Alnylam and Sanofi Genzyme Report Positive Results from Ongoing Phase 2 Open-Label Extension Study with Investigational RNAi Therapeutic Fitusiran in Patients with Hemophilia A and B With or Without Inhibitors
- With up to 20 Months of Dosing, Fitusiran Safety and Tolerability Profile Remains Encouraging -
- Once Monthly, Subcutaneous Fitusiran Achieves Median Annualized
Bleeding Rate (ABR) of One for All Patients and Zero for Patients with
- Alnylam Management to Discuss New Clinical Data in Webcast
The updated clinical results in the fitusiran Phase 2 OLE study showed that the safety and tolerability profile of fitusiran remains encouraging, with no thromboembolic events, including during co-administration of replacement factor or bypassing agents. The majority of adverse events (AEs) were mild or moderate in severity, with the most common AEs consisting of transient, mild injection site reactions (ISRs). In addition, once-monthly subcutaneous (SC) administration of fitusiran achieved lowering of AT, increases in thrombin generation, and, in a post-hoc exploratory analysis, reductions in the median estimated annualized bleeding rate (ABR) in patients with and without inhibitors. Based on these results, the companies announced last week the initiation of the ATLAS Phase 3 program for fitusiran in patients with hemophilia A and B with or without inhibitors.
"With up to 20 months of dosing in patients, we are encouraged by the
results from our fitusiran clinical studies presented at the ISTH
meeting today, demonstrating what we believe to be promising support for
further clinical development," said
"We've achieved an encouraging safety and tolerability profile and low
median ABRs with a monthly subcutaneous dosing regimen, highlighting
fitusiran's potential to become a differentiated and innovative
treatment option for patients with hemophilia," said
The ongoing fitusiran Phase 2 OLE study includes patients (N=33) with
hemophilia A (N=27) and hemophilia B (N=6). The study includes 14
patients with inhibitors, including one with hemophilia B. Fitusiran was
administered as a low volume (less than 1 mL), monthly, subcutaneous,
fixed dose of 50 mg (N=13) or 80 mg (N=20). All results are as of a
Patients were treated for up to 20 months in the Phase 2 OLE, with a median of 11 months on study. The majority of AEs were mild or moderate in severity, with the most common non-laboratory AEs consisting of transient, mild ISRs (18 percent of patients). There was one discontinuation due to an AE, an asymptomatic alanine aminotransferase (ALT) elevation in a patient with chronic hepatitis C virus (HCV) infection. Serious adverse events (SAEs) considered possibly related to drug were reported in two patients: asymptomatic ALT elevation in one patient with chronic HCV infection, as noted above, and seizure with confusion in one patient with a prior history of seizure disorder. Asymptomatic ALT increases greater than 3x the upper limit of normal (ULN), without concurrent elevations in bilirubin greater than 2x ULN, were observed in 11 patients, all of whom were hepatitis C antibody positive; at current follow-up, all ALT elevations are resolved (N=10) or resolving (N=1). No thromboembolic events, laboratory evidence for pathological clot formation, or instances of anti-drug antibody (ADA) formation were reported.
Regarding clinical activity results, treatment with fitusiran resulted in approximately 80 percent lowering of AT with corresponding increases in thrombin generation. Increases in thrombin generation remained within the lower end of the range of values observed in normal healthy volunteers. In an exploratory post-hoc analysis of bleeding events, a median ABR of one (interquartile range [IQR]: 0-3) was achieved for all patients (N=33), and a median ABR of zero (IQR: 0-3) was achieved for the subset of patients with inhibitors (N=14), corresponding favorably to pre-study median ABR values of 20 (IQR: 4-36) in all patients and 38 (IQR: 20-48) in inhibitor patients. There was a high proportion of patients (16 of 33; 48 percent) who remained bleed-free in the observation period, and most patients (22 of 33; 67 percent) experienced zero spontaneous bleeds. All breakthrough bleed events were successfully managed with replacement factor (recombinant factor VIII or recombinant factor IX) or bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate).
As noted above, the companies also announced today that a paper titled,
"Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy," was
published online today in
"Current hemophilia management is based on factor replacement therapies
that require frequent intravenous infusions to maintain adequate factor
trough levels. Significant unmet need remains for additional therapeutic
To view the fitusiran clinical results described in this press release, please visit www.alnylam.com/capella.
Conference Call Details
Management will discuss these results via conference call on Monday, July 10, 2017 at 11:30 a.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 50998303. A replay of the call will be available beginning at 2:30 p.m. ET on July 10, 2017. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 50998303.
Hemophilia is a hereditary bleeding disorder characterized by an underlying defect in the ability to generate adequate levels of thrombin needed for effective clotting, thereby resulting in recurrent bleeds into joints, muscles, and major internal organs. There are approximately 200,000 persons diagnosed worldwide with hemophilia A and hemophilia B.
Standard treatment for people with hemophilia currently involves replacement of the deficient clotting factor either as prophylaxis or "on-demand" therapy which can lead to a temporary restoration of thrombin generation capacity. However, as many as one third of people with severe hemophilia A will develop a neutralizing antibody to their replacement factor - a very serious complication; individuals with these ‘inhibitors' become refractory to standard replacement factor therapy.
Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders. Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding. Fitusiran utilizes Alnylam's ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability. The clinical significance of this technology is under investigation.
The safety and efficacy of fitusiran have not been evaluated by the
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding protein synthesis 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, with the goal of preventing disease-causing proteins from being made.
Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of patients who have limited or inadequate treatment options. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust discovery platform and deep pipeline of investigational medicines, including three product candidates that are in late-stage development or will be in 2017. Looking forward, Alnylam will continue to execute on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam.
Sanofi Genzyme focuses on developing specialty treatments for debilitating diseases that are often difficult to diagnose and treat, providing hope to patients and their families. Learn more at www.sanofigenzyme.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 the potential for fitusiran for the treatment of patients with
hemophilia A and B, with or without inhibitors, conduct of its ATLAS
Phase 3 program for fitusiran, and its expectations regarding its
"Alnylam 2020" guidance for the advancement and commercialization of
RNAi therapeutics, constitute forward-looking statements for the
purposes of the safe harbor provisions under
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 the safety or effectiveness of fitusiran.
Sanofi Forward-Looking Statements
This press release contains forward-looking statements as defined in the
Private Securities Litigation Reform Act of 1995, as amended.
Forward-looking statements are statements that are not historical facts.
These statements include projections and estimates and their underlying
assumptions, statements regarding plans, objectives, intentions and
expectations with respect to future financial results, events,
operations, services, product development and potential, and statements
regarding future performance. Forward-looking statements are generally
identified by the words "expects", "anticipates", "believes", "intends",
"estimates", "plans" and similar expressions. Although Sanofi's
management believes that the expectations reflected in such
forward-looking statements are reasonable, investors are cautioned that
forward-looking information and statements are subject to various risks
and uncertainties, many of which are difficult to predict and generally
beyond the control of
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