Balancing the humors: an opinionated take on NEJM highlights for March 2021

A new approach to schizophrenia

Antipsychotic agents treat schizophrenia by manipulating the dopaminergic system. While they are effective at treating psychosis, they can have major side effects and they lack the ability to address so called negative symptoms e.g. apathy, lack of social connection, poverty of thought.  Enter the muscarinic cholinergic system which is tricky to manipulate in the CNS without untoward systemic effects as Lilly found out with their M1/4 agonist xanomeline.  Karuna Therapeutics has now licensed the molecule and cleverly combined with it with trospium, an antagonist with limited CNS penetration. As a result, this mitigates systemic effects without impeding the therapeutic effect of xanomeline in the CNS. (This approach is not completely unprecedented, for example alvimopan antagonizes the effect of opioids in the gut without diminishing pain relief). They have applied this combination in a 5-week phase-2 placebo-controlled trial (N=182) with reasonable overall efficacy but especially interesting, a clear signal of effect on negative symptoms. Given the enormous unmet need, worth following… Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia


Once more unto the breach

We have results from a phase 2 placebo-controlled trial using donanemab (Eli Lilly) in early Alzheimer’s.  This antibody specifically targets Abeta in plaque form, whereas other antibodies tested so far are less active against plaque. The participants were exquisitely selected for early cognitive dysfunction with some – but not too much – tau burden on imaging. After 76 weeks of infusions every 4 weeks, the treated group had a small but statistically significant benefit on cognition, much less amyloid on imaging, unchanged progression on tau burden, and a greater decrease in brain volume (!). Even though the signal seems real and the mechanism of action is interesting, the clinical effect is no better than the acetylcholine esterase inhibitors that are on the market (typically understood as essentially equivalent to delaying disease progression by 6 months). Given how fickle the whole beta amyloid field has been I imagine Lilly will wait to see what happens around June 9th 2021 (the PDUFA date for aducanumab) before deciding what’s next.  Donanemab in Early Alzheimer’s Disease


A new dawn in metabolism?

Finding ways to treat metabolic disease has been almost as frustrating as with Alzheimer’s.  Recent studies examining once weekly SQ semaglutide (Ozempic, Novo), however, are hinting at a major change. Semaglutide is a GLP-1 analogue approved for diabetes that has shown potential for weight loss beyond reduction of glycemia. This has led Novo to execute a large (N=1,961) 68-week placebo controlled study in non-diabetic patients who are obese (or overweight with >=1 risk factor). And the results are impressive:  average decrease in body weight of 15% on treatment, but also improved metabolic metrics: blood pressure, fasting glucose, C-reactive protein, physical functioning. The one shadow on this picture – nausea is common on treatment (and one wonders if it plays a role in weight loss). The study was too small/short for hard clinical end-points (an N=17,500 trial is on-going for that) but it is not that great a leap of faith to think that the impact is there to be found.  But until that, payers will have a hard time swallowing the ~$1000/month price tag.

Given the mechanism of action and impact on metabolic profile, it was also reasonable to hypothesize that semaglutide might be therapeutic in NASH. In a phase 2 (N=320) 72-week randomized study, the results are reported as mixed based on before/after histology of liver biopsies. On the one hand, liver inflammation was significantly decreased on treatment, on the other hand, fibrosis was not. But in my book, this is a very pessimistic read of the outcome, because transaminases (markers of on-going liver damage) as well liver stiffness (a less coarse measure of fibrosis) were markedly improved on treatment. The complexity here comes from the uncertainty in the correlation to clinical end-points which is not a problem of semaglutide but one of NASH in general. Once-Weekly Semaglutide in Adults with Overweight or Obesity; A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis


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.