CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 21, 2024
Expiration: March 20, 2025
Rapid Progress in Development of New Therapy for Hemophilia: Proposed Approaches to Hemophilia Treatment
Runhui Wu, MD, PhD:
In treating patients with hemophilia, HCPs should first consider those who would benefit from restoring hemostatic balance via therapy. When narrowly defined, treatment options for this refer to reference nonfactor therapies such as fitusiran and TFPIs; when broadly defined, they refer to any treatment that restores one’s decreased coagulation ability to normal levels, such as factor concentrates such as standard factor EHL agents, as well as gene therapy. Continuous innovation in technology has accelerated the development of these novel therapies, so HCPs may better manage hemophilia and optimize patient outcomes.63,64
Goals of Hemophilia Treatment: New Drug Development Complements Patients’ Needs
Runhui Wu, MD, PhD:
Although these new treatment options are complementing the needs of patients, they are also a necessary supplement and enhancement to traditional hemophilia treatments. As existing needs are being met with novel therapies, patients will uncover previously unrecognized needs—thereby promoting the continuous innovation and upgrading of hemophilia treatment.65
One important goal of hemophilia treatment is to gradually transition from the prevention of premature death and survival to optimized health of patients by returning them to a normal coagulation state.66 On the other hand, the best treatment outcome is expected with care from a multidisciplinary team at HTCs.2 As discussed by Hermans and Pierce, optimum patient outcomes comprise 4 points of freedom: being free from arthropathy, pain, bleeding events, and burden.67 Therefore, any new therapy dedicated to treating hemophilia should be used to help patients achieve all treatment goals.
What Do Patients With Hemophilia Need?
Runhui Wu, MD, PhD:
Treating hemophilia globally can be categorized into 2 scenarios: an ideal situation that can occur in fully developed countries and nonideal situations that are often seen in developing countries with decreased economic and healthcare growth.68
In developed countries such as the United States, patients with hemophilia have greater access to the full gamut of traditional current standard-of-care treatment strategies, resulting in better clinical results. In a study describing HCP prescribing trends for managing hemophilia in the United States from 1999-2021, high-dose factor prophylaxis (>40 units/kg) prescriptions increased by 29.3% and 65.3% for hemophilia A and hemophilia B, respectively. Furthermore, 94.7% of HCPs reported prescribing emicizumab (a nonfactor prophylaxis) to pediatric patients with hemophilia A with inhibitors and 91.4% to adults with hemophilia A with inhibitors. Finally, the majority of prescribers recommend gene therapy to patients “at least some of time.”69
In developing countries with limited economic and healthcare growth, however, traditional therapies are not sufficient to meet treatment goals. According to patient-reported outcomes data on children with moderate to severe hemophilia A in China, 86.2% of those without inhibitors were prescribed low- or intermediate-dose prophylaxis—and only 13.8% were prescribed the standard high-dose regimen. Furthermore, for those with inhibitors, almost 100% were prescribed low-dose immune tolerance induction.70
Innovative Treatments Meet Patients’ Clinical Needs
Runhui Wu, MD, PhD:
Many developing countries are limited in their options to treat patients with hemophilia because of the unmet clinical needs as a result of the nation’s economy and general healthcare infrastructure. Therefore, ideal innovative therapies, including prophylaxis agents, should both meet the clinical needs of patients with hemophilia and address patient needs of those in the unideal state. For example, EHL agents reduce the number of injections needed and, therefore, lower overall treatment costs.25 Emicizumab and rebalancing agents such as fitusiran further reduce the number of injections needed and optimize the cost-effectiveness ratio of hemophilia treatment in the long term.71,72 Finally, although the upfront cost is large, gene therapy poses the potential to cure patients regardless of having hemophilia A or B.73
All of the therapies discussed here actually increase treatment demand globally—but they also provide the opportunity for developing countries to achieve treatment equity in hemophilia, optimizing patient outcomes worldwide.68
Therefore, when new treatment technologies transition from their research and development phase to the market after approval or authorization, HCPs should fully consider the depth and breadth of their application. Furthermore, for researchers, these innovations should meet the unmet clinical needs of the existing treatment landscape and provide new possibilities for patients who are fully using existing treatments.
