Phase 2b study comparing rilpivirine (TMC-278) to efavirenz in treatment-naive patients: 48-week results
4 April 2007. Related: Conference reports, Antiretrovirals, CROI 14 (Retrovirus) 2007.
Simon Collins, HIV i-Base
48-week results from the primary endpoint of the Phase 2b TMC-278 C204 dose-finding study, of a second generation diarylpyrimidine NNRTI in development from Tibotec were presented in an oral session by Anton Pozniak from Chelsea and Westminster Hospital, London. Rilpivirine (TMC-278) is a once-daily compound that has a similar resistance profile to TMC-125 which is being researched as a second-line treatment after first NNRTI failure.
TMC278-C204 is an ongoing, randomised, active-controlled, partially blinded (efavirenz was unblinded), dose-finding phase 2b trial.
368 patients (33% women) were randomised 1:1:1:1 to TMC278 25, 75, or 150 mg once daily, or to EFV 600 mg once daily. All arms included investigator-selected background nucleosides: AZT/3TC (Combivir) was used by 76% of patients and tenofovir/FTC (Truvada) by 24%. The primary endpoint was the proportion of patients with confirmed viral load <50 copies/mL (TLOVR definition, non-completer = failure) at 48 weeks.
Baseline median CD4 and viral load were 203 cells/mm3 (range 3-970) and 4.85 log copies/mL (range 2.16-7.13). Median duration of HIV infection was 1 year (range 0-21 years).
48-week results by intent-to-treat analysis (Time to Loss of Virological Response, TLOVR) showed a similar 80% patients achieving viral suppression <50 copies/mL across all arms and are detailed in Table 1. All arms showed a mean viral load change of approximately -2.5 logs at week 48 with no differences between arms.
Table 1: Responses at week-48 in TMC-278 C204
| TMC-278 | efavirenz | |||
|---|---|---|---|---|
| 25mg | 75mg | 150mg | ||
| N | 93 | 95 | 91 | 89 |
| % <50 copies/mL | 81% | 80% | 77% | 81% |
| Mean change VL | -2.63 log | -2.65 log | -2.63 log | -2.64 log |
| Change in CD4 | +125 | +145 | +143 | +127 |
The tolerability and side effect profile was also similar between groups but there were fewer CNS side effects in the rilpivirine arm and a slightly better lipid profile compared to efavirenz (see Table 2). Mean (SD) changes from baseline of total and LDL cholesterol were 5 mg/dL (30) and 0 mg/dL (24) in combined rilpivirine arms versus 31 mg/dL (30) and 16 mg/dL (26), respectively with efavirenz. There was one death due to sepsis, not attributed to study drug in the 75mg rilpivirine arm.
Table 2: Side effects and tolerability in TMC-278 C204
| 25mg | 75mg | 150mg | EFV | |
|---|---|---|---|---|
| % any side effect | 10.8% | 10.5% | 9.9% | 9.0% |
| % any grade 3/4* | 25.8% | 24.3% | 24.2% | 15.7% |
| % D/c adverse event | 6% | 5% | 10% | 6% |
| % D/c other reasons | 4% | 8% | 7% | 8% |
| Side effects (% pts) | ||||
| Nausea | 15.1 | 25.3 | 20.9 | 18.0 |
| CNS disorders | 34.4 | 34.7 | 30.8 | 52.8 |
| Headache | 6.5 | 11.6 | 5.5 | 7.9 |
| Dissyness | 5.4 | 5.3 | 5.5 | 27.0 |
| Somnolence | 2.2 | 3.2 | 4.4 | 10.1 |
| Psychiatric disorders | 14.0 | 12.6 | 13.2 | 15.7 |
| Vertigo | 1.1 | 2.1 | 0 | 10.1 |
| Abnormal dreams | 1.1 | 6.3 | 0 | 10.1 |
| Skin, cutaneous reactions | 22.6 | 25.5 | 25.7 | 33.7 |
| All rash** | 5.4 | 6.3 | 12.1 | 15.1 |
| Vomiting | 3.2 | 7.4 | 3.3 | 9.0 |
* Reported as higher investigator reporting as there were no differences in lab reporting between the TMC and EFV arms.
**All grade 1/2 except one pt in 75mg arm probably related to dapsone.
Resistance data was not presented for patients failing to achieve or maintain viral suppression.
Tibotec have selected the 75mg dose to take forward in Phase 3 studies.
Reference:
- Pozniak A, Morales-Ramirez J, Mohap L et al. 48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naive Patients. Oral abstract 144LB.
http://www.retroconference.org/2007/Abstracts/30659.htm
The oral presentation can be viewed online from the CROI website (see Wednesday, 10.00-12.00am Clinical Trials).