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Notes And Quotes

Notes and Quotes

Susman, Ed

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New drugs give hints of promise in treating HIV/AIDS

The inability of current medications to eradicate HIV/AIDS means that the search continues for new weapons that can be added to the arsenal of drugs that is available to fight the disease throughout an infected person's lifetime.

At the Eighth Annual Retrovirus Conference in Chicago, a few new promising compounds were unveiled which may, in countries where resources are available, give hope that the spread of the disease can be arrested.

One of the more promising compounds, just beginning human trials, is a new type of protease inhibitor – a drug designed to prevent the emergence of resistant HIV. Researchers from Tibotec, Inc., a pharmaceutical research and development company headquartered in Mechelen, Belgium, presented data on TMC-126.

Repels resistance

John Erickson, PhD, chief scientific officer at Tibotec's Rockville (MD, USA) offices, said that TMC-126 is designed to fit snugly into the activation center of the protease with such tight protein binding that it vastly reduces the chances that HIV could develop a mutation to counter the drug's ability to inhibit replication.

`‘We have never seen anything quite so potent as this first drug in the new class of resistance repellent protease inhibitors,’’ said Erickson, ‘‘This drug has the extraordinary capability to block formation of mutations.’’ His research teams have identified several similar variants of the drug, all with high effectivity in preventing resistance.

Erickson said that one measure of TMC-126's potency is to look at the virus’ ‘‘vitality’’ profile if the virus had to mutate to overcome the drug. In the case of the entire library of TMC protease inhibitor drugs, the virus would have a negative vitality, Erickson said.

`‘What that means,’’ explained John Mellors, MD, professor of medicine at the University of Pittsburgh, ‘‘is that faced with TMC-126 the virus has two choices: either not to replicate or to create a mutation that severely defeats its ability to infect cells. We are excited about the potential of this drug.’'

Mellors said it might even be possible to use TMC-126 as a single agent. ‘‘There is no theoretical reason it couldn't do the job,’’ he said. ‘‘Certainly to use a drug as a single agent against HIV is setting its feet to fire. I think it will be used in combination with other drugs to lessen any chance of mutations emerging.’'

Roy Gulick, MD, medical director of the Cornell Clinical Trials Unit at New York Presbyterian Hospital, said that past experience with even the most promising protease inhibitors have always shown that resistance emerges rapidly with only one drug, so combination use, he agreed, is the probable path to the clinic.

Erickson said TMC-126 could be especially potent in treating people in developing countries where compliance with treatment can be problematic. With current drug treatments, lack of compliance is associated with emergence of resistant virus, but TMC-126's ability to repel resistance might make it a drug of choice under those conditions.


Among other drugs under development that were described at the conference is Tibotec's second generation non-nucleoside reverse transcriptase inhibitor, TMC-120.

Rudi Pauwels, PhD, chief executive officer of Tibotec, said that TMC-120 reduced the virus replication by 95% (1.5 log), compared to almost no reduction in viral load in patients who received placebo pills.

`‘TMC120 was well tolerated and safe,’’ he said. ‘‘No resistance-associated mutations were found among the 28 patients receiving TMC120.’’ He said that all of the patients receiving the drug demonstrated a response. Side effects were infrequent and minimal, he said.

`‘The 1.5 log drop in HIV levels is as good as we've seen with anything,’’ said Mellors. ‘‘The data presented were limited, but it is a good start.’'

Pauwels reported that 63 patients in Russia and Poland participated in the randomized, double-blind, Phase I/II study in which two doses of TMC120 were compared with placebo. The 1.5 log drop was seen after the first week of treatment, and the patients were switched to combination therapy following the initial trial.

In addition to the fall in HIV, Pauwels said that the average patient on the treatment drug showed an increase of 120 CD4-positive cells per microlitre blood.

Mellors said that he believes that TMC120 and other new, stronger binding compounds may only require one other drug to provide adequate viral suppression. ‘‘Dual combinations are likely to be just as good as triple combination,’’ he said.

Once-a-day PI

Another protease inhibitor, BMS-232632, from Bristol-Myers Squibb, was found to be well-tolerated and effective in a once-a-day formula. All currently approved protease inhibitors have to be taken twice or three times a day.

`‘The key point is that with this drug you feel comfortable with only once-a-day administration,’’ said Kathleen Squires, MD, associate professor of medicine at the Keck School of Medicine, University of Southern California, Los Angeles.

In her presentation, Squires reported the Phase II, two-stage randomized study which looked at safety and antiretroviral activity of three dose levels of BMS-232632, manufactured by Bristol-Myers Squibb. BMS-232632, was compared with nelfinavir. In each arm two nucleoside reverse transcriptase inhibitors were used in combination with the protease inhibitor.

Among the 400 subjects treated in the 48-week study, Squires said that BMS-232632 was as effective as nelfinavir – in a combination therapy that included stavudine and didanosine – in lowering circulating virus. She noted that five to 10 times the amount of nelfinavir was required to produce the same HIV-lowering effect as BMS-232632. The BMS-232632 doses were 200 mg, 400 mg and 500 mg, once a day, versus 750 mg of nelfinavir three times a day.

Patients on BMS-232632 decreased their viral load by an average of 2.5 logs, she said, or about 99.5%. Up to 70% of patients on doses of BMS-232632 were able to achieve undetectable viral loads.

Squires said that the ability to deliver BMS-232632 once-a-day implies that it will be easier for patients to comply with regimens containing the drug. She said that patients are asked to take BMS-232632 with a light meal, and most take the drug at breakfast.

`‘There do seems to be some advantages of BMS-232632 over other protease inhibitors,’’ said Mellors. ‘‘It will ease compliance and it doesn't appear to increase LDL cholesterol. It seems to do as well as nelfinavir, one of the standard protease inhibitors.’'

New fusion inhibitor

Another experimental drug, T-1249, a membrane fusion inhibitor which is designed to prevent the virus from attaching to cells, showed potent ability to reduce circulating virus in the blood of patients.

In the study, 72 patients were given three different doses of T-1249, a peptide that requires subcutaneous administration. Patients received 6.25 mg; 12.5 mg or 25 mg once a day, or 12.5 mg, 25 mg or 50 mg in two injections each day either in one injection or in two injections a day.

The patients receiving the highest doses of T-1249, developed by Trimeris, Inc., Durham, NC, demonstrated a 1.5 log decrease in circulating HIV virus, Joseph Eron, MD, associate professor of medicine at the University of North Carolina-Chapel Hill, said.

He said that higher levels of the drug might be used in treatment – most probably in combination with other drugs – because there did not appear to be any leveling off of activity at the highest dose used in the study. And, he noted, there did not appear to be any emergence of adverse affects that could limit treatment.

T-1249 was developed as a follow-up on compound to T-20, which has been used extensively in treatment. Eron said that T-1249 has demonstrated unique potency against a broad range of HIV-1, HIV-2, and SIV isolates and a non-overlapping resistance profile with respect to T-20. T-20 requires at least two injections a day which might give a once-a-day injection an advantage.

While the new drugs seem to offer some hope and the early results appear impressive, Mellors cautioned, ‘‘Every new drug looks best the first time we see it. How well these drugs become in the treatment of HIV/AIDS will have to await long-term studies.’'

© 2001 Lippincott Williams & Wilkins, Inc.