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 RA) did not outperform adalimumab in a similarly designed study (but with less power).  Given that baricitnib is an oral vs the injectable adalimumab, there is a real possibility that the crown will be passed on (likely to a cancer drug). Baricitnib was just approved in Europe and we should hear shortly from the FDA. Just as I have seen for a while happy faces dancing across the pages of the Journal promoting Humira and Xeljanz (even in this very issue), I look forward to enjoying the creativity of the baricitinib marketing team adorning the NEJM.  Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis (subscriber access)


Steady progress in the mechanical support of the failing heart

Advanced congestive heart failure carries a dismal prognosis for which transplantation is the best remedy, but there are not enough cadaveric hearts for all who need them, and we have not figured out how to grow new hearts yet. Since the implantation of the Jarvik 7 in 1982 there has been a broad push to replace or supplement the heart with implantable mechanical pumps – the first generation being pulsatile piston-like systems, the second generation being axially driven pumps. Two papers compare the most recent generation of centrifugal pumps with magnetically levitated rotor with the axially-driven pumps. The Heartmate 3 (Thoratec) out-performed the previous generation while the Heartware device (Heartware) matched it. The rate of stroke and infection makes it still an iffy pitch for permanent placement (destination therapy), but the usage in bridge-to-transplant has become routine. But perhaps the strongest sign that this approach is now becoming mature is that since those trials, Thoratec was acquired by St Jude (in turn acquired by Abbott) and Heartware was acquired by Medtronic. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure; Intrapericardial Left Ventricular Assist Device for Advanced Heart Failure; Mechanical Circulatory Support Devices — In Progress (subscriber access)


Stopping the swelling

Hereditary Angioedema (HAE) is a debilitating inherited disease characterized by episodes of massive swelling which are often disabling and occasionally fatal when the airway is affected. For sufferers (a few thousand in the US), existing treatment options are only moderately effective and with substantial inconvenience. Lanadelumab (Dyax now owned by Shire) is a monoclonal antibody directed against kallikrein which is an intermediate component of the inflammatory cascade implicated in HAE, which can be administered subcutaneously every 4 weeks. In a phase 1b trial, there was a clear dose-response relationship with near cessation of episodes at the higher dosage.  Cinryze (Shire), the next best therapy, was priced at more than $200k/patient/year. Lanadelumab should scale new heights given that it appears to be both more efficacious and more convenient (Cinryze is IV, lanadelumab is SQ).  Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis; Kallikrein Inhibition for Hereditary Angioedema (subscriber access)


Stopping the blocking

Sickle cell is a debilitating inherited disease characterized by extremely painful episodes during which blood cells deform into sickle-like shapes, clogging small vessels, and leading to organ damage. There are about 100,000 individuals affected in the US, with many hospitalized more than once a year for the management of their symptoms. Crizanlizumab (Selexys) is a monoclonal antibody directed against P-selectin which an adhesion molecule expressed on the wall of blood vessels, and therefore expected to decrease the clogging of vessels in sickle cell. Indeed, in a double-blind, placebo-controlled study those patients who received monthly intravenous high doses of crizanlizumab had their rate of sickle crises decrease by half. It will be interesting to see how the commercial fate of this product compares to Lanadelumad and/or Cinryze (above) given that the target population is black, often poor and on Medicaid. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease; Go with the Flow (subscriber access)


The eye of the beholder

As opposed to fee-for-service systems, the implementation of performance-based or capitated payment systems is highly dependent on the ability to properly risk adjust for the underlying health status of the covered population, because an allowance needs to be made for organizations that cover sicker populations. Beyond the influence of basic demographics (age, sex), this risk adjustment is not at all easy to do, and has given rise to a billion-dollar industry dedicated to the mapping of a galaxy of medical conditions onto a one-variable scoring system for healthcare consumption.  With this in hand, risk scoring of a population is determined by the medical diagnoses of its members. But in a clever analysis, it is shown that there are significant variations in the diagnostic intensity depending on region. The way this was done was by looking at the set of individuals with Medicare coverage who move from one region to another and measuring how their diagnosis list evolves relative to individuals who make the opposite move.  The analysis translates in variations of plus or minus 10% in risk scores, with higher rate of diagnoses inflating risk scores in the North-East, in Texas, in Florida, and in California, and with lower rate of diagnoses deflating risk scores in the West (ex-CA) – a pattern that may be correlated with the penetration of managed care (i.e. physicians are pushed to be more comprehensive in their diagnoses because it is good for risk adjustment).   Given that the financial margins on coverage tend to be small, this is a significant effect that adds to the already significant challenge of risk-adjustment. Adjusting Risk Adjustment — Accounting for Variation in Diagnostic Intensity (subscriber access)