Alnylam
Pharmaceuticals, Inc. (Nasdaq:ALNY), a
leading RNAi therapeutics company, today announced initial positive
results from its ongoing Phase 1/2 clinical trial with ALN-CC5, an
investigational RNAi therapeutic targeting complement component C5 for
the treatment of complement-mediated diseases. These new
clinical data are being presented at the 20th Congress of
the European Hematology Association (EHA) held June 11 – 14 in Vienna,
Austria. Initial study results from 12 healthy volunteer subjects showed
that single subcutaneous dose administration of ALN-CC5 resulted in
potent, dose-dependent, durable, and statistically significant knockdown
of serum C5 of up to 96%. In addition, single dose administration of
ALN-CC5 achieved inhibition of serum complement activity of up to 92%,
including an up to 61% inhibition of serum hemolytic activity. Further,
ALN-CC5 has been found to be generally well tolerated to date. The
company is continuing to dose healthy volunteer subjects in both the
single ascending dose (SAD) and multiple ascending dose (MAD) stages of
the study, and expects to present additional data from the trial in late
2015. Consistent with previous guidance, the company also plans to begin
enrolling patients with paroxysmal nocturnal hemoglobinuria (PNH) into
the trial by the end of 2015.
“We believe that ALN-CC5 – as a first-in-class C5 synthesis inhibitor –
represents an innovative, differentiated, and well-validated approach
for the treatment of complement-mediated diseases. Our initial
single-dose data from our ongoing Phase 1/2 clinical trial demonstrate
clinical activity for ALN-CC5 with an up to 96% knockdown of serum C5
and up to 92% inhibition of serum complement activity, including an up
to 61% inhibition of serum hemolytic activity. We believe these are
encouraging initial proof-of-concept results, and we expect – based on
our experience in non-human primates, or NHPs – that this level of
single-dose activity should meet our target profile as we progress in
multi-dose cohorts. In addition, we are encouraged that ALN-CC5 has been
generally well tolerated to date,” said Akshay Vaishnaw, M.D., Ph.D.,
Executive Vice President of R&D and Chief Medical Officer at Alnylam.
“ALN-CC5 now becomes our fourth RNAi therapeutic program to demonstrate
clinical activity and excellent translation from NHP to humans,
continuing to highlight the reproducible and modular features of our
RNAi therapeutics platform. Indeed, in the case of ALN-CC5, we appear to
observe a three- to five-fold enhanced potency in humans compared with
NHPs. We are now advancing ALN-CC5 in the multi-dose phase of the Phase
1/2 study, and look forward to reporting additional data from healthy
volunteer subjects in this trial in late 2015. Furthermore, we remain on
track to begin enrolling PNH patients in the trial by the end of this
year.”
“Significant progress has been made in the treatment of
complement-mediated diseases, including PNH, but we continually strive
for even further improvements for our patients. I believe that a new
medicine to treat excessive complement activity that could be given by
infrequent, subcutaneous administration would be a welcome addition to
the treatment landscape,” said Anita Hill, M.D., Ph.D., MRCP, FRCPath,
Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and
Lead Clinician for the National PNH Service in England. “I am encouraged
by the emerging initial single dose data from this Phase 1/2 trial, and
I look forward to the continued clinical development of this novel
therapeutic approach.”
The Phase 1/2 trial of ALN-CC5 is being conducted in the U.K., in three
parts. Parts A and B are randomized (3:1, drug:placebo), double-blind,
placebo-controlled, single-dose (Part A) and multi-dose (Part B),
dose-escalation studies, designed to enroll up to a total of 60 healthy
adult volunteers. To mitigate against the risk of Neisseria
meningitides, subjects received meningococcal vaccination and oral
ciprofloxacin. Subjects in Part A are receiving a single subcutaneous
administration of ALN-CC5 at fixed doses of 50, 200, 400, or 600 mg.
Subjects in Part B are receiving multiple ascending doses of ALN-CC5, at
a fixed dose level of 100 mg in the first cohort, administered once
weekly for up to five weeks; bi-weekly and monthly dosing schedules may
also be evaluated. The primary objective of these first two parts of the
study is to evaluate safety and tolerability of single and multiple
subcutaneous doses of ALN-CC5. Additional objectives include evaluation
of clinical activity for ALN-CC5 as measured by knockdown of serum C5
and inhibition of serum complement activity, including measurements of
complement alternative pathway (CAP) and complement classical pathway
(CCP) activity by ELISA and serum hemolytic activity toward sheep
erythrocytes. Part C will be an open-label, multi-dose study in up to
eight patients with PNH, and will assess safety, tolerability, and
clinical activity of ALN-CC5, administered as multiple subcutaneous
doses for up to 13 weeks. This part of the study will include an
exploratory evaluation of the effects of ALN-CC5 on levels of lactate
dehydrogenase (LDH), a measure of endogenous red blood cell hemolysis.
