NEJM Highlights March 2015: Progress against Crohn’s, PCSK9 inhibitors coming through, comparative effectiveness for diabetic macular edema, Eric Lander encourages the FDA on genomic testing regulation


A promising agent for Crohn’s Disease, a miserable illness
Crohn’s is an inflammatory bowel disease that is notoriously unpredictable; flares can affect any part of the digestive tract and lead to grave complications. In this double-blind phase 2 study, patients were dosed with mongersen (licensed by Celgene) an anti-sense oligonucleotide that down-regulates the expression of a protein implicated in the inflammatory cascade. In general these classes of medications have to be given parenterally but in this case the target is the gut so it can be taken orally. At two weeks of treatment, the response rate was about 60% in the treatment arm compared to 10% in the placebo group, an unheard of result in the context of past experience with Crohn’s. A cautionary note that subjects in this study were chosen among a very specific subgroup of Crohn patients which may not be representative of the broader group. To be confirmed in phase 3…
The next Lipitor step in cardiovascular event prevention; PCSK9s inhibitors show clinical efficacy
PCSK9 targeted monoclonal antibodies (mAb) inhibitors have been shown to reduce LDL (bad) cholesterol levels and have triggered a race to market in which several pharmas are participating: Sanofi/Regeneron (alirocumab/Praluent), Amgen (evolocumab/Repatha), and somewhat behind, Pfizer (bococizumab, although they are also going for a small molecule oral agent). In results shared at the American College of Cardiology meeting and simultaneously online in the NEJM, two studies showed that in high risk patients, the rate of major cardiovascular events was reduced by about half in the treatment arm compared to placebo (from about 2% per year to about 1% per year). Interestingly, in neither study was this a pre-specified end-point but the fact that both studies show an effect of the same magnitude gives confidence that the finding is real and not a fluke. Both drugs are on track to be approved this summer and many of us will be curious to see the pricing for these life-long monthly or bi-weekly self-injected agents. Who will get them? Most likely individuals who are at very high risk for cardiovascular disease, and those who have failed statin therapy.
An NIH-funded comparative effectiveness research for diabetic macular edema with clear winners and losers
Blindness is a long term effect of diabetes, and several anti-angiogenic agents have been shown to be beneficial. In this randomized trial comparing aflibercept (Eyelea, Regeneron), ranibizumab (Lucentis, Genentech), bevacizumab (repackaged Avastin, Genentech), the investigators found that for patients with moderate vision loss, all three agents provide a similar level of benefit, whereas for severe vision loss aflibercept was better than both ranibizumab and bevacizumab. While the authors of the study tread carefully around making treatment recommendations, an accompanying editorial is not so delicate – for them the choice is clear: use repackaged bevacizumab at $50 per dose for patients with moderate disease, and keep aflibercept ($1950/dose) for more severe cases leaving ranibizumab ($1200/dose) in the cold. The editorial also bemoans the incentives which frequently drive use of the more expensive drugs.
FDA’s continued struggle with the regulation of genomic testing
A letter from Eric Lander calling attention to current efforts at the FDA to come up with a workable regulatory framework for genomic testing. This has been a challenging endeavor for at least two reasons – a rapidly evolving technology landscape which might make any regulation irrelevant as soon as it sees light of day, and a sheer number of clinical readouts (potentially in the thousands) for a single test which makes the validation procedures used for a classic “one readout” test unworkable. The FDA proposed framework centers on splitting test analytical performance from clinical performance, and attempts to balance the interest in properly exploiting the technology using public reference databases, for instance those curated by the NIH (ClinGen). This FDA discussion paper is well worth a read for those with an interest in that domain.


The New England Journal of Medicine is a premier medical journal covering many issues of interest to the health sector. In this monthly series we offer a brief overview of highlights of the past month issues that might be of interest to our clients and others.