Author: Marc Herant

Recon takes an analytical look behind select developments in healthcare

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

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Clinicaltrials.gov 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 clinicaltrials.gov 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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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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An ADC renaissance: a resurgence of antibody drug conjugates for cancer

Summary: Antibody-drug conjugates (ADCs) have seen a record number of approvals in 2020. This comes after a first era of intense activity in the early 2000s followed by a period of relative quiescence from the late 2000s to mid-2010s. To understand how the nature of the ADC pipeline has changed over time, we have reviewed all 88 ADC oncology programs that have reached phase 2 development and beyond from 1997 onward. We found that, currently, the main contributor to growth is the development of ADCs which use antibodies directed to

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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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