Integration Considerations for Fitusiran
Runhui Wu, MD, PhD:
As with any new agent, it is important to educate the multidisciplinary care team in HTCs on administration and safety considerations for these novel therapies. For example, fitusiran, an siRNA agent that is delivered via SC injection monthly, is a new class of therapy for patients with hemophilia.55 Before this agent is approved, HCPs should educate themselves on applicable clinical trials and how to use new agents such as fitusiran in their clinical practice. They also must understand mechanisms of action and how these new agents work in the body, which can be done by reviewing in vitro and/or predictive modeling data. Further education should come from deep discussions with investigators, as well as expert-informed educational activities provided by one’s organization or HTC to ensure that all staff understand and will use a new therapy appropriately.
Integration Considerations for Gene Therapy
Runhui Wu, MD, PhD:
Another example of staff education for hemophilia includes basic knowledge of gene therapy. With the new approval of valoctocogene roxaparvovec for patients with hemophilia A, HCPs must understand the fundamentals of gene therapy, as well as the limitations of its use from preclinical safety and efficacy outcomes.73 Determine who is eligible to receive gene therapy in your HTC, and emphasize the importance of long-term data collection to all staff.
Security Exploration: What Can We Learn From Fitusiran Research Milestones?
Runhui Wu, MD, PhD:
Education on the use of novel therapies starts with clinical research and trial data. On one hand, through global multicenter clinical research, we can understand the variations that may present in the application of these new therapies among different patient populations. On the other hand, before a product is released to the market, many HCPs around the world could gain firsthand experience with the agent, helping them attain a deeper understanding of any special characteristics and key points of use. This provides crucial technical and background education in real time that supports the smooth integration and promotion of new agents in clinical practice once they officially hit the market.
Security Exploration: What Can We Learn From Fitusiran Research Milestones?
Runhui Wu, MD, PhD:
Using fitusiran as an example, the countries and HTCs involved in each phase of the drug’s development are critical to HCP education. This was demonstrated when the phase II study was paused in September 2017 because of a fatal thrombotic event and then resumed after protocol revision and updating of clinical materials. In October 2020, the phase II trial was paused because of the risk of nonfatal vascular thrombotic events (listed in the table). After protocol revision and updating of clinical materials, the trial was resumed in December 2020.
Security Exploration: What Can We Learn From Fitusiran Research Milestones?
Runhui Wu, MD, PhD:
As these HTCs reach research milestones throughout the development process, including publishing their findings in journals, HCPs can better understand the twists and turns in the clinical trial process, such as how safety data may affect their patients and reasons for trial suspension, protocol modification, and trial restart.73 Therefore, HCPs attain an education on fitusiran that will allow them to feel confident when using this new therapy in their clinical practice.
Research and Development: Postmarket Clinical Studies of Emicizumab Are Adding Direct Evidence
Runhui Wu, MD, PhD:
Emicizumab is a novel therapy that is approved by the FDA for routine prophylaxis to prevent or reduce bleeding in adult and pediatric patients with hemophilia A regardless of their inhibitor status. This agent was created to meet patients’ need to allow for shared decision-making in determining which administration schedule works best for them.31
Many postmarket clinical studies of emicizumab are being conducted and providing evidence of its use in day-to-day clinical practice. Some examples of those being conducted in Japan include:
In summary, it is critical to include all care teams more deeply in each stage of the new drug development process. This will help HCPs better understand how to effectively use novel treatments and technology, avoid safety issues in patients, and develop new applications.
