The Population Council’s lead microbicide candidate moves forward
by Chael Needle

How do you assemble a microbicide candidate with anti-HIV and other properties? In some cases, much like one of those Mission Impossible-type movies where the leader goes around recruiting one gal who’s good at safecracking, another who is expert at acrobatic feats, and someone who is good behind the wheel, and so on. Except here, instead of Tom Cruise, Ving Rhames, and Thandie Newton, the “team” consists of MIV-150, zinc acetate, and a carrageenan gel.

A recently published study of the Population Council’s microbicide candidate, PC-1005, showed that the vaginal gel provided complete protection against a simian version of HIV in macaques for up to twenty-four hours after two weeks of once-daily application. In an interview with Melissa Robbiani, PhD, senior scientist and director of Biomedical HIV Research at the Population Council, A&U learned how the microbicide “team” came to be assembled for a mission that is looking more and more possible every day.

Let’s first meet the “driver”—a seaweed-derived carrageenan-based gel that is unique to the Population Council, a nonprofit NGO that conducts research in HIV/AIDS; poverty, gender and youth; and reproductive health. The Council had earlier studied the carrageenan-based gel to see if it alone could prevent male-to-female vaginal transmission of HIV, and, although researchers brought it successfully through a Phase III clinical trial (a first for the microbicide field), they were not able to demonstrate the concept. “But what was very interesting is that we learned more about the fact that this gel is safe—acceptable for use in women with repeated usage,” says Robbiani, “and in fact, for that reason, serves as a very good delivery vehicle in which we can put other antiviral drugs that can be delivered vaginally or potentially rectally.”

Carrageenan became the go-to gel developed for a few reasons: It has been used in thousands of women with no adverse effects; there is a possibility, as preliminary data shows, that it would cause no damage rectally; and it has chemical properties that allow for the formation of stable products and formulations that maintain their activity over time, Robbiani notes.

The antiviral agent the Council decided to test in combination with carrageenan is MIV-150, a nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV infection. Let’s call it the “muscle”—its strength against HIV shown in earlier studies overseen by its developer, Medivir, in partnership with Chiron.

Although MIV-150 was shown to have potent activity against wild type and drug-resistant strains of HIV in vitro and in vivo, it was dropped from Medivir’s pipeline and later licensed to the Council for microbicide research.

What made it a less likely candidate for HAART, however, might just make it a more likely candidate for a microbicide. That reason is MIV-150’s lackluster bioavailability, the amount of time a drug sticks around to do its job. “From our perspective, we think that is actually a big plus for a microbicide. The good news is it would get into the tissue and be there, we’re assuming, for the length of time needed to control infection at that local site, but even if there is some drug absorbed into the blood it would be cleared very, very rapidly and therefore should lessen the chances of development of drug-resistant virus and drug-related toxicities,” explains Robbiani.

The likelihood that drug resistance being an initial problem is lessened too if MIV-150 does not exist as an anti-HIV drug in the first place.

“While there is some possibility for cross-reactivity between different types of NNRTIs, one of the several attributes of MIV-150 is that it’s very potent and has a good resistance profile, which means it has good activity against other known viruses that are resistant to other known drugs,” she says. “While it’s not one-hundred percent black-and-white, it’s actually therefore quite promising for limiting the chance of transmission or emergence of drug-resistant viruses because it’s not already being used to treat people.”

Zinc acetate, a naturally occurring salt that has antiviral properties, is also attractive in part because it is less likley to create drug resistance and, importantly, holds the potential to broaden the activity of a combination gel.

Every “team” needs to work together better than each member works alone. The combination of all these elements are being looked at as a way to broaden the activity of PC-1005, that is, to target not only HIV but other sexually transmitted infections, as well.

For example, “the presence of zinc acetate significantly enhances the anti-herpes activity,” says Robbiani, referring to data from another Council study by Fernández-Romero et al., whose results are being submitted for publication. “And in fact the formulation needs to be delivered in the carrageenan gel and not in the universal placebo, HEC [hydroxyethyl cellulose], to have this anti-herpes activity.”

Also, additional analyses by Marais et al., from data gathered in the Phase III testing of the carrageenan gel suggested that, in women reliably using the gel, the incidence of human papillomavirus (HPV) was also reduced. Studies to specifically address whether carrageenan can prevent HPV in women, as has been shown in mice, are being carried out by the Einstein Medical Center in New York in collaboration with the Council. More studies will look at the biological mechanisms of these activities.

For now, the present study looked at the duration of the combination gel’s protective effect, measuring it for four hours, eight hours, and twenty-four hours. If the gel is eventually shown to be useful in humans, the longer an application lasts the less a woman (in this case) needs to be concerned about when she will have intercourse. “Obviously a product that needs to be applied thirty minutes, an hour, or maybe even two hours prior to intercourse, is more difficult for someone to manage to use,” notes Robbiani.

A product proven safe and effective for individuals and offering twenty-four-hour-long protection would be “nice in the sense that you could imagine someone might apply the gel in the morning and they would still be protected in the evening and would not have to apply it just before, or in the middle of a date.”

This type of durability would help women who are in situations where they do not have complete control over when they have intercourse. “A major focus from the Council’s perspective is to empower women to protect themselves for exactly that reason. They may not know when they’re going to have intercourse. And may not, at the time they’re having intercourse, let their partner know that they’re using something to protect themselves.”

Multiple delivery methods would also give women more options. While the current study looked at a gel directly applied to the vagina, the Council is studying the use of rings, made of either silicone rubber or a plastic material called EVA, that would release MIV-150 and zinc for longer time periods (e.g., months).

“A ring and a gel are different modes of delivering the drugs that you’re interested in and there’s a potentially longer lasting protection with a ring, if you can have that, in that you wouldn’t have to think about applying it every day or on days when you need protection,” notes Robbiani about a ring’s potential appeal. “Clearly that would be what many people would like to have but it’s quite apparent too, depending on people’s personal choice, and definitely cultural differences, that not all people are going to want to use a ring and that’s why the Council is also very interested in having options for women.”

A gel, with its potential for rectal application, might also increase options for men who have sex with men as well as women who have anal intercourse with male partners.

The length of time between application and intercourse is maximized by finding the right balance between dosing and safety and efficacy.
In earlier studies as an anti-HIV agent, MIV-150 was shown to have a good safety profile, with no toxicity noted in the blood, and that was with higher doses of the drug being administered. Council researchers now have to test for safety and toxicity of drug agents in this current formulation as a vaginal-topical gel. “There’s no indication that there would be adverse effects but until those studies are done we can’t say otherwise,” says Robbiani.

The PC-1005 combination gel is starting with low doses—0.002 percent MIV-150 and 0.3 percent zinc acetate—that are still so far effective. “That’s another plus—we don’t have to use much of it. And when it’s in combination with the zinc acetate, it’s still effective in preventing infection,” says Robbiani. “So, a low amount is important in limiting the potential effects of toxicity and also ultimately cost.”

Currently, researchers at the Council are working toward preclinical trials that would focus on optimizing the gel and studying the properties of the gel itself, “making sure that the optimized gel remains stable and active over longer periods of time under various levels of stress such as higher temperatures and levels of humidity,” says Robbiani. Once researchers settle on a formulation, they will proceed with more extensive toxicity testing. Phase I testing in humans of both the MIV-150/zinc acetate gel and the zinc acetate–alone gel could begin in early 2012.

Chael Needle wrote about a lipodystrophy-related excessive abdominal fat treatment in the January issue.

February 2011