– New Interim Data from Ongoing Phase 1 Study
in Hemophilia Subjects Demonstrate an up to 86% AT Knockdown and a
Re-Balancing of Hemostasis with Normalization of Thrombin
Generation up to a Mean Increase of 350% and Marked Improvements in
Whole Blood Clotting –
– In Exploratory Post Hoc Analysis, Reduced
Bleeding Events Associated with AT Knockdown, with a Maximum
Bleed-Free Interval of 114 Days –
– ALN-AT3 Administration Remains Generally Well
Tolerated, Including No Clinically Significant Increases in D-Dimer
–
– Based on Promising Results, Company Now
Expects to Advance ALN-AT3 into Pivotal Studies in Mid-2016 –
– Company to Host Conference Call Today, June
23, at 4:30 p.m. ET to Discuss Data –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, today announced that new positive data from
its ongoing Phase 1 clinical trial with ALN-AT3 – an
investigational RNAi therapeutic for the treatment of hemophilia
and rare bleeding disorders (RBD) – were reported in an oral
presentation at the International Society on Thrombosis and
Haemostasis (ISTH) 2015 Congress being held June 20 – 25, 2015 in
Toronto, Ontario, Canada. Additional study results from 12
hemophilia A and B subjects demonstrated that subcutaneous
administration of ALN-AT3 achieved potent and dose-dependent
knockdown of AT of up to 86%. AT knockdown was highly durable, with
effects lasting over two months after the last dose, supporting
further evaluation of a once-monthly subcutaneous dose regimen. In
addition, AT knockdown was associated with statistically
significant increases in thrombin generation with a mean increase
of up to 350% and marked improvements in whole blood clotting;
these results demonstrate a re-balancing of hemostasis in severe
hemophilia subjects. In an exploratory post-hoc analysis, a reduced
frequency of bleeding was observed at higher AT knockdown levels
including a maximum bleed-free interval of 114 days. Importantly,
ALN-AT3 was found to be generally well tolerated, including no
clinically significant increases in D-dimer, a biomarker of
pathologic clot formation. Based on these data, the company expects
to accelerate the advancement of ALN-AT3 with pivotal studies
planned to begin in mid-2016.
“With the potential for infrequent subcutaneous dose
administration and possible correction of disease phenotype, we
believe that ALN-AT3 represents an innovative investigational
medicine for the treatment of hemophilia and rare bleeding
disorders. We regard these new results from our ongoing Phase 1
study as very promising, as they demonstrate clinical activity for
ALN-AT3 toward AT knockdown and a re-balancing of hemostasis with a
normalization of thrombin generation and improved whole blood clot
formation. Moreover, we’re encouraged by results from an
exploratory analysis of effects on bleeding, where we’ve observed a
reduced estimated annualized bleeding rate (ABR) at higher levels
of AT knockdown. Importantly, ALN-AT3 has continued to be generally
well tolerated in the study, including no clinically significant
increases in D-dimer levels,” said Akshay Vaishnaw, M.D., Ph.D.,
Executive Vice President of R&D and Chief Medical Officer at
Alnylam. “Based on these results and upon completion of the Phase 1
study, we now intend to proceed to pivotal Phase 3 studies of
ALN-AT3 that we expect to start in mid-2016. In addition, we plan
to initiate an open-label extension study later this year for
subjects from the Phase 1 study, and we expect to present data from
that study on an ongoing basis at least once per year beginning in
2016. In the meantime, we also look forward to presenting
additional data from our ongoing Phase 1 study, including results
from hemophilia subjects receiving a once-monthly subcutaneous dose
regimen, later this year.”
