CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive interim results from Part D of its ongoing Phase 1 study with fitusiran, an investigational RNAi therapeutic, in patients with hemophilia with inhibitors. These results were presented today in a poster at the 58th Annual Meeting of the American Society of Hematology (ASH), held December 3 – 6, 2016 in San Diego, California.
New clinical data showed that once-monthly subcutaneous administration of fitusiran achieved lowering of AT and increases in thrombin generation, resulting in a median estimated annualized bleeding rate (ABR) of zero in patients with hemophilia A or B with inhibitors (N=16). In addition, fitusiran was generally well tolerated through the data cut-off date, October 6, 2016, with no thromboembolic events, including in circumstances when bypassing agents were administered to treat breakthrough bleeding events. Additional data on longer-term administration of fitusiran in patients without inhibitors will be presented in a separate poster presentation at ASH tomorrow, Sunday, December 4.
“As many as one-third of severe hemophilia A patients will develop inhibitors, one of the most serious treatment-related complications of hemophilia. We believe that achievement of a median ABR of zero in this study population is very encouraging, as the prophylactic treatment options for patients with inhibitors are limited and may be suboptimal for many patients,” said Akin Akinc, Ph.D., Vice President and General Manager, Fitusiran. “We look forward to continuing to study fitusiran in hemophilia patients with and without inhibitors, and plan to initiate our Phase 3 program in early 2017.”
New results as of an October 6, 2016 data cut-off date were presented from Part D of the ongoing fitusiran Phase 1 study, which included patients with hemophilia A or B with inhibitors who were enrolled in two separate dose cohorts of 50 mg, once-monthly (N=6) or 80 mg, once-monthly (N=10). Treatment with fitusiran resulted in potent and dose-dependent lowering of AT and increases in thrombin generation. In an exploratory analysis of bleeding events, a median ABR of zero was achieved for patients in combined dose cohorts in the observation period, compared to the pre-study median ABR of 31. The majority of patients treated in both cohorts (9 of 16; 56 percent) were bleed-free and most patients (11 of 16; 69 percent) experienced zero spontaneous bleeds. In the 80 mg cohort, 70 percent (7 out of 10) of patients were bleed-free and 90 percent (9 out of 10) of patients experienced zero spontaneous bleeds.
Fitusiran was generally well tolerated in the study. All adverse events (AEs) were mild or moderate in severity, with the most common AEs consisting of mild injection site reactions (ISRs) in 8 out of 16 patients (50 percent). Asymptomatic and reversible alanine aminotransferase (ALT) increases greater than 3 times the upper limit of normal (ULN), without concurrent elevations in bilirubin greater than 2 times ULN, were observed in three patients, all of whom have medical history of hepatitis C infection (HCV). Non-clinically significant increases in D-dimer were observed in some patients; none were associated with laboratory signs of pathologic clot formation. There were no drug-related serious adverse events (SAEs), no discontinuations due to AEs, and no thromboembolic events through the data cut-off date. All breakthrough bleed events were successfully managed with bypassing agents (recombinant factor VIIa and/or activated prothrombin complex concentrate). As of the data cut-off date, seven inhibitor patients have transitioned to the Phase 2 open-label extension (OLE) study, and continued dosing with fitusiran for up to seven months has been generally well tolerated.
To view the fitusiran clinical results described in this press release, please visit www.alnylam.com/capella.
Conference Call Information
Alnylam management will discuss
these clinical data in a webcast conference call tomorrow, Sunday,
December 4, at 1:00 p.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 28671881. A replay of
the call will be available beginning at 4:00 p.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 28671881.
