– Fitusiran Achieves Median Estimated
Annualized Bleeding Rate of Zero in Patients without Inhibitors
–
– In Initial Low Dose Cohort of Patients with
Inhibitors, Fitusiran Achieves Antithrombin Lowering, Increased
Thrombin Generation, and Preliminary Evidence for Reduced Bleeding
–
– Fitusiran Administration Generally Well
Tolerated in Hemophilia Patients with and without Inhibitors –
– Company Updates Guidance for Phase 3, and Now
Plans to Start Studies in Early 2017 –
– Company has Rescheduled its Conference Call,
which will Now Occur Today, Monday, July 25, at 1:00 pm ET –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today new positive results from its
ongoing Phase 1 study with fitusiran, an investigational RNAi
therapeutic targeting antithrombin (AT) for the treatment of
hemophilia A and B and rare bleeding disorders (RBD). 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. These new data will
be presented in an oral presentation at the World Federation of
Hemophilia (WFH) 2016 World Congress, on Wednesday, July 27, 2016
in Orlando, Florida. Due to an inadvertent posting for a short
period this morning of a draft version of the presentation on the
WFH website, the Company will now host a conference call today,
Monday, July 25, at 1:00 pm ET, to discuss these results.
New clinical data showed that once-monthly subcutaneous
administration of fitusiran achieved dose-dependent lowering of AT
and increases in thrombin generation, resulting in a median
estimated annualized bleeding rate (ABR) of zero in evaluable
patients with hemophilia A or B without inhibitors (N=17). In
addition, data from an initial cohort of hemophilia patients with
inhibitors (N=6) demonstrated AT lowering, increased thrombin
generation, and preliminary evidence for reduced bleeding.
Importantly, fitusiran was found to be generally well tolerated to
date in patients with and without inhibitors, including no
thromboembolic events. Finally, the Company announced that it now
plans to initiate fitusiran pivotal studies in people with
hemophilia with and without inhibitors in early 2017.
“As a once-monthly, fixed dose, subcutaneous prophylactic
treatment option that could be shown to provide durable and
consistent bleed prevention, fitusiran has the potential to
transform the management of hemophilia and RBD, including patients
with inhibitors. We believe these new data bring us closer to
realizing that potential, as our exploratory analysis indicates
that fitusiran can achieve a median estimated ABR of zero in
patients with hemophilia A or B without inhibitors,” said Akin
Akinc, Ph.D., Vice President and General Manager, Fitusiran.
“Moreover, we believe our preliminary data in the first cohort of
inhibitor patients receiving a low monthly subcutaneous fixed dose
of 50 mg are promising, and we look forward to additional data at
higher fitusiran doses in this patient sub-group with very high
unmet need. Importantly, we continue to be encouraged by the
tolerability profile for fitusiran.”
New results were presented from Part C (N=18) and Part D
(N=6) of the ongoing Phase 1 study, and include all available data
as of the data transfer up to July 11, 2016. Part C evaluated
a monthly subcutaneous regimen at doses ranging from 225 micrograms
per kilogram (mcg/kg) to 1800 mcg/kg, and also includes a cohort of
six patients that received a fixed dose of 80 mg. Part D is
evaluating monthly subcutaneous dosing in people with hemophilia A
and B with inhibitors, and is designed to enroll up to a total of
18 patients. The first cohort of six patients with inhibitors
received a 50 mg fixed, once-monthly, subcutaneous dose regimen.
The second cohort has completed enrollment with six inhibitor
patients receiving an 80 mg fixed, once-monthly, subcutaneous dose
regimen.
Phase 1 Part C Interim Study Results in Hemophilia A or B
without InhibitorsTreatment with fitusiran resulted in potent,
dose-dependent, and statistically significant lowering of AT. At
the 80 mg fixed monthly dose, fitusiran achieved 87 ± 1 percent
mean maximal AT lowering with low inter-patient variability. The
association between AT lowering and increased thrombin generation
was assessed in a post hoc exploratory analysis in which AT
lowering was grouped by 25 percent increments for completed
patients in Parts B (N=12) and C (N=17) of the study. In the
highest quartile of greater than or equal to 75 percent AT lowering
(N=16), fitusiran administration resulted in mean increases in
thrombin generation of approximately 290 percent relative to
baseline (p less than 0.001, as compared to the lowest AT lowering
quartile). Furthermore, there was a statistically significant, AT
lowering-dependent reduction in bleeding frequency, with the
greatest effect seen at greater than or equal to 75 percent AT
lowering (p less than 0.05, based on a negative binomial regression
model). These data support the therapeutic hypothesis that AT
lowering of 75 percent or greater is associated with attenuation of
the hemophilia phenotype in non-inhibitor patients.
