An opinionated take on NEJM highlights for October 2019

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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 use genomic information to predict the metabolism of clopidogrel, would a clopidogrel prescribing strategy informed by genotype analysis be as effective as using the newer agents? A Dutch randomized study following ~2,500 patients for a year after having received a stent(s) says yes – and even hints at superiority of clopidogrel over newer agents, as long as the “abnormal” metabolizers are weeded out, and for a lower cost.

Batten’s disease is a rare syndrome which leads to neurological regression and eventual death of children in their first decade of life.  A case report describes a young girl who was diagnosed at the age of 6 after a thorough and somewhat challenging search for a genetic cause which identified an abnormal transposon insertion in intron 6 of the MFSD8 gene. Further investigation showed that this was causing missplicing of exon 6 with a piece of intron 6. The team then designed a range of antisense RNAs (ASOs) to prevent missplicing and after testing those in a culture of the patient’s own cells determined the sequence that would optimize the normal to abnormal mRNA ratio as well as normalize the cellular phenotype. After 1 month of toxicology testing in rats, the best ASO was administered to the patient with an alleviation of seizure symptoms and stabilization of overall neurological state.

While they are at opposite ends of the spectrum of genomic applications, these approaches are both triumphs of genomics, but also a reminder of a gap to scalability which can only be filled when a full genome becomes a part of our medical record.

In the case of antiplatelet agents, is it plausible to expect a physician to order a special test for clopidogrel pharmacogenomics, wait for the results and adjust the treatment when there are (albeit expensive) alternatives?  On the other hand, if the patient had already been sequenced, it would just be a matter for the EHR to pop-up a window on the antiplatelet order tab making a recommendation for/against clopidogrel.  In the case of the unfortunate child with Batten’s disease the heroic effort that eventually led to some therapeutic benefit (but well short of preservation of function) is unlikely to be broadly replicable to other single cases in the foreseeable future. But, if again the genome was part of the medical record, standard prenatal / preconception counseling could include a fully scalable analysis of the risks for recessive diseases.

A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI; Clopidogrel Pharmacogenetics — Why the Wait?; Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease; Drug Regulation in the Era of Individualized Therapies (subscriber access)

 

Is THC the cause of most cases of vaping-associated serious lung injury?

The NEJM publishes correspondence and reports on the on-going surge in severe pulmonary illness associated with vaping. A vast majority (80%, but not 100%) of those affected report vaping THC. However, in the absence of good data on the source population (i.e. what’s the prevalence of any THC use among vapers), it is hard to interpret whether there is indeed an association with THC use, or whether this is just because most people who vape at least occasionally vape THC. The University of Michigan Monitoring the Future report seems to show that vaping both nicotine and THC is common.  Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin — Preliminary Report; Real-Time Digital Surveillance of Vaping-Induced Pulmonary Disease; Pathology of Vaping-Associated Lung Injury (free access)

 

An interesting ad

The prime location on the back-cover says in big letters: “EGFR TKIs are the recommended first-line option, independent of PD-L1 expression” and further down “There is no evidence to support first-line treatment with IO in EGFRm patients”. It seems that the buzz around Keyrtuda (pembrolizumab, Merck) in lung cancer has become so strong that some docs are using it in situations where a driver mutation in the epidermal growth factor receptor (EGFR) exists and where EGFR tyrosine kinase inhibitors (TKIs) ought to be the first choice. AstraZeneca is attempting to set the record straight and remind docs to use Tagrisso (osimertinib) – or is it for the payers?

 

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