Covid, iPSCs, and ADCs: An opinionated take on NEJM highlights for May 2020

By

Remdesivir works… but not enough to change the public health perspective

The eagerly awaited results of the remdesivir NIH trial are out, and it’s solid but not smashing, although this is a partial read since the study was interrupted before completion because of evidence of benefit (and we should get more data in the coming months).  Overall, the primary end-point of faster improvement in the treatment group was met while mortality showed a benefit that was just short of statistical significance. Also important is that remdesivir is clearly safe. But there is a lot more to digest in the data of this rigorous placebo-controlled trial and I will risk some exploratory subgroup analysis that’s not in the paper. Post hoc, one can essentially divide the patients in three cohorts: A) patients who were not on supplemental oxygen at enrollment, B) patients who were receiving oxygen but not intubated C) patients who were intubated. The study seems to show is that there is little effect in group C – probably because they are too far into their disease.  For group A, the study also shows no appreciable effect – but most likely because there were too few patients (only 1 died in each arm). It is for group B that the advantage is most obvious with a relative reduction in mortality of ~50% (5% vs. 11%). So, once deployed, it seems possible that remdesivir will save tens of thousands of patients (hundreds of thousands if we get a second wave) and in that sense it could be a triumph. On the other hand, it does not fundamentally change the public health calculus – instead of being 10x worse than the flu, Covid-19 may now be 5x worse which is still dismal. Remdesivir for the Treatment of Covid-19 — Preliminary Report; Remdesivir — An Important First Step (free access)

 

iPSCs slowly entering the clinic

Despite iPSC’s promise, the last time an article on the therapy appeared in the pages of the NEJM was more than 3 years ago. A brief report describes animal studies and then an N-of-1 study in which skin fibrobasts from a patient with long-standing Parkinson’s were collected, dedifferentiated and then redifferentiated in vitro into dopaminergic neurons which were then implanted in the putamen of the patient.  Although there was evidence of efficacy in the animal studies, the patient had little evidence of objective improvement through imaging or structured assessment of Parkinson symptoms, even though subjective quality of life was significantly improved. It’s a long road ahead, but at least, the road seems to be open given that there did not appear to be any safety issues. Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease

 

The ADC renaissance continues with a spiced up biosimilar

As flagged previously, after a long eclipse, antibody drug conjugates (ADCs) are having a renaissance. Latest to add news to this space is fam-trastuzumab deruxtecan-nxki (such a mouthful that I will use the brand name Enhertu, Daiichi Sankyo). Enhertu couples a HER2 antibody (biosimilar to Roche’s Herceptin) with a classic topoisomerase inhibitor in a substantial stoichiometric ratio (8!). Cancers that express HER2 are often successfully treated with Herceptin for long lasting remissions, but when progression eventually occurs, the situation becomes dire. In a couple studies in breast and gastric cancer on patients with HER2+ cancers that had been heavily pretreated, Enhertu showed a strong survival advantage over standard alternatives. It was not obvious that this would work in patients who are clearly refractory to Herceptin, but it does – and opens up a path to a world of opportunity. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer; Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

 

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.