Wall Street Journal - February 1, 2007
Marilyn Chase, marilyn.chase@wsj.com.

Topical anti-HIV gels, called microbicides, have received a big push by governments, advocates and philanthropies who want to put protective products in the hands of women whose partners don't use condoms. The Bill and Melinda Gates Foundation, a leading sponsor, has invested $125 million in microbicide research, including $12 million for the trial involving 1,300 women that was closed, which was led by Conrad, the U.S. nonprofit group based in Arlington, Va.

In a separate but related move, the nonprofit Family Health International also halted a similar study involving 1,644 women in Nigeria as a precaution, although it hadn't seen any evidence of increased infections linked to the gel. But it also found no evidence that the product was effective in preventing HIV.

The Gates Foundation said it still believes microbicides will prove valuable in fighting the spread of AIDS. "It's a disappointment," Nick Hellmann, the Gates Foundation's interim director of HIV/AIDS and Tuberculosis, said in an interview. He noted that developing drugs is a "long, tortuous road," but said "we have to proceed, stay the course, and learn more lessons about what is required for the optimum microbicide product."

Bill and Melinda Gates have taken up the cause of microbicides -- HIV-blocking drugs in colorless, odorless gels, creams or rings -- as a way for women to gain control over their HIV risk in Africa and throughout the developing world.

The couple have made microbicide research a centerpiece of AIDS-prevention advocacy at their $31.9 billion Seattle-based foundation. They featured microbicides in their keynote speech opening the International AIDS Conference in Toronto last August. Mrs. Gates has taken a special interest, querying women in South Africa about how they like the products, and, according to associates, even trying gels on her hand.

In addition to its overall $40 million in grants to Conrad for several microbicide studies, the foundation has given $25 million to the Population Council, which is conducting an efficacy trial in South Africa of a microbicide product called Carraguard; and $60 million to the International Partnership for Microbicides, which is investigating a number of next-generation candidate compounds in earlier stages of research.

The Conrad study in question used the product, Ushercell, which contains the chemical cellulose sulfate made by Polydex Pharmaceuticals Ltd. of Toronto. Shares of the company fell nearly 55% to close at $3 a share on the Nasdaq Capital Market. The active ingredient has been used as an ingredient of contraceptive gels in Europe, sponsors said.

Of 1,300 women in the study in South Africa, Benin, Uganda and India, 35 women became infected in both the treatment and control groups -- with more infections in the cellulose sulfate group. A breakdown wasn't given because the situation is in flux and numbers will change, said Conrad, which is a nonprofit reproductive research affiliate of Eastern Virginia Medical School.

While far from signalling the demise of the field, the immediate disappointment of one collapsed Conrad trial, and its domino effect on the similar one, has wider ripples because the microbicide field badly needs a good result to sustain support and momentum in the wake of an earlier failure years ago.

It isn't known yet whether scientists can find a chemical that is tough enough to repel or kill HIV, yet gentle enough to spare the female genital tract from corrosive chemical effects that have the effect of favoring infection. Still, it's premature to declare defeat, as researchers have other trials under way.

In addition to a raft of early-stage compounds, the World Health Organization and UNAIDS noted there are three other Phase III efficacy trials of microbicides now under way. The Carraguard study, sponsored by the Population Council and conducted in South Africa, is nearing completion and results are expected by the end of 2007. A second study of another product, PRO 2000, is being sponsored by the UK Medical Research Council in South Africa, Tanzania and Uganda, with results expected in 2009. In a third efficacy study, sponsored by the U.S. National Institutes of Health in Malawi, South Africa, Zambia and Zimbabwe, PRO 2000 is coupled with BufferGel, a so-called vaginal defence enhancer, with results expected in 2008, WHO and UNAIDS said.

So far condoms and abstinence are the main tools of prevention in the absence of a vaccine against HIV/AIDS, which now affects nearly 40 million people world-wide. Male circumcision, though recently proven to reduce risk to men, raises religious and cultural quandaries. Ongoing studies of a promising prevention pill by Gilead Sciences Inc. have raised controversy over a its potential to undermine "safe sex" practices.

The collapse of the cellulose sulfate trials came as a shock because the drug had passed 11 safety and contraceptive studies without any red flags, Henry Gablenick, Executive Director of Conrad, said in an interview. Treatment and care for infected volunteers is planned and budgeted, he added.

For the $34 million Phase III efficacy trial of cellulose sulfate, a Conrad spokeswoman said about $22 million from U.S. Agency for International Development was used, in addition to $12 million of the Gates monies.

Despite acknowledging "total surprise" and "extreme disappointment," Dr. Gablenick said, "We are determined to go on. We have other compounds in our pipeline."

The setback deals a double blow to morale in the field, which has not forgotten the failure many years ago of an earlier compound, the contraceptive nonoxynol-9. In those earlier studies, nonoxynol-9 increased risk of contracting HIV because it inflamed cells of the reproductive tract, accelerating infection. By contrast, cellulose sulfate wasn't believed to be irritating or inflammatory, and risk factors are still under investigation.

Zeda Rosenberg, CEO of the International partnership for Microbicides, called the study halt "a profound disappointment" and "a stark reminder" of the steep challenges and unpredictability of drug development against the wily AIDS virus.

"This development saddens everyone," Dr. Rosenberg added. But she stressed, "We cannot let it paralyze us. Globally, 17.7 women are living with HIV, and thousands more are infected every day. Prevention is the only way out of this epidemic."

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