Disease Analysis: Hemophilia

Definition

The therapeutic strategies for hemophilia were revolutionized after the introduction of replacement factors during the late 1990s and early 2000s, which were followed by EHLs over the past decade. Currently, the hemophilia market is undergoing a third revolution, with an anticipated shift towards alternative coagulation promoters and gene therapy.

Latest key takeaways

• Hemophilia is a rare, inherited X chromosome-linked bleeding disorder in which deficiencies in clotting factors prevent blood from clotting normally. Injuries therefore result in prolonged periods of bleeding. Datamonitor Healthcare estimates that in 2021, there were approximately 185,340 diagnosed prevalent cases of hemophilia A and 36,870 diagnosed prevalent cases of hemophilia B worldwide. These figures are forecast to increase to 193,730 cases and 38,570 cases, respectively, by 2027. There were approximately 83,890 diagnosed prevalent cases of von Willebrand disease (VWD) worldwide in 2021, which is forecast to increase to 86,150 cases by 2027.
• Current treatments are largely focused on replacing factor VIII (fVIII) or factor IX (fIX), the deficiency of which causes hemophilia A or B, respectively. Recombinant fVIII and fIX are at the top of algorithms in the US and EU treatment guidelines. Until recently, full-length recombinant fVIII agents Advate and Kogenate, and the fIX agent BeneFIX, dominated the hemophilia space and held the largest portion of market share. However, these drugs have been steadily losing market share to extended half-life recombinant factor products (EHLs) and Hemlibra as physicians switch patients to newer-generation products with improved dosing frequencies. During 2018–20, sales of Advate more than halved due to fierce competition primarily from Roche’s Hemlibra, which was awarded a label expansion in the US and EU in the first quarter of 2019.
• Therapeutic strategies for hemophilia were revolutionized after the introduction of replacement factors during the late 1990s and early 2000s, which were followed by EHLs over the past decade. Currently, the hemophilia market is undergoing a third revolution, with an anticipated shift towards alternative coagulation promoters and gene therapy.
• While the 2017 launch of Roche’s Hemlibra for the treatment of hemophilia A patients with fVIII inhibitors did not make a large impact on the hemophilia market, the extension of its US and EU labels in 2018 to include hemophilia A patients without inhibitors triggered a large increase in sales. Hemlibra has captured market share from a host of replacement factors and EHLs, and is expected to continue to be the market leader over the forecast period. Hemlibra is clinically more attractive than rival products because of its novel inhibitor-independent mechanism of action, its dosing schedule of once every two weeks (up to once-monthly dosing), and its ability to be self-administered subcutaneously in a market dominated by intravenous (IV) agents.
• There are a number of pipeline candidates in the hemophilia space which may make a significant impact in the market over the forecast period. Based on discussions with key opinion leaders (KOLs), Datamonitor Healthcare expects that Roche’s Hemlibra will further extend its lead in the hemophilia space, having captured market leader status from Takeda’s Advate in 2019. Gene therapies are expected to have initially muted uptake because of a high upfront cost for payers ($2m–$3m) and an initial reluctance from prescribers owing to uncertainty over their long-term efficacy and safety.
• Sanofi’s efanesoctocog alfa (BIVV001), a next-generation replacement fVIII, is expected to launch in the hemophilia A market in late 2022. Although efanesoctocog alfa has an extended dosing frequency of once weekly and has achieved higher fVIII expression levels compared to established replacement fVIII therapies, Datamonitor Healthcare expects the drug to struggle against market leader Hemlibra. Hemlibra benefits from a superior dosing frequency of once every two weeks, is not inhibited by the development of neutralizing antibodies (nABs), and is administered subcutaneously. As older therapies in the hemophilia A market are gradually cannibalized by Hemlibra, the market share that efanesoctocog alfa can potentially capture from replacement fVIII therapies is diminishing.
• In the hemophilia B space, pipeline alternative coagulation promoters such as the siRNA agent fitusiran and the tissue factor pathway inhibitors (TFPIs) concizumab and marstacimab may struggle to gain uptake due to safety concerns. These drugs meet the need for an effective therapy for hemophilia B patients with inhibitors, provide a more convenient subcutaneous route of administration, and, in the case of fitusiran, provide an impressive two-monthly dosing regimen. However, whether these drugs will come to market is still unclear given substantial safety concerns. These concerns include two thrombotic events in Phase II trials for fitusiran, one of which was fatal, and three thrombotic adverse events in Phase III trials for concizumab, as well as the suspension of four previous TFPI inhibitor candidates. Concerning safety events have not yet been observed in a single Phase I/II study of marstacimab, but the safety of the class as a whole is in doubt. Given these safety concerns and a lack of physician familiarity, it seems unlikely these drugs will rival recombinant fIX market leaders BeneFIX and Alprolix for the treatment of hemophilia B patients without inhibitors.
• Despite receiving a complete response letter in 2020, Roctavian (valoctocogene roxaparvovec) remains the most advanced gene therapy in the hemophilia A space, and assuming EU and US approvals in late 2022 and 2023, respectively, BioMarin is expected to launch the product at a price of $2m–$3m per patient. This delay in approval was a significant blow for BioMarin; however, recent setbacks for Pfizer/Sangamo’s giroctocogene fitelparvovec (SB-525) have re-established the gap between competitors. Current timelines indicate that BioMarin will launch its gene therapy at least a year ahead of Pfizer and Roche, which have greater commercial resources, giving it time to establish itself in the hemophilia market without the pressure of competing with major pharmaceutical companies. In addition to being the first-to-market gene therapy in the hemophilia A space, Datamonitor Healthcare believes that Roctavian is the most clinically attractive pipeline candidate, since it has shown consistent safety, efficacy, and durability in trials, and benefits from five years of follow-up data.
• However, the extremely high upfront cost of Roctavian will be a significant deterrent to uptake, and Datamonitor Healthcare expects its initial use to be limited to severe hemophilia patients on chronic prophylaxis therapy. While the gene therapy meets the high unmet need for a long-term therapy, with a projected eight-year interval between doses, Roctavian may face initial payer resistance due to the lack of long-term safety and efficacy data, as the follow-up period in current studies has been limited to five years.
• There is also considerable competition to be the first-in-class hemophilia B gene therapy, with uniQure and Pfizer the current frontrunners. UniQure’s EtranaDez (formerly known as AMT-061) is expected to launch a year ahead of Pfizer’s PF-06838435, assuming there are no additional obstacles to approval. With the FDA having raised the bar to approval to include one-year follow-up data from the point of fIX stabilization, both uniQure and Pfizer will face similar delays, pushing back their respective launch dates by approximately six months. Both therapies have shown strong efficacy (ABRs <1), in line with the current standard of care, and favorable safety profiles, with PF-06838435 having the added benefit of four years of follow-up data from its Phase II trial, while the establishment of a licensing agreement between uniQure and CSL Behring will provide the commercial resources needed to maximize sales of EtranaDez. Freeline Therapeutics’ FLT180a, a late entrant into the hemophilia B gene therapy race, remains well behind its competitors. Notably, the drug has demonstrated higher fIX levels in a Phase I/II trial and has the potential to be a best-in-class therapy.