Jan 11, 2015 Press Release for Alnylam
Alnylam Reports Initial Evidence for Potential Correction of the Hemophilia Phenotype in Phase 1 Study of ALN-AT3, a Subcutaneously Administered, Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia
Jan 11, 2015
- 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
"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
"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.
The ongoing Phase 1 trial of ALN-AT3 is being conducted in
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
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 (
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
Summary of AT Knockdown and Improvement in Whole Blood Clotting in Most Advanced Subject
| Day | % AT Knockdown |
Clotting Time (CT), |
Clot Formation Time (CFT),
|
|||
| 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
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 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,
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
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