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 issues occur, but hyperactivity of fibroblasts which are cells that lay and modify connective tissue has been observed, and they have abundant IGF-1R.  This eventually led to a proper double-blind RCT with 87 patients for which excellent clinical activity and minimal adverse events are reported. Three takeaways:

  1. Affected patients will have an option when previously they had minimal alternatives, a fact not lost on Horizon Pharmaceutical, a company with talent for monetizing value, which has since acquired River Vision;
  2. Issues of tissue architecture have typically been left to the surgeons with drugs focused on fixing cellular metabolism – but with fibroblasts becoming a target, it is increasingly possible to envision tissue remodeling via drugs;
  3. The universe of agents with highly specific biological targets is growing fast and it is likely a fair guess that there is a mapping between the thousands of compounds biopharma has put through their paces, and thousands of unaddressed rare diseases – therapies are on our shelves, we just don’t know which shelf!

Teprotumumab for Thyroid-Associated Ophthalmopathy (subscriber access)


A small step toward cells replacing drugs

The omentum is essentially a large sheet of well-vascularized fat that hangs inside the abdominal cavity from the bottom edge of the stomach and covers the rest of the gut, blanket-like.  In a letter to the editor, a group from the University of Miami reports on the transplant of pancreatic insulin-producing islet cells from a deceased donor to a patient with Type I diabetes. The cells were seeded laparoscopically into the omentum where they apparently took hold and thrived so that the patient was able to discontinue insulin over the 12 months of follow-up (but did have to take immunosuppressants to prevent rejection). This has much broader implications than a cadaveric transplant approach to Type I diabetes – given the current rate of progress in bioengineered cell lines, one can imagine a future where the omentum will regularly be used as a nidus for a variety of interventions based on engineered cells that secrete a therapeutic agent (with a kill switch of course). Bioengineering of an Intraabdominal Endocrine Pancreas (free access)


Beware of biomarkers

The latest (and possibly last) CETP inhibitor study looked at the effect of evacetrapib (Lilly) on cardiovascular outcomes on a cohort of ~12,000(!) high risk patients (half got placebo), and was halted early due to a futility analysis. Cholesteryl ester transfer protein (CETP) plays an important role in determining levels of circulation cholesterol/lipids and as such has been a key target of interest in cardiovascular disease.  In addition, rare mutations of CETP have been observed that increase and decrease cardiovascular risk. Two prior major attempts in inhibiting CETP failed – torcetrabip (Pfizer) which was interpreted as the result of an off-target effect of increased blood pressure —  dalcetrabib (Roche) which only increased HDL and left LDL (bad) cholesterol unchanged. Now comes, evacetrabip, which did not increase blood pressure meaningfully, increased HDL, and lowered LDL by about 30%. By all that we know about atherosclerosis, this drug should have worked. Well, it did not, and there are two lessons:  there are some fundamental things we don’t understand about atherosclerosis, and biomarkers often lie, and there is unfortunately no short-cut from end-points of clinical value. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease (subscriber access)


Beware of expensive, unproven drugs mostly supported by biomarkers

The FDA’s accelerated pathway allows a biopharma company to bring to market a drug for which there is high unmet need on the basis of clinical data that meets a lesser burden of evidence, in exchange for a commitment to run confirmatory post-approval studies. For obvious reasons, this is a highly sought after pathway, and accounts for about 10% of new approvals. In a thoughtful perspective article, the authors highlight the problem that because these are areas of high unmet need, once approval is obtained, the pricing power of the manufacturer is enormous (frequently resulting in costs > $100,000 per patient), but the true value of the drug is uncertain until the confirmatory studies are done – and there is no economic incentive for the manufacturer to complete those quickly.  The proposal of the authors is to put in place a mechanism that ensures public payers (Medicare and Medicaid) will pay considerably less for drugs that have gone through accelerated approval until the value of the drug is confirmed by post-approval studies. As they imply, this is likely only feasible if a broader framework of value-based pricing for expensive drugs is put in place – something that is a hot area of interest currently, but would require a major reconfiguration of the drug pricing system. Accelerated Approval and Expensive Drugs — A Challenging Combination (free access)


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.