Category: NEJM Highlights

Recon takes an analytical look behind select developments in healthcare

An opinionated take on NEJM highlights for August 2018

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

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What’s harder, making new drugs or improving care delivery at scale? An opinionated take on NEJM highlights for July 2018

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

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An opinionated take on NEJM highlights for June 2018

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

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Struggling: An opinionated take on NEJM highlights for May 2018

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

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An opinionated take on NEJM highlights for April 2018

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

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EHRs + Genomics = Drugs? – An opinionated take on NEJM highlights for March 2018

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

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An opinionated take on NEJM highlights for February 2018

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

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Two steps forward, one step back: an opinionated take on NEJM highlights for January 2018

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

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A golden age for gene therapy: an opinionated take on NEJM highlights for December 2017

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

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Gene therapy, headaches, and tattoos: an opinionated take on NEJM highlights for November 2017

Two new therapies against a horrible congenital disease – but trouble ahead on pricing… Spinal Muscular Atrophy (SMA) is a genetic disease that declares itself at a few months of age, and typically leads to death before the second birthday. Two studies for two different therapies are reported in the Journal. First, the final results for a phase 3 placebo-controlled trial studying nusinersen (Spinraza, Sarepta, approved by FDA Dec 2016) therapy which involves monthly injections into the infant’s spine of an RNA-based drug. These show a clear beneficial effect over

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Between the very common and the very rare – An opinionated take on NEJM highlights for October 2017

Between the very common and the very rare – An opinionated take on NEJM highlights for October 2017   Another tool for prevention in cardiovascular disease Taking aspirin daily has been standard of care for cardiovascular disease for decades, but attempts to demonstrate the additive usefulness of other agents to prevent clot formation have not been successful. Now things have changed: in a large study of patients with established cardiovascular disease, those who took rivaroxaban (Xarelto, Bayer) daily on top of aspirin did markedly better than with aspirin alone, although

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An opinionated take on NEJM highlights for September 2017

A new drug to address hard-to-treat severe asthma In ~10% of people with asthma, traditional therapies do not work well and they have recurrent exacerbations leading them to the ED. Over the past few years, a number of biologics (mAbs) have been developed to treat such patients, but each of these agents is targeted to a small subgroup with specific biomarker characteristics for which it has been shown to be effective, resulting in ultra-niche therapies with limited uptake.  For broader penetration of those modalities, what is needed is a drug

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Price, costs, value, and rules: An opinionated take on NEJM highlights for August 2017

At last, drug prices influence physician usage patterns Association of Reference Pricing with Drug Selection and Spending (subscriber access); Nitroprusside and Isoproterenol Use after Major Price Increases (free access) Not that long ago, the share of mind US physicians devoted to the cost of the drugs they prescribe was essentially zilch. Thankfully, times have changed as demonstrated in two interesting papers that describe natural experiments. The first compared trends in prescribing patterns at a payer that instituted reference pricing in 2013 vs. one that did not (reference pricing means that

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An opinionated take on NEJM highlights for July 2017

Taking stock: two decades of progress in heart failure: Here comes a clever study using existing clinical trial data to assess progress in standard of care over time for heart failure. For each trial, the authors assessed the rate of sudden cardiac death during the early part of the study (excluding patients with ICDs), and it appears that between 1995 and 2014, it decreased by nearly half.  As always, in observational retrospective studies, one has to worry about systematic biases around the population that are included (i.e. are they really

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June was negative-to-ambiguous: an opinionated take on NEJM highlights for June 2017

Stent news First there was angioplasty, then bare stents, then drug-eluting stents, and now the next generation: bioresorbable stents: each generation commanding a significant price premium for the manufacturers (but only for a few years). But, while bare stents and drug eluting stents were clear improvements on the previous standard of care, the case is not at all obvious for bioresorbable stents.  Now the latest news is that the Absorb stent (Abbott), instead of showing a benefit over the previous standard of care, appears to lead to a higher rate

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An opinionated take on NEJM highlights for May 2017

A hammer finds new nails (which happen to be eyeballs) The insulin growth factor receptor 1 (IGF-1R) was once upon a time a popular cancer target pursued by multiple biopharmas each with their own humanized antibody, and each without much success. In 2013, River Vision licensed the Roche compound teprotumumab, to treat Graves’ ophthalmopathy, a condition in which hyperactivity of the thyroid gland causes (among many other issues) bulging eyeballs with esthetic, comfort, and sometimes severe visual implications for which treatment options are limited. Nobody quite knows why the ocular

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April was a light month: an opinionated take on NEJM highlights for April 2017

Calendaring care The length of our sidereal year is an accident – we happen to be circling a G2 star from which the habitable zone where free surface liquid water can exist lies at around 150,000,000 km; by Newton’s laws this in turn corresponds to an orbital period that is our year.  Even if it is not particularly strongly connected to the underlying human biology, a lot of healthcare cycles are aligned to the Earth Year for convenience but is it effective and efficient? Individuals with diabetes are at risk

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Regeneration and mitigation: an opinionated take on NEJM highlights for March 2017

Gene therapy for sickle cell disease Typical diseases targeted by gene therapy are those for which there is a defect that prevents the production of a functional protein needed for normal life; remediation is achieved by inserting functioning copies of the gene, and fortunately, it is usually the case that expression at a low level is sufficient to greatly improve outcomes. The situation is different in sickle cell where the defective hemoglobin is actually harmful, and where success of gene therapy requires not only production normal hemoglobin, but replacement of

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It’s in the blood: an opinionated take on NEJM highlights for February 2017

A knock at the door of a monster franchise Adalimumab (Humira, Abbvie) is the best-selling drug on the planet with the bulk of sales coming from patients suffering from rheumatoid arthritis (RA). It is therefore quite a coup for Lilly/Incyte to have shown in a double blind controlled study that baricitinib, an inhibitor of JAK (an important intracellular signaling molecule), performed better in relieving the symptoms of patients with RA than adalimumab. It was all the more surprising given that another JAK inhibitor, tofacitinib (Xeljanz, Pfizer, now also approved for

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Keeping the pipes clean and the wires intact: an opinionated take on NEJM highlights for January 2017

An innovative modality to suppress PCSK9 Antisense technology relies on the concept that it is possible to interfere with the cellular genetic machinery in very specific ways by deploying short RNA sequences that are complementary to the message that one wants to suppress. The idea has been around for a while, but has only achieved limited success in very niche indications (see here for the two latest). This is what makes the publication of phase 1 trial of the antisense agent inclisiran (Alnylam and the Medicines Company) targeting the synthesis

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