TMC 125: some good and bad news

11 February 2006. Related: Conference reports, Antiretrovirals, EACS 10 Dublin 2005.

Mark Mascolini for NATAP.org

Two late-breaker talks at the Dublin EACS meeting laid out phase 2 salvage results with TMC125, the Tibotec NNRTI that trimmed viral loads by a median 0.89 log copies/mL when given for 7 days to 16 people taking a failing efavirenz or nevirapine regimen [1].

One of the two new studies suggested TMC125 may do something no NNRTI has done before – control HIV replication after failure of another NNRTI. The other study, however, charted an unimpressive difference in antiviral vigor between TMC125 and placebo – but the trial design apparently explains this middling result. Then, a few weeks after EACS, Tibotec called a halt to another phase 2 study because a protease inhibitor (PI) regimen outdid TMC125 in people with NNRTI-but not PI-experience [2].

Two ongoing phase 3 studies-the DUET trials-will determine whether this much-heralded NNRTI will fulfill its potential. In the meantime this report examines the evidence from EACS and the scant data released on the TMC125-versus-PI trial.

Other work headlined at the Dublin gathering featured data on how efavirenz affects the new lopinavir/ritonavir tablets-and how the proton pump inhibitor omeprazole affects saquinavir/ritonavir. Several intriguing analyses addressed two vexing questions of rescue-regimen planning: What does virologic failure mean clinically? And how fast should people switch from an incompletely suppressive regimen?

TMC125-good news and bad news

A 48-week dose-escalation and safety trial of TMC125, presented by the University of British Columbia’s Julio Montaner, enrolled 306 people with triple-class experience and a viral load above 1000 copies/mL [3]. With other Canadian and European colleagues, Montaner randomised them to a salvage regimen including 800 or 1200 mg of TMC125 twice daily or placebo.

A crucial trial design feature gave people in the placebo arm a good chance of responding: All enrollees had to have virus sensitive to two or more antiretrovirals that they could add to TMC125 or placebo. Besides placebo or the Tibotec nonnuke, they could start three to four antiretrovirals, including nucleosides with or without lopinavir/ritonavir or saquinavir/ritonavir, and with or without the fusion inhibitor enfuvirtide.

The median starting viral load stood at 4.09 log copies/mL (about 12,300 copies/mL) in the 60 people randomised to placebo and 4.25 log copies/mL (about 17,800 copies/mL) in the 240 assigned to TMC125. So most of these people did not have runaway viral replication. But many people had CD4 counts in or near the danger zone, with median baseline tallies of 230 cells/mm³ in the placebo group and 211 cells/mm³ in the TMC125 arm. Both groups had an 11-year history of HIV infection, and almost half in each group had AIDS.

After 24 weeks a noncompleter-equals-failure analysis figured an almost identical viral load drop in the two TMC125 arms, between 1.0 and 1.5 log copies/mL. Confidence intervals almost overlapped with the 24-week drop in the placebo group, which lay between 0.5 and 1.0 log copies/mL. The reasonable treatment options available to the placebo group surely contributed to their decent 24-week response.

A graph of time to treatment discontinuation through more than 50 weeks showed virtually overlapping lines for the placebo group and the TMC125 groups. At the 24-week primary analysis, a slightly higher proportion quit in the placebo arm because of virologic failure, while a much higher proportion stopped TMC125 because of side effects (Table 1).

Table 1: Discontinuation of TMC125 or placebo at 24 weeks

OBR = Optimised background regimen

Gastrointestinal problems proved the most frequent cause of discontinuation in the TMC125 group. Pancreatitis accounted for three of the six serious toxicities with TMC125. Everyone in whom pancreatitis developed had risk factors for this condition, but Montaner and colleagues could not exclude TMC125 as the cause. Diarrhea was the most common side effect in the NNRTI group, affecting 26% after a median 29 weeks of follow-up.

Overall rates of grade 3 or 4 lab abnormalities did not differ between the TMC125 arm (31% grade 3 and 11% grade 4 after a median 29 weeks) and the placebo arm (29% grade 3 and 12% grade 4 after a median 40 weeks). Grade 3 or 4 pancreatic amylase readings turned up in 5% taking TMC125 and 3% taking placebo.

Phase 3 studies will use a 200-mg twice-daily formulation of TMC125 (two tablets twice daily) that yields TMC125 levels equivalent to those attained with 800 mg twice daily in this trial.

