Innovative Hemophilia Treatments Offer Hope Amid Lingering Clinical Challenges

Annette von Drygalski, MD, PharmD

Credit: University of California San Diego

Advancements over the past few decades in novel therapies and improved imaging techniques have substantially improved the prognosis for patients with the once-debilitating disorder hemophilia, Annette von Drygalski, MD, PharmD, RMSK, highlighted in a session at the 2024 ASH Annual Meeting.

"Over the past decade, there were remarkable scientific and technical advancements, and those have propelled hemophilia care on all levels," said von Drygalski, from the University of California San Diego. "Outcomes have gone from incurable and untreatable, where patients died in childhood in the 1960s, to treatable and now potentially curable with normal lifespans due to innovative prophylactic treatments including novel clotting factor molecules, factor-less treatments, and gene therapy."

With a focus on clinical advancements, von Drygalski outlined the evolution of care, particularly the mechanisms behind bleeding and the growing array of therapeutic and imaging options for patients.

Mechanisms of Bleeding and the Evolution of Hemophilia Care

The incidence of hemophilia is approximately 25 cases per 100,000 males for hemophilia A and 5 per 100,000 for hemophilia B. "It is characterized by a deficiency in clotting factors—factor VIII in hemophilia A and factor IX in hemophilia B. This leads to spontaneous joint and muscle bleeds presenting in childhood," said von Drygalski.

The severity of the disease is categorized by the level of clotting factor activity present in the blood. Severe cases, defined as having less than 1% of normal clotting factor activity, are typically characterized by spontaneous joint and muscle bleeds. These often begin in childhood and can lead to debilitating musculoskeletal damage if left unaddressed.

For many years, the primary treatment for hemophilia involved frequent intravenous infusions of clotting factors. These infusions were necessary to maintain clotting factor levels above a certain threshold and prevent spontaneous bleeding; however, these therapies often led to inconsistent clotting factor levels, characterized by "sawtooth" patterns of high peaks and low troughs. This fluctuation left patients vulnerable to breakthrough bleeds between infusions, said von Drygalski.

Advances in Prophylaxis and Novel Treatment Strategies

The introduction of extended half-life clotting factor products helped to address these challenges by providing more stable levels of factor activity in the blood, reducing the frequency of infusions and minimizing the risk of bleeding. These advances represented the beginning of a new era in hemophilia care.

"The pillars of prophylaxis are still clotting factor, either conventional half-life or extended half-life products with at least once weekly intravenous infusions," said von Drygalski. "Then we have so-called rebalancing agents with factor VIII mimetic and just recently with the TFPI inhibitor. These are subcutaneous treatments weekly to monthly. And then we now have gene therapy, with 3 approved ones: 2 for hemophilia B and 1 for hemophilia A. These are an intravenous infusion presumably once in a lifetime."

Rebalancing agents, such as factor VIII mimetics, work by replacing or mimicking the activity of missing clotting factors. Marstacimab (Hympavzi) helps to rebalance by inhibiting TFPI, which prevents inhibition of factor Xa. Emicizumab (Hemlibra) is a bispecific antibody that is specific to factor IXa and X, which activates the coagulation cascade. "This agent mimics or replaces factor XIII activity," von Drygalski said.

Additionally, gene therapy has emerged as a potential long-term solution for hemophilia. By introducing a functional copy of the clotting factor gene, these therapies aim to restore normal clotting factor production in a single infusion. The 3 agents approved by the FDA are etranacogene dezaparvovec (Hemgenix) and fidanacogene elaparvovec (Beqvez) for hemophilia B and valoctocogene roxaparvovec (Roctavian) for hemophilia A.

Hemophilic Arthropathy: A Persistent Challenge

Despite the significant advancements in prophylactic treatments, hemophilic arthropathy remains a major concern for patients. Hemophilic arthropathy refers to the progressive joint damage caused by recurrent bleeds into the joint space. Although prevention of joint bleeding through prophylaxis has improved, von Drygalski emphasized that breakthrough and spontaneous bleeds still occur, leading to long-term musculoskeletal complications.

The pathobiology of hemophilic arthropathy is complex and involves multiple factors. One key factor is iron deposition in the joint space, which occurs when red blood cells are lysed and their contents, including iron, are released into the tissue. "Iron is a toxic payload," von Drygalski said. "Iron is the incendiary agent propelling joint deterioration."

Iron accumulation, specifically in the form of hemosiderin, is a hallmark of hemophilic arthropathy, she noted. The early signs of this process are typically synovial hypertrophy, accompanied by neovascularization and vascular remodeling. These newly formed vessels are particularly fragile, making them prone to rebleeding, which exacerbates joint damage.

"The prevention of joint and other bleeding complications is key," von Drygalski stated. "Absent the elimination of joint bleeding, we will have progression of musculoskeletal complications with a need for understanding the pathobiology of hemophilic arthropathy and also optimization of point of care imaging tools to support prompt and tailored management."

Imaging Advancements: Point-of-Care Ultrasound

For years, the primary tools for monitoring joint health were X-rays and MRIs; however, these methods are not always sensitive to early joint changes and are often costly and cumbersome. Point-of-care musculoskeletal ultrasound has emerged as a valuable tool for detecting joint bleeds and monitoring long-term joint health. "With ultrasound, we can easily differentiate between synovium and fluid in the joint," von Drygalski said.

To this end, von Drygalski detailed the Joint Activity and Damage Exam (JADE), which is a specialized musculoskeletal ultrasound (MSKUS) protocol designed to assess the condition of joints in patients with hemophilia. This protocol provides a comprehensive evaluation by measuring several key parameters, including cartilage thickness, soft tissue expansion, and osteochondral changes.

"It's incorporated into clinical trials and it's suitable for handheld pocket ultrasounds that have taken over our clinics," said von Drygalski. "It is attached to a very effective CME accredited training program that's easily taught to non-radiologists and even patients. Int the future, there could be musculoskeletal ultrasound for rapidly detection and joint health assessments including perhaps patient self-imaging paired with artificial intelligence."