Taking on tough indications: An opinionated take on NEJM highlights for October 2021

What makes an indication especially tough? The combination of a lack of understanding about the mechanism of disease and a lack of clarity on what endpoints would be sufficient for approval of a therapy in studies of reasonable duration. This month, two good examples in the NEJM.


A phase 2b success in NASH

Non-alcoholic steatohepatitis (NASH) is a common slow-progressing disease and for most affected individuals the timescale to liver-related morbidity is at least 20 years, although some progress much faster. NASH is also a graveyard of clinical programs which is why, when a robust study shows a plausible efficacy signal, one takes notice. In this case, a double-blind placebo controlled study of lanifibranor (a PPAR agonist from Inventiva Pharma) in 194 patients who underwent liver biopsy before and after the completion of 24 weeks of therapy showed a clear dose-dependent histologic response. In the high dose group, more than half had a substantial decrease in inflammation vs a third in the placebo, but even more interesting (though this was not the primary endpoint), 35% had improvement in fibrosis vs. 9% on placebo. Laboratory markers (e.g., transaminases) were equally convincing. A 72-week, 2000-patient phase 3 is on-going with results expected in 2024. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH


Going after autism

Autism Spectrum Disorder (ASD) is a huge unmet need especially at the more severe end of the spectrum, but despite that, it is not an indication that has seen much biopharma R&D activity. It’s easy to understand why – a heterogeneous population, little understanding of the mechanism of disease (with some saying that it is not a disease), and no good regulatory precedents to guide development. This is why it is especially gratifying to read an actual interventional study to ameliorate the symptoms of autism in the pages of the Journal (first time ever for me, and a quick search reveals there have only been 2 prior interventional studies in ASD published in the NEJM, most recently in 2002).  The blinded, placebo-controlled study in 290 subjects of intranasal oxytocin failed to show the hoped-for effect of improved social functioning as assessed by caretakers. While it’s disappointing the study failed, the fact that a rigorous study was designed, funded (by the NIH), executed, and published in the NEJM is laying down the infrastructure and precedent that, as it accumulates, will hopefully make this space more attractive for the biopharma R&D enterprise at some point in the future. Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder;


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.