Initial
Phase 1/2 study results from 12 healthy volunteer subjects are being
presented in an oral presentation at EHA and include all available data
out to as long as 98 days from the 50, 200, and 400 mg SAD cohorts.
Safety data are as of a data cut-off date of May 26, 2015, and clinical
activity data are as of a data cut-off date of June 4, 2015. In the
ongoing study, single doses of ALN-CC5 were found to be generally well
tolerated, with no serious adverse events (including infections), study
discontinuations, or significant clinical laboratory findings reported
to date.
The key additional objectives of the study were to evaluate the clinical
activity of ALN-CC5 as measured toward C5 knockdown and effects on serum
complement activity, including serum hemolytic activity. Single
subcutaneous doses of ALN-CC5 resulted in potent, dose-dependent,
statistically significant, and highly durable knockdown of serum C5
demonstrating human proof-of-concept. Specifically, a single ALN-CC5
dose resulted in an up to 96% knockdown of serum C5. A mean maximum
knockdown of 94 +/- 2.0% (p less than 0.003 compared with placebo) was
achieved in the 400 mg SAD cohort. Nadir C5 knockdown for all treated
subjects was achieved between days 28 and 70 and effects were durable
over a period of months. For example, an up to 94% knockdown of serum C5
was achieved at day 70 after a single dose of drug. The company believes
that the durable and clamped nature of C5 knockdown could potentially
support a once-monthly, fixed dose subcutaneous regimen. Finally, the
level of C5 knockdown in humans after single dose administration was
found to correlate closely (r2=0.83, p less than 0.0001) with
corresponding single dose data in non-human primates. From these data,
there appears to be an approximately three- to five-fold increased
potency for ALN-CC5 in humans as compared with NHPs.
In addition, single dose administration of ALN-CC5 was associated with
potent, dose-dependent, and durable inhibitory effects toward complement
activity. In particular, single dose ALN-CC5 administration resulted in
an up to 87% inhibition of CAP activity (mean maximum 75 ± 7.2%), an up
to 92% inhibition of CCP activity (mean maximum 82 ± 6.1%), and an up to
61% inhibition of serum hemolytic activity (mean maximum 43 ± 9.1%).
These effects on complement activity were statistically significant (p
less than 0.005 compared with placebo). In addition, the inhibitory
effects of ALN-CC5 toward complement activity were found to be highly
durable. For example, an up to 82% inhibition of CCP activity was
observed at day 70 following a single dose administration. As seen in
NHP studies with ALN-CC5 and consistent with all other Alnylam
GalNAc-conjugate programs, further increases in inhibitory effects
toward serum complement activity are expected with multi-dose
administration. As
reported at the American Society of Hematology meeting in December 2014,
results in NHPs showed that a twice-monthly subcutaneous dose regimen of
ALN-CC5 at 5 mg/kg achieved inhibition of serum hemolytic activity of
over 80%. In contrast, additional NHP studies show that a single dose of
ALN-CC5 at 5 mg/kg (comparable to the 400 mg fixed dose in the Phase 1/2
study) achieved a 49 ± 4.5% mean maximal inhibition of serum hemolytic
activity. The company expects to present initial multi-dose data from
the ongoing Phase 1/2 study in late 2015.
Genzyme Alliance
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. Alnylam
retains product rights in North America and Western Europe, while
Genzyme obtained the right to access certain programs in Alnylam's
current and future Genetic Medicines pipeline, including ALN-CC5, in the
rest of the world. In certain defined instances, Genzyme has
co-development/co-commercialization and/or global product rights.
Genzyme's rights are structured as an opt-in that is triggered upon
achievement of human proof-of-principle.
Conference Call Information
Alnylam management will discuss these new Phase 1/2 clinical results
with ALN-CC5 for the treatment of complement-mediated diseases in a
webcast conference call on Friday, June 12 at 7:00 a.m. ET. A slide
presentation will also be available on the 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 64369692. A replay of
the call will be available beginning at 10:00 a.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 64369692.
About ALN-CC5
ALN-CC5 is an investigational RNAi therapeutic targeting the C5
component of the complement pathway for the treatment of
complement-mediated diseases. 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, membranous nephropathy, amongst others. Complement
component 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 Merck, Medtronic, Novartis, Biogen, Roche, Takeda,
Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The
Medicines Company, and Genzyme, a Sanofi company. 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 for the treatment of complement-mediated diseases,
expectations regarding the reporting of data from clinical studies, in
particular the ongoing Phase 1/2 clinical trial of ALN-CC5, expectations
regarding the durability of ALN-CC5, the clinical activity that could be
achieved with multiple doses of ALN-CC5 and the market opportunity for
ALN-CC5, expectations regarding its STAr pipeline growth 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 be replicated
or continue to occur in other subjects or in additional studies or
otherwise 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.
View source version on businesswire.com: http://www.businesswire.com/news/home/20150612005151/en/
Copyright Business Wire 2015