Isis Pharmaceuticals (ISIS) revealed impressive numbers from its Phase II trial of ISIS-APOCIIIRx in patients with high triglycerides and type 2 diabetes yesterday at the American Diabetes Association Scientific Sessions in Chicago. APOCIIIRx, as a triglyceride-lowering therapy, would compete directly with Amarin’s Vascepa, and the mid-stage results suggest that Isis’ candidate is far more effective than Amarin’s ultra-pure fish oil pill (although evaluated in a very small trial), causing today’s weakness in AMRN and the transverse in ISIS. ISIS is up 23% on Monday to $27 — here’s what we wrote in March when shares were trading around $18.00 (we currently have no position in ISIS).
Isis reported that in the Phase II trial, patients with high triglycerides (between 200 and 500 mg/dL) and type 2 diabetes treated with ISIS-APOCIIIRx experienced an 88% reduction in apolipoprotein C-III (apoC-III), a 72% reduction in triglyceride levels, and a 40% increase in high-density lipoprotein cholesterol (HDL-C), or “good” cholesterol. Patients also showed consistent trends toward enhanced insulin sensitivity with improvements in multiple measures of glucose control. 11 patients were randomized 2:1 to receive a 300 mg dose of ISIS-APOCIIIRx or placebo via weekly subcutaneous injections for 13 weeks.
Although we’re comparing across trials and patient types (only 73% of patients in Amarin’s Anchor trial were diabetic), Vascepa at 4g/day in the Phase III, 702-patient Anchor trial evaluating patients with high triglycerides (≥200 mg/dL and <500 mg/dL) who were also on statin therapy achieved reductions in Apo C-III levels of 19.2% (p < 0.0001). Vascepa decreased TG levels in the 12 weeks of treatment by a mean of 21.5% (4g/day, p <0.0001) and non-high-density lipoprotein (non-HDL) cholesterol by 13.6% (p <0.0001).
Amarin, then, has been confronted with a potential competitor that reduces TG levels almost 4 times as well as Vascepa. Nevertheless, Isis is a long way from taking APOCIIIRx to market, and even if successful in large Phase III trials, the drug’s vehicle — weekly injection — could be prohibitive of widespread adoption. ISIS plans to bring ISIS-APOCIIIRx to the market for patients with severe hypertriglyceridemia — Vascepa is already approved in this “Marine” indication — and will report data from an ongoing Phase II program in very high triglyceride patients later this summer, evaluating APOCIIIRx in combination with fibrates and as a monotherapy.
APOCIIIRx is an antisense drug that targets apoC-III, a gene produced in the liver that plays a role in the regulation of serum triglycerides. In the trial, APOCIIIRx was well tolerated with no discontinuations, no clinically meaningful elevations in liver enzymes, and no significant adverse events. The treatment incurred infrequent mild injection site reactions, which typically resolved within a day or two. Isis believes APOCIIIRx won’t have the same issues that plague Kynamro, the company’s therapy for patients with severely high levels of cholesterol. Kynamro was approved late last year (the EU rejected Kynamro for safety reasons), and the two work by similar mechanics. While APOCIIIRx is clearly an exciting treatment option, n=7 patients is a tiny population on which to hinge expectations for a class of therapies that have proven troublesome regarding safety. Kynamro has gotten off to a slow start commercially.
While the incremental read-through today is that Vascepa has strong new competition, APOCIIIRx is years from the market. ISIS’ rally today added almost $500M to its market capitalization, in our view overdone given that n=7 in the trial and understanding Kynamro’s safety profile. AMRN is valued at $900M. Here’s why we began a small position in AMRN last week. A close below $6.00 today may signal further declines, but the 2nd half of this week should bring on AMRN’s monthly pre-Orange Book rally, macro-forces aside.
In connection with AMRN, PropThink has taken a long position.