A golden age for gene therapy: an opinionated take on NEJM highlights for December 2017

Successes in gene therapy for hemophilia B and A

Hemophilia A and B are X-linked genetic diseases which prevents the formation of functional coagulant factors VII and IX respectively and cause a propensity to bleeding in about 20,000 people in just the US. The standard of care of intravenous administration of recombinant factors is effective but also burdensome, expensive, and does not fully prevent the disabling sequellae of the disease caused by repeated bleeding in the joints. A possible cure is to deliver a functional copy of the defective gene piggy-backed on a viral vector. The proof of concept for this is now firmly established in two phase 1b/2a studies (10 patients for hemophilia B with the Spark product, 9 patients for hemophilia A with the Biomarin product) where treated patients started to produce endogenous factor, stopped having bleeding episodes and no longer required factor infusions. This lays the groundwork for pivotal studies that should lead to approval in a few years (if all goes well). Two thoughts for those who don’t follow this space closely: First, treatment with recombinant factors costs several hundred thousand dollars a year per patient, so a cure priced at the substitution cost could be worth several million dollars. Second, the viral vector carrying the replacement gene targets the liver (where factor VIII and IX are produced in normal individuals) – and so the potential for liver injury exists and is closely monitored.  But it is worth keeping in mind that a single case of cirrhosis or hepatocellular carcinoma in the pivotal trials could crash the entire field. Such are the risks and rewards of drug R&D…  Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant; Closing In on Treatment for Hemophilia B; AAV5–Factor VIII Gene Transfer in Severe Hemophilia A; A Cure for Hemophilia within Reach (subscriber access)


CAR-T at scale

You had to be living under a rock over the last year to have missed the excitement of CAR-T therapies. But, so far, most peer-reviewed reports have been single or small number case series rather than significantly sized controlled studies. Even though the controlled aspect will have to wait, two studies of recently approved therapies (axicabtagene ciloleucel – Yescarta, Kite; tisagenlecleucel – Kymriah, Novartis) incorporate enough patients and sites to show that this approach is quickly moving from cottage industry to mainstream oncology.  Both studies enrolled patients with B-cell lymphomas who had progression despite multiple other therapies and most of whom were looking at a dismal short-term prognosis. About 50% of the patients had a complete response, and for most of these patients the response seems to be durable enough that it might possibly represent a cure. On the other hand patients who did not have a complete response typically died of their disease within 18 months.  At this time, it is unclear what determines a responder vs. a non-responder and figuring this out will clearly be a major area of effort in the coming year(s). Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma; Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas; A Milestone for CAR T Cells (subscriber access)


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.

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