HIV/AIDS Therapy Express Report
8th Annual Retrovirus Conference
Chicago, Illinois

Promising New Drugs and Avenues of Research for HIV Therapy

This report was reviewed for medical and scientific accuracy by William Blake, MD , Fellow, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia.

Attendees at the 8th Annual Retrovirus Conference learned about some promising new drugs for patients with HIV infection and AIDS. There are currently 15 approved antiviral agents that fall into three classes: protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). On the horizon are new versions of these familiar drugs, as well as drugs that have different targets.


The drug that is furthest along in development and closest to being approved by the USFDA (United States Food and Drug Administration) is a new protease inhibitor (PI) called BMS-232632. This is the first PI that can be given in a once- daily dose.

"The key point of this drug, BMS-232632, is that it truly is the first of the PIs that you can feel comfortable with on once-a-day administration," said Katherine E. Squires, MD, Keck School of Medicine, University of Southern California, Los Angeles.

The study compared three once-daily doses of BMS-232632 (200 mg, 400 mg, and 500 mg) with another PI, nelfinavir (Viracept®) (750 mg), as monotherapy for 14 days (stage I, 98 patients randomized and 92 treated). In stage II of the study, 265 (and 166 treated) antiretroviral naĞ¿ve patients were randomized to BMS-232632 at 1 of 3 doses plus stavudine (d4T) (Zerit®) and ddI or nelfinavir plus the same. Patients included in the study had not been previously exposed to antiretroviral drugs. After 24 weeks of the second phase of the study (1 of the 4 treatment groups in combination with d4T and ddI), it was apparent that all 4 treatment groups were equally effective in suppressing the viral load and in boosting the CD4+ cell count.

All treatments were generally well tolerated, with a low rate of serious adverse events. More diarrhea was seen in the nelfinavir group in stage II of the study compared with BMS-232632-treated patients (51% versus 17%, respectively). The most common laboratory abnormality seen with BMS-232632 was elevated unconjugated bilirubin (found in 71% of patients treated with the drug). This effect was related to the dose of BMS-232632, noted Dr. Squires, and was mainly mild. In the small number of patients with more serious elevations, the dose of BMS-232632 was reduced.

"These elevations in total bilirubin levels were not clinically significant and did not interfere with the drug's antiviral efficacy," Dr. Squires told the audience. The new BMS-232632 drug is anywhere from two to 19 times more potent than currently available PIs and there are no dietary restrictions, except that it should be taken with food. [In a 48-week study, the drug was safe, well tolerated, and at least as effective in suppressing viral load as other PIs.] Moreover, BMS- 232632 does not appear to cause elevations in total cholesterol, LDL cholesterol, and triglycerides-unwanted effects that occur with currently available PIs.
"No elevations in total cholesterol, LDL-cholesterol, and triglycerides are seen [with BMS-232632], but these unfavorable effects are seen with all currently available PIs as well as with efavirenz [Sustiva®]," observed Dr. Squires.

In contrast to nelfinavir, BMS-232632 had a favorable impact on lipid values. A modest rise in total cholesterol was seen in the groups treated with the new PI, in contrast to an early, persistent risk in total cholesterol observed in the nelfinavir-treated group (45 mg/dL by week 4, she said). A rise in HDL- cholesterol was seen in the BMS-232632 groups, with no change in LDL-C; a persistent rise in LDL-C was seen in the nelfinavir arm. No change or a reduction in triglyceride level was seen in the BMS-232632 groups, whereas a persistent rise was seen in the patients randomized to nelfinavir.

The 400 mg once-daily dose will be studied in future trials. Currently, a Phase III study is comparing BMS-232632 400 mg once daily with efavirenz, noted Dr. Squires.


TCM-126, another new PI, is in a more preliminary phase of development than BMS-232632. According to the researchers involved in the drug's development, TCM-126 is a "resistance repellant PI" and is thought to prevent resistance because it fits so tightly into a critical position of the HIV virus that little chance remains for the virus to create a mutation that will lead to resistance.

Early studies of this drug are being conducted in Europe, and thus far, results suggest that this drug and other variants of it appear to prevent resistance. John Erickson, MD, Chief Scientific Officer for Tibotec, the developer of the compound, said: "We have never seen anything quite so potent as this first new drug in the class of resistance repellant PIs. [It] has the extraordinary capability to block formation of mutations. It gives us new hope in the fight against the disease."

Other experts cautioned that these are preliminary results and long-term, larger studies are needed to see if the promise of this drug, and other derivatives of the compound, will hold up.


Another Tibotec drug, TMC-120, is a new NNRTI that has shown promise in trials in patients with HIV infection. The point of attack on the HIV virus is different from that of PIs. In one Phase I trial that included 43 patients, TMC-120 reduced viral load in HIV-infected patients by 95% compared to almost no reduction in patients who took placebo pills. TMC-120 was well tolerated and safe, and thus far, no evidence of resistance has been seen. Side effects were infrequent and minimal.

Membrane Fusion Inhibitors

Membrane fusion inhibitors are a new class of antiviral agents that attack the virus in a novel way, they prevent the virus from entering the CD4 cells. Theoretically, there are three steps involved in the entry of the virus into the CD4 cells, and drugs are being developed to target each of these steps, explained Roy Gulick, MD, Cornell University, New York City. PRO-542 (developed by Progenics Pharmaceuticals), in the early stages of development, is targeted at the first step-attachment to the CD4 cell. The second step is reacting with the CD4+ co-receptor, called CCR5 (sometimes CXCR4). A number of companies are in the early stages of developing drugs to target the CCR5 co-receptor, explained Dr. Gulick; these include Schering C, a CCR5 inhibitor with potent in vitro activity that has been in Phase I trials but is currently on hold, and AMD 3100, a CXCR4 inhibitor also with potent in vitro activity with Phase I data available. "The fusion inhibitors that are furthest along in development include those targeted to the third step in preventing viral entry," explained Dr. Gulick. These include T20 (developed by Trimeris) and T1249 (marketed by Trimeris). Both drugs have been studied in humans, and they have shown activity in preliminary studies of patients who are resistant to multiple strains of the AIDS virus. T1249, now in Phase I/II development, has increased potency over T20 and may have activity against those viruses resistant to T20. T20 is given by injection twice a day, and T1249 is given by injection once a day.


"There are a host of other potential targets and candidate compounds under consideration. Hopefully these new drugs will be easier to use and will have less toxicity than the 15 approved drugs we have today. We need drugs for people who have taken all the available drugs and have developed resistance to them. We need drugs with new mechanisms of action or that have better activity against resistant strains of [the HIV] virus," concluded Dr. Gulick.