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Managing Hemophilia B Using Gene Therapy


Dr Pipe discusses the impact of gene therapy in the Hemophilia B landscape, for both the payer and patient.

Steven Pipe, MD: There's no question there are unknown aspects related to a new platform of therapy like gene therapy. We're uncertain about the durability, but we do have long-term data from the phase 1 and 2 trials that are showing consistent durability at 5, even 10, years for the gentleman who participated. The adverse events have been tolerable for the most part. There are issues related to unknowns. Could there be any adverse impact of having this gene inserted into the nucleus of the cell? Does this carry any unexpected possible adverse outcomes, such as inducing a malignancy? We've not seen that in any of the preclinical data that went into the design of these trials. We've not observed any malignancies in the clinical trials that can be linked back to the AV treatment. If we look broadly across gene therapy as it's been applied to hemophilia, there are probably more than 500 patients worldwide who've received gene therapy to date. The unknowns are there, but I think when they're weighed in the balance against the other aspects of safety and efficacy, it will come out on top that this is a potentially transformational therapy.

As far as how payers may apply reimbursement criteria for gene therapy, they're probably going to closely follow the eligibility and exclusion that went into this treatment. For instance, to date, adults have only been treated. They must have a good liver health assessment since we're putting the gene into the liver directly. Of course, patients with hemophilia over the years have had some legacy liver issues related to prior infection with hepatitis B and C, as well as HIV. We do detailed assessments of the liver to make sure they meet certain bars, that it's safe to give them this liver-directed therapy. All patients in the phase 3 trials were compared against a leading phase of standard of care prophylaxis. It's also possible that payers may require patients who are eligible for gene therapy to have already been on some form of prophylaxis beforehand. However, when I think more globally about utility of gene therapy, most patients around the world don't have access to factor 9 replacement products, and they certainly aren't on a regular prophylactic therapy. They have significant complications from their disease. In that context, gene therapy becomes a real game changer because you can do a single treatment event, and the patients will, hopefully, no longer need any factor 9 replacement from that point forward. End gene therapy doesn't have to be limited to people who've already been on prophylaxis.

Even though the approaches for gene therapy for hemophilia A and B are the same, they both use AV vectors. They both package either the factor 8 or the factor 9 gene inside. It's possible that the efficiency of the expression of factor 9 could be more consistent than it is for factor 8, or patients might easily achieve the non-hemophilic range for factor 9 expression as compared to hemophilia A. Because we know about the challenges of a cell to synthesize and secrete factor 8 compared with factor 9, this may have some implications for either levels that patients will achieve with factor 8 in hemophilia A gene therapy or the durability of that expression. We're going to see differences in outcomes, but those outcomes are linked back directly to the level and stability of the factor expression after gene therapy.

After an 18-month follow up in the pivotal HOPE-B trial, etranacogene dezaparvovec reached its primary endpoint and demonstrated sustained factor 9 activity and bleed protection that was superior to what was observed with standard of care factor 9 prophylaxis during a lead-in period before they got treated. Improvements in health-related quality of life measures have also been observed in the HOPE-B clinical trial. These suggest that this treatment can reduce the burden associated with hemophilia and the prophylactic treatment using infused factor 9 concentrates, which is the current standard of care. This impact may contribute to how people with hemophilia B view their work or school performance, as well as providing a sense of optimism for the future. We are observing a significant impact on quality of life and a substantial improvement of the burden of having this disease.

How will we justify the cost of gene therapy treatment? It's an easy equation. We know how much standard of care prophylaxis with factor 9 replacement therapy costs in direct dollars for the patient. If you get gene therapy treatment and are liberated from needing to remain on prophylaxis, that's an immediate cost savings every month, every year, and hopefully for decades afterwards. Depending on the upfront cost for the gene therapy, you'll realize the benefits in a small number of years, that you can remain off prophylaxis. That's an easy justification. What I hope will also be part of that equation is the fact that it's superior to standard of care factor 9 prophylactic therapy. Again, this comes from achieving steady state of factor levels instead of these peaks and troughs that we normally get with IV infusions. With that steady state hemostasis, we have reduced breakthrough bleeding and can hopefully reduce, or even eliminate, the progression of joint disease. The health-related quality of life is another aspect of the justification. This should be deemed highly cost-effective and made available to those who meet all the eligibility criteria.

Transcript edited for clarity.

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