By Frances Bishopp
Based on successful results of a Phase II study on patients with Crohn's disease, Isis Pharmaceuticals Inc. and Boehringer Ingelheim GmbH will proceed with full-scale development of Isis 2302, an antisense inhibitor of Icam-1, a cell adhesion molecule implicated in a wide range of inflammatory diseases and conditions.
The double-blind, placebo-controlled clinical trial, which enrolled 20 patients with chronic, steroid-dependent Crohn's disease, demonstrated that 47 percent of patients treated with Isis 2302 were in disease remission vs. none in the placebo group at the end of the one-month treatment phase. The mean duration of remission in responding patients was almost five months, following a single course of treatment.
Crohn's disease is an inflammatory bowel disease affecting approximately 200,000 patients in the U.S.
"Both Isis and Boehringer Ingelheim are very encouraged by these data," Stanley Crooke, CEO of Isis, said. "They represent an important step forward in the treatment of what is a chronic, debilitating and very poorly treated inflammatory bowel disease."
The data also represents the first evidence of therapeutic benefit with a systemically administered antisense drug, Crooke said.
The clinical trials for Isis 2302 included four other indications other than Crohn's disease: ulcerative colitis, rheumatoid arthritis, renal transplantation and psoriasis, Bruce Yacyshyn, clinical investigator on the study, said. The Crohn's disease study targeted patients who had the more severe form of the disease and were dependent on steroids on a daily basis, he explained.
The 20 patients in the trial were randomized in a three-to-one ratio of drug to placebo. Efficacy was assessed by change from baseline in three indices: the Crohn's Disease Activity Index (CDAI), a clinical scoring scale, the Endoscopic Index of Severity (EIS), based on colonoscopic examination, and the Inflammatory Bowel Disease Questionnaire (IBDQ), a quality of life scale. Changes in corticosteroid requirements were recorded and analyzed.
Patients were evaluated at intervals during the four-week treatment phase and then for six months, or until disease progression was documented. The study results showed that the CDAI trends clearly favored Isis 2302 over placebo in both magnitude and duration of response, Yacyshyn said. These trends were supported by similar trends in EIS and IBDQ requirements and lower steroid requirements in the Isis 2302 group than in the placebo group from the first through the sixth month of the study.
Improvements were seen in CDAI at the end of the first week of treatment; however, in the remitting patients the mean time to remission was 24.9 days. The mean duration of remission for Isis 2302 responding patients was 147.6 days.
Also, statistically lower steroid requirements for the Isis 2302 group were observed than for the placebo group. At the end of the trial, five of 15 patients were completely weaned from corticosteroids compared to zero placebo patients.
Side effects were minimal or non-existent, Yacyshyn said.
"One of the striking things about this study," Dan Kisner, president of Isis, said, "is the remarkable consistency across these various parameters of efficacy that suggest all in the same direction a clinical benefit for patients treated with Isis 2302."
Potential: To Ween Patients From Steroids
The study indicates that patients can be weaned from dependency on steroids, an often ineffective and highly toxic treatment, Kisner said.
Analyst Peter Drake, of Vector Securities International, of Deerfield, Ill., said he had increased projections of worldwide sales of Isis 2302 from $30 million to $75 million in 2000. However, due to sluggish trial enrollment for Isis' lead product, Fomivirsen, an antiviral agent to treat CMV-induced retinitis in AIDS patients, he reduced projections for the product from $32 million to $10 million in 1998 and from $92 million to $40 million in 2000.
Kisner said Isis and Boehringer Ingelheim will commence a 300-patient, sixth-month Phase IIb pivotal trial in the spring.
In an approximately $100 million collaboration with Boehringer Ingelheim, of Ingelheim, Germany, Isis received a $28.5 million equity investment up front when the agreement was signed in March 1995. That stock purchase, at $15 per share, represented a significant premium to Isis' trading price.
Boehringer Ingelheim provided Isis, of Carlsbad, Calif., with $8.3 million in October 1996 from a $40 million line of credit included in the deal, and a $10 million milestone in December 1996 following successful completion of a Phase IIa trial.
Isis' stock (NASDAQ:ISIP) closed Friday at $19.375, up $0.50 *