Isis Alicaforsen Crohn’s Disease Failure Switches Focus To Ulcerative Colitis

Isis re-focusing alicaforsen Phase III development on ulcerative colitis after failure in Crohn’s disease. The antisense agent did not show difference in clinical remission versus placebo in two Phase III Crohn’s trials. Results from recently completed Phase II UC studies show potentially greater duration of response than standard of care, firm says

Isis will re-focus development of alicaforsen on ulcerative colitis following the antisense agent's failure to show efficacy in Phase III trials in Crohn's disease.

"As a result of these studies, we will not be investing further in the development of alicaforsen for Crohn's disease. Instead, we will focus on developing the alicaforsen enema to treat ulcerative colitis," Chief Medical Officer Mark Wedel, MD, told a Dec. 2 investor call. The firm had been developing an intravenous formulation for Crohn's.

"Moving forward, our next steps for alicaforsen enema will be to sit down with representatives of the FDA and to discuss our Phase III plans for patients with ulcerative colitis," Wedel said.

Isis believes durability of response is a potential marketing point for alicaforsen. "The prolonged duration of remission we've observed compared to mesalamine enema should represent a substantial benefit to patients and a true competitive advantage," Wedel said. According to Isis, mesalamine (Axcan's Canasa and others) is the standard of care in UC.

The Phase III UC program will "focus not only on safety and efficacy but also flushing out an attractive commercial profile," Wedel said. "For example, we may focus on duration of response and the ability of alicaforsen enema to allow patients to reduce steroid or high-dose oral mesalamine use."

Isis remains optimistic about alicaforsen's potential based on a recently completed commercial assessment. "We think, depending on whether we can confirm the profile that we have seen…alicaforsen is a several hundred million dollar product opportunity," CEO Stanley Crooke, MD/PhD, said. "We think it's certainly over $100 mil."

The two failed Crohn's trials enrolled a total of 331 patients in the EU, Israel and North America. In the North American study, alicaforsen had a p-value of 0.99 for the primary endpoint of clinical remission (Crohn's Disease Activity Index score <150) at 12 weeks. The EU/Israel study's p-value was 0.85.

For the secondary endpoint of percent of patients achieving a clinical response (defined as a 100-point CDAI decrease by week 12), the North American study showed a 63% response rate for alicaforsen vs. 48% for placebo (p=.08). In the European study, alicaforsen yielded a 62% response rate vs. 58% in placebo patients.

Isis' Phase II ulcerative colitis program included four trials in over 300 patients; the firm reported "successful" results for three of the trials Dec. 2.

A six-week, 112-patient, placebo-controlled study determined that 240 mg nightly is the optimal dosage regimen. "Based on an intent-to-treat analysis, 59% (13/22) of patients treated with 240 mg alicaforsen enema achieved a response, as measured by DAI," Isis said.

"At the end of the six month follow-up, after the completion of dosing, alicaforsen treated patients were continuing to benefit," investigator Philip Miner, MD, noted. "This suggests that the duration of effect…might be even greater than the six months of the study follow-up period." Seventy-seven percent (10/13) of the responding patients continued to respond at six months.

Another study compared two doses of alicaforsen (120 mg and 240 mg) to mesalamine 4 mg. The trial evaluated 159 patients treated nightly for six weeks, with 12 months of follow-up. Acute response was "comparable" to mesalamine, Isis said. "Many patients treated with alicaforsen who achieved a response maintained their response for six months or longer compared to an average duration of response of less than three months for mesalamine," the firm added.

"Alicaforsen certainly induced more prolonged responses than mesalamine enema and once again the study results show that alicaforsen enema is very well tolerated. Netted out, no matter which measurement you use - disease activity index, mucosal healing, rectal bleeding, stool frequency, physician global assessment - all track in favor of the activity of the drug and the durability of its effect," Miner said.

Alicaforsen is an inhibitor of ICAM-1, a cellular adhesion molecule that "plays a key role in a wide range of inflammatory and autoimmune conditions," according to Isis.

The company previously cancelled development of alicaforsen for rheumatoid arthritis and plaque psoriasis after Phase II. According to F-D-C Reports' ¹ NDA Pipeline, Isis also has a Phase II trial underway in pouchitis.