Shares of Isis Pharmaceuticals Inc. took little notice Monday of the company's decision to pull the plug on mid-stage candidate ISIS-CRPRx in rheumatoid arthritis (RA).

The drug demonstrated rapid, dose-dependent mean reductions of up to 67 percent in C-reactive protein (CRP) in a Phase II RA study, and patients in the treatment arm showed improvements in signs and symptoms of RA. However, the improvements were not statistically significant compared to the placebo group, which the company said demonstrated a higher than expected response in both symptom score and CRP reduction.

A Phase II study of ISIS-CRPRx in patients with atrial fibrillation (AF) continues, with data expected in the first half of next year.

Shares (NASDAQ:ISIS) of Carlsbad, Calif.-based Isis slipped 58 cents, to close at $28.65. Trading was light, with investors likely awaiting the bigger picture from the company's second quarter earnings call Tuesday morning.

The randomized, placebo-controlled, multiple-dose study in RA patients with chronically elevated CRP enrolled 51 patients, who received 100-mg, 200-mg or 400-mg dose of ISIS-CRPRx or placebo for 12 weeks. Patients in the treatment arm achieved dose-dependent reductions in CRP early in treatment that persisted through the study as well as improvements in the signs and symptoms of RA, as measured by ACR20 and ACR50 scores. But "while the efficacy actually looked great in the early going in the trial, the placebo response gradually progressed, and we really didn't see enough difference," company founder, chairman and CEO Stanley Crooke told BioWorld Today.

CRP remains a controversial target, Crooke acknowledged. "There's a debate about whether it's causative or just associated, and the list of diseases in which CRP is elevated and the outcome is worse is enormous," he said.

Isis is conducting what Crooke characterized as "an exploratory Phase II exercise" to examine potential indications. RA was selected as the first target to collect safety data on patients who were not acutely ill, unlike those in many other potential indications with elevated CRP.

"What we saw were reductions in CRP that correlated with disease response," Crooke explained. "What we didn't see was sufficiently greater efficacy than placebo to justify developing the drug for RA."

The differentiator is that RA is well treated – unlike more serious indications, such as AF.

"The experiment went as we expected," Crooke said. "But the commercial opportunity is a stretch for this drug in that particular space."

The company continues to review the drug in AF, and Crooke suggested the company is looking at cardiac surgery patients and individuals with end-stage renal disease with elevated CRP.

Most analysts have assigned little value to ISIS-CRPRx, particularly in relation to ISIS-SMNRx, optioned by Biogen Idec Inc., ISIS-TTRRx, optioned by Glaxosmithkline plc, and unpartnered ISIS-APOCIIIRx. Subtracting the RA indication further diminished that outlook. On Monday, Piper Jaffray & Co. analyst Edward Tenthoff wrote in a research note that he was "removing $100 million we had assigned to ISIS-CRPRx in our sum of the parts valuation."

In May, following release of the company's first quarterly earnings as a public company with commercialization of the antisense drug Kynamro (mipomersen), Leerink Swann analyst Joseph Schwartz suggested "a 23 percent likelihood of success" for ISIS-CRPRx and ISIS-APOCIIIRx, given their developmental immaturity. (See BioWorld Today, May 10, 2013.)

In late June, investors sent shares of Isis to what was then a 52-week high of $28.42 based on data from a Phase II study of ISIS-APOCIIIRx showing that 11 patients with high triglycerides (200 mg/dL to 500 mg/dL) and Type II diabetes treated with the drug experienced statistically significant reductions of 88 percent from baseline in apolipoprotein C-III and 72 percent from baseline in triglyceride levels with a concurrent 40 percent increase in HDL cholesterol and improvements in other atherogenic lipid parameters.

A month later, however, investors were more dubious when the company reported additional Phase II data on ISIS-APOCIIIRx in patients with high to severely high triglycerides on stable doses of fibrates. Isis also is evaluating the compound in the ongoing Phase II study as a single agent in patients with severely high triglycerides and plans to report those data Aug. 31 at the European Society of Cardiology in Amsterdam. (See BioWorld Today, July 23, 2013.)

In general, enthusiasm for the stock, which has drifted 16 percent from its 52-week high of $34.31 on July 15, is based "on the success of the technology and excitement about a number of elements in the pipeline," Crooke said. The Street's assessment of ISIS-CRPRx accurately reflects that "CRP is a minor component of our pipeline," he admitted.

"This is an enormous opportunity if we find an indication, and we have the tool to ask the questions," Crooke added. "But these are real experiments."