To obtain a more comprehensive assessment of potential fitusiran
effects on bleeding, a post hoc analysis was performed in evaluable
patients from all five cohorts in Part C (N=17). Specifically,
bleed events that occurred over the six month period prior to study
entry (based on review of medical records) and bleed events that
were assessed prospectively during days 0-28 following the initial
fitusiran dose (the “onset period”) were compared with bleed events
that occurred beyond day 29 up to day 112 (the “observation
period”), the time period during which fitusiran achieves its
therapeutic pharmacodynamic effect. Median estimated ABR values
were determined accordingly. In addition, bleed events classified
as “spontaneous” were analyzed separately to determine the
estimated annualized spontaneous bleeding rate (AsBR).
Prior to study entry, evaluable patients (N=17) had an estimated
median ABR of 28 for patients receiving on-demand factor therapy
(N=4) and an estimated median ABR of two for patients receiving
prophylactic factor therapy (N=13). During the prospectively
monitored “onset period” interval, the estimated median ABR was 13
among all evaluable patients. In contrast, during the observation
period, fitusiran administration achieved an estimated median ABR
of zero. In all Part C dose cohorts during the observation period,
the majority of patients (9 of 17; 53 percent) were bleed-free, and
82 percent of patients reported no spontaneous bleeds. In the 80 mg
fixed dose cohort, the estimated median ABR of zero compared
favorably with the pre-study ABR of 6 for the same patients when
they were receiving prophylactic replacement factor therapy. While
not based on direct comparative studies, the median estimated ABR
achieved with once-monthly, subcutaneous fitusiran compares
favorably to the range of median ABR values of zero to four
reported in clinical studies of frequent prophylactic intravenous
infusions of recombinant Factors VIII or IX.
Initial Phase 1 Part D Study Results in Hemophilia A or B
Patients with InhibitorsPatients with hemophilia A or B with
inhibitors were enrolled in the initial Part D dose cohort. Prior
to study entry, all patients utilized bypass agents, including
recombinant Factor VIIa and activated prothrombin complex
concentrate (aPCC), to manage their bleeds, and had a notably high
pre-study ABR of up to 80, based on review of medical records.
In order to obtain an initial experience with fitusiran, the
first cohort (N=6) of inhibitor patients received a once-monthly,
fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal
AT lowering of 81 ± 2 percent and a mean maximal thrombin
generation increase of approximately 368 percent, comparable to
results observed from Part C in non-inhibitor patients at similar
doses. In addition, preliminary evidence for reduced bleeding was
observed, with a 49-100 percent reduction in estimated ABR during
the observation period compared with pre-study values. Dose
escalation has occurred, and the next cohort of inhibitor patients
has been fully enrolled with once-monthly subcutaneous dosing at 80
mg (N=6). The Company expects to present additional data from
inhibitor patients in Part D of the study in late 2016.
Interim Phase 1 Study Safety ResultsAs of the data
transfer on July 11, 2016, fitusiran continues to be generally well
tolerated in patients with hemophilia with or without inhibitors
(N=31, with five patients participating in both Parts B and C).
There have been no serious adverse events (SAEs) related to study
drug, and no thromboembolic events or laboratory evidence (based on
D-dimer, platelet count, fibrinogen, and/or PT/INR) of pathologic
clot formation. All bleeds were successfully managed with standard
replacement factor or bypass agent administration. One
non-inhibitor patient in Part C at the 80 mg fixed dose cohort
discontinued due to an adverse event considered severe and possibly
related to study drug per. This event was described as non-cardiac
chest pain and was accompanied by transient elevations of ALT (10x
upper limit of normal, ULN), AST (8x ULN), C-reactive protein, and
D-dimer, without increase in total bilirubin. Extensive evaluation
was unremarkable, and venous thromboembolism was excluded by serial
CT angiograms and liver and lower extremity ultrasound. This
patient’s event resolved with symptomatic management, including
antacids and analgesics. Eleven patients (35 percent) reported
mild, drug-related injection site reactions (ISRs), which were
mostly pain or erythema at the injection site. Additional AEs
reported in greater than or equal to 10 percent of patients
included upper respiratory tract infection (10 percent) and
arthralgia (10 percent); the majority of these AEs were mild or
moderate in severity. With the exception of the case noted above,
there were no other clinically significant drug related changes in
laboratory parameters. Finally, there have been no instances of
anti-drug antibody formation to fitusiran.