A 48-week trial presented by the University of South Florida’s Jeffrey Nadler found better 24-week RNA and CD4 responses to TMC125 than to an “active control” regimen in 199 people with resistance to NNRTIs and three or more primary protease mutations [4]. Nadler and colleagues at other US centers randomised them to take 400 or 800 mg of TMC125 twice daily plus a background regimen or to the control regimen.

Baseline viral loads were similar in the three treatment arms-about 4.7 log copies/mL (50,000 copies/mL). The starting CD4 count-about 100 cells/mm³. Two thirds in each treatment group had AIDS.

One trait appeared to favor the TMC125 arms-virus susceptible to more antiretrovirals. More than 40% of people randomised to TMC125 had virus sensitive to two or three antiretrovirals besides the new NNRTI, compared with 25% in the control group. Whereas 40% in each of the TMC125 arms had virus sensitive to only one other antiretroviral, 49% in the control group had only one promising drug to use. While 46% in the 400-mg TMC125 arm and 42% in the 800-mg arm had never tried enfuvirtide and used it as part of their salvage regimen, only 27.5% in the control arm had never tried enfuvirtide and used it in this study.

Yet the TMC125 regimen outperformed the control combination after 24 weeks regardless of how many drugs in the regimen had a phenotypic sensitivity score indicating a good chance of antiviral activity (Table 2).

Table 2: Response by active drugs in regimen – TMC 125

The most-used active drug was enfuvirtide, and its use correlated with virologic response in every treatment arm (P < 0.001). This finding adds to a growing mount of data showing the value of having at least two active drugs in a salvage regimen.

About one third of study participants reached a viral load below 400 copies/mL in a 24-week time-to-loss-of-virologic-response analysis, significantly more than reached that mark with the control regimen (Table 3). CD4 counts also climbed higher with TMC125.

Table 3: Results at week 24 – TMC 125 BD

BD = twice daily; NS = not significant

Rates of grade 3 or 4 side effects proved high but consistent across the three treatment groups-36% with 400 mg of TMC125, 41% with 800 mg, and 38% with the control combo. Grade 3 or 4 lab abnormalities affected about 30% in each group. Twelve people taking TMC125 (8%) had abnormal pancreatic amylase, and pancreatitis cropped up in 3 (2%). Three people (2%) had a TMC125-related rash, 10 (6%) had grade 3 or 4 triglyceride jumps, 9 (6%) had neutropenia, and 5 (3%) had abnormal creatinine.

Five people died during the study, 4 while taking 400 mg of TMC125 twice daily and 1 while taking a control regimen. Researchers blamed TMC125 for one death from cardiopulmonary failure and myocardial infarction.

Nine days after EACS attendees left Dublin, Tibotec slammed the brakes on another phase 2 study, this one pitting TMC125 plus two nucleosides against a PI plus two nukes [2]. Unlike the just-reviewed salvage trial, no one in the abandoned trial had tasted a PI before, and only one NNRTI regimen had failed in these people.

After only 12 weeks of follow-up researchers noted that substantially fewer people taking TMC125 reached the primary response target-a viral load below 50 copies/mL. Tibotec scuttled the study and recommended that everyone taking TMC125 – even those responding well – switch to a regimen of licensed antiretrovirals. The shutdown will not affect phase 3 studies.

Researchers will look at the potential roles of baseline resistance, the nucleosides used (which were not mentioned in the Tibotec press release), and TMC125 plasma levels attained in the halted trial. Unless they find something striking, the results could mean TMC125 is a second-rate option after failure of efavirenz or nevirapine in people still naive to PIs.

Source: www.natap.org

References:

1. Gazzard BG, Pozniak AL, Rosenbaum W, et al. An open-label assessment of TMC 125-a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 2003;17:F49-F54.
2. PRNewswire. Tibotec discontinues exploratory trial with TMC125. November 29, 2005. See HTB November/December 2005.
3. Montaner J, Domingo P, Junod P, et al. Safety and tolerability of TMC125 in 3-class-experienced HIV-infected patients: 24-week primary analysis of trial TMC125-C203. European AIDS Conference. November 17-20, 2005. Dublin. Abstract LBPS3/7B.
4. Nadler JP, Grossman HA, Hicks C, et al. Efficacy and tolerability of TMC125 in HIV patients with NNRTI and PI resistance at 24 weeks: TMC125-C223. European AIDS Conference. November 17-20, 2005. Dublin. Abstract LBPS3/7A.