Gene therapy, headaches, and tattoos: an opinionated take on NEJM highlights for November 2017

Two new therapies against a horrible congenital disease – but trouble ahead on pricing…

Spinal Muscular Atrophy (SMA) is a genetic disease that declares itself at a few months of age, and typically leads to death before the second birthday. Two studies for two different therapies are reported in the Journal. First, the final results for a phase 3 placebo-controlled trial studying nusinersen (Spinraza, Sarepta, approved by FDA Dec 2016) therapy which involves monthly injections into the infant’s spine of an RNA-based drug. These show a clear beneficial effect over placebo (good enough for FDA approval), but still a high rate of death and disability in the treated group. Second, the results of a phase 1/2 trial of a gene replacement therapy (AVXS-101, AveXis) based on a viral vector given as a one-time intravenous infusion. Although not a cure, the impact of this treatment on outcomes appears to be greater than what is seen with nusinersen, and the convenience of a one-time treatment should make AVX-101 preferred if results are confirmed in a pivotal study (on-going).  Pricing will be a major issue though: nusinersen therapy costs $500,000/yr and above, something that has already resulted in pushback from some payers. A one-time life-saving treatment with greater effectiveness could well be argued to be worth 2-3 million dollars, especially considering the announced intent by Spark to price a sight preserving gene therapy (Luxturna) for Leber’s retinopathy for more than 1 million dollars.  Within our current model, it is hard to imagine how this will be sustainable if many genetic diseases are going to be covered by these types of treatment. A potential side effect may be that payers will become very generous in their coverage of prenatal genetic testing. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy; Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy; The Dilemma of Two Innovative Therapies for Spinal Muscular Atrophy (subscriber access)


Progress on migraine

With the possible exception of botulinum-related compounds, there has not been a truly new drug (in terms of mechanism of action) for migraine in many years even though migraine and especially chronic migraine remains a very large unmet need.  It looks like this is about to change with results from phase 3 studies for two new monoclonal antibodies – fremanezumab (Teva), erenumab (Novartis/Amgen) targeting the CGRP (calcitonin gene-related peptide) pathway, the first directed at the ligand and the second at the receptor. Both studies showed an overall clinically and statistically significant improvement over placebo, with some patients becoming migraine free. If the effect is durable (the studies were 12 weeks and 6 months respectively) and the safety profile continues to be reassuring, this class of drug will become an important component of migraine therapy. And given that CGRP seems to be a pleiotropic neurological intermediary, there might be other potential applications (IBS, neuropathic pain?).Fremanezumab for the Preventive Treatment of Chronic Migraine; A Controlled Trial of Erenumab for Episodic Migraine; CGRP — The Next Frontier for Migraine (subscriber access)


Advance directives by tattoo

One of the most intriguing letters to the editor I have read in years relates the story of an unresponsive patient brought to the hospital in significant respiratory and cardiovascular distress who had “DO NOT RESUSCITATE (signature)” tattooed on his chest (picture included in the journal). Apparently the validity of this inscription was not clear enough for the care team who, out of an abundance of caution, decided to go ahead and deploy full support to the patient until an ethics consult told them to knock it off. After additional research, a DNR form was found filed with another organization; meanwhile the patient expired without further invasive interventions.   Given the level of disagreement about the proper course of action within the Recon office (you can probably guess where I stand), I eagerly anticipate the follow-up journal correspondence that is sure to come. An Unconscious Patient with a DNR Tattoo (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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