Phase 2 Study Shows Efficacy of Six-Month Regimen of Lenacapavir, Teropavimab, and Zinlirvimab for HIV-1
Onyema Ogbuagu, MBBCh, FACP, FIDSA discussed 96% virologic suppression with lenacapavir-based therapy, showing similar results to daily oral regimens.
At CROI 2025, Onyema Ogbuagu, MBBCh, FACP, FIDSA, associate professor at Yale School of Medicine, presented key findings from a Phase 2 study evaluating the efficacy and safety of switching to lenacapavir (LEN), teropavimab (TAB), and zinlirvimab (ZAB) (LTZ) every 6 months (Q6M) compared to staying on a stable baseline oral regimen (SBR) in virologically suppressed individuals with HIV-1 susceptible to both broadly neutralizing antibodies (bNAbs). At Week 26, 96% of participants in both the LTZ and SBR arms maintained virologic suppression (HIV-1 RNA <50 copies/mL). The study involved 53 participants in the LTZ arm and 27 in the SBR arm, with a median age of 51 (range 20-65), 15% female, and 36% Black. Baseline mean CD4 count was 749/μL (SD 245), increasing by 23/μL (SD 143) in the LTZ group and 69/μL (SD 203) in the SBR group.
The open-label study included participants who had been on antiretroviral therapy (ART) for at least 12 months and had HIV-1 highly susceptible to both bNAbs (IC90 ≤2 μg/mL). Participants were randomized 2:1 to receive either LTZ (subcutaneous LEN 927 mg Q6M, intravenous TAB 2550 mg Q6M, and intravenous ZAB 2550 mg Q6M) or continue with SBR. The primary endpoint was the proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 26, with secondary endpoints focusing on changes in CD4 count and adverse events (AEs).
Treatment-emergent adverse events (TEAEs) were reported in 85% of the LTZ arm and 63% of the SBR arm. The most common TEAEs in the LTZ group were mild injection site reactions related to subcutaneous LEN. No infusion-related reactions to TAB or ZAB, Grade ≥3 TEAEs, serious TEAEs, or discontinuations due to AEs were observed in the LTZ arm. One participant in the SBR arm discontinued due to a serious TEAE.
The study concluded that the efficacy of Q6M LTZ was comparable to that of daily oral ART through Week 26, with LTZ being well tolerated. These results support further investigation of LTZ as the first Q6M combination treatment for people with HIV-1.
“We’ve shown great data at six months, both in the Phase 1 and now the Phase 2 study,” Ogbuagu said. “We’ve seen equivalent suppression between those who received lenacapavir, teropavimab, and zinlirvimab compared to those staying on their oral regimen. We do acknowledge that our data is six months out, but the study will continue for a longer period to evaluate the durability of virologic suppression.”
Ogbuagu highlighted that safety remains a top priority in the trial. “We looked at two categories of safety signals: general adverse events, like clinical and laboratory abnormalities, and injection site or infusion reactions. For bNAbs like TAB and ZAB, infusion reactions are important. For lenacapavir, injection site reactions are key, since it’s subcutaneously administered,” he explained.
“There were no severe treatment-emergent adverse events related to the investigational compounds, and no discontinuations due to adverse events. The more common adverse events were upper respiratory tract infections and diarrhea, but they occurred at low proportions,” Ogbuagu said. “As for injection site reactions, under 40% of participants experienced a palpable nodule, and less than 20% had injection site pain, erythema, or induration. These reactions were short-lived and did not impact tolerability.”
Looking ahead, Ogbuagu emphasized the importance of continuing the study. “We’re excited to present the six-month data, which is reinforced by earlier Phase 1 studies. The trial will go up to a year, and even after the year, we’ll have an open-label extension phase. We hope to continue studying the longer-acting efficacy and safety.”
He added that LTZ could address long-standing challenges in HIV treatment. “This could be the advanced, longer-acting regimen we need for HIV. These are injection or infusion agents dosed every six months, which is appealing to both providers and patients who struggle with daily oral therapy. Long-acting therapies can overcome issues like inadvertent disclosure and the inconvenience of carrying pills,” Ogbuagu noted.
He also emphasized that lenacapavir and the broadly neutralizing antibodies could serve as a promising option for individuals who have developed resistance to other antiretroviral drugs. “This regimen offers simplification compared to daily oral regimens,” he said. “We believe this regimen could meet the unmet needs of many people living with HIV.”
