Detailed phase 3 results suggest the two-drug combination of Gilead Sciences’ lenacapavir and Merck & Co.’s islatravir has what it takes to become the first complete weekly pill for the treatment of HIV.
Two Islend clinical trials confirmed that a once-weekly, single-tablet combination of islatravir and lenacapavir (ISL/LEN) matches daily treatments like Gilead’s Biktarvy at maintaining HIV viral suppression, according to data slated for presentation at the 26th International AIDS Conference in Rio de Janeiro, Brazil.
Positioned to become the first complete weekly oral HIV treatment, ISL/LEN combines a major scientific leap with the promise of meeting diverse patient needs, Jared Baeten, M.D., Ph.D., Gilead’s clinical development lead in virology, said in an interview with Fierce Pharma.
“Many people living with HIV struggle with adherence,” Baeten said. “Once-a-week pills take […] the psychological challenges of HIV adherence from seven days a week to one.”
The weekly ISL/LEN pill was efficacious and well tolerated at least up to Week 48 in the two Islend trials.
In the Islend-1 study among 607 participants who already had their HIV well under control with Biktarvy, no individuals who switched to ISL/LEN had detectable HIV of at least 50 copies/mL at Week 48, compared with one (0.3%) case in those who remained on Biktarvy.
Patients who got ISL/LEN saw their CD4+ T-cell count changed by an average minus 10 cells/μL, compared with minus 18 cells/μL in the control arm. The patients started the trial with CD4 counts at around 740 cells/μL, well above the 500 cells/μL threshold considered normal.
As for Islend-2, that study enrolled 626 individuals who were virologically suppressed by various daily regimens. At Week 48, one (0.3%) ISL/LEN recipient and four (1.3%) patients who continued their standard treatments had HIV RNA levels reach 50 copies/mL or above.
Average change in CD4 counts was minus 45 cells/μL with ISL/LEN and minus 8 cells/μL with daily orals. As the researchers noted in an abstract, the ISL/LEN group had higher baseline CD4 counts, while the two groups’ numbers converged at Week 48.
The FDA once temporarily placed several Merck studies of islatravir on clinical hold in 2021 after some patients had experienced notable declines in total lymphocyte and CD4 T-cell counts. As Baeten pointed out, the safety signal was triggered by high dose levels of islatravir that was significantly higher than used in the Islend trials. In both Islend trials, investigators reported “no between-group differences” in lymphocyte counts at Week 48, according to their abstracts.
In both trials, ISL/LEN demonstrated a safety profile that’s comparable to daily orals. All study arms had treatment-emergent adverse events of any grade in the high-70s percentage range. The rate of any-grade adverse events deemed treatment-related was 13.5% and 13.2% for ISL/LEN and Biktarvy, respectively, in Islend-1; and 18.5% and 0.3% for the weekly pill and control arm, respectively, in Islend-2.
Treatment-related serious adverse reactions or treatment-related problems leading to discontinuation were generally low across both trials, in the low single digits or below.
Before ISL/LEN’s clinical success, GSK already introduced the world’s first complete long-acting HIV treatment, Cabenuva, which replaces daily pills with injections given once a month or every two months.
Still, many patients prefer taking pills over injecting themselves, Baeten noted. On the flip side, many patients who’re comfortable taking pills every day may stick with their daily routine. What ISL/LEN offers is another option, he said.
“We are laser-focused on getting enough options to patients so that every one of them can find the thing that’s going to work for them for the long term because HIV treatment is a decades-long exercise,” Baeten said.
While ISL/LEN could offer a once-weekly treatment option, the California pharma is developing new antivirals in the hopes of matching lenacapavir’s six-month dosing capability. In one approach, Gilead is launching two phase 3 studies in the Daybreak program combining lenacapavir with two broadly neutralizing antibodies, teropavimab and zinlirvimab.
The positive HIV treatment readout comes as Gilead is making commercial inroads for lenacapavir, an HIV capsid inhibitor, as a twice-yearly PrEP injection for HIV prevention. Approved by the FDA a year ago under the brand name Yeztugo, the long-acting injectable booked $166 million in sales in the first quarter.
At AIDS 2026, Gilead provided updated results from the landmark Purpose trials for Yeztugo through a year of open-label extension that Baeten said reinforce the drug’s profile.
Of 4,417 cisgender women enrolled in the Purpose 1 trial who were eligible to join the open-label stage following the original randomized blinded phase, 95% chose to start or continue Yeztugo. There were zero HIV infections among all those individuals during the 52 weeks of follow-up. By comparison, one infection was reported in a woman who switched from blinded Yeztugo to Gilead’s daily PrEP Truvada during the open-label phase.
In Purpose 2, which enrolled cisgender men and gender-diverse individuals, a similar 95% of participants opted to take Yeztugo during the open-label phase. One case of HIV occurred in a person who received all Yeztugo injections on time.
Despite that additional case, Yeztugo still boasts the lowest chance of breakthrough infection as seen in a PrEP clinical trial, Baeten said. All told, in Purpose-2, there were four HIV infections for Yeztugo over 5,295 person-years of follow-up so far. Typically, in this population, the expected HIV incidence rate is around 3% to 5% per year, the Gilead exec noted.
The fact that 95% of participants chose to take Yeztugo is in itself “a striking number,” Baeten noted. Besides, adherence to timely injections was high, at 96% and 92%, respectively, at week 52 between the two trials.
“Adherence is the Achilles’ heel of PrEP, and lenacapavir, by being an injection of just twice a year, takes much of that adherence out of people’s hands,” Baeten said.
Both Gilead and researchers are evaluating in various studies how best to keep adherence to Yeztugo high, Baeten noted.
For its part, Merck recently got FDA approval for islatravir, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), as part of a daily combination with doravirine under the brand name Idvynso.
After failing to turn islatravir into a PrEP option because of the dosing strength problem, Merck is developing a follow-on NRTTI, alimatravir (MK-8527), as a potential once-monthly oral pill for PrEP.
Trying to build its own once-weekly oral treatment without Gilead’s lenacapavir, the New Jersey pharma is investigating pairing islatravir with an NNRTI called ulonivirine in phase 2.