Report from ICAAC
Some novel antiretroviral treatments that the HIV community has been watching for the past few years are approaching reality, giving clinicians hope for new drugs and new approaches for patients who are close to exhausting existing HIV therapy. Integrase inhibitors, fusion inhibitors, once-daily protease inhibitors, and some other new drugs were in the spotlight at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in San Diego in September. ICAAC is organized by the American Society for Microbiology in Washington, DC.
"What I saw at ICAAC was very encouraging," says Joseph Eron, MD, an associate professor of medicine in the infectious diseases division of the University of North Carolina at Chapel Hill. "It looks like several drugs are moving to the point where not only will we have them in clinical trials, but we’ll be able to give them to patients." Eron spoke about the recent advances in HIV therapy at the National HIV/AIDS Conference held in Atlanta in October. "The biggest news: The new agent that is going to have the most significant impact would be T-20, a fusion inhibitor. The reason I say this is because it’s a drug that’s in a totally new class of agents, an anti-retroviral that works at the step of entry."
Entry inhibitors, including fusion inhibitors, hold hope in defeating HIV in even the most treatment-experienced patients who have drug-resistant virus, he notes. T-20, also named enfuvirtide, is the first fusion inhibitor that targets HIV gp41. In a phase III study in which enfuvirtide was added to an optimized background regimen and compared with an optimized background regimen only, it was found that the enfuvirtide group of highly antiretroviral experienced patients had additional viral suppression when compared to the group on an optimized background regimen alone.1
T-20 has been developed by Trimeris of Durham, NC, and it’s administered through subcutaneous injection twice a day, so it may not be for every patient, Eron says. "But in the grand scheme of things, to have an agent that targets a whole new process gives a lot of encouragement to patients and physicians. But we may see this drug by the spring." Trimeris has submitted a new drug application to the Food and Drug Administration (FDA), and it has to be reviewed at an FDA meeting before it can be brought to market, Eron says. "The virus will be susceptible to this drug, so there’s one active agent we can work with to build a successful therapy for them. Whereas right now, for some of our patients, we have very little to work with."
This latest approach involves the creation of drugs that will stop one of the processes involved in HIV’s entry into human cells. The three-stepped entry process involves the gp120 protein that exists on the surface of HIV, explains Richard W. Krawiec, PhD, vice president of investor relations and corporate communication for Progenics Pharmaceuticals Inc. of Tarrytown, NY. "For HIV to enter a human cell, gp120 must bind to a CD4 receptor, and the second step is for a small cleft to open up and the gp120 protein binds to another receptor called CCR5," he says. "When that happens, it’s really accomplished opening the first two doors, and the third step is the fusion of the membrane of the virus of the cell."
The way this happens is that a portion of gp120 protein called gp41, a coiled-up protein, uncoils and pierces the cell membrane and permits the membrane of the virus and the membrane of the cell to fuse, Krawiec says. "So there’s now an opening, and through that opening can come the RNA material of the virus to infect the cell."
T-20 was designed to stop that last step, preventing the fusion between the HIV protein and the human cell. Progenics has been studying a drug called PRO 140 that is designed to block the HIV protein gp120 from attaching to the CCR5 receptor at the second step of the process. Developed by Progenics, PRO 140 is a monoclonal antibody that has been humanized, he says. PRO 140 was found in an in vitro study to broadly and potently block HIV-1 entry through CCR5 without interfering with the receptor’s normal activity.2
Progenics has entry an inhibitor in Phase II clinical studies, called PRO 542. This one is designed to thwart the virus at the first step in the entry by preventing the gp120 protein from binding to the CD4 receptor, Krawiec says. "PRO 542 and 140 block the binding and attachment steps," he explains. "PRO 542 is designed to block binding; and unlike drugs out there now that work on human cells, it’s designed to neutralize the virus, so there’s a fundamental difference there."
A fusion protein, PRO 542 mimics the structure of CD4 on its tip, so when normally HIV would target CD4 cells, it would be diverted to the PRO 542 antibody-like molecule, which prevents the virus from completing the first step in infecting the cells, Krawiec says. Phase II testing of PRO 542 showed that the agent broadly protects primary cells from HIV-1 infection by neutralizing free and dendritic cell-associated virus.3
"PRO 542 and 140 are modifications of human monoclonal antibodies, and they’re very clever," Eron notes. PRO 542 looks like an antibody and serves as a decoy for HIV, he says. "The thing about that drug is that it has to be given by IV infusion, but it has been studied in adults and children and appears to have some activity." PRO 140 is another CCR5 inhibitor that has to be administered by infusion, Eron adds.
Clinical studies have shown that a single intravenous infusion of PRO 542 lowered viral loads for as long as six weeks and that the lowered viral load was statistically significant for a month, Krawiec says. The drug has had clinical activity in some of the sickest AIDS patients, who have high viral loads and low CD4 counts. It holds promise as a salvage therapy for patients who are failing conventional antiretroviral therapy, he says. "One IV infusion lasts at least a month with these patients, and that’s a single dose," he says. "The next step is to learn how to better use the drug."
