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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, but they are very expensive. Given that we can now… Read More

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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) unmet need is unpredictable. On its face, the risk-reward… Read More

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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 normal huntingtin, and WVE-120101/2 (Wave Therapeutics and Takeda) which… Read More

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Target assessment with genetic polymorphisms Please bear with me for a long (but interesting!) story. Bempedoic acid (Esperion) is an inhibitor of ATP citrate lyase (ACLY), an enzyme in the cholesterol synthesis pathway (upstream of HMG-CoA reductase, the target of statins). In a study of 2,230 patients at high risk for cardiovascular events, on maximum statin therapy, and LDL > 70 (basically the PCSK9 target population), bempedoic acid was well tolerated and lowered the LDL by around 16% – a substantial effect. This would potentially position bempedoic acid, an oral drug, to take on the parenteral PCSK9 inhibitors as main… Read More

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Genetic trade secrets In 2012, the US Supreme Court decided a case known as “Prometheus” establishing that therapeutic methods based on biomarkers were not patentable – this essentially blocked one of the two main avenues to monetizing intellectual property from the very hard clinical work of figuring out personalized medicine, i.e. what works for whom. The other avenue that would remain is that of trade secrets, and I for one, have been waiting for the other shoe to drop.  A hint comes from a study on ovarian cancer just published in the NEJM: patients were selected on the basis… Read More

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GWAS, Regeneron and Geisinger, and liver disease Genome wide association studies (GWAS) look at broad populations for gene variants associated with a particular phenotype. Often, like in Type II diabetes, one finds hundreds of genes correlated with disease, and that’s obviously not very helpful. In lucky cases there are only a few variants, and that gives clues on potential underlying mechanisms of disease. But for the very lucky, there is a jackpot which is finding a variant that is actually protective against the disease – this is what happened with PSCK9.  It’s as good as one can imagine in defining… Read More

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There is such a thing as too much hygiene The prevalence of asthma in children has increased dramatically over the last few decades. Observational studies have shown that children in “dirty” environments such as farms seem to be relatively protected from asthma.  A theory is that the lack of exposure to microbes leads to higher sensitivity to allergens, but this causality has been hard to show. Amish and Hutterite farm communities are genetically similar, but Amish rely on animals instead of machinery, and Amish children have much lower incidence of asthma. In a fascinating study comparing Amish and Hutterite, it… Read More

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Surgical volume and referral for surgery: The impact of surgical volume on outcomes has been well documented, but is it top of mind with physicians referring patients to surgery? Readers of the Journal were polled on a hypothetical scenario whereby a community physician would be referring a patient in need of a major surgical procedure to either a nearby community hospital with a well-respected general surgeon doing approximately 5 of these cases a year versus a tertiary medical center 40 miles away. The great majority of readers chose the option to refer to the tertiary medical center. This does not… Read More

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The rise, fall, and rebirth of the Chinese healthcare system A fascinating account of the evolution of the Chinese healthcare system which almost seems to be an upside-down picture of the rest of the country’s development. Tremendous public health improvements occurred in the 50s, 60s, and 70s but the transition to a free market model of healthcare in the 80s seems to have been a disaster only mitigated by the general increase in wealth of the population. Seeing this as a major threat to social stability, the Chinese government has been trying to pick up the pieces with reforms in 2003… Read More

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A promising agent for Crohn’s Disease, a miserable illness Crohn’s is an inflammatory bowel disease that is notoriously unpredictable; flares can affect any part of the digestive tract and lead to grave complications. In this double-blind phase 2 study, patients were dosed with mongersen (licensed by Celgene) an anti-sense oligonucleotide that down-regulates the expression of a protein implicated in the inflammatory cascade. In general these classes of medications have to be given parenterally but in this case the target is the gut so it can be taken orally. At two weeks of treatment, the response rate was about 60% in the… Read More