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New Protease Inhibitor TMC-114
Preliminary 24-Week Late Breaker Results of the Phase II Trial

By Daniel S. Berger, M.D.

March/April 2005

Daniel S. Berger, M.D.
Developing medications effective against HIV resistance is a challenge, but has become a very important priority for pharmaceutical companies.

Drugs without therapeutic advantages, or without additional treatment niches, will eventually lose their usefulness over the coming years because of the slow, steady climb in the pervasiveness of resistant mutations among the HIV-positive population. TMC-114 is a new protease inhibitor being developed that should have great application due to its ability to answer a tremendous unmet need in treatment-experienced patients.


Late Breaker

At the 12th Conference on Retroviruses and Opportunistic Infections (CROI), held in Boston in February, the first interim results of the Phase II studies with TMC-114 -- C202 (conducted in the U.S.) and C213 (conducted outside the U.S.) -- was highly newsworthy and was presented as a "late breaker."

The study was carried out in the U.S., Europe and South America. Three-hundred patients were enrolled in each study; however, data from the study participants who reached the timeline for this analysis was presented here (497 patients). Having participated as a lead investigator in this Phase II trial, I have great confidence in describing these results.


Background

Uniquely, in the laboratory, TMC-114 has shown to be sensitive to almost all protease inhibitor (PI) mutations. It also binds to the protease substrate (chemical ingredient) evenly across the volume of cleavage sites so that it becomes embedded in the substrate. Moreover, it does so at higher magnitudes than other PIs, so that it stays within the substrate like glue.


The Phase II Study

Among the patients in the study, 89% were male with an average of 44 years of age; 74% were Caucasian and 14% were African American. All had triple class HIV drug experience, and their HIV had resistance mutations from each class of antiviral. The most frequent protease inhibitor used during the failed regimen at baseline was Kaletra, with many of the participants having previous Kaletra use.

Also, 17% of patients showed no sensitive drugs from all of the three main HIV classes -- that is, there were not any drugs that could be expected to work well for them. There was an even distribution of mutations in each treatment arm, with 40% having greater than three primary PI mutations and 66% having resistance to all PIs. Participants who had prior T-20 (Fuzeon) usage made up 16% of all participants, and 8% had prior tipranavir use (another protease inhibitor in development).

Thus, to summarize the type of patient population in this study, the participants were among individuals with the fewest treatment options.


Study Design

The study was designed so that patients were randomized to receive one of four doses of TMC-114, either once daily or twice daily. Every TMC-114 dose, within each arm, was boosted with ritonavir (Norvir). The fifth arm served as a control, meaning that the physician picked the best regimen from already available antivirals. The background antiviral agents were all chosen by the physician based on genotyping and treatment history, to provide the most optimum therapy.


Results

At 24 weeks of treatment, the results showed significant improvements in all TMC-114 arms compared to the control. Looking at the control group first, 71% were on single boosted protease inhibitors and 27% on double boosted; viral loads only decreased by 0.27 logs. This is not a significant drop.

In contrast, of the TMC-114 treatment arms, the lowest dose (400 mg, once daily) demonstrated a highly significant 1.28 log drop. The 800 mg once-daily and 400 mg twice-daily doses resulted in a 1.4 log decrease in HIV-RNA, while the patients on the 600 mg twice-daily administration demonstrated a 1.85 log decline in viral load.

Also, patients taking the 600 mg dose twice daily demonstrated a rise in 75 CD4+ T-cells versus a 15 cell increase in the control arm. Approximately 47% of the patients in the study were also were taking T-20, which was evenly balanced throughout each treatment arm. (T-20 is the only approved drug in the latest class of HIV antivirals, fusion inhibitors.)


Unprecedented

As an experienced clinician, it is unexpected for individuals who have previously been aggressively treated and have already derived the biggest possible bang out of their regimen, to realize this kind of further viral load decrease. The occurrence of a further 1.85 log suppression and significant improvement in T-cell count in this very experienced HIV population is enormous.


Side Effects

Regarding observed side effects and adverse events in this study, there was no dose relationship or dose response changes; this means that taking higher doses of TMC-114 did not increase any side effects. Nor were there any differences observed compared to the patients in the control arm. Additionally, no liver-related grade 3 or 4 adverse events were reported. There was a small incidence of elevated (blood fats) cholesterol (4.8% versus 2.0% in the control) and triglycerides (17% versus 23% in the control) but again, there was no dose response with these blood fat abnormalities.


Summary

Thus, in summary, TMC-114 was studied in a patient population at great need. The patients had a very high degree of resistance to most available antivirals. Despite this, the study participants derived significant benefit with a dramatic decline in viral load and increased CD4+ T-cells.

During the study, many treatment-experienced patients witnessed their viral loads decrease to undetectable levels for the first time. When contrasting these results to other salvage-type trials, including the T-20 Fuzeon (TORO I and TORO II) and the tipranavir (RESIST) studies, it appears that preliminary treatment with TMC-114 has shown an unparalleled and extraordinary benefit. Continued study with this exciting compound for long-term safety and effectiveness is ongoing and other studies are being planned.

Daniel S. Berger, M.D., is Medical Director of NorthStar Healthcare in Chicago. He can be reached at DSBergerMD@aol.com or 1-773- 296-2400.


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