The company is studying different options for administering the drug, including developing a formulation for subcutaneous injections, Krawiec adds. "We know it reduces viral load, and now it’s incumbent upon us to continue to substantiate the favorable safety profile and become more comfortable with that. We have to understand how best to give the drug in the clinic, whether to administer it with more frequency." PRO 140 has not yet been studied in human subjects, but it will enter clinical trials next year, he says.
Integrase inhibitors attracting interest
Another type of new HIV medications that are worth noting are the integrase inhibitors, Eron says. "HIV has three enzymes that it uses, makes itself, and takes over human cells and brings along these three enzymes of reverse transcriptase, protease, and integrase," he explains. "We’ve known about integrase for a long time but never had an inhibitor of integrase before."
Then in the past year, Shionogi USA Inc. of Florham Park, NJ, and Merck Research Laboratories of West Point, PA, have been developing integrase inhibitors that they’re about to study in humans. The in vitro and animal studies have looked promising, Eron adds. S-1360, Shionogi’s new HIV-1 integrase inhibitor for oral use, was found in a recent study to not have an effect on fat metabolism, retinoid signaling, and other problems associated with protease inhibitor use.4
Merck researchers presented an abstract at ICAAC highlighting the discovery of a series of novel 8-hydroxy-1,6-naphthyridine HIV-1 integrase inhibitors.5
Eron notes that S-1360 is synergistic with all three current classes of antiretrovirals, has minimal animal toxicity, and is comparable to some common nucleoside reverse transcriptase inhibitors (NRTIs) in mouse models of HIV. "The other area where I think we’ll make progress in the next six months to a year is in making some improvements in our current treatments," he says. "What we’re going to have are drugs that are less cumbersome and perhaps less toxic."
One example is Wallingford, CT-based Bristol-Myers Squibb’s investigational protease inhibitor atazanavir. Atazanavir proved to have potency comparable to efavirenz in a clinical trial where it was administered in combination with zidovudine and lamivudine to treatment-naïve HIV-infected subjects. The 48-week study demonstrated that a combination containing atazanavir suppressed HIV RNA below 400 copies/mL of blood of 72%, compared with a response rate of 69% for the efavirenz regimen.6
"In a very large phase III trial, atazanavir was compared to the most potent of non-NRTIs [NNRTIs], and it had equivalent potency," says Kathleen Squires, MD, associate professor of medicine at the Keck School of Medicine at the University of Southern California in Los Angeles. What makes atazanavir unique is that, unlike other protease inhibitors, it can be administered as two pills once a day. This way it can be combined with other once-daily antiretrovirals, she says. "In terms of side effects, it looks like this drug doesn’t really effect serum lipids, such as triglycerides and cholesterol, and that is different from what is described of other [protease inhibitors]," Squires points out.
Generally, such side effects will occur quickly after a patient begins taking a protease inhibitor, so if the side effect was not found in atazanavir during a 48-week study, that is a good sign, she adds. Also, the drug-resistance profile looked good with the most common mutation found among research subjects taking the atazanavir/ NRTI combination was a mutation suggesting resistance to lamivudine, Squires says.
Interestingly, test tube studies have shown that when HIV is exposed to atazanavir and then placed with other protease inhibitors, it appears that the virus is more sensitive to the other protease inhibitors, suggesting that it has the opposite effect of drug resistance, she says. "The good point is that it looks like patients will be able to be treated with other [protease inhibitors] without any compromising of activity," Squires adds.
Another notable new drug discussed at ICAAC included TMC 125, a next generation NNRTI that has demonstrated potent activity against HIV in both treatment-naïve and NNRTI-resistant patients.7
1. Lalezari JP, Henry K, O’Hearn M, et al. Enfuvirtide (T-20) in combination with an optimized background (OB) regimen vs. OB alone: Week 24 response among categories of treatment experience and baseline (BL) HIV antiretroviral (ARV) resistance. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego; September 2002. Abstract: H-1074.
2. Olson WC, Gardner JP, Ketas TJ, et al. Inhibition of HIV-1 entry without receptor antagonism by the humanized anti-CCR5 antibody PRO 140. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego; September 2002. Poster: H-178.
3. Ketas TJ, Frank I, Sullivan BM, et al. PRO 542, a novel inhibitor of HIV-1 attachment and entry, blocks infection in trans of T Cells by dendritic cell-associated virus. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego; September 2002. Poster: H-179.
4. Weiel JE, Clancy DC, Winegar DA, et al. Differential effects between HIV-integrase inhibitor S-1360 and HIV-protease inhibitors on fat metabolism and retinoid signaling in vitro. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego; September 2002. Poster: H-1919.
5. Zhuang L, Wai JS, Embrey MW, et al. Design and synthesis of 8-hydroxy-1,6-naphthyridines as novel HIV-1 integrase inhibitors. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego; September 2002. Abstract: LB-21.
6. Squires KE, Thiry A, Giordano M. Atazanavir (ATV) QD and efavirenz (EFV) QD with fixed-dose ZDV+3TC: Comparison of antiretroviral efficacy and safety through Week 24 (AI424-034). Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego; September 2002. Abstract: H-1076.
7. Baede P, Piscitelli S, Graham N, et al. Drug interactions with TMC 125, a potent next generation NNRTI. Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego; September 2002. Poster: A-1827.