By Vicki Brower

Special To BioWorld Today

Following the recent publication of positive Phase II results with its rheumatoid arthritis drug, Colloral, and a meeting with the FDA, AutoImmune Inc. plans to begin a Phase III study with the drug next month.

Colloral is an oral tolerance drug produced from the sterna of chickens that triggers the production of certain T cells to suppress an autoimmune attack.

AutoImmune recently met with the FDA for a comprehensive review of its Phase II safety and efficacy data, and after a thorough examination of the company's 1,200-patient database, the agency commented on the drug's good safety profile and agreed to allow AutoImmune to move into Phase III testing, said President and CEO Robert Bishop.

The FDA has agreed to require only one successful Phase III trial for regulatory filing.

AutoImmune will begin an 800-patient, double-blind trial by the end of March that will employ traditional measures of disease activity using a 60 microgram dose of Colloral once daily compared to placebo for six months. The trial is expected to be completed in mid-1999, Bishop told BioWorld Today.

Data from AutoImmune's dose-ranging, 274-patient Phase II trial were published in the February 1998 issue of Arthritis & Rheumatism.

The trial, the second of five Phase II studies, was completed in 1995 and showed a statistically significant benefit for low-dose therapy with Colloral in one of three composite scales of rheumatoid arthritis: swollen and tender joints along with patient and physician assessment.

In addition, the presence of serum antibodies to cartilage-derived type II collagen, or Colloral, at baseline was significantly associated with an increase in likelihood of responding to treatment. These results were consistent with findings of preclinical trials, and with known mechanisms of oral tolerance in which lower doses of orally administered autoantigens preferentially induce disease-suppressing regulatory cells, the journal article stated.

Company Experienced Setbacks

An earlier Phase II trial showed statistically significant response from baseline, but not from placebo. Those data, and data from a failed Phase III trial with another oral tolerance drug, Myloral, for multiple sclerosis, caused AutoImmune's stock price to plunge and forced a reduction in staff last year.

The company tabled development of Myloral after its April 1997 Phase III failure, but Bishop told BioWorld Today that it is now in negotiations to license out its multiple sclerosis technology to another company. While bovine myelin will not be used, oral tolerization using certain antigens it has identified may be, he said.

At the end of the year, AutoImmune had $30 million in cash, and it expects to have one and a half years' worth of cash left after its Phase III trials with Colloral.

The researchers who reported on the positive Phase II Colloral trial and authors of an accompanying editorial in Arthritis & Rheumatism said low-dose oral antigen delivery increases expression of inhibitory cytokines, transforming growth factor-beta and interleukin-4 (IL-4), and decreases expression of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, tumor necrosis factor-alpha and interferon-gamma. And the result, they said, is a lessening of brain inflammation.

On the other hand, high doses of antigens also lead to clonal anergy or deletion. The Phase II Colloral study's authors admitted the trial had limitations: the use of three sets of criteria for evaluation; the use of five doses; the small number of patients in each treatment group; the inclusion of patients with severe, long-standing disease; and the use of relatively high doses.

Oral Tolerance Given Vote Of Confidence

The editorial authors, Joachim Kalden and Joachim Sieper, said oral tolerance has been shown in three separate studies to be a useful treatment strategy for autoimmune diseases such as rheumatoid arthritis. They suggested that rather than using animal-derived collagen-II, it may be more effective to use a human recombinant version.

"Recombinant human collagen-II would have the advantage of purity and homology with the host protein and, in addition, peptides could be delivered at a constant dosage," wrote Kalden and Sieper, scientists with the University of Erlangen-Nuremberg and the Berlin-based Free University, respectively. They suggested additional trials in different populations of rheumatoid arthritis patients with a human version of the drug delivered orally and nasally.

AutoImmune's Bishop told BioWorld Today the protein his company uses is about 93 percent identical to the human protein, but it may consider developing a human recombinant version of Colloral.

"Until relatively recently, it was fairly difficult to produce a human recombinant version in cell culture — it meant inserting two genes," said Bishop. Now, with production of human proteins in the milk of transgenic animals, it is easier and may be an option for AutoImmune in the future, he added. *