Keeping the pipes clean and the wires intact: an opinionated take on NEJM highlights for January 2017


An innovative modality to suppress PCSK9

Antisense technology relies on the concept that it is possible to interfere with the cellular genetic machinery in very specific ways by deploying short RNA sequences that are complementary to the message that one wants to suppress. The idea has been around for a while, but has only achieved limited success in very niche indications (see here for the two latest). This is what makes the publication of phase 1 trial of the antisense agent inclisiran (Alnylam and the Medicines Company) targeting the synthesis of PCSK9 so exciting: one subcutaneous injection appears to lower cholesterol for 6+ months – this is to be compared with injections every 2-4 weeks for antibody therapy. It’s great convenience, but at the same time, a drug that acts on endogenous genetic material with an effect that lasts for many months, and might even be permanent… one would expect the FDA to be hard-nosed about its assessment of the safety profile (especially with potential signs of liver toxicity uncovered subsequently). A Highly Durable RNAi Therapeutic Inhibitor of PCSK9; Oligonucleotide Therapeutics — A New Class of Cholesterol-Lowering Drugs; Targeting Therapeutic Oligonucleotides (subscriber access)


At last, progress in primary progressive MS

MS is a disabling disease, but for most patients the last two decades have brought great progress with disease modifying therapies. Unfortunately this has not been the case for the 10-15% of patients with primary progressive form of MS (PPMS) for whom there are no good treatment options. In a first, the monoclonal antibody ocrelizumab (Roche, with some rights to Biogen) was shown in a randomized blinded phase 3 trial to decrease (although by a small amount) the disability progression in PPMS. This positions ocrelizumab as a treatment of choice not only for PPMS, but also for other forms of MS that have progressed (as tends to eventually be the case). Interestingly ocrelizumab is directed at the B cell marker CD20, which is the same target as the stalwart rituximab (Biogen, approved in 1997) and which had not been shown to be effective in prior trials. Clearly not all antibodies are equal, but several other anti-CD20 (ublituximab – TG therapeutics; ofatumumab – GSK) are waiting in the wings and we will likely hear more from them in MS in the next few years. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis; Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis; B-Cell Depletion — A Frontier in Monoclonal Antibodies for Multiple Sclerosis (subscriber access)


Notable from former President Obama

Repealing the ACA without a Replacement — The Risks to American Health Care (free 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.