Some very disappointing failures: An opinionated take on NEJM highlights for August and September 2022

Is Parkinson’s α-synuclein going to be as elusive a target as β-amyloid has been for Alzheimer’s?

Alpha-synuclein aggregates are characteristic of Parkinson’s disease and genetic variants of this protein clearly lead to familial forms of Parkinson’s; it was therefore reasonable to target alpha-synuclein with antibodies in the hope of modifying disease progression. Sadly, two well designed placebo-controlled studies have now crushed this hope. Both showed absolutely no impact on the progression of patients with early Parkinson’s over times that extended to 1.5 year of follow-up. If there is silver lining, it’s that imaging of the dopamine transporter (through SPECT) did not lie and showed no effect which makes one more confident that it might be a good biomarker for the day when we have a good target. Trial of Cinpanemab in Early Parkinson’s Disease; Trial of Prasinezumab in Early-Stage Parkinson’s Disease; Monoclonal Antibody Therapy in Parkinson’s Disease — The End?


ALS patients can’t catch a break

Two years ago, we had the first sign of an ALS therapy supported by a strong mechanistic hypothesis with antisense RNA in patients with SOD-1 “familial ALS”. The phase 1/2 study looked promising, and expectations for a pivotal study were high. Sadly, it all came crashing down with a phase 3 study that showed no clinical difference between the treatment and placebo arm at 28 weeks. To make things even worse, plasma levels of neurofilament light chain (NfL) which had been thought to be a marker of neuronal injury and disease progression decreased in the treatment arm relative to the placebo arm. So on top of a clinical failure, we have also shown that what had been thought to be a promising biomarker for ALS cannot be relied on as a proxy for effectiveness.  There is no silver lining here – it’s awful news for an awful disease.  Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS


The alternative to CAR-T

The CAR-T approach is based on reengineering patients’ T-cells with a receptor that will home in on a specific tumor antigen. But there is an alternative – to leave patients’ T-cells as-is, and guide them to the tumor by via a bispecific antibody targeting a tumor antigen on one hand and a T-cell specific marker (CD3) on the other hand (sometime called BiTEs for Bispecific T-cell Engagers). This is what is now being done for Multiple Myeloma (MM, using the BCMA antigen) with multiple programs, one of which, teclistamab (Janssen) is reporting results from a phase 1/2 study that enrolled 165 very heavily pre-treated MM patients (median time since diagnosis 6 years, median prior lines of therapy 5). Median response was 1.5 years.  How does this compare with CAR-T therapies that also target BCMA for MM? Probably a bit better than idecabtagene (Abecma, BMS) and not quite as good as ciltacabtagene (Carvykti, Janssen). But CAR-T therapy is complex, time-consuming, and not always available, whereas a bispecific antibody is ‘off-the-shelf.’ It’ll be especially interesting to see how Janssen positions its bispecific vs. CAR-T offerings. Teclistamab in Relapsed or Refractory Multiple Myeloma; T-Cell Engagers — Modern Immune-Based Therapies for Multiple Myeloma


Lightening the burden in Type I diabetes management

The cognitive and decisional workload of managing Type I diabetes cannot be underestimated – maintaining glucose in an optimal range is a never-ending effort, requiring adjustment of the insulin regimen at all hours. Some manage to do this and it is a huge burden, but many do not, especially in challenging socio-economic environments, and the consequence is poor control with high HbA1c and long-term complications. There has been steady progress to fully automate the dosing of insulin and now, beta bionics reports another step forward with a randomized trial comparing usual care vs. their iLet Bionic Pancreas which incorporates an algorithm to autonomously manage insulin delivery with only qualitative input from the user regarding meals (usual, less, more). At 13 weeks, the iLet beat usual care on HbA1c (difference of difference -0.6%), and was equivalent on hypoglycemia. It is a promising step on shifting mindshare from the next insulin dose to “life” (disappointingly the effect on quality of life is not reported here, but is promised for a future publication). And for those who struggle (and which are likely not represented in this study, because their lives tend to be too chaotic to enroll in a trial) a potential solution to massively improve glycemic control. Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes; Seeking Simpler Solutions with Diabetes Technology


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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