After many years and much ado, The Immune Response Corp. canbegin preparing a Phase III trial of its HIV-1 Immunogen product,the first therapeutic vaccine to enter that phase of the clinicaldevelopment process.

Immunogen is being developed by a joint venture of the companyand Rhone-Poulenc Rorer Inc., called Immunization Products Ltd.Results of the venture's Phase II/III trials presented in 1993 in Berlinwere viewed negatively by some because they weren'toverwhelming, and some member of the FDA's Vaccines andRelated Biologicals Advisory Committee expressed reservationsabout the product's potential in a meeting Thursday that lasted morethan 12 hours.

Nevertheless, the advisory committee recommended that the FDAallow the Phase III trial, which is expected to include about 5,000patients.

Immune Response, of Carlsbad, Calif., still must get validation of itsmanufacturing facility in King of Prussia, Pa., FDA approval of theprotocol and approval from the sites participating in the study. Thecompany is working on those simultaneously and, under best-caseconditions, hopes to start enrolling patients this spring.

Matthew Geller, an analyst with New York-based Oppenheimer &Co. Inc., and other investors weren't entirely persuaded by theadvisory committee's recommendation.

Immune Response' stock (NASDAQ:IMNR) closed at $6.38Tuesday. Wednesday, after a warning letter sent to the company bythe FDA was made public, the stock lost $1.38, closing at $5 pershare. It gained 12 cents Thursday, and dropped 56 cents Friday,closing at $4.56.

What appeared to be positive news for the company turned intoskepticism, partly because of reservations expressed by panelmembers.

"The panel said there's not much evidence this works, that it'sunlikely you'll get success in Phase III," Geller told BioWorld. "Noone's ever had success with a therapeutic vaccine, in terms of reallyproving it works. The whole principal is questionable."

Charles Cashion, vice president and chief financial officer forImmune Response, granted that there was debate among panelmembers. "That's the kind of forum where there are questions thatneed to be answered," he told BioWorld. "It's the nature of thoseforums to have debate on issues."

Steve Basta, Immune Response's executive director of productdevelopment, said that doubts about efficacy might be a result ofdifference in the vaccine's effect vs. that of an antiviral drug.

"There's a difficulty in interpreting surrogate marker effects," Bastatold BioWorld. "[Antivirals] have significant but short-term effectson some markers. With immunotherapy, it's a much more gradualprocess, where you strengthen the immune system. We saw trendsthat were widening over a year in control vs. treated patients.

"We clearly know the product is safe," Basta said. "We know theproduct is immunogenic. It stimulates both the antibody and cell-mediated immune response. We believe the cell-mediated part to bethe most important. Given that it stimulates those responses, we'veseen it has an impact on key surrogate markers. We believe stronglythat it will have a clinical benefit based upon the consistency of thebiological effects we're seeing."

Surrogate markers will be one of the endpoints measured in thethree-arm trial being proposed by Immune Response. (The followingtrial details still must be approved by the FDA, and are subject tochange.)

One of the arms will involve about 300 patients with CD4 countsgreater than 550. Endpoints are viral load and CD4 cell counts.

The largest arm will involve about 3,000 patients with CD4 countsbetween 300 and 549. It's designed to monitor patients to theendpoint of an AIDS-defining clinical condition, or progression toAIDS. Basta said that can be measured by the first opportunisticinfection categorized as AIDS-defining.

The final arm would involve 1,500 patients with CD4 counts below300. They will be monitored to determine if survival is extended.

The study participants will remain on whatever course of therapythey already are on. In addition, an intramuscular injection will begiven every three months. Each of the three study arms will bedivided into thirds. One third of will get incomplete Feund'sadjuvant (IFA) as control, one-third will get 100 micrograms of theHIV-1 Immunogen in IFA, and the final third will get 400micrograms of the product in IFA.

The HIV-1 Immunogen was cultured, purified then inactivated by achemical-killing process and irradiation of the virus. The inactivatedHIV then was stripped of its outer envelope protein, gp120, purified,then emulsified with the adjuvant.

"The advantage of that final product is that the mineral oil [adjuvant]is an irritant of sort to the immune system," Basta said. "It activatesthe system to come in and fight whatever it sees there, in this casethe HIV proteins." n

-- Jim Shrine

(c) 1997 American Health Consultants. All rights reserved.

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