Both drugs address an unmet need for patients with hemophilia A or B.
Patients with hemophilia and sickle cell both have unmet treatment needs, according toSandra Cuellar, a clinical associate professor and clinical oncology pharmacist at UI Health/University of Illinois at Chicago College of Pharmacy. During her Hematology/Oncology Pipeline Update presentation at the 2022 American Society of Health-System Pharmacists Summer Meetings and Exhibition,1 Cuellar dove into the drugs being researched for these conditions.
Check out our coverage of the 2022 ASHP Summer Meetings and Exhibition to learn more about the latest in the specialty drug pipeline.
Severe hemophilia is defined as <1% endogenous factor VIII activity resulting in both frequent and spontaneous bleeding episodes and excessive bleeding after injury. Patients with the disease, explained Cuellar. “Treatment goals with these patients are to decrease to low annualized bleeding rates; that’s a common endpoint that you’ll see in trials,” she said.
Current therapies include extended half-life recombinant FVIII (rFVIII) therapies that have reduced the dosing of prophylactic therapies from 3 or 4 times a week to 2 times a week, but as Cuellar explained, this dosing frequency still comes with a “residual treatment burden. There’s an unmet need to improve on the pharmacokinetics of these currently available products.”
Factor VIII circulates in a tight complex with von Wildebrand Factor, both stabilizing the FVIII and modulating the plasma half-life. Efanesoctocog alfa is designed to shield FVIII from “von Wildebrand Factor-imposed half-life limitations.” The design represents a new class of FVIII replacement therapies.
In the multicenter, open-label, nonrandomized XTEND-1 clinical trial (NCT04161495), investigators evaluated patients 12 years or older with severe hemophilia A who had been treated previously with a FVIII replacement therapy. One hundred fifty-nine patients received once weekly efanesoctocog alfa 50 IU/kg intravenously. In arm A, prophylaxis was administered for 52 weeks, and in arm B, it was administered on-demand for 26 weeks followed by 26 weeks of prophylactic administration. The primary study endpoint was annualized bleeding rate (ABR); in terms of efficacy, ABR was 0 (mean 0.71). In terms of safety, efanesoctocog alfa was well-tolerated.
The FDA granted efanesoctocog alfa a Breakthrough Designation on June 1, 2022. This first-in-class drug is a fusion protein FVIII replacement with tentative dosing of 50 IU/kg IV once weekly.
Both hemophilia A and B are characterized by ineffective clot formation due to insufficient thrombin generation, explained Cuellar. Fitusiran is designed to lower antithrombin and promote thrombin generation to restore hemostasis. It is a subcutaneous, small interfering RNA (siRNA) that both interferes with antithrombin translation and finds and degrades RNA antithrombin.
In the open-label, randomized, phase 3 Atlas-A/B trial (NCT03417245), 120 patients aged 12 or older with severe hemophilia A or B, previously treated with on-demand factor therapy, were randomly assigned to receive either once-monthly 80 mg subcutaneous fitusiran as a prophylactic therapy, or on-demand factor therapy. Once monthly dosing, Cuellar noted, has not been seen before.
Like efanesoctocog alfa, the primary endpoint was ABR. Investigators found a reduction of ABR of 89.9% vs factor on-demand therapy. Median ABR for treated bleeds was 0.0, vs 21.8. Two patients experienced vascular thrombotic events, 1 of which was deemed not associated with the therapy. More safety data are being collected before the drug is submitted to the FDA.
Fitusiran is an RNA interfering therapy targeting antithrombin in the liver. Tentative administration is 80 mg subcutaneously once a month, with other dosing options under investigation.
In sickle cell, the pipeline is primarily focused on gene therapy and gene editing therapy. “That’s where it’s all going,” said Cuellar. “That’s where a lot of the evidence is.”
Drug therapies in sickle cell are still in the early phases of research, with several agents under investigation targeting hemoglobin (HbS) polymerization, pro-adhesive molecules, and inflammation. Agents include mitapivat, in phase 1/2 research; rivipansel and inclacumab, in phase 2 and 3 research, respectively; crizanlizumab, which is FDA approved; and regadenoson and canakinumab, both in phase 2 research.