At the American Society of Hematology (ASH) Annual Meeting 2024, physicians looked back at the progress made in the prophylactic and curative care of hemophilia since the approval of Roche’s Hemlibra (emicizumab). The weekly or monthly subcutaneous injection has significantly decreased the disease burden for patients with haemophilia A (factor VIII deficiency). In the last few years, there have been several approvals for curative adeno-associated virus (AAV) gene therapies, starting with CSL Behring’s Hemgenix (etranacogene dezaparvovec) for haemophilia B in 2022, Biomarin’s Roctavian (valoctocogene roxaparvovec) for haemophilia A in 2023, and Pfizer’s Beqvez (fidanacogene elaparvovec) for haemophilia B in 2024. Pfizer’s Hympavzi (marstacimab), a weekly subcutaneous injection, also received an FDA approval in 2024 and is indicated for both haemophilia A and B without inhibitors.
Despite the new therapies that are available for patients, significant unmet needs remain in the haemophilia space. Patients on regular prophylaxis are often still susceptible to spontaneous bleeds, and the regular injections result in a high disease burden for patients. Access to the currently available gene therapies is also limited. This need was perfectly demonstrated when a room full of physicians at ASH 2024 was asked whether they had prescribed a gene therapy product for haemophilia in a commercial context, and only a handful had done so, despite many more having used such products in clinical trials. Physicians were still worried about the long-term risks of gene therapies, particularly the risk of the development of hepatocellular carcinoma or the effects of long-term use of corticosteroids to manage liver toxicity.
Pfizer presented Phase III results from the AFFINE trial of its new gene therapy giroctocogene fitelparvovec in moderately severe to severe hemophilia A patients without inhibitors. While the primary efficacy and safety results were presented earlier this year, longer-term data was presented at ASH. Two years after dosing, about 10% of patients had a factor VIII level below 1%, indicating a need to return to prophylaxis. This longer-term efficacy data is comparable to Roctavian, which also requires patients to return to prophylaxis after reduced factor VIII expression. However, only 62.7% of patients who received giroctocogen fitelparvovec experienced elevated alanine aminotransferase (ALT) of any grade, while 85.8% of patients receiving Roctavian had elevated ALTs. Better safety data for giroctocogene fitelparvovec might give it a competitive edge over Roctavian, resulting in more uptake. GlobalData expects an approval decision for giroctocogene fitelparvovec by the US Food and Drug Administration (FDA) in 2025.
While physicians debate the merits of AAV gene therapies, most patients continue prophylaxis treatment. Sanofi presented the results of its Phase III open-label expansion trial for fitusiran, a first-in-class small-interfering RNA (siRNA) currently in pre-registration for haemophilia A and B with or without inhibitors. Fitusiran significantly reduces annual bleeds compared to bypassing agents and delivers efficacy similar to clotting factor replacement therapy. While many people are still using these older prophylaxis treatments that require multiple intravenous infusions per week, most physicians will be comparing fitusiran to the monoclonal antibodies, Hympavzi and Hemlibra or Sanofi’s Altuviio (efanesoctocog alfa), a fusion protein approved in 2023 for hemophilia A, delivered by a weekly injection. Fitusiran requires weekly subcutaneous injections, which still results in a high disease burden for patients. Hemlibra will likely maintain a high market share as it requires only monthly subcutaneous injections.
Despite the convenience of prophylactic treatment regimens, the cost burden is still high, leaving room for on-demand treatment options for more price-sensitive markets and for patients with mild haemophilia for whom spontaneous bleeds are less common. Staidson, a Chinese biotech company, presented data for its novel, first-in-class fusion protein, bemiltenase alfa, which acts by activating factor X, allowing it to function in both haemophilia A and B with or without inhibitors. Bemiltenase alfa achieved a 12-hour bleed clearance rate of 83%. This compares favorably to Novo Nordisk’s NovoSeven (inneptacog alfa), which has a 12-hour bleed clearance rate of 60%. Bemiltenase alfa has not induced any grade 3 or higher adverse events in patients so far. Staidson has completed a Phase II pivotal trial in China and has received Investigational New Drug (IND) clearance from the FDA to expand into the US.
While there are still significant challenges in haemophilia treatment, large advances are being made in all three major categories of treatment: curative, prophylaxis, and on-demand. Newer modalities and mechanisms of action are increasing the number of options available to physicians and patients, and will help alleviate unmet patient needs. While patients look forward to living a haemophilia-free life with curative therapies, currently available options for haemophilia A may not provide a life-long cure, and the return to prophylaxis or on-demand treatment will be needed. Access to the most advanced therapies is still a major hurdle to haemophilia patients, which means that a significant market exists for prophylaxis and on-demand treatments.
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