When compared with efavirenz (Sustiva), Tibotec’s investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 demonstrated equally potent and sustained antiretroviral efficacy as first-line therapy over 48 weeks, according to phase IIb study data presented as a late-breaker to the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles on Wednesday. Incidence of rash and central nervous system (CNS) events and total cholesterol and triglycerides were, however, lower in the participants on TMC278 than those on efavirenz.
TMC278 appears to be highly active against both wild-type and NNRTI-resistant HIV-1 in vitro. With a half-life of 45 hours, allowing for once-daily dosing, a seven day dose-ranging monotherapy study presented to this conference two years ago demonstrated TMC278’s potent short-term activity.
Design and objectives
In order to evaluate the efficacy and safety of three blinded, once-daily doses of TMC278 (25mg, 75mg, or 150mg) compared with open-label once-daily efavirenz (600mg), in combination with either AZT/3TC (Combivir) or tenofovir/FTC (Truvada), investigators for Tibotec’s phase IIB C204 study enrolled 368 antiretroviral-naive individuals with viral loads over 5,000 copies/mL and without resistance mutations to nucleosides (NRTIs) or NNRTIs, as defined by the International AIDS Society (IAS).
The primary objective of the study was to select a TMC278 dose for further development. The study’s primary endpoint was the proportion of patients with confirmed viral load below 50 copies/mL at 48 weeks. Although 48-week results were reported here, the study is planned to continue until Week 96.
A total of 89 participants were randomised to receive open-label efavirenz plus two NRTIs, whereas 93, 95 and 91 participants were randomised to receive blinded doses of 25mg, 75mg or 150mg TMC278 plus two NRTIs, respectively. All NRTIs were investigator-selected: 76% received Combivir and 24% received Truvada.
Virological and immunological efficacy
All analyses were intention-to-treat (ITT), where non-completer equalled failure. There were no statistically significant differences seen in the efficacy results between any of the treatment arms, with 81, 80 and 77% of the participants randomised to TMC278 25mg, 75mg and 150mg, and 81% of the participants on efavirenz achieving a viral load below 50 copies/mL at 48 weeks, respectively.
Similarly there were no differences seen at 48 weeks in the viral load changes from baseline, with mean 2.63, 2.65, and 2.63 log10 decreases seen in the participants randomised to TMC278 25mg, 75mg and 150mg, respectively, and a mean 2.64 log10 decrease seen in the participants on efavirenz.
Although efavirenz appeared to suppress viral load slightly faster than TMC278, Dr Anton Pozniak, of London’s Chelsea & Westminster Hospital, presenting, said that this was entirely due to the fact that twice as many participants on TMC278 had baseline viral loads above 300,000 copies/ml compared with those on efavirenz. He added that by twelve to sixteen weeks, participants in all four arms showed a mean change in viral load by 2.6 logs10.
CD4 cell count increases at week 48 were also broadly similar across the four arms, with mean 125, 145 and 143 cell/mm3 increases seen in the participants randomised to TMC278 25mg, 75mg and 150mg, respectively, and a mean 127 cell/mm3 increase seen in the participants on efavirenz, respectively.
All four arms had a similar distribution of patient demographics. The median age was 33 years. Around one-third were female, around 44% were white, 25% were black and the remainder were Hispanic or Asian (representing the variety of study sites, which included Puerto Rico, South Africa; Mexico; Thailand; the United States and United Kingdom.)
At baseline the median log10 viral load was 4.85 copies/mL – although there was a wide range seen, from below 500 to several million copies/ml – and the median CD4 cell count was similar in both arms at 203 cells/mm3.
Resistance and interactions
During the question and answer session that followed, Dr Pozniak revealed early analysis of genotypic resistance mutations in the individuals that had experienced virological failure whilst on TMC278: around 25% had wild type virus; mutations at codons 101E and 230L appeared, and although a further mutation at codon 138K was seen, this, noted Dr Pozniac “didn’t affect phenotype to TMC278”.
He added that phase III studies would provide more rigorous analysis of the mutations that conferred resistance to TMC278.
He also noted that an interaction with the tuberculosis (TB) treatment, rifamipicin, was seen with TMC278, resulting in reduced rifampicin levels, and suggested that dose adjustments or use of alternative TB drugs were warranted.
TMC278's developer, Tibotec, is now pursuing phase III licensing studies of the drug, with a view to marketing TMC278 as a direct competitor to efavirenz for first-line treatment.
No differences were seen between the four arms for serious adverse events: 10.8%, 10.5% and 9.9% in the participants randomised to TMC278 25mg, 75mg and 150mg, respectively; and 9% in those on efavirenz. There was one death in the study – due to septicaemia and pneumonia – in an individual in the TMC278 75mg arm, although this was considered unrelated to the study drug.
Dr Pozniak showed data suggesting that neither clinical nor laboratory adverse events appeared to be related to the dose of TMC278, and so the three arms were combined to compare with efavirenz.
No major differences between the two drugs were seen with the most commonly observed clinical adverse events: nausea (TMC278 doses combined 20% vs. efavirenz 18%); headache (7.9% vs. 7.9%); and vomiting (4.7% vs. 9%).
However, CNS disorders and psychiatric events were seen less frequently with TMC278: dizziness (TMC278 doses combined 5.4% vs. efavirenz 27%); somnolence (3.2% vs. 10.1%); vertigo (1.1% vs. 10.1%); and abnormal dreams (1.8% vs. 5.6%).
Rash events were also seen less frequently for TMC278 (0.4%) vs. efavirenz (5.6%). However, during questioning, Dr Pozniac noted that since no-one on the two lower doses of TMC278 experienced rash, compared with one individual on the highest dose; this may suggest a dose-related effect.
In addition, 10% of participants on the highest dose of TMC278 discontinued the study due to adverse events, compared with 6% and 5% on the two lower doses, respectively, and 5% on efavirenz. Consequently, the 75mg TMC278 has been chosen for phase III study.
Grade 3/4 investigator-reported events were seen more frequently in individuals on the combined TMC278 arms compared with those on efavirenz (24.7% vs. 15.7%). Dr Pozniak explained that this was due to underreporting of laboratory adverse events by investigators, and showed data supporting this: 22% of individuals on the combined TMC278 arms versus 20% of individuals on efavirenz had grade 3/4 laboratory adverse events.
However, twice as many participants on TMC278 experienced grade 3/4 increases in liver function tests (5% vs. 2.4%) and whilst no-one in the efavirenz arm experienced abnormally high haemoglobin, this was experienced by 2.3% in the TMC278 arms.
Mean changes from baseline of total and LDL cholesterol were lower in the combined TMC278 arms (5mg/dL [0.13mmol/L] and 0mg/dL [0mmol/L], respectively) whereas these were much higher in the participants in the efavirenz arm, at 31 mg/dL [0.8mmol/L] and 16 mg/dL [0.41mmol/L], respectively. Similar differences were seen in triglyceride levels: there was a mean reduction in triglycerides observed in the combined TMC278 arm (-10mg/dL [-0.11mmol/L]) whereas a mean increase was observed in the participants on efavirenz (18mg/dL [0.2mmol/L]).
In addition, in patients treated with Combivir, anaemia or neutropenia led to switches off zidovudine (AZT, Retrovir) in 6% of participants receiving TMC278 and 1% of those on efavirenz.
Pozniak A et al. 48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naïve patients. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 144LB, 2007.