Author: Marc Herant

Recon takes an analytical look behind select developments in healthcare

An opinionated take on NEJM highlights for the second quarter of 2023

Preparing for the next pandemic: don’t waste the value of waste During the Covid-19 pandemic, I got in the habit of checking weekly the Boston sewage report, as a reliable, unbiased way of monitoring trends of infectious activity. There is clearly much more information to extract from waste monitoring and a recent report from the National Academies of Sciences, Engineering, and Medicine makes a number or recommendations. The CDC is implementing some of them, but in the end, exploiting this source of information will depend on 100s of local actors

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Trends and strategy in oncology development

PDF: Trends and strategy in oncology development Summary We review a sample of oncology programs from the past decade and arrive at the following key findings: The use of expansion cohorts in first-in-human (FIH) studies has grown significantly in the last decade, with an accompanying decrease in separate phase 2 studies Commercial-stage sponsors and early-stage companies backed by established VCs are much more aggressive in discontinuing programs quickly compared to other early-stage companies For drugs that achieve approval, the time from FIH to approval is much shorter for big pharma

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An opinionated take on NEJM highlights for the first quarter of 2023

Hypertension?! Antihypertensive drugs are so 80s and 90s (well, except for pulmonary hypertension) to the point that I cannot recall when I last read research in the NEJM about a new blood pressure drug. One of the reason is that we have so many existing drugs (most of them cheap generics) but despite this, a fraction of hypertensive patients are refractory and cannot get to their blood pressure goal despite using multiple agents. This is where baxdrostat (CinCor Pharma) comes in; it is an oral drug blocking the synthesis of

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An opinionated take on NEJM highlights for December 2022

An unusual article on road safety Motor vehicle accidents are a major share of morbidity and mortality in the young, and as such prevention has long been considered a medically adjacent area (e.g. with pediatricians asking about infant car seats etc.).  Still it was a surprise to see an article on an intervention specifically designed to improve road safety in the NEJM, but it applies specifically to teens with an ADHD diagnosis, for whom distraction while driving is a significant risk factor. In the study, 152 teen drivers with ADHD

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Hearts and souls: An opinionated take on NEJM highlights for October and November 2022

A psychedelic for refractory depression While major depression is awful, treatment-resistant depression (as defined not responding to at least two different courses of therapy) is worse with sufferers stuck in a long dark tunnel of anguish without a light at the end of it. Since psilocybin (the psychedelic agent in so-called magic mushrooms) has shown some effectiveness in depression, it seemed reasonable to test its differentiated mechanism of action in this high need patient population.  In this study that was mostly Europe-based but included sites in the US (finally), patients

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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,

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Trends in oncolytic virus therapeutics: then and now

PDF: Trends in oncolytic virus therapeutics: then and now The idea of using pathogens to treat disease is not new; ranging from phage therapy to malariotherapy (resulting in the only Nobel in medicine to a psychiatrist – in 1927), but it was really only with the onset of the biotech revolution in the 1990s that an old concept of using viruses as tumor killing agents started to come into its own.  As the ability to characterize viruses at the genetic level grew, it was followed by the techniques to genetically modify

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An excellent July vintage: an opinionated take on NEJM highlights for July 2022

Tirzepatide in pole position As previously described in this blog, GLP-1 agonists initially designed to treat glycemia in Type-2 diabetes are emerging as powerful weight loss agents in obesity independent of diabetic status. Recently, tirzepatide (Mounjaro, Lilly, approved May 2022) which combines GLP-1 and GIP activity has shown potential to be best in class, and this is supported by a 72-week study that randomized 2539 obese individuals to 3 different tirzepatide doses or placebo. The results are nothing short of spectacular with ~-21% mean change in weight at the optimal

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An opinionated take on NEJM highlights for June 2022

A cell therapy success against a solid tumor In CAR-T therapies, T-cells are transformed to express an antibody on their surface that allows them to home in on cancer cells and effect killing. This approach has seen remarkable successes in hematological tumors but not so much in solid tumors. However, efforts have been underway to use the intrinsic killing mechanism by T-cells which relies on the native T-cell receptor. The idea is that instead of inserting an antibody construct (i.e., the CAR-T approach), the T-cell receptor is modified to be

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An opinionated take on NEJM highlights for May 2022

A step forward for kidney xenotransplantation A report on the recent, well-publicized, temporary transplantation of kidneys from genetically modified pigs in two deceased individuals at NYU. The kidneys functioned well and there was no sign of acute rejection, but because these experiments took place over only 54 hours, this is not indicative of longer term compatibility of the transplant of kidneys from this particular strain of pigs. A question in my mind is why there have not been kidney xenotransplants in live patients yet – especially given a recent porcine

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An opinionated take on NEJM highlights for March-April 2022

