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Note: The below is an edited press release from Alnylam Pharmaceuticals, Inc. The original release can be read in its entirety here


Alnylam Pharmaceuticals, Inc. announced on Monday, March 14, 2016, that it has initiated dosing of hemophilia patients with inhibitors in Part D of an ongoing Phase 1 clinical trial evaluating a once-monthly subcutaneous dose regimen of fitusiran (ALN-AT3). Patients with hemophilia A with inhibitors and with hemophilia B with inhibitors have now been dosed with fitusiran. Fitusiran is an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia A and B and rare bleeding disorders (RBD). Fitusiran is designed to prevent bleeding in patients with hemophilia by lowering levels of AT with the goal of promoting sufficient thrombin generation and fibrin clot formation to restore hemostasis. Hemostasis is the process that stops bleeding after an injury. Consistent with previous guidance, the Company expects to report additional data from the Phase 1 trial in mid-2016 and again in late 2016. In addition, the Company remains on track to begin pivotal studies of fitusiran in hemophilia A and B, including patients with and without inhibitors, in mid-2016.

“As many as one third of people with hemophilia develop inhibitory antibodies and become refractory to their replacement factor therapy. As a result, their clinical course becomes more difficult to manage and these patients generally have poorer clinical outcomes,” said Akin Akinc, Ph.D., General Manager of Fitusiran at Alnylam. “Because of its novel mechanism of action, we believe that fitusiran represents a promising potential therapy for the management of hemostasis in people with hemophilia with and without inhibitors. We look forward to our continued evaluation of fitusiran activity and safety in this ongoing Phase 1 study, and expect to report new data from this study during the course of the year.”

“In recognition of Bleeding Disorders Month, we are pleased to demonstrate our continued commitment to people with hemophilia by advancement of our fitusiran study in inhibitor patients,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Alnylam and its employees are dedicated to developing innovative new treatments for people living with hemophilia around the world.”

About the Fitusiran Phase 1 Study

The ongoing Phase 1 trial of fitusiran is being conducted in 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 is ongoing – is an open-label, multi-dose, dose escalation study of up to 18 patients with moderate or severe hemophilia A or B in which patients are receiving three monthly subcutaneous doses of fitusiran. Four cohorts of three patients each have been enrolled at doses of 225, 450, 900, or 1800 mcg/kg, and two additional cohorts of three patients each have been enrolled at a fixed dose. Part D of the study – which has recently commenced – is an open-label, multi-dose study in hemophilia A or B patients with inhibitors. 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. 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.

Fitusiran Clinical Data

Clinical data from the ongoing Phase 1 clinical study with fitusiran were presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 – 8 in Orlando, Florida, showing that:

  • Fitusiran achieved potent, dose-dependent, and statistically significant lowering of AT of up to 88 percent in patients with hemophilia. In addition, AT lowering was associated with statistically significant and clinically meaningful increases in thrombin generation and, in an exploratory post-hoc analysis, was associated with statistically significant decreases in bleeding frequency.
  • In another post-hoc analysis, there was an 85 percent reduction in median estimated annualized bleeding rate (ABR) during the observed period of fitusiran administration, as compared with median historical on-demand ABR in nine evaluable patients.
  • Fitusiran was found to be generally well tolerated through the data cutoff date of November 12, 2015, including no serious adverse events, discontinuations or thromboembolic events, no clinically significant changes in laboratory parameters or clinically significant increases in D-dimer, a biomarker of excessive clot formation. Three reported drug related adverse events were all mild, including two transient injection site reactions. Not related to fitusiran, one patient was hospitalized due to reactivation of hepatitis C.

As noted above, and consistent with previous guidance, the Company expects to report additional safety and clinical activity data from the Phase 1 study in mid-2016 and again in late 2016.

Also at the 2015 ASH conference, Alnylam and collaborators presented pre-clinical data demonstrating that AT lowering in vitro led to increased thrombin generation in plasma from patients with hemophilia who have developed inhibitory antibodies to replacement factor therapy.

The clinical and pre-clinical datasets described above can be accessed at www.alnylam.com/capella.

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.

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.

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