Data on blood disease drugs from Alnylam has people watching closely

Company reports on ALN-AT3 for hemophilia and ALN-CC5 for complement-mediated diseases at ASH 2015 meeting

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CAMBRIDGE, Mass.—RNAi therapeutics company Alnylam Pharmaceuticals Inc. announced positive results from its ongoing Phase 1 clinical study with fitusiran (ALN-AT3), an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia A and B and rare bleeding disorders, during the American Society of Hematology (ASH) 2015 Annual Meeting held December 5-8 in Orlando, Fla.
Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to restore hemostasis, thereby preventing bleeding in patients with hemophilia. The new clinical results demonstrated that subcutaneous administration of fitusiran achieved potent and dose-dependent lowering of AT of up to 88 percent. In addition, AT lowering was associated with statistically significant and clinically meaningful increases in thrombin generation and decreases in bleeding frequency in patients with hemophilia. In particular, fitusiran administration resulted in an 85-percent reduction in median estimated annualized bleeding rates (ABR) in nine evaluable patients. Importantly, fitusiran was found to be generally well tolerated to date, including no clinically significant increases in D-dimer, a biomarker of excessive clot formation. Consistent with previous guidance, the company expects to begin pivotal studies of fitusiran in mid-2016.
“We regard these new results from the ongoing Phase 1 clinical trial as very promising, as they demonstrate clinical activity for once-monthly, subcutaneous fitusiran with robust AT lowering and clinically meaningful increases in thrombin generation. In addition, while exploratory and only in a limited number of patients, the reduction in the median estimated ABR resulted in bleeding rates that are comparable to those reported in the literature for prophylactic intravenous infusions of replacement factors or ‘bypass agents’ in patients with hemophilia. We’re also encouraged by our overall safety results, that now include patients with an aggregate of over 300 days of exposure at levels of AT lowering greater than 75 percent,” said Dr. Akshay Vaishnaw, executive vice president of research and development and chief medical officer of Alnylam. “We have now initiated enrollment of patients in our Phase 1 open-label extension study, and expect to present data from that study on an ongoing basis at least once per year beginning in 2016. In addition, we expect to start our fitusiran Phase 3 program in hemophilia A and B, including patients with and without inhibitors, in mid-2016.”
Also at the ASH meeting, Alnylam announced positive interim results from its ongoing Phase 1/2 clinical study with ALN-CC5, an investigational RNAi therapeutic targeting complement C5 for the treatment of complement mediated diseases. New results show that ALN-CC5 achieved up to 99-percent knockdown of serum C5 and up to 98-percent inhibition of serum hemolytic activity, an assay for complement activity. In addition, ALN-CC5 administration resulted in low levels of residual C5, which—based on comparisons from separate studies—were at or below the estimated levels of free C5 observed at therapeutic doses of eculizumab, an approved anti-C5 monoclonal antibody. The effects of ALN-CC5 were also found to be highly durable, with C5 knockdown and complement inhibition results supporting a once monthly and possibly a once quarterly subcutaneous dose regimen. Importantly, ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date. Consistent with previous guidance, the company remains on track to initiate dosing by year’s end in Part C of the Phase 1/2 study, which is being conducted in patients with paroxysmal nocturnal hemoglobinuria (PNH), and expects to present initial results from this part of the study in mid-2016.
“We believe that these new ALN-CC5 results meet our goal of achieving both inhibition of serum hemolytic activity at the 80 percent target level and highly robust knockdown of serum C5 to residual levels at or below those estimated—in separate studies—for free C5 at therapeutic doses of eculizumab. We’re also very pleased with the consistency and durability of ALN-CC5 clinical activity, which we believe supports at least a once monthly, and possibly a once quarterly subcutaneous dose regimen,” said Vaishnaw. “With these data in hand, we’re now transitioning our study to PNH patients, and plan to initiate dosing by the end of this year. We look forward to presenting initial results from this new stage of our Phase 1/2 study, including effects of ALN-CC5 on levels of lactate dehydrogenase—a disease marker of endogenous red blood cell hemolysis—in mid-2016.”
Even before the result were officially presented in oral sessions at ASH 2015, people were beginning to take notice. As the Boston Business Journal noted in a Dec. 3 article, “For most of the past two years, Alnylam Pharmaceuticals has been the biggest drug developer in Massachusetts (by market cap) that doesn’t yet have an approved product on the market. And while expectations are high for its potential amyloidosis drug, which will most likely be the first to gain approval in as soon as two years, much of the Cambridge-based biotech firm’s $8.8 billion in market value is tied up in the other many other drugs in its pipeline.”
As such, the article noted, word of positive data for the two potential blood disease treatments was much anticipated and very welcome.
As Leerink Partners analysts Dr. Michael Schmidt and Dr. Jonathan Chang noted after the ALN-AT3 data announcement, “This morning, ALNY [Alnylam] presented updated fitusiran (ALN-AT3) Phase I (Part C) hemophilia A and B data at ASH which we believe provides additional incremental validation for the program. We’re particularly impressed with the consistency of the data, showing dose-dependent and AT3 knock-down dependent thrombin generation and reduction in bleeding rates in hemophilia A and B patients.”
They added, “We believe that ALNY’s ability to show dose-dependent AT lowering places it uniquely in the hemophilia space. We also find the safety data very promising as no serious adverse effects (SAE), no discontinuations, and no instance of ADA formation were reported” and also noted, “Although the thrombin generation data variability is high, the impact of very high AT lowering on thrombin generation is appreciable, in our view. Based on a correlation analysis, achieved peak thrombin generation values appear to be equivalent to >40% factor VIII levels, which we think is impressive in these severe hemophilia A and B patients.”
Finally, of the lowering of ABR events, the analysts said, “ABR events are commonly used as an indicator for clinical benefit in hemophilia setting, and we view this data set as promising.”

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