Isis Oral TNF-Alpha Inhibitor For Rheumatoid Arthritis To Enter Phase II

Isis is ramping up efforts to develop an oral tumor necrosis factor alpha inhibitor for rheumatoid arthritis, with plans to begin a Phase II trial of its oral anti-TNF antisense agent ISIS 104838 in mid-2005

The study will compare subcutaneous and oral formulations of the drug in RA patients. Positive Phase II results for subcutaneous 104838 were reported earlier in the year.

The trial, to be conducted outside the U.S., will assess efficacy of 104838 in combination with methotrexate. The study is expected to take "awhile" due to scope and complexity, Isis CEO Stanley Crooke, MD/PhD, told an Aug. 5 earnings call.

"It'll be a fairly large trial because we'll be comparing a couple of doses and schedules of subcutaneous with oral administration, and it'll take some time to enroll, and we're going to be...treating patients for three months and following them for at least three more months," Crooke explained.

The exec highlighted the study's importance in light of the highly competitive TNF-alpha inhibitor market. "Obviously, that's a crucial study, because we have to see in the background of methotrexate that the drug can compete with the Enbrel s of the world," he said. "It sets the stage for making a decision about what its commercial potential is."

The marketed TNF-alpha inhibitors for RA - Amgen's Enbrel (etanercept), Abbott's Humira (adalimumab) and Johnson & Johnson/Schering-Plough's Remicade (infliximab) - are all injectables.

Isis' decision to focus on the oral formulation of 104838 was partly prompted by "recognition that the profile of injectable drugs to treat RA must be outstanding in light of the performance of competitive products," the company said. In contrast, an oral TNF-alpha inhibitor presents a "significant opportunity," the firm declared.

To "move…forward aggressively" with the oral formulation, the company is suspending further trials of a cream formulation of the drug for psoriasis, which had reached Phase II.

Isis is not planning any direct comparisons of 104838 to the marketed anti-TNF alpha agents, Crooke indicated. "We think the data with Enbrel and the other drugs is consistent enough that we have a reasonable idea of what the target level of activity has to be for us to have a competitive drug here," he said.

As an antisense agent that targets RNA, 104838 differs from the protein-based anti-TNF RA drugs in having wider distribution outside the bloodstream, Crooke maintained. Remicade and Humira are monoclonal antibodies, while Enbrel is a soluble receptor.

"Broader distribution gives us an opportunity to...ask some questions with this drug about diseases that may be amenable to it that would not be amenable to protein therapeutics," he said.

If successful, 104838 could have a chance to be the first oral TNF inhibitor to enter the RA market: there are no oral anti-TNF RA drugs in Phase III, and only a handful in earlier development, according to F-D-C Reports' ¹ NDA Pipeline.

Oral agents in clinical development include AtheroGenics' Phase II TNF-alpha modulator AGIX-4207, and Wyeth/Amgen's Phase I TNF-alpha converting enzyme inhibitor/metalloproteinase inhibitor TMI-005.

The oral formulation of ISIS 104838 was originally developed under a collaboration between Isis and Elan, but Elan exited the partnership in late 2002 due to restructuring efforts.

In addition to the planned ex-U.S. Phase II trial, Isis plans to conduct two additional preclinical safety studies to evaluate high-dose toxicities and longer dosing. "Both trials are required to support further clinical trials in the U.S.," the company noted.

Isis reported a 24% decrease in revenue for the first six months of 2004 to $22.1 mil. compared to the same period last year. The firm attributed the decline largely to completion of Phase III trials of the oncologic antisense agent Affinitak for non-small cell lung cancer.

Isis and partner Lilly suspended enrollment in the second pivotal Affinitak trial for NSCLC in late 2003 following failure of the first pivotal trial for the indication. The companies have continued to follow previously enrolled patients and expect to report results by the end of the year. ¨ ¨