Hemophilia Care: A Future for Gene Therapy?

The first gene therapy trial conducted in 1990 generated big headlines until it was reported in 1999 that a participant in one of the trials died. Much funding and development of these agents halted as a result. It wasn’t until 2012 that Europe approved the first gene therapy. That effort too fizzled after only one paying patient was treated and the manufacturer pulled the product in 2017 due to regulatory constraints. Finally, last year, the United States approved its first gene therapy: voretigene neparvovec for the treatment of Leber’s congenital amaurosis.

There is still much to learn, but gene therapy appears to be an important treatment option in the future of hemophilia management, according to Susan Trieu, PharmD, director of enterprise specialty clinical solutions at MedImpact Healthcare Systems, Inc., in Texas. She discussed the use of gene therapy in hemophilia during the Specialty Connect program, a pre-Annual Meeting event.

Dr. Trieu began with some of the challenges associated with these agents. “The size of the gene makes a big difference,” she said. For example, the development of gene therapy for factor IX (FIX) has been faster than factor VIII (FVIII) because of the smaller size of FIX (1.4 kb vs 4.4 kb, respectively). Gene therapy is not a good fit for every U.S. patient with hemophilia because not all vectors are the same and the immune response will be different; this poses a barrier to proper patient selection for this treatment.

In addition, the duration of clinical response to these therapies remains unknown, and there is a lack of understanding of long-term issues. “There has been some transparency in [clinical trial] reporting,” said Dr. Trieu, “but there are a lot of variables, and we cannot compare [the findings] head-to-head.”

She then gave an overview of two gene therapies in development:

  • BMN270 for adult patients with severe hemophilia A: Phase I/II trials found that patients treated with the high-dose regimen (6×1013 vg/kg) achieved FVIII activity level of ≥5 IU/dL, while those treated at the two lower dose levels did not. The study also reported a decrease in annualized bleeding ratio (ABR) and use of FVIII products. No patient developed inhibitors to FVIII or thrombosis. However, Dr. Trieu cautioned that more information is needed on vector shedding. Because this is excreted in saliva and other bodily fluids, its impact to people around the patient (i.e., partner, parents, siblings) must be analyzed, she said.
  • SPK – 9001 for adults with hemophilia B (factor VIX activity level <2 IU/dL): In the phase I/II trial, a one-time 5×1011 vg/kg dose was administered to patients with nine different types of FIX genotypes. The study also reported a decrease in ABR and use of FVIII products. No patient developed inhibitors to FVIII.

Dr. Trieu then discussed the pros and cons of these agents. Pros include a hypothetical one-time infusion, a potential “cure” with no further treatment necessary, high response rates, objective response measures, and a predictable cost. Cons include the high costs, unknown duration of response, inability to currently use in the inhibitor population, limited data on patients with HIV and hepatitis, and unknown consequences of vector integration.

She continued with a discussion of payment models for these costly therapies. Proposed options include direct to payer, outcomes-based for short- and long-term agreements, and payment installments. “I’m not sure how installment payments will work in the commercial space,” she said, “but they could work for single-payer Centers for Medicare & Medicaid Services coverage.”

Dr. Trieu predicted that perhaps by 2020 or 2021, the United States may have its first approved gene therapy for hemophilia. She noted that many gene therapies for hemophilia are moving into phase III testing, so payers need to be prepared.

Presentation: Gene Therapy for Hemophilia: Hope for a Cure? AMCP Annual Meeting 2018 Specialty Connect.