Remodel, rewire, repopulate: an opinionated take on NEJM highlights for April 2021

Remodeling to health?

Chronic disease progression is often due to a maladaptive tissue response which leads to remodeling – such as cardiac hypertrophy with hypertension.  While most therapeutics focus on tamping down the injury, sotatercept (Acceleron Pharma) in pulmonary arterial hypertension (PAH) breaks new ground by focusing on the remodeling. This modulator of the TGF-beta superfamily looks to inhibit the remodeling of the pulmonary vasculature that worsens the PAH over time, and eventually leads to the demise of most patients. In a 24-week placebo-controlled phase 2 trial (N=106), the pulmonary vascular resistance decreased in the active treatment groups and their 6 minute walk test improved. It wasn’t a huge effect but there is a real possibility that this approach could help stop the relentless progression of this disease and afford those afflicted with a more normal lifespan. Furthermore, this treatment may have potential applications to other types of pulmonary hypertension which represent much larger patient populations. Sotatercept for the Treatment of Pulmonary Arterial Hypertension; Molecular Rescue in Pulmonary Arterial Hypertension


After ketamine, psilocybin

Despite renewed interest in the use of psychedelic drugs for therapeutic purposes, rigorous studies have been hard to come by, not least because the regulatory/legal hurdles are high. The journal reports on a UK study of psilocybin (the active ingredient of hallucinogenic mushrooms) versus standard therapy with escitaprolam (Lexapro) in patients with moderate depression.  The findings were essentially one of equivalence – 2 doses of psilocybin 3 weeks apart were equivalent to 6 weeks escitaprolam but with trends favoring psilocybin. With the caveat that there need to be larger studies, I will flag three interesting elements: 1) Although patients were randomized and blinded, everyone was told they would get psilocybin – but those who received daily Lexapro only got 1 mg of psilocybin (a negligible dose) vs. those who received a daily placebo got 25 mg of psilocybin. This is an interesting way to set expectations and “to help keep the blind” that I hadn’t seen before. 2) In depression therapies, there are always responders and non-responders.  Even if two drugs are equivalent on aggregate, there is benefit if the responder sets don’t fully overlap. Try one drug first, if it doesn’t work, try the second for a response. 3) When managed properly this appears pretty safe – we need more of these kind of trials. Trial of Psilocybin versus Escitalopram for Depression; Back to the Future — The Therapeutic Potential of Psychedelic Drugs


Malnutrition and the microbiome: an update

Child malnutrition and stunting impose enormous health burdens on the developing world. As I mentioned previously, Jeff Gordon has made it his mission to find a way through manipulation of the microbiome to alleviate this issue, and now, after painstakingly laying down the scientific groundwork for years, here is an actual test of the approach in the field: a phase 2 study in malnourished Bangladeshi children compared standard nutritional supplements with a microbiota-directed supplement (MDCF-2). Over 3 months, there was greater growth with MDCF-2, and that growth was correlated with plasma biomarkers and the reestablishment of favorable fecal bacteria taxa. And to top it off, MDCF-2 can be manufactured from locally sourced ingredients. We will have to wait for a large, longer term study, but of all the interventions documented NEJM I have reviewed in this series, this has the potential to have the largest impact on human health.  A Microbiota-Directed Food Intervention for Undernourished Children; Microbial Nourishment for Undernutrition (open 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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