It’s in the brain: An opinionated take on NEJM highlights for April 2019

He’s dead, Jim

As previously widely advertised, the BACE-1 inhibitor verubecestat (Merck) (and in journal correspondence atabecestat, Janssen) has now failed in a population with very early signs of cognitive impairment (this after a failure of those agents in mild-moderate Alzheimer’s). Target engagement clearly occurred with a decline of the amyloid detected through PET imaging in the treatment arms and an increase in the placebo arm. However, if anything, cognition declined more in the treatment arm than in the placebo arm after 2 years on study. A silver lining is that the study does show the feasibility to execute studies on early cognitive impairment with a starting near-normal MME (Mini Mental Status) with a mean of 26.3 out of 30 and follow a decline of about 4 points in the next 2 years. This will be the approach of the future – but not with the Abeta pathway.  Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease; Preliminary Results of a Trial of Atabecestat in Preclinical Alzheimer’s Disease; Lowering of Amyloid-Beta by β-Secretase Inhibitors — Some Informative Failures (subscriber access)


Pembro as an anti-infective

A few months ago, the journal published a report on the use of CAR-T against Progressive Multifocal Leukoencephalopathy (PML) caused by JC virus infection in immunocompromised patients.  This month, it’s another I/O approach in the form of checkpoint inhibitors. In a series of 8 PML patients treated with pembrolizumab, 5 had a clinical and viral response induced by an increase in T-cells reactive to JC antigens.  Will this be an approach for other infections in chronically immune-suppressed patients? Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy; Treatment of Progressive Multifocal Leukoencephalopathy with Nivolumab; Treatment of Progressive Multifocal Leukoencephalopathy with Pembrolizumab; Can Immune Checkpoint Inhibitors Keep JC Virus in Check? (subscriber access)


A note from the front-lines of human misery

The case report starts thus: “The patient was homeless but had recently been enrolled in an addiction treatment program in a residential clinical stabilization service. He reportedly left the program 4 days before admission to this hospital and then “blacked out” daily in tandem with drinking 0.5 to 1 gallon of vodka throughout the day. On the evening before admission, he decided to stop drinking alcohol. Approximately 10 hours later, he awoke on the ground without recollection of lying down; he had had vivid dreams and tremulousness and was worried that he may have had a seizure. He presented to the emergency department of this hospital”.

After hospitalization and gradual improvement, the patient was found to be confused on day 5. A prolonged investigation detected acetone (a metabolic product of isopropanol) in the blood – the patient had tried to relieve his alcohol cravings by drinking hand sanitizer. Case 13-2019: A 54-Year-Old Man with Alcohol Withdrawal and Altered Mental Status


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.