“New therapeutic options are needed to manage bleeding in
hemophilia and other rare bleeding disorders. This is particularly
important for patients who experience multiple annual bleeds when
receiving replacement factor ‘on demand’ or patients who have
developed inhibitory antibodies. I believe that the availability of
a subcutaneously administered therapeutic with a long duration of
action – such as a once-monthly regimen – that is shown to be safe
and effective would represent a marked improvement over currently
available approaches for prophylaxis,” said Claude Negrier, M.D.,
Ph.D, Professor of Medicine at the Claude Bernard University and
Chairman of the Hematology Division at Edouard Herriot University
Hospital and Louis Pradel Cardiology Hospital in Lyon, France. “I
am very encouraged by the continued tolerability and new clinical
activity results emerging from the ongoing Phase 1 study of
ALN-AT3. Indeed, the ability of ALN-AT3 to potentially increase
thrombin generation in severe hemophilia subjects toward normal
levels is an important finding, and this appears to be associated
with improvements in whole blood clotting and bleeding frequency. I
believe that these new findings support the continued advancement
of this novel investigational therapeutic agent.”
The ongoing Phase 1 trial of ALN-AT3 is being conducted in
Bulgaria, Russia, Switzerland, and the U.K. as a single- and
multi-dose, dose-escalation study comprised of three 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 ALN-AT3: placebo) in healthy volunteer
subjects. This part of the study was completed after the first dose
cohort received a single subcutaneous dose of ALN-AT3 at 30
micrograms per kilogram (mcg/kg). Part B of the study – which is
now complete – was an open-label, multi-dose, dose-escalation study
that enrolled 12 subjects with severe hemophilia A or B. Subjects
in Part B received 3 weekly subcutaneous doses of ALN-AT3 at doses
of 15, 45, or 75 mcg/kg with a volume per injection ranging from
0.2 to 0.7 mL. Part C of the study – which is ongoing – is an
open-label, multi-dose, dose escalation study of up to 12 subjects
with moderate or severe hemophilia A or B in which subjects are
receiving 3 monthly subcutaneous doses of ALN-AT3. The initial dose
cohort of Part C has received ALN-AT3 at a dose of 225 mcg/kg
(volume less than 1mL), which is equivalent to the cumulative dose
level from 3 weekly doses of 75 mcg/kg that was found to be
generally well tolerated in Part B. The primary objective of Parts
B and C of the study is to evaluate the safety and tolerability of
multiple doses of subcutaneously administered ALN-AT3 in hemophilia
subjects. Secondary objectives include assessment of clinical
activity as determined by knockdown of circulating AT levels and
increase in thrombin generation at pharmacologic doses of ALN-AT3.
For subjects enrolled at select sites in the U.K. and Switzerland,
the effects of ALN-AT3 are also being monitored by ROTEM®
thromboelastometry, which measures clotting time and clot strength
in whole blood following a physiologic coagulation stimulus. In
addition, exploratory analyses of bleeding are being performed. In
the U.K., enrollment has been aided by the Southern Academic
Coagulation Consortium (SACC).
New results were presented from 12 hemophilia subjects in Part B
of the ongoing Phase 1 study in an oral presentation at ISTH and
include all available data as of the data cut-off date of June 2,
2015. Subcutaneous doses of ALN-AT3 resulted in potent,
dose-dependent and statistically significant knockdown of plasma AT
of up to 86%. At the top dose of 75 mcg/kg (n=3), the mean maximum
AT knockdown was 59 ± 7% (p less than 0.05), with nadir
levels achieved between days 28 and 42. AT knockdown was found to
be highly durable, with effects lasting over two months after the
last dose. For example, at the 45 mcg/kg dose, mean AT knockdown
was 36 ± 11% at day 70.
AT knockdown with ALN-AT3 was associated with statistically
significant increases in thrombin generation and improvements in
whole blood clot formation, providing continued evidence for a
re-balancing of hemostasis and potential correction of the
hemophilia phenotype in severe hemophilia subjects. The association
between levels of AT knockdown and thrombin generation was assessed
in a post hoc exploratory analysis in which AT knockdown was
categorized into tertiles. In the highest tertile (greater than 66%
AT knockdown), ALN-AT3 administration resulted in mean increases in
thrombin generation of 350 ± 239% (p less than 0.05). In
this same tertile, the observed level of thrombin generation (120
± 81 nM peak thrombin) was comparable to levels observed in
healthy volunteers (120 ± 33 nM peak thrombin) from Part A
of the Phase 1 study, demonstrating an apparent normalization of
thrombin generation. Thrombin generation is known to be a biomarker
for bleeding frequency and severity in people with hemophilia
(Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)).
