Disease Analysis: Hemophilia

Definition

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. There are two types of hemophilia, A and B, with similar signs and symptoms but different genetic defects.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2018, there were approximately 180,750 diagnosed prevalent cases of hemophilia A and 35,950 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 82,550 diagnosed prevalent cases of von Willebrand disease (VWD) worldwide in 2018, 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, have dominated the hemophilia space and have 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 (from $2,806m in 2018 to $1,167m in 2020) 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.
• 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.
• 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 set to achieve market-leader status 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, and its ability to be self-administered subcutaneously in a market dominated by intravenous 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.
• BIVV001, a next-generation replacement fVIII, is expected to launch in the hemophilia A market in 2022. Although BIVV001 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 BIVV001 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 once-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 now 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 2022 and 2023, respectively, BioMarin is expected to launch the product at a price of $2m–$3m per patient. This delay in approval is a significant blow for BioMarin, which had hoped to establish itself in the space 2–3 years ahead of major competitors Pfizer and Roche, which have greater commercial resources. With the projected launches of Roctavian and SB-525 now within months of one another, BioMarin will face competition from Pfizer earlier than previously expected.
• Additionally, 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 slightly ahead of Pfizer’s PF-06838435, assuming there are no additional obstacles to approval. With the FDA recently raising 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. 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 several years 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.