Category: NEJM Highlights

Recon takes an analytical look behind select developments in healthcare

Balancing the humors: an opinionated take on NEJM highlights for March 2021

A new approach to schizophrenia Antipsychotic agents treat schizophrenia by manipulating the dopaminergic system. While they are effective at treating psychosis, they can have major side effects and they lack the ability to address so called negative symptoms e.g. apathy, lack of social connection, poverty of thought.  Enter the muscarinic cholinergic system which is tricky to manipulate in the CNS without untoward systemic effects as Lilly found out with their M1/4 agonist xanomeline.  Karuna Therapeutics has now licensed the molecule and cleverly combined with it with trospium, an antagonist with

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All immunity: an opinionated take on NEJM highlights for February 2021

We can cure Hep C but not immunize against it Sovaldi and other drugs have made curing chronic Hepatitis C a routine, if expensive, proposition. Still, given how common Hep C infection is, and how it can irreversibly damage the liver without overt signs, a vaccine would be highly valuable. Unfortunately, an NIH sponsored trial with a GSK vaccine in 548 IV drug users at high risk of contracting the disease failed to show any protection: 28 participants developed chronic Hep C evenly divided between the placebo and treatment groups. 

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While we wait for our shot(s); an opinionated take on NEJM highlights for January 2021

Incremental progress in the fight to treat heart failure After a decade or more of relative quiescence in the 2000s, a volley of new therapies have come to the forefront in the pages of the NEJM: sacubitril valsartan (2014 – Novartis’ Entresto), various SGLT2 inhibitors such as dapagliflozin (2019, AstraZeneca’s Farxiga), vericiguat (2020 – Merck’s Verquvo), and now a 2021 entry from Amgen in the form of the cardiac myosin activator omecamtiv mecarbil. None of those are a panacea, and of the four listed, omecamtiv has the lowest efficacy profile

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Closing a tough year: An opinionated take on NEJM highlights for December 2020

Cardiovascular health – go big or go narrow? A follow up on the development of evinacumab (Regeneron), an inhibitor of ANGPLT3 (see this opinionated take from 2017), confirming the safety and LDL reduction effect in a population of individuals with cholesterol levels refractory to other therapies (including PCSK9 inhibitors).  Given the history of PCSK9 inhibitors, the development path of this asset will be interesting to follow. Of the 6 trials listed on clinicaltrials.gov not one has anything close to a clinical endpoint – it’s all biomarker based. That will probably

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We are back and catching-up: An opinionated take on NEJM highlights for Sep, Oct, and Nov 2020

Small but real progress in ALS: Despite enormous public attention and significant effort, ALS remains a disease for which the development of new therapies has been challenging. Animal models showed potential activity against ALS by sodium phenylbutyrate and taurursodiol, both old (generic) molecules. Now, their effect in combination therapy has been confirmed in a randomized controlled trial.  What’s especially interesting is that the effect at 24 weeks (the original duration of the trial) was a modest though statistically significant improvement in functional scores. However, the trial was extended with all

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A slow summer: An opinionated take on NEJM highlights for August 2020

A cheap, low tech intervention for a common Achilles’ heel When I am out and about, for instance at the grocery store, I am always surprised at the number of people I see with swollen legs. About half a million times a year in the US, these folks end-up in a hospital bed with cellulitis (a skin and subcutaneous infection) of the leg. In a single center randomized trial with 84 patients who had an episode of cellulitis, an Australian group tested whether compressive stockings would make a difference in

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An opinionated take on NEJM highlights for July 2020

Stunting and the microbiome Stunting (low growth for age) affects > 20% of children across the globe and has major impact on the brain, on health, and on opportunities for success in life. The precise mechanism of stunting has remained elusive. Sanitation and diet diversity play a role but targeted interventions in these areas have had less impact than hoped for. Jeff Gordon from WashU has spent the last decade exploring the relationship between stunting and the microbiome, and now his group reports on a study that shows a clear

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Covid, medical education, and a bit of RNAi: An opinionated take on NEJM highlights for June 2020

What’s your blood type? The first report of a genome wide association study of Covid-19 severity on approximately 4000 patients and controls conducted in Spain and Italy identifies a locus on the 3rd chromosome that spans 6 potential genes for which polymorphisms appear to drive severe disease. Once the culprit gene is determined, this may help us think about drug targets. Reassuringly the study also recovers the correlation of severity with blood group that has empirically been noted in the past (on chromosome 9 although the signal is not as

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

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

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Covid and the rest: An opinionated take on NEJM highlights for April 2020

Hydroxychloroquine does not seem to help much in Covid-19 (with caveat) There has been significant attention to the use of the antimalarial hydroxychloroquine in Covid-19, but data on impact has been scarce. In the absence of clarity, New York Presbyterian Hospital left the use of this drug to the discretion of individual treating physicians from mid-March to early April. This has led to two cohorts of Covid-19 patients which can be compared in retrospective analysis: patients treated with hydroxychloroquine (N=811) and those who did not receive the drug (N=565).   The