Additional evaluation of the effects of ALN-AT3 employed the use
of ROTEM® thromboelastometry in 3 severe hemophilia subjects in
which ALN-AT3 administration resulted in statistically significant,
AT knockdown-dependent improvements in whole blood clot formation,
including a shortening of clot formation time (CFT). At day 35, the
CFT for all 3 subjects was significantly shorter than on day 1,
with an over three-fold shortening of CFT from 1166 ± 614
sec to 323 ± 46 sec (p less than 0.05).
While the Phase 1 study was not designed to evaluate the effects
of ALN-AT3 on bleeding, an exploratory post hoc analysis was
performed by examining the frequency of on-study bleeding events in
all subjects in Part B of the study. During the period of time when
subjects had AT knockdown less than 33%, a total of 33 bleeding
events were reported, and the mean estimated annualized bleeding
rate (ABR) was 22 ± 5; this ABR is generally consistent with
values reported in prospective clinical trials for hemophilia
subjects treated “on-demand” with factor replacement. The mean
estimated ABR was reduced to 14 ± 5 at levels of AT
knockdown between 33 and 66% and was reduced yet further to a mean
estimated ABR of zero during the period of time when AT knockdown
exceeded 66%. The reduced ABR associated with increased AT
knockdown was statistically significant (p less than 0.001 based on
negative binomial regression model). The maximum bleed-free
interval for any given subject was 114 days, observed in a subject
who achieved an up to 86% level of AT knockdown. This subject with
severe hemophilia had a self-reported ABR of over 20 bleeds per
year prior to entering the ALN-AT3 Phase 1 study.
AT Knockdown
Less than 33% 33-66%
Greater than 66% Subjects (N) 12
9 2
Cumulative Days 509
414 106
Peak Thrombin Generation
(nM, Mean +/- SD) 18
± 8 35
± 24 120
± 81*
% Increase in Peak
Thrombin Generation (Mean +/- SD) 25
± 72%
69
± 92% 350
± 239%*
Cumulative Bleeds 33 18
0
Estimated Annualized Bleeding Rate (ABR) (Mean +/-
SEM)** 22
± 5 14
± 5
0
*p less than 0.05, compared with AT knockdown less than 33%**p
less than 0.001, based on negative binomial regression model
As of the current data cut off, ALN-AT3 continues to be
generally well tolerated in all subjects. There have been no
serious adverse events, no discontinuations, and no significant
changes in physical exams, vital signs, or electrocardiography. One
subject experienced mild injection site pain lasting two minutes,
but otherwise there were no injection site reactions. Further,
there have been no clinically significant changes in any laboratory
parameter, including liver function tests, hematology, and
coagulation measures. There have been no clinically significant
increases in D-dimer, a marker of pathologic clot formation, and no
thromboembolic events. The most common adverse event observed in
hemophilia subjects was the occurrence of mild to moderate bleeds
unrelated to study drug. All bleeds were successfully managed with
replacement factor administration, with no adverse events
associated with factor administration.
Based on these promising results, Alnylam plans to advance
directly to pivotal studies for ALN-AT3 and is providing new
guidance that it intends to start a pivotal Phase 3 clinical trial
in mid-2016. The company also intends to open a Phase 1 open label
extension (OLE) study in late 2015 to provide hemophilia subjects
enrolled in the Phase 1 study the opportunity for continued dosing;
Alnylam intends to report data from the Phase 1 OLE at least once
per year with initial data expected in 2016. Finally, the company
still plans on presenting additional data from the ongoing Phase 1
study in late 2015.