The opioid crisis and patient abandonment A perspective from a February issue that I originally missed highlighting the plight of patients who have been on a long-term opioid regimen for chronic pain. They are often stable, but it is when their physician retires or leaves that all hell breaks loose because, in this day and age, they cannot find another physician to continue the regimen. For someone who has been taking large doses of opioid for many years, going cold-turkey, or even tapering, is just not an option. These folks

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The growth of small molecule drug classes over time

Modern drug discovery is largely based on the identification and validation of a biochemical target, and then screening and optimizing molecules that engage that target. Over time, this has given rise to an extensive set of small molecule drugs approved for human use with activity at specific biological targets. We wanted to answer the question of how many different targets are addressed by existing agents, and how the rate of addition of newly addressed-target has varied over time. To do this, we reviewed every small molecule drug approved since 1970

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An opinionated take on NEJM highlights for January-February 2021

Gene therapy in beta-thalassemia and sickle cell anemia Beta-thalassemia and sickle cell anemia are common genetic diseases of hemoglobin (Hb) which manifest themselves in the former through transfusion dependence, in the latter through painful vaso-occlusive crises that frequently land patients in the hospital in a pitiful state. BlueBird’s lentiglobin therapy is an ex-vivo gene therapy in which autologous stem cells are harvested, transfected with new HbA gene, and then returned to the patient. Because the HbA is slightly modified via a single amino-acid substitution (HbAT87Q), expression is trackable.  Now in

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Wrapping up 2021: An opinionated take on NEJM highlights for November-December 2021

In search of a diagnosis: deploying genomics at scale A substantial number of children have a disease identified as “rare” without having any kind of causative diagnosis (autism is not a causative diagnosis!). In a UK pilot study, 2,183 proband children were referred for exome sequencing with additional sequencing of family members if warranted. The overall diagnostic yield was surprisingly high, about 25% overall. Of the approximately half of probands who had neurological or sensory disorder, an explanatory diagnosis was reached in almost 40% of the cases. Two thoughts: 1)

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Taking on tough indications: An opinionated take on NEJM highlights for October 2021

What makes an indication especially tough? The combination of a lack of understanding about the mechanism of disease and a lack of clarity on what endpoints would be sufficient for approval of a therapy in studies of reasonable duration. This month, two good examples in the NEJM.   A phase 2b success in NASH Non-alcoholic steatohepatitis (NASH) is a common slow-progressing disease and for most affected individuals the timescale to liver-related morbidity is at least 20 years, although some progress much faster. NASH is also a graveyard of clinical programs

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From bleeding edge to basics: an opinionated take on NEJM highlights for August and September 2021

The weird world of synthetic biology In biology 101, one learns about the alphabet that translates DNA/RNA code into amino acids sequences ultimately resulting in proteins. Given that there are 64 possible triplet codons and 20 amino acids, multiple codons can map to the same amino acids. But this mapping can be reassigned including incorporating new amino acids – it has been done in E. coli with the promise of generating biologics with novel properties, although applications are not yet clear. A more practical application is to create strains of

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Summer catch-up: an opinionated take on NEJM highlights for May-July 2021

Cancer and mutational complexity Probably the biggest news in cancer treatment this year is the approval of sotorasib (Lumkras, Amgen) which received accelerated approval in lung cancer with mutated KRAS (G12C) and has potential for use in other cancers (see here). Mirati is hot on the trail with adagrasib, but unusually for a drug in the approval process, their paper in the NEJM is a deep dive into the mechanisms of resistance to KRAS G12C inhibition that lead to treatment failure. They present very detailed in vitro studies in which

Read More and AI-related studies: a brief status check in April 2021

Healthcare is by nature conservative; despite a huge level of interest for artificial intelligence (AI) and machine learning (ML) techniques, significant penetration in standard workflows of care will depend on demonstrations of safety and efficacy. As a result, it is today’s pipeline of clinical studies using AI/ML that will determine mainstream usage tomorrow.  In order to better understand this pipeline, we have mined for characteristics and trends of registered studies making use of AI/ML. Unsurprisingly we see strong growth, but starting from a very small baseline. Although most of

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Remodel, rewire, repopulate: an opinionated take on NEJM highlights for April 2021

Remodeling to health? Chronic disease progression is often due to a maladaptive tissue response which leads to remodeling – such as cardiac hypertrophy with hypertension.  While most therapeutics focus on tamping down the injury, sotatercept (Acceleron Pharma) in pulmonary arterial hypertension (PAH) breaks new ground by focusing on the remodeling. This modulator of the TGF-beta superfamily looks to inhibit the remodeling of the pulmonary vasculature that worsens the PAH over time, and eventually leads to the demise of most patients. In a 24-week placebo-controlled phase 2 trial (N=106), the pulmonary

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