– In New Data from Hemophilia Subjects, ALN-AT3
Achieves Antithrombin Knockdown of up to 70%, Increases Thrombin
Generation by up to 334%, and Markedly Improves Whole Blood
Clotting –
– ALN-AT3 Administration Remains Generally Well
Tolerated –
– Company to Webcast Conference Call at 8:30
a.m. ET (5:30 a.m. PT) Tomorrow, January 12, to Discuss Data –
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi
therapeutics company, announced today updated results from its
ongoing Phase 1 study of ALN-AT3, a subcutaneously administered,
investigational RNAi therapeutic targeting antithrombin (AT) for
the treatment of hemophilia and rare bleeding disorders (RBD). New
results were presented at the 2015 Goring Coagulation Conference,
being held January 11 – 12 in London. Specifically, data were
presented from the study’s second dose cohort in hemophilia
subjects (n=3), where subcutaneous administration of ALN-AT3
resulted in an up to 70% knockdown of AT. New results provide
initial evidence for potential correction of the hemophilia
phenotype associated with ALN-AT3 administration and AT knockdown.
Specifically, ALN-AT3 administration resulted in an increase in
thrombin generation of up to 334% and a marked improvement in whole
blood clotting. In addition, the most advanced severe hemophilia A
subject in the cohort has remained bleed free for 47 days without
replacement factor prophylaxis. Finally, ALN-AT3 administration
continues to be generally well tolerated. Alnylam intends to
provide additional results from the ongoing Phase 1 study in
mid-2015 and then in late 2015, and expects to start a Phase 2
study of ALN-AT3 in late 2015.
“We believe that these new results from our ongoing Phase 1
study with ALN-AT3 provide initial evidence for potential
disease-modifying effects in hemophilia. Specifically, data from
the study’s second dose cohort provide clinical evidence for the
first time suggesting that AT knockdown with ALN-AT3 has the
potential to correct the hemophilia phenotype. In particular, we’ve
observed clear increases in thrombin generation and marked
improvements in whole blood clotting, as if the severe hemophilia A
disease phenotype has been modified to a milder form. Further, we
are encouraged to see that the most advanced subject has remained
free from bleeding for a significant period without need for
replacement factor prophylaxis. Importantly, ALN-AT3 treatment
continues to be generally well tolerated, with no serious adverse
events and no study discontinuations reported to date,” said Akshay
Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical
Officer of Alnylam. “While early and based on a limited number of
subjects, we believe that these new data support human
proof-of-concept for ALN-AT3, a promising and innovative strategy
for the treatment of hemophilia and rare bleeding disorders.
Indeed, we believe that once-monthly subcutaneous administration of
ALN-AT3 could provide a functional correction of the hemophilia
phenotype, representing an attractive disease-modifying therapy. We
look forward to the continued data from this Phase 1 study and
expect to present additional results in mid-2015 and then later in
the year.”
“New therapeutic options are needed to manage bleeding in
hemophilia and other rare bleeding disorders, particularly 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 safe
and effective, subcutaneously administered therapeutic with a long
duration of action would represent a marked improvement over
currently available approaches for prophylaxis,” said Dr. Savita
Rangarajan, MBBS, FRCP, FRCPath, Director of the Southern
Haemophilia Network and Consultant Haematologist at the
Haemophilia, Haemostasis & Thrombosis Centre at Hampshire
Hospitals NHS Foundation Trust, UK. “I am very encouraged by these
new results emerging from the ongoing Phase 1 study of ALN-AT3. In
particular, the increased thrombin generation and improved whole
blood clotting results provide initial, yet compelling evidence for
the potential of disease modification in severe hemophilia. Of
great interest, these results are consistent with case reports
documenting a milder clinical phenotype in people with bleeding
disorders who have co-inherited AT deficiency or other
thrombophilic traits. Together, I believe that these new findings
strongly support the continued advancement of this novel,
investigational therapeutic agent.”
The ongoing Phase 1 trial of ALN-AT3 is being conducted in
Bulgaria, Switzerland, and the U.K. as a single- and multi-dose,
dose-escalation study comprised of two parts. In the U.K.,
enrollment has been aided by the Southern Academic Coagulation
Consortium (SACC). 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 that received a single subcutaneous
dose of ALN-AT3 at 30 micrograms/kilogram (mcg/kg). Part B of the
study – which is ongoing – is an open-label, multi-dose,
dose-escalation study enrolling up to 18 subjects with moderate or
severe hemophilia A or B. The primary objective of this part 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.