Alnylam scientists and collaborators also are presenting new
pre-clinical data on ALN-AT3 at the ISTH meeting. Earlier this
morning, the company presented data from an oral presentation
entitled “Antithrombin Reduction Improves Coagulation in Rare
Bleeding Disorder Plasma.” Specifically, ex vivo AT depletion was
demonstrated to result in increased thrombin generation in plasma
from donors with deficiencies in factors V, VII, and XI. These new
pre-clinical data support the clinical evaluation of ALN-AT3 in
these rare bleeding disorders. Additional data reports from the
meeting will be made available on the company’s website following
their presentation.
Genzyme AllianceIn 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-AT3, in the rest of the world. In certain defined instances,
Genzyme has co-development/co-commercialization and/or global
product rights. Genzyme has the right, under specified
circumstances, to elect to co-develop and co-promote ALN-AT3, with
Alnylam maintaining development and commercialization control.
Genzyme's rights are structured as an opt-in that is triggered upon
achievement of human proof-of-principle.
Conference Call InformationAlnylam management will
discuss these new interim Phase 1 results with ALN-AT3 in a webcast
conference call on Tuesday, June 23 at 4:30 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 64377549. A replay of the call will be
available beginning at 7:30 p.m. ET. To access the replay,
please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 64377549.
About Hemophilia and Rare Bleeding DisordersHemophilias
are hereditary disorders caused by genetic deficiencies of various
blood clotting factors, resulting in recurrent bleeds into joints,
muscles, and other major internal organs. Hemophilia A is defined
by loss-of-function mutations in Factor VIII, and there are greater
than 40,000 registered persons in the U.S. and E.U. with Hemophilia
A. Hemophilia B, defined by loss-of-function mutations in Factor
IX, affects greater than 9,500 registered persons in the U.S. and
E.U. Other Rare Bleeding Disorders (RBD) are defined by congenital
deficiencies of other blood coagulation factors, including Factors
II, V, VII, X, and XI, and there are about 1,000 persons worldwide
with a severe bleeding phenotype. Standard treatment for persons
living with hemophilia involves replacement of the missing clotting
factor either as prophylaxis or on-demand therapy. However, as many
as one third of people with severe hemophilia A will develop an
antibody to their replacement factor - a very serious complication;
persons in this ‘inhibitor’ subset become refractory to standard
replacement therapy. There exists a small subset of persons living
with hemophilia who have co-inherited a prothrombotic mutation,
such as Factor V Leiden, antithrombin deficiency, protein C
deficiency, and prothrombin G20210A. People who have co-inherited
these prothrombotic mutations are characterized as having a later
onset of disease, lower risk of bleeding, and reduced requirements
for Factor VIII or Factor IX treatment as part of their disease
management. 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 as
an important endogenous anticoagulant by inactivating Factor Xa and
thrombin. AT plays a key role in normal hemostasis, which has
evolved to balance the need to control blood loss through clotting
with the need to prevent pathologic thrombosis through
anticoagulation. In hemophilia, the loss of certain procoagulant
factors (Factor VIII and Factor IX, in the case of hemophilia A and
B, respectively) results in an imbalance of the hemostatic system
toward a bleeding phenotype. In contrast, in thrombophilia (e.g.,
Factor V Leiden, protein C deficiency, antithrombin deficiency,
amongst others), certain mutations result in an imbalance in the
hemostatic system toward a thrombotic phenotype. Since
co-inheritance of prothrombotic mutations may ameliorate the
clinical phenotype in hemophilia, inhibition of AT defines a novel
strategy for improving hemostasis.
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 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 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 therapeutics, including ALN-AT3
for the treatment of hemophilia and rare bleeding disorders and the
potential clinical activity and durability of ALN-AT3, expectations
regarding the reporting of data from clinical studies, in
particular the ongoing Phase 1 clinical trial of ALN-AT3, as well
as the Phase 1 OLE for ALN-AT3, expectations regarding the
initiation of pivotal Phase 3 studies for ALN-AT3, expectations
regarding its STAr pipeline growth strategy, and its plans
regarding commercialization of RNAi therapeutics, including
ALN-AT3, 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.
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Alnylam Pharmaceuticals, Inc.Michael Mason,
617-551-8327Vice President, Finance and TreasurerorSpectrumLiz
Bryan (Media), 202-955-6222 x2526
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