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 patients on therapy, without breaking the blind (i.e. patients remained unaware of whether they had received active treatment or placebo during the first 24 weeks). In the additional 12-35 month follow-up there was a clear survival advantage of 6 months accrued to the patients who had originally been assigned to treatment. This will probably be approved by the FDA (and surely is already getting prescribed off-label). Unfortunately, the reward to the company who took the risk of testing this clinical hypothesis is likely to be limited: you can buy taurursodiol on Amazon as a supplement, and phenylbutyrate is already sold for urea cycle disorders. Which begs the question: how many potential treatments do we have on our shelves in the form of generic drugs that will never be tested because the outcome offers limited financial upside? Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis; Long‐term survival of participants in the CENTAUR trial of sodium phenylbutyrate‐taurursodiol in amyotrophic lateral sclerosis (open access)
New uses for drones:
Because a picture is worth a thousand words: Drone Delivery of an Automated External Defibrillator
KRAS in the cross-hairs
Clear oncologic driver mutations can make great targets: think BRAF in melanoma, or MET in lung cancer. KRAS is frequently mutated in CRC and NSCLC and many other cancers. Yet KRAS has frustrated efforts to drug – but it now appears that Amgen has finally succeeded. A phase 1 study on a broad range of cancers harboring the KRAS G12C mutation in patients with progressive, advanced disease (despite prior therapies) showed extremely promising results: the majority of patients achieved stable disease. Amgen’s main push is now in NSCLC – and they have been driving awareness buying up the back cover of every other NEJM issue with exhortations to “Find the unseen 13%” (a reference to the estimated share of KRAS G12C mutated NSCLC). KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors; One Step at a Time — Clinical Evidence That KRAS Is Indeed Druggable
Demonstrating the ultimate benefit of HPV vaccination
The theory behind HPV vaccination is that it will protect against cervical cancer, by preventing HPV infections. However, to date studies had insufficient follow-up duration to prove decreased rates of cancer, relying instead on the surrogate markers of HPV infection & precancerous lesions A new study from Sweden with 11 years of follow-up now provides direct evidence of cancer prevention: the data shows an overall benefit of 50 to 60% reduction of cervical cancer rate. Impressively, when only those vaccinated before the age of 17 are considered, that benefit increases to 90% reduction. Once established, cervical cancer is an awful actor – so parents, vaccinate your daughters! HPV Vaccination and the Risk of Invasive Cervical Cancer
Colchicine in heart disease continues to impress
As reported a year ago, colchicine (a generic drug typically used for gout) reduces the rate of major cardiovascular events in patients with a prior myocardial infarction (MI). Now a large Australian randomized controlled trial follows suit in a broader population of patients (beyond prior MI, it includes patients with known coronary disease) shows a hazard ratio of 0.69 (vs. placebo). There is a certain cheekiness in the article as they report their main results in a figure that precisely mirrors the article on the FOURIER trial of the PCSK9 inhibitor evolocumab (which achieved a hazard ratio of 0.85 in a very similar population). Now comes the interesting part: will colchicine, a low-cost generic, lacking the muscle of a large commercial sales operation, achieve sufficient clinical uptake to meaningfully affect CV health-outcomes? Colchicine in Patients with Chronic Coronary Disease
Algorithms coming to a hospital near you, and saving lives
With 21 hospitals integrated on a single EMR (EPIC), Kaiser has at its disposal a vast trove of clinical data and the ability to learn at scale. Kaiser investigators used the data to construct a scoring system to predict the likelihood of general medical/surgical ward patients transferring to an ICU in the upcoming 12 hours. The score was used for real-time alerts to remote monitoring nurses who could contact the local rapid-response nurse on the ward for further assessment, and cascade to the attending physician for a management decision if necessary. (The idea behind these two screening layers being to avoid alert fatigue.) Because deployment was staggered across hospitals, this enabled a natural experiment comparing patients who would have been identified by the alert system but where the new system was not yet rolled out (N=28,462) to those who were identified and received the intervention (N=15,487). The results are impressive: the death rate decreased 25% for the new system (16% vs. ~20%); surprisingly, a decreased rate of transfer to the ICU was also observed. The authors admit that the driver of change is uncertain, but I have my own theory. Put simply, “more eyes on the patients who need attention” improves outcomes. Two questions are on my mind: (1) Is it possible to continuously improve the predictive value of the scores using machine learning? (2) Will Google’s collaboration with Ascension deliver a similar, or even better, predictive model and tool? Automated Identification of Adults at Risk for In-Hospital Clinical Deterioration
The power of the nocebo
Many patients who begin statin therapy will experience unpleasant side effects (often muscle aches). However, since blinded trials failed to show an increased rate of these AEs in treatment vs. placebo arms, it remains possible that these side effects are driven by the power of suggestion. A clever study from Imperial College London recruited patients who had recently stopped statins due to side-effects and gave them 12 medication bottles (one for each month of the year), of which 4 contained a statin, 4 placebo, and the remaining 4 were empty. Over the course of the year, patients used the medication bottles (in random order) and recorded their side-effects and symptoms through a cell phone app. The upshot: there was almost no correlation between symptoms and taking actual statin pills. After completion of the trial, 50% of patients had restarted their statin. Reminds me of the aphorism: “I don’t believe in bad luck because it’s bad luck to believe in bad luck”. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects
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.