Additional Data and Development Plans“Turning to our
development plans, we’ve completed constructive initial discussions
with regulatory authorities and as an update to previous guidance,
we now plan to initiate our Phase 3 studies in patients with and
without inhibitors in early 2017 following completion of the second
inhibitor patient dose cohort in the Phase 1 study,” Dr. Akinc
added. “Moreover, we plan on presenting additional data later this
year, including additional results from inhibitor patients and
initial data from the ongoing Phase 1/2 open-label extension study,
where patients have now received up to 13 monthly doses of
fitusiran.”
Alnylam plans to report additional data from fitusiran studies
in late 2016. These data are expected to include additional results
from Part D of the ongoing Phase 1 study and initial results from
the Phase 1/2 open-label extension (OLE) study. Twenty-one patients
who have completed treatment in the Phase 1 study have now rolled
over to the OLE study, where they are receiving monthly fitusiran
administration. Additional patients are expected to enroll in the
OLE study as they become eligible.
To view the clinical results presented by Alnylam at the WFH
meeting, please visit www.alnylam.com/capella.
Conference Call InformationAlnylam management will
discuss these data in a webcast conference call
today, Monday, July 25, 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 51834298. A replay of the
call will be available at 3:00 p.m. ET. To access the replay,
please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 51834298.
About the Fitusiran Phase 1 StudyThe ongoing Phase 1
trial of fitusiran is being conducted in 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 will receive three 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).
Fitusiran is an investigational compound, currently in early
stage clinical development. The safety and efficacy of fitusiran
have not been evaluated by the U.S. Food and Drug
Administration or any other health authority.
About Hemophilia and Rare Bleeding DisordersHemophilia is
a bleeding disorder characterized by insufficient thrombin
generation following hemostatic challenge and resulting in
recurrent bleeds into joints, muscles, and other internal organs.
There are approximately 200,000 diagnosed patients with hemophilia
worldwide. Hemophilia A is defined by loss-of-function mutations in
Factor VIII, and represents approximately 80 percent of the
hemophilia population. Hemophilia B, is defined by loss-of-function
mutations in Factor IX, and represents approximately 20 percent of
the hemophilia population. Other Rare Bleeding Disorders (RBD) are
defined by deficiencies of blood coagulation factors, including
Factors II, V, VII, X, and XI. There are an estimated 1,000 persons
worldwide with a severe bleeding phenotype because of these
conditions. The goal of treatment for persons living with
hemophilia is to prevent bleeding, establish prompt management of
bleeds, and manage the complications of bleeding and treatment.
Current guidelines recommend management of hemophilia with regular
intravenous infusions of recombinant or human-derived clotting
factors. However, the most serious treatment-related complication
is the development of antibodies, known as "inhibitors", to
replacement factor. Inhibitor development can occur in both
hemophilia A and hemophilia B, impacting as many as one-third of
people with severe hemophilia A, and persons in this ‘inhibitor'
subset become refractory to standard replacement therapy. There
exists a significant need for novel therapeutics to treat people
living with hemophilia.
About Antithrombin (AT)Antithrombin (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.
Sanofi Genzyme AllianceIn 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 North America 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 (ROW) through the end of 2019, together with certain broader
co-development/co-commercialization rights and global product
rights for certain products. In the case of fitusiran, Sanofi
Genzyme has elected to opt into the program for its ROW rights,
while retaining its further opt-in right to co-develop and
co-promote fitusiran with Alnylam in North
America and Western Europe, subject to certain
restrictions.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
(ESC)-GalNAc ConjugatesGalNAc-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 RNAiRNAi (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 PharmaceuticalsAlnylam 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 StatementsVarious 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 investigational therapeutics,
including fitusiran (ALN-AT3), the potential implications of
reported results from its ongoing Phase 1 trial, its expectations
regarding the timing of clinical studies, including its updated
guidance regarding the initiation of pivotal Phase 3 studies, and
the expected timing for the presentation of clinical data from
fitusiran studies, its 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 or advice 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20160725005993/en/
Alnylam Pharmaceuticals, Inc.(Investors and
Media)Christine Regan Lindenboom, 617-682-4340or(Investors)Josh
Brodsky, 617-551-8276
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