About Fitusiran Phase 1 Study
The ongoing Phase 1 trial of
fitusiran is being conducted in the United States, Bulgaria, Russia,
Switzerland, and the U.K. as a single- and multi-dose, dose-escalation
study comprised of four parts. Part A – which is complete – was a
randomized, single-blind, placebo-controlled, single-dose,
dose-escalation study (N=4 per cohort; 3:1 randomization of
fitusiran:placebo) in healthy volunteers. This part of the study was
completed after the first dose cohort received a single subcutaneous
dose of fitusiran at 30 mcg/kg. Part B of the study – which is also
complete – was an open-label, multi-dose, dose-escalation study that
enrolled 12 patients with severe hemophilia A or B. Patients in Part B
received three weekly subcutaneous injections of fitusiran at doses of
15, 45, or 75 mcg/kg. Part C of the study – which has completed dosing –
is an open-label, multi-dose, dose escalation study that enrolled 18
patients with moderate or severe hemophilia A or B without inhibitors.
Twelve patients in Part C received three monthly subcutaneous doses of
fitusiran at doses of 225, 450, 900, or 1800 mcg/kg. In addition, six
patients in Part C received three fixed monthly subcutaneous doses of
fitusiran at 80 mg. Part D of the study is designed to enroll up to 18
patients with inhibitors. Patients in Part D received 3 fixed monthly
subcutaneous doses of fitusiran at 50 mg or 80 mg. The primary objective
of Parts B, C, and D of the study is to evaluate the safety and
tolerability of multiple doses of subcutaneously administered fitusiran
in patients with hemophilia, with and without inhibitors. Secondary
objectives include assessment of clinical activity as determined by
lowering of circulating AT levels and increase in thrombin generation at
pharmacologic doses of fitusiran. In addition, exploratory analyses of
bleeding are being performed. In the U.K., enrollment has been aided by
the Southern Academic Coagulation Consortium (SACC).
About Fitusiran
Fitusiran is a subcutaneously administered,
investigational RNAi therapeutic targeting antithrombin (AT) for the
treatment of hemophilia A and B and rare bleeding disorders (RBD)
currently in early stage clinical development. Fitusiran is designed to
lower levels of AT with the goal of promoting sufficient thrombin
generation to restore hemostasis and prevent bleeding in patients with
hemophilia and RBD. AT, also known as "antithrombin III" and "SERPINC1"
is a liver-expressed plasma protein and member of the "serpin" family of
proteins that acts by inactivating thrombin and other coagulation
factors. AT plays a key role in normal hemostasis by helping to limit
the process of fibrin clot formation. However, in hemophilia,
insufficient thrombin generation results in impaired fibrin clot
formation. Lowering AT in the hemophilia setting may promote the
generation of sufficient levels of thrombin needed to form an effective
fibrin clot and prevent bleeding. This rationale is supported by human
genetic data suggesting that co-inheritance of thrombophilic mutations,
including AT deficiency, may ameliorate bleeding in hemophilia. Lowering
of AT is a unique and innovative strategy for restoring hemostasis in
people with hemophilia. Fitusiran utilizes Alnylam's ESC-GalNAc
conjugate technology, which enables subcutaneous dosing with increased
potency and durability and a wide therapeutic index.
Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi
Genzyme, the specialty care global business unit of Sanofi, 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 the United States, Canada and Western Europe,
while Sanofi Genzyme obtained the right to access certain programs in
Alnylam's current and future Genetic Medicines pipeline in the rest of
the world through the end of 2019, together with certain broader
co-development/co-commercialization rights and global rights for certain
products. Sanofi Genzyme has elected to opt in to co-develop (through
Sanofi R&D) and co-commercialize fitusiran in the United States, Canada
and Western Europe, in addition to developing and commercializing
fitusiran in its rest of world territories.
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 fitusiran, its
expectations regarding the timing of clinical studies and the
presentation of clinical data, including for its studies of fitusiran,
its expectations regarding its STAr pipeline growth strategy, its
“Alnylam 2020” guidance for the advancement and commercialization of
RNAi therapeutics, and its plans regarding the pursuit of pre-clinical
programs 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 fitusiran is preliminary and investigative. Fitusiran 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.
