CC5 dosing and in
the setting of ongoing ALN-CC5 pharmacology, investigators elected
to treat patients with 600 mg or 900 mg of eculizumab every 4
weeks, enabling an exploratory analysis of the potential of ALN-CC5
to reduce the dose and frequency of eculizumab. As of the data
transfer date of October 13, 2016, results showed that PNH patients
who had previously been naive to eculizumab (N=3) achieved
sustained control of disease hemolysis with normalization of
lactate dehydrogenase (LDH) to less than or at approximately 1.5
times upper limit of normal (ULN) for up to 6 months while on a
spared eculizumab regimen of 600 mg every 4 weeks. For patients who
entered the study on background eculizumab (N=3), effective disease
control with normalization of LDH to less than or at approximately
1.5 times ULN was achieved for up to 5 months while on a spared
once-monthly regimen of 900 mg eculizumab. Using an assay for
eculizumab plasma levels, both sparing regimens achieved stable
eculizumab trough levels greater than 100 mcg/mL during the 5 to 6
month period. In aggregate, these results support the potential to
achieve effective management of hemolysis in PNH during ALN-CC5
pharmacology with a spared eculizumab dosing regimen representing a
50 to 67 percent reduction in dose and a 2-fold extension of dose
interval relative to the labeled eculizumab maintenance dose and
regimen.
Safety Results
As previously reported, ALN-CC5 was generally well tolerated in
patients with PNH after multiple doses for up to 16 weeks of
dosing. During the course of spared eculizumab dosing, as of the
data transfer date of October 13, 2016, there were no serious
adverse events (SAEs) or discontinuations due to adverse events
(AEs) in the study, and the majority of reported AEs were mild or
moderate in severity. One patient developed an episode of
breakthrough hemolysis in the setting of an upper respiratory tract
infection; this AE was moderate in severity and was considered
unrelated to study drug by the investigator.
To view the ALN-CC5 clinical results described in this press
release, please visit www.alnylam.com/capella.
About the ALN-CC5 Phase 1/2 Study Design
The Phase 1/2 trial of ALN-CC5 was conducted in three parts.
Parts A and B were randomized (3:1, drug:placebo), double-blind,
placebo-controlled, SAD and MAD studies, respectively, which
enrolled 56 healthy adult volunteers. These parts of the study were
designed to evaluate safety and tolerability of single and multiple
subcutaneous doses of ALN-CC5. Additional objectives included
clinical activity as measured by knockdown of serum C5 and levels
of residual C5, and by effects on inhibition of serum complement
activity, including measurements of CAP and CCP activity, as well
as serum sheep red blood cell hemolytic activity. A total of 5 SAD
cohorts were enrolled in the study, with fixed doses ranging from
50 to 900 mg. A total of 6 MAD cohorts were enrolled in the study
with fixed doses of 100, 200, 400, or 600 mg, where healthy adult
volunteers received subcutaneous doses of ALN-CC5 or placebo for up
to 14 weeks. Part C is an open-label, multi-dose study that
enrolled 6 patients with PNH, to assess safety, tolerability, and
clinical activity of ALN-CC5, administered for up to 16 weeks. This
part of the study included an exploratory evaluation of ALN-CC5
effects on levels of LDH, a measure of endogenous red blood cell
hemolysis.
About ALN-CC5
ALN-CC5 is an investigational RNAi therapeutic targeting
component 5 of the complement pathway (C5), currently in early
stage clinical development for the treatment of complement-mediated
diseases. The safety and efficacy of ALN-CC5 have not been
evaluated by the U.S. Food and Drug Administration or any
other health authority. The complement system plays a central role
in immunity as a protective mechanism for host defense, but its
dysregulation results in life-threatening complications in a broad
range of human diseases including paroxysmal nocturnal
hemoglobinuria (PNH), atypical hemolytic-uremic syndrome (aHUS),
myasthenia gravis, neuromyelitis optica, and membranous
nephropathy, amongst others. C5, which is predominantly expressed
in liver cells, is a genetically and clinically validated target;
loss of function human mutations are associated with an attenuated
immune response against certain infections and intravenous anti-C5
monoclonal antibody (mAb) therapy has demonstrated clinical
activity and tolerability in a number of complement-mediated
diseases. A subcutaneously administered RNAi therapeutic that
silences C5 represents a novel approach to the treatment of
complement-mediated diseases. ALN-CC5 utilizes Alnylam's ESC-GalNAc
conjugate technology, which enables subcutaneous dosing with
increased potency and durability and a wide therapeutic index.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
(ESC)-GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery
platform and are designed to achieve targeted delivery of RNAi
therapeutics to hepatocytes through uptake by the
asialoglycoprotein receptor. Alnylam's Enhanced Stabilization
Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous
dosing with increased potency and durability, and a wide
therapeutic index. This delivery platform is being employed in
nearly all of Alnylam's pipeline programs, including programs in
clinical development.
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. Alnylam's pipeline of investigational RNAi therapeutics
is focused in 3 Strategic Therapeutic Areas (STArs): Genetic
Medicines, with a broad pipeline of RNAi therapeutics for the
treatment of rare diseases; Cardio-Metabolic Disease, with a
pipeline of RNAi therapeutics toward genetically validated,
liver-expressed disease targets for unmet needs in cardiovascular
and metabolic diseases; and Hepatic Infectious Disease, with a
pipeline of RNAi therapeutics that address the major global health
challenges of hepatic infectious diseases. In early 2015, Alnylam
launched its "Alnylam 2020" guidance for the advancement and
commercialization of RNAi therapeutics as a whole new class of
innovative medicines. Specifically, by the end of 2020, Alnylam
expects to achieve a company profile with 3 marketed products, 10
RNAi therapeutic clinical programs – including 4 in late stages of
development – across its 3 STArs. The company's demonstrated
commitment to RNAi therapeutics has enabled it to form major
alliances with leading companies including Ionis, Novartis, Roche,
Takeda, Merck, Monsanto, The Medicines Company, and Sanofi Genzyme.
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 about Alnylam's
pipeline of investigational RNAi therapeutics, 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 ALN-CC5 to be used either as a monotherapy
or and in combination with anti-C5 monoclonal antibodies for the
treatment of complement-mediated diseases, its expectations
regarding its STAr pipeline growth strategy, and 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 our
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.
The scientific information referenced in this news release
relating to ALN-CC5 is preliminary and investigative. ALN-CC5 has
not been approved by the U.S. Food and Drug Administration,
European Medicines Agency, or any other regulatory authority and no
conclusions can or should be drawn regarding its safety or
effectiveness.
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version on businesswire.com: http://www.businesswire.com/news/home/20161205005299/en/
Alnylam Pharmaceuticals, Inc.Investors and MediaChristine
Regan Lindenboom, 617-682-4340orInvestorsJosh Brodsky,
617-551-8276
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