Updated results were presented from the second dose cohort of
hemophilia subjects – which is now fully enrolled (n=3) – where
ALN-AT3 is administered subcutaneously once weekly for three weeks
(qW x 3) at a low dose of 45 mcg/kg. All preliminary results are as
of a data cut off on January 6, 2015. ALN-AT3 administration
resulted in an up to 70% knockdown of AT. The mean AT knockdown was
44 +/- 6.5% at day 16 (n=3; p=0.02, relative to baseline) and 64
+/- 6.8% at day 21 (n=2; p=0.09, relative to baseline). Based on
the most advanced subject in the cohort, the nadir effect appears
to occur at approximately day 28. Based on the essentially complete
time course for AT knockdown from the first dose cohort receiving
15 mcg/kg (qW x 3), the effects of ALN-AT3 were also found to be
highly durable, lasting about 60 days.
Initial evidence for the potential correction of the hemophilia
phenotype was observed in the severe hemophilia A subjects.
Specifically, ALN-AT3 administration resulted in thrombin
generation increases of up to 334%. Increase in thrombin generation
was closely correlated with degree of AT knockdown. When AT
knockdown levels exceeded 50%, the mean increase in thrombin
generation was 112 +/- 38% (p less than 0.05) relative to baseline.
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)), and the results achieved
following ALN-AT3 administration are consistent with thrombin
generation levels measured in mild hemophilia. Moreover, the
observed maximal increase in thrombin generation in the hemophilia
subjects (peak thrombin of 71 nM) remained at the low end of the
range for peak thrombin levels in the healthy volunteers enrolled
in Part A of the study (mean of 92 +/- 15 nM; range from 69-135nM).
These data show that AT knockdown of up to 70% in hemophilia
subjects should not lead to an excessive increase in thrombin
generation beyond normal.
Further evaluation of the effects of ALN-AT3 employed the use of
ROTEM® thromboelastometry, which measures clotting time and clot
strength in whole blood following a physiologic coagulation
stimulus; this assay method was available for a single severe
hemophilia A subject in the second dose cohort, who happens to be
the most advanced subject. ALN-AT3 administration was found to
result in AT knockdown-dependent improvements in whole blood
clotting in this subject. As described in the table below, ALN-AT3
administration resulted in marked improvements in clotting time
(CT) – which is a measure of the initiation phase of clot formation
– and clot formation time (CFT) – which is a measure of the
propagation phase of clot formation; both parameters that are known
to be significantly impaired in people with hemophilia. As with
observed effects on thrombin generation, the improved CT and CFT
values following ALN-AT3 administration were found to be similar to
those reported in the literature in subjects with mild hemophilia.
Finally, as of the current data cut-off date of January 6, 2015,
this hemophilia subject was free of any bleeds for 47 days, which
compares favorably to his physician-reported Annual Bleeding Rate
(ABR) of 10-12 bleeds/year during on-demand therapy prior to
enrolling in the study.
Summary of AT Knockdown and Improvement in
Whole Blood Clotting in Most Advanced Subject
Day % AT Knockdown
Clotting Time (CT),seconds(Mean +/-
SEM)
Clot Formation Time (CFT),seconds(Mean +/-
SEM)
1 1 1254 +/- 280 1441 +/- 394 8 30
1105 +/- 57 625 +/- 43 21 57 547 +/- 14
289 +/- 5
As of the current data cut off, ALN-AT3 continues to be
generally well tolerated in all subjects receiving study drug in
the study (n=9), including subjects enrolled in the second dose
cohort (n=3). There have been no serious adverse events, no
discontinuations, no injection site reactions, and no significant
changes in physical exams, vital signs, or electrocardiography.
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 fibrin clot formation, or any
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. In the second dose cohort and as
of the data cut-off date, all five reported bleeds occurred on day
6 or earlier – at low levels of AT knockdown – with the exception
of a trauma-related bleed in one subject at day 16, which was
managed with a low, 1000 IU dose of Factor VIII.
The ALN-AT3 Phase 1 study continues to enroll hemophilia
subjects in additional dose cohorts, including the potential to
explore a once-monthly subcutaneous dose regimen following a
protocol amendment. The company plans to present additional data
from the Phase 1 study in mid-2015, and then additional results in
late 2015. In addition, Alnylam expects to initiate a Phase 2 study
of ALN-AT3 in late 2015.
Conference Call Information
Alnylam management will discuss these new results with ALN-AT3
in a webcast conference call on Monday, January 12 at 8:30 a.m. ET
(5:30 a.m. PT). 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
65072960. A replay of the call will be available beginning at 11:30
a.m. ET. To access the replay, please dial 855-859-2056 (domestic)
or 404-537-3406 (international), and refer to conference ID
65072960.
About Hemophilia and Rare Bleeding Disorders
Hemophilias 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 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 Idec, 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-AT3 for the treatment of hemophilia and
rare bleeding disorders, the design and timing of clinical studies,
the reporting of data from clinical studies, its expectations
regarding the potency and therapeutic index of GalNAc-siRNA
conjugates, including Enhanced Stabilization Chemistry (ESC)-GalNAc
conjugates, 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 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.
Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations andCorporate
CommunicationsorMediaLiz Bryan, 202-955-6222 x2526Spectrum
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