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The infectiologists have the floor: An opinionated take on NEJM highlights for March 2020

A first Covid-19 interventional study – unfortunately negative The first of what promises to be a series of many interventional studies for acute Covid-19 disease to appear in the Journal. Lopinavir is an HIV drug that had shown in-vitro activity against SARS, another corona virus, and ritonavir is a drug that boosts lopinavir concentration by reducing its rate of metabolization – so it was worth trying the combo in sick patients with Covid-19.  The study was clearly conducted in quasi-battlefield conditions in one of Wuhan’s main hospital from mid-January to

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Coronavirus and more: An opinionated take on NEJM highlights for January/February 2020

Keeping up with COVID-19 It’s not easy for a refereed weekly print periodical to keep up with an epidemic that evolves on a daily basis, but the NEJM is doing its best and all articles are free on-line. Most interesting beyond the description of the initial cluster in Wuhan are: (1) the first US case was quite severe and the patient received the antiviral remdesivir (was in development by Gilead for Ebola, but showing activity against coronaviruses) – it is now in testing in China; (2) the rigorous documentation of

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Tax dollars doing good work: An opinionated take on NEJM highlights for December 2019

The loneliness of the patent-less drug Colchicine is a very old drug commonly used in gout with an anti-inflammatory mechanism of action that is not well defined. It is a generic (although in the US, the story is somewhat peculiar) and therefore incentives are lacking for further development in new indications by private companies. Given a well-established (but not well-understood) connection between inflammation and cardiovascular events, some researchers have hypothesized and explored potential utility in patients with high cardiovascular risk – but this would have to be validated by a

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An opinionated take on NEJM highlights for November 2019

A triumph for cystic fibrosis patients (and for Vertex) Phase 3 confirmation that the benefits seen in early trials from triple-combination therapy of elexacaftor, tezacaftor, and ivacaftor, are sustained and applicable to 90% of the cystic fibrosis patients.  Every metric is unambiguously better: sweat chloride concentration, forced expiration volume (FEV1), respiratory symptom questionnaire, pulmonary exacerbations (down 60%), hospitalizations (down 70%). If anything, with 400 subjects, the study was probably overpowered by at least a factor of 4 to show effect.  It is great news for CF patients most of whom

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An opinionated take on NEJM highlights for October 2019

Genomic applications and scalability Two very different papers about applications of genomics, one for a very common clinical scenario, the other for an ultra-rare disease. It is well known that while clopidogrel (now available as a generic but branded as Plavix) is an excellent antiplatelet agent for a majority of patients, it works poorly in some due to individual genetic idiosyncrasies of cytochrome driven drug metabolism. Since then, other agents (tigracrelor AKA Brilinta, prasugrel AKA Effient) with a similar mechanism of action but more consistent metabolism have come on market,

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An opinionated take on NEJM highlights for September 2019

Best care vs. good care In wealthy countries, the recommended standard of care can often lead to complex medication regimens requiring frequent follow-ups: this can be very challenging for people who though they live in wealthy countries but are poor themselves. In developing countries, efforts have been made to prioritize simplicity and population level impact through one-size fits all polypill interventions, but that has not been tested in the US. Here the authors report on a randomized study including 303 individuals living in poverty and at risk for cardiovascular disease.

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Busy summer: An opinionated take on NEJM highlights for July/August 2019

Is the lack of new (non-viral) antibiotics a market failure? A lament about the lack of success in getting the biopharma industry to invest sustainably in the development of new antibiotics against highly-resistant organisms, and a recommendation “it is time to seriously consider the establishment of nonprofit organizations for developing these lifesavings drugs”.  Let’s be clear; the reason economic viability of this therapeutic area is problematic is due to three confluent factors: (1) treatment is curative – i.e. does not provide recurrent revenues (2) the targeted population is small (3)

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Fishing for nucleic acids: An opinionated take on NEJM highlights for June 2019

Huntington’s disease: light at the end of the tunnel? The awful thing about Huntington’s is that in most cases, people know they are going progressively lose their mind at an early age, but there is absolutely nothing they can do about it.  Recently there has been tremendous excitement around suppressing toxic huntingtin production in the brain by using antisense oligonucleotides (ASOs) administered intrathecally (i.e. in the cerebrospinal fluid through the spine). Two ASOs are in full blown clinical testing: HTTRx (Ionis and Roche) which does not discriminate between mutant and

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An opinionated take on NEJM highlights for May 2019

TAVR for all? TAVR has become the standard of care for patients who need an aortic value replacement but are at high/medium surgical risk.  But what about those at low-risk? Two studies answer that question, one with the Edwards device and the other with Medtronics. Both show that TAVR is superior along a number of end-points (stroke, hospitalization duration, atrial fibrillation) both at 30 days and at 1-2 year. Long-term outcomes remain a question though. Low-risk patients are younger (mean age 73-74) and will live with their valves longer, which

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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

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