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Transthyretin heats up Last month saw a couple landmark papers about the use of parenteral RNA drugs (from Alnylam and Ionis) in hereditary transthyretin amyloidosis with a focus mainly on mitigating the progression of polyneuropathy. But what matters most for the survival of these patients is cardiomyopathy and although the Alnylam paper did show some impact on that pathology, this was based on exploratory analyses of biomarkers, not pre-specified hard outcomes.  A few weeks later, Pfizer comes out with their oral Tafamidis with clear improved cardiac outcomes including survival, in a placebo-controlled RCT that included not only patients with… Read More

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RNA drugs coming of age Hereditary Transthyretin Amyloidosis (ATTR) is a genetic disease in which one of the alleles of Transthyretin (TTR), a protein produced by the liver and with a role in thyroid hormone metabolism, is mutated resulting in amyloid fiber deposits mainly in nerve and cardiac tissues. Patisiran (Alnylam) and inotersen (Ionis) are both oligonucleotides designed to knock down translation of TTR mRNA, the first through the silencing mechanism, the second through an antisense effect.  Phase 3 placebo-controlled studies published back-to-back in the journal show clear efficacy for both in reducing progression of neuropathy (and sometime improving it). Read More

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It’s hard to quit (and E-cigs don’t help) A large trial (6000 participants) comparing free cessation support, e-cigarettes, and a $600 cash incentive for sustained abstinence shows that none of these approaches are particularly effective with 1-3% overall success rates depending on the arm.  Prevention is where it’s at. A Pragmatic Trial of E-Cigarettes, Incentives, and Drugs for Smoking Cessation (free access)   NPs and PAs numbers are growing fast A look back at the last 15 years and forward to the next 15 shows that the physician workforce is growing at about ~1% per year while mid-level… Read More

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One more on the chin for Alzheimer’s A report of a large phase 3 study of the highly potent oral BACE inhibitor verubecestat (Merck) with yet again a lack of therapeutic effect, despite a dramatic reduction of the cerebrospinal fluid content of beta amyloid in various forms.  With a string of prior failures, this may be the near final blow for amyloid as a treatment target for Alzheimer’s disease (and Biogen’s adacanumab would be the end of the line if it also comes up tails). But note that the study population, although described as “mild-to-moderate”, clearly has sustained substantial brain… Read More

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Are we nearing an asymptote with implantable cardiac pumps? Severe heart failure is common, and spare hearts for transplant are rare, which has led to the development of implantable mechanical alternatives. In the last few decades, progress has been immense, and in the latest installment of a 3rd (4th?) generation pump, outcomes have reached a level where survival of several years is the rule. Still, at every iteration incremental improvement is less, and performance remains well behind what happens with transplant in terms of complications such as infection, stroke, or bleeding. One is left with the impression that perhaps, there… Read More

Posted by on in Biopharma

One way to think about disease[1] is as a loss of information[2] from the operating blueprint for human physiology.  Broadly speaking, there are three main possible types of informational defects depending on the nature of the informational encoding that is compromised. The first is genetic through loss of information due to corruption of the genetic (and sometime epigenetic) code, for instance in congenital disease or in cancer. The second is spatial through loss of architectural information due to cumulative changes away from a structural template. This prevents turnover of tissue – either routine or after injury… 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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A-fib in heart failure – time to be aggressive Over the last 15 years, there has been a growing body of evidence for the effectiveness of catheter ablation to treat atrial fibrillation (a-fib), a condition for which the standard of care has been anti-arrhythmic medications. A-fib commonly coexists with heart failure but until now it has not been clear whether medication or catheter ablation would be the preferred treatment – we now have the answer, at least for patients with a substantially reduced ejection fraction. In a randomized trial of ~350 patients, the medication arm’s death rate was about 25%… Read More

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Playing chess against cancer Tumors are not intelligent, but, because they have escaped mutational control, they constantly probe for mutations that will allow them to escape chemotherapeutic suppression. The epidermal growth factor receptor (EGFR) is a frequent driver of malignancy in the lung and as such, a target for EGFR inhibitors such as erlotinib (Tarceva, Roche) or gefitinib (Iressa, Astra Zeneca); unfortunately, tumors initially responsive to these agents quickly develop mutations which make them resistant. Osimertinib (Tagrisso, Astra Zeneca) was designed to overcome the most common resistance mutations and has been approved as rescue therapy for cancers that progress under… Read More

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Successes in gene therapy for hemophilia B and A Hemophilia A and B are X-linked genetic diseases which prevents the formation of functional coagulant factors VII and IX respectively and cause a propensity to bleeding in about 20,000 people in just the US. The standard of care of intravenous administration of recombinant factors is effective but also burdensome, expensive, and does not fully prevent the disabling sequellae of the disease caused by repeated bleeding in the joints. A possible cure is to deliver a functional copy of the defective gene piggy-backed on a viral vector. The proof of concept for… Read More