Although Gene Therapy Is a Curative New Technology, Suitable Patients for Use Are Incredibly Limited
Runhui Wu, MD, PhD:
Next, I will discuss how HCPs can best identify patients who would benefit from and be eligible for clinical trials. Identifying eligible patients for clinical trial enrollment is a necessary practice. One must choose appropriate patients for the treatment method being evaluated. For example, although gene therapy is widely considered the curative and ultimate treatment option for patients with hemophilia A, these clinical trials posed several limitations because of their strict inclusion and exclusion criteria, such as age (no children), inhibitor status, gender, existing adeno-associated virus antibodies, and insufficient exposure to prior treatments. These limitations further affected patients once the therapy was approved because the number of patients who meet the trial-informed requirements and can withstand the procedure is limited.78,79
Limitations, Uncertain Outcomes, and High Costs: Balancing Risks vs Benefits of Gene Therapy
Runhui Wu, MD, PhD:
Key considerations for selecting ideal patients for gene therapy include its limitations in clinical practice and financial impact to patients. Significant treatment limitations arise from notable challenges seen in clinical trials, including the durability and variability of expression and safety (eg, infusion reactions and liver damage) in long-term data.80 In addition, gene therapy poses a serious financial impact to patients, which can become a significant barrier to those who can take advantage of this new treatment option.81
Emicizumab: The Cost-effective Balance
Runhui Wu, MD, PhD:
By contrast, emicizumab has the potential to generate savings for healthcare systems and patients alike by delaying the development of FVIII inhibitor by approximately 13 years among previously untreated patients with severe hemophilia. In addition, this therapy offers cost savings of approximately $2 million per patient (over 20 years) because it reduces breakthrough bleeding and the need for immune tolerance induction therapy. Finally, emicizumab takes away the need for the surgical implantation of central venous access devices, especially among pediatric patients, therefore reducing severe bleeding events that would require hospital admission.
With the benefits of emicizumab in effectiveness, safety, and convenience of application, alongside its own high cost to access, the uptake of this therapy has grown rapidly over the past few years.82
The selection of suitable patients for clinical trials is bidirectional—choosing novel therapies that are suitable for patients and choosing patients who are suitable for novel therapies. Therefore, new agents and technology must meet these requirements to have an application in clinical practice as seen with emicizumab.
Many Patients Unable to Undergo Gene Therapy due to Various Limitations
Runhui Wu, MD, PhD:
Finally, I want to discuss how multidisciplinary care teams can address global and regional barriers to implementing novel therapies for treating hemophilia.
The barriers to address regarding gene therapy include the limited number of patients who qualify for this treatment, the need to optimize the existing technological means of gene therapy, and the expensive costs associated with this treatment. There are many unresolved issues regarding strict patient selection limitations, especially considering that it is most important to prevent bleeding in children,83 but gene therapy is not indicated for use in children.84 Finally, some long-term data have shown a decrease in efficacy and need for glucocorticoids due to a rise in liver enzyme levels.85
These challenges are all significant obstacles to effectively integrating gene therapy into clinical practice. In addition, these challenges lead to a small number of patients who choose to proceed with gene therapy.
In response, research and development teams around the world are working hard to improve this technology to address the above issues, ensuring that new gene therapy options are suitable and accessible for more patients. On the slide, the left part of the figure illustrates a new gene editing approach that can be applied to the pediatric population. Then, on the right is the engineered variant. Engineered variants (eg, optimization of both coding and regulatory elements of the expression cassette) enable higher FVIII levels and lower immunogenicity are an example of technological innovation that aims to reduce inflammation after gene therapy.86
Expanding Clinical Applications of Emicizumab
Runhui Wu, MD, PhD:
On the other hand, emicizumab solves the significant barrier of patient selection posed by gene therapy. It also solves the insurmountable and limited efficacy of traditional treatments for patients with hemophilia A without FVIII inhibitors, including improved safety and administration, which positively affects patients’ overall quality of life.
With the excellent clinical integration and application of emicizumab since its FDA approval in 2018, the scope of its use is continuing to expand. Researchers are attempting to personalize this treatment option to the required concentration (and lower dosage) needed for patients in developing countries.82,87
Conclusion
Runhui Wu, MD, PhD:
In summary, barriers to using novel treatments such as gene therapy and emicizumab to treat patients with hemophilia often arise from the cost-effectiveness—the ability to achieve maximum result with minimal cost—of the treatment. Therefore, optimal outcomes can be achieved after addressing 2 questions.
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