Cure for hemophilia

References

Iorio A, Skinner MW, Clearfield E, et al; coreHEM panel. Core outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project. Haemophilia. 2018 Jul;24(4):e167-e172. doi: 10.1111/hae.13504. Epub 2018 May 20. PubMed PMID: 29781145.
Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy. N Engl J Med. 2017 Aug 31;377(9):819-828. doi: 10.1056/NEJMoa1616569. Epub 2017 Jul 10. PubMed PMID: 28691885.
Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017 Dec 28;377(26):2519-2530. doi: 10.1056/NEJMoa1708483. Epub 2017 Dec 9. PubMed PMID: 29224506.
George LA, Sullivan SK, Giermasz A, et al. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med. 2017 Dec 7;377(23):2215-2227. doi: 10.1056/NEJMoa1708538. PubMed PMID: 29211678; PubMed Central PMCID: PMC6029626.

Can we really cure hemophilia today?

Alfonso Iorio, MD, PhD: Yes. We are close to having a definitive cure in terms of gene therapy. Before getting there, we have now mimetics, antibodies mimicking the activity of factor VIII, binding factor IX and factor X, and solving the problem of factor VIII absence without giving inhibitors. These medications can be given subcutaneously every week for now, but there are already trials testing dosing every month. This is not a cure, but it is a much easier treatment, particularly in kids. It is a once-monthly subcutaneous injection as compared to intravenous infusion every other day or once a week.

But more than that, we have now 5 clinical trials published in the New England Journal of Medicine over the last 6 months showing that you can cure hemophilia by transfecting back the gene for factor IX or factor VIII through an adeno-associated virus. You can get levels that were unthinkable before. Patients get 30%, 40%, 50% factor VIII as a stable level. There are patients now who received the gene therapy transfer 3 years ago and are fully healthy, never required any more factor infusion.

The problem with gene therapy will be showing that it is worth paying for it. Of course it is difficult to set the price for a new medication. In this case you are saving hundreds of thousands of dollars over time, but imagining to pay those upfront is not straightforward. We will need to find a way to afford this treatment, maybe with a delayed treatment against proven effect.

There is also the need of showing the real value for patients. I have been personally involved in a project we call coreHEM. We had identified a core outcome set to be used in all the ongoing clinical trials in gene therapy to prove not only that the treatment is effective—you measure normal values of factor VIII or IX, that is enough—but you also want to show the effect on pain, on function, and how this kind of treatment transforms, for the good or for the bad, the life of a patient. For the good if they are cured, for the bad if they cannot get it because of a preexisting antibody against the virus or because they fail for some reason. So this is a completely new area where we still need to completely exploit the value, but yes, the cure is at reach.

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