ORLANDO—Results from an ongoing phase 1 study suggest fitusiran, a small interfering RNA therapeutic targeting antithrombin (AT), can restore hemostasis and prevent bleeding in patients with hemophilia A or B, with or without inhibitors.
In patients with inhibitors, fitusiran exhibited preliminary evidence of reduced bleeding. In patients without inhibitors, fitusiran reduced the median estimated annualized bleeding rate (ABR) to 0.
In addition, researchers said fitusiran was generally well tolerated, and none of the patients developed anti-drug antibodies.
These results were presented at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Alnylam Pharmaceuticals, Inc.
Study design
This phase 1 trial consists of 4 parts. Part A enrolled healthy volunteers who were randomized 3:1 to fitusiran or placebo. 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, which is also complete, enrolled 12 patients with severe hemophilia A or B. Patients received 3 weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg.
Part C, in which dosing is complete, enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients received 3 monthly subcutaneous doses of fitusiran at 225, 450, 900, or 1800 mcg/kg. Six patients received 3 fixed monthly subcutaneous doses of fitusiran at 80 mg.
Part D is designed to enroll up to 18 patients with inhibitors. The first cohort of 6 patients received a 50 mg, fixed, once-monthly, subcutaneous dose. The second cohort has completed enrollment, with 6 patients receiving an 80 mg, fixed, once-monthly, subcutaneous dose.
Results from Parts C and D were presented at the meeting.
Part C results
Treatment with fitusiran resulted in a dose-dependent, statistically significant decrease in AT and increase in thrombin generation. At the 80 mg monthly dose, fitusiran achieved 87±1% mean maximal AT lowering with low inter-patient variability.
Researchers assessed the association between AT lowering and increased thrombin generation in a post-hoc exploratory analysis in which AT lowering was grouped by 25% increments for completed patients in Parts B (n=12) and C (n=17) of the study.
In the highest quartile of ≥75% AT lowering (n=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290% relative to baseline (P<0.001, as compared to the lowest AT-lowering quartile).
There was a significant, AT-lowering-dependent reduction in bleeding frequency as well.
To obtain a comprehensive assessment of fitusiran’s potential effects on bleeding, researchers performed a post-hoc analysis in evaluable patients from Part C (n=17).
The team compared bleeding events that occurred over the 6-month period prior to study entry, bleeding events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the onset period), and bleeding events that occurred beyond day 29 up to day 112 (the observation period).
Prior to study entry, the estimated median ABR was 28 for patients receiving on-demand factor therapy (n=4) and 2 for patients receiving prophylactic factor therapy (n=13).
The estimated median ABR was 13 among all evaluable patients during the onset period and 0 during the observation period.
In all Part C dose cohorts during the observation period, 53% of patients (9/17) were bleed-free, and 82% of patients reported no spontaneous bleeds.
Part D results
Prior to study entry, all patients in Part D utilized bypass agents, including recombinant factor VIIa and activated prothrombin complex concentrate, to manage their bleeds. They had a pre-study ABR of up to 80.
The first cohort (n=6) of patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81±2% and a mean maximal thrombin generation increase of approximately 368%.
In addition, there was preliminary evidence of reduced bleeding, with a 49% to 100% reduction in estimated ABR during the observation period compared with pre-study values.
Safety results
As of July 11, 2016, fitusiran appears to be generally well tolerated in hemophilia patients, with or without inhibitors (n=31, with 5 patients participating in both Parts B and C).
There have been no serious adverse events related to the drug and no thromboembolic events or laboratory evidence of pathologic clot formation.
One non-inhibitor patient in Part C treated with the 80 mg fixed dose discontinued treatment due to an adverse event that was considered severe and possibly related to the study drug.
This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal), AST (8x upper limit of normal), C-reactive protein, and D-dimer, without an increase in total bilirubin. The event resolved with symptomatic management, including antacids and analgesics.
Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site.
Additional adverse events reported in at least 10% of patients included upper respiratory tract infection (10%) and arthralgia (10%). The majority of these events were mild or moderate in severity.
