An opinionated take on NEJM highlights for the first quarter of 2024

Hitting reset for the immune system

Every time I get into a new issue of the NEJM, I have a sense of anticipation as in “will this one have an article that blows my mind?” It doesn’t happen very often, perhaps once or twice a year, but when it does, it’s an awesome feeling. From Germany, an application of CAR-T (CD19 directed) therapy to severe autoimmune disease reporting on 15 patients, 8 with severe SLE with renal involvement, 3 with myositis, and 4 with scleroderma, all progressing despite treatments with other immune suppressive agents. Post CAR-T therapy, all went into sustained remission and were able to discontinue all immune suppression.  Baseline vaccine-related antibodies were largely retained and new vaccinations showed the expected IgG responses.  One question left is the relative contribution of the lymphodepleting conditioning regimen (fludarabine and cyclophosphamide prior to infusion of autologous chimeric T-cells) vs. the CAR-T themselves. Will this be used broadly? Probably if the results hold – these are bad diseases, expensive to treat. And given the use of the Miltenyi CliniMACS system, one could well imagine this becoming a differentiated “transplant procedure” offered by one or two dozen specialized centers in the US rather than a drug as CAR-Ts have been treated until now.  CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up


Drugs as a major profit center for hospitals

Recent years have seen much controversy over PBMs and manufacturers with respect to drug pricing, but less has been said about the position of hospitals in that ecosystem even though they play a major role in the physician-administered drugs.  Though hospitals are typically limited in what they can bill through government insurance schemes (i.e. Medicaid and Medicare), their ability to charge private payers is less constrained and it turns out they make full use of that freedom. In a study of over 4 million drug infusion visits in hospital outpatient department, the charge to the payer for the drug was on average more than triple(!) the acquisition price. As my colleagues at Recon have pointed out in this piece, eventually payers will demand change. I thought there might be follow-up letters to the editor on this but so far, it’s been crickets. I guess nobody wants to talk about this. Hospital Prices for Physician-Administered Drugs for Patients with Private Insurance


A slow fuse to Alzheimer’s

We kind of already knew it, but a longitudinal 20-year aging study conducted in China confirms it, physiological changes begin a long time before the clinical diagnosis of Alzheimer’s disease. By comparing selected matched cohorts of 648 individuals who developed Alzheimer’s vs. 648 who did not, it is apparent that levels of Abeta begin to follow a separate trajectory about 18 years before diagnosis, tau 11 years before diagnosis, and neurofilament (light chain) 9 years before diagnosis. Cognition itself starts to be measurably impaired 6 years before diagnosis.  Let’s hope now that this will be like dyslipidemia which takes decades to cause overt cardiovascular disease, but where even late interventions (e.g. with statins) can make a very meaningful difference in progression and outcomes. Biomarker Changes during 20 Years Preceding Alzheimer’s Disease


Jiggling the Alzheimer brain to improve drug penetration

I did not know that, but apparently, focused ultrasound can loosen the blood brain barrier (BBB) and locally improve drug penetration. A group out of WVU tried it with aducanumab and report on a series of three patients with early Alzheimer’s in whom they subjected one hemisphere to ultrasound and left the other one alone as a control. Sure enough, the decrease in amyloid deposits was much larger on the ultrasound side. Does this matter? Not sure given how good at mopping up amyloid recent entrants are (particularly Lilly’s donanemab), but of real interest would be whether this is a way one could get fewer ARIA (Amyloid-related imaging abnormalities) adverse events that bedevil anti-beta amyloid therapies. Ultrasound Blood–Brain Barrier Opening and Aducanumab in Alzheimer’s Disease


CRISPR vs RNA, the sequel

Anything gene product reversibly blocked with RNA (ASO or RNAi) can in principle be permanently blocked by disruption of the original gene via CRISPR. Continuing on a previous pattern established with TTR,  this time Intellia is looking at hereditary angioedema, a genetic disease where the production of kallikrein (and downstream bradykinin) is uncontrolled. Ionis has an ASO in development against (pre)kallikrein with encouraging preliminary results. In comes Intellia with CRISPR construct against the same target; with a one-time treatment, they were able to show in an initial cohort permanent reduction in kallikrein, and >90% reduction in angioedema attacks, and no meaningful adverse events. It does help to know that there are individuals without functional prekallikrein genes that live healthy lives (apparently this is known as Fletcher factor deficiency). It probably ought to be the case that any RNA inhibition project should seriously consider the potential for CRISPR competition.  CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema


Progress against NASH, but has the world changed?

A couple weeks ago saw the first FDA approval of a drug specifically to treat NASH (Rezdiffra, Madrigal), and in parallel the phase 3 pivotal study was just presented in the Journal.  The results are undeniably strong with highly statistically significant improvement in before and after liver biopsies at 52 weeks, and metabolic amelioration of markers of dyslipidemia and liver injuries. However, two thirds of the trial population had diabetes, the average BMI was 35, but only 15% were on GLP-1 receptor agonists. The world had changed since; today, this class of patient should be on Ozempic/Mounjaro, and although no one knows for sure, there are strong hints that in and of themselves, GLP-1 receptor agonists may already remedy NASH. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis



When the best is the enemy of the good, sometimes the good is the enemy of the best: or the conundrum of colorectal cancer (CRC) screening

Colonoscopy is an outstandingly accurate cancer screening procedure, but it’s burdensome and kind of expensive and a lot of folks just skip it.  Fecal occult blood testing is easy, but accuracy is poor, and this is why major efforts have been made to create better non-invasive tests. Two back-to-back articles describe the performance of a cell free DNA blood-based test (Guardant) and a stool DNA test (Exact Sciences). Both generally improve on FIT, but fall way short of colonoscopy, because of low detection of precancerous lesions (<50%), as well as the low PPV (~3-4%) of a positive test. So, what is a PCP to do? Ideally tell the patient who has already declined a pure screening colonoscopy to do these tests and then get a colonoscopy if they come back positive (and then get slammed by a co-pay because it is a diagnostic colonoscopy, not a screening one)?  But what of the patients who are going to forego the colonoscopy, because they put excessive trust in these not very accurate tests – aren’t these tests in a way “harming” them? The problem of CRC screening lives on. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening; Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.

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