Budigalimab, a monoclonal antibody that blocks the PD-1 receptor on immune cells, was associated with delayed HIV rebound or sustained low viral load in a majority of people who interrupted antiretroviral therapy (ART), according to a small pilot study presented at the 19th European AIDS Conference (EACS 2023) in Warsaw last week. Two out of 11 study participants who received four doses of the drug have maintained viral suppression without ART for a year and a half.
“Budigalimab administered for finite duration at very low doses was well tolerated in phase Ib studies of people living with HIV,” Professor Jean-Pierre Routy of McGill University Health Centre in Montreal reported. “Biweekly administration of budigalimab 10mg IV for four doses led to delayed viral rebound and/or ART-free viral control in six of nine participants completing treatment, with two participants remaining off ART until the end of the study.”
PD-1 is an immune checkpoint receptor on exhausted immune cells. Normally, it suppresses T-cell activity, preventing the immune system from attacking the body’s own tissues, but some tumours can hijack PD-1 to turn off immune responses against malignant cells. Likewise, people with chronic HIV infection typically have upregulated PD-1 expression and dampened T-cell responses.
Checkpoint inhibitors that block PD-1 can restore T-cell activity. PD-1 inhibitors – monoclonal antibodies such as pembrolizumab (Keytruda) and nivolumab (Opdivo) – are widely used for cancer immunotherapy. In theory, Routy said, PD-1 inhibitors could also potentially reverse T-cell exhaustion and restore immune function in people living with HIV, and they might also act as a latency reversal agent to push virus out of cells.
Budigalimab (ABBV-181), an investigational PD-1 inhibitor from pharmaceutical company AbbVie, is being studied as an approach for achieving durable control of HIV without ART, also known as remission or a functional cure. Routy presented results from two small randomised phase I trials of budigalimab for people living with HIV, conducted in the United States and Canada.
In these studies, budigalimab was used at doses 50 to 100 times lower than the checkpoint inhibitor doses typically used for cancer treatment. What’s more, the HIV treatment is expected to require only a few doses, whereas cancer immunotherapy typically continues for multiple cycles or until disease progression or unacceptable side effects occur.
The first study, M19-972 (NCT04799353), evaluated the safety and pharmacokinetics of a single IV infusion (10mg) or subcutaneous injection (10-20mg) of budigalimab in 32 people on suppressive ART, with no treatment interruption.
The second study, M19-939 (NCT04223804), included a carefully monitored analytical treatment interruption. This study enrolled 41 people on suppressive ART. All but one were men, most were White and the median age was approximately 45 years. They had been living with HIV for about 10 years and had maintained viral suppression on ART for nearly as long. CD4 counts were high, in the 600-900 range. All had typical chronic HIV infection – none were elite controllers.
In the first stage of the latter study, 20 participants received two doses of 2mg or 10mg budigalimab administered via intravenous infusion four weeks apart, while five people received a placebo. They stayed on antiretrovirals for four weeks and were scheduled to stop ART when they received their second dose of budigalimab or placebo; two people opted out of the interruption.
In the second stage, 11 people received four doses of 10mg budigalimab spaced two weeks apart, while five received a placebo. They all stopped ART at the time of their first budigalimab or placebo dose. This group was the focus of the exploratory efficacy analysis.
The study protocol called for participants to restart ART if their viral load reached 1000 copies or higher for four weeks, their CD4 count fell below 350 or declined more than 30% from baseline, they experienced HIV-associated symptoms or they become pregnant. The participants or investigators could also decide to restart antiretrovirals at any time.
In both studies combined, budigalimab was generally safe and well tolerated. About one third of participants experienced treatment-related adverse events, with a slightly higher frequency in the budigalimab groups versus the placebo groups, Routy reported. Three budigalimab recipients experienced mild to moderate reversible immune-mediated side effects (two cases of thyroiditis and one skin reaction), which can occur when the immune response unleashed by checkpoint inhibitors leads to excessive inflammation. There were no serious or severe treatment-related adverse events in any group.
In study M19-939, budigalimab pharmacokinetics varied according to the dose and timing, with the 10mg IV dose administered every two weeks yielding the highest serum concentrations. People who received the 10mg IV dose either two times four weeks apart or four times two weeks apart achieved nearly complete PD-1 receptor saturation, meaning receptors were all occupied by the monoclonal antibody, but this did not occur with the 2mg dose.
Among the 11 people in the second stage who received four infusions of 10mg budigalimab every two weeks, a few had viral kinetics mimicking those of placebo recipients. Others, however, had delayed viral rebound (more than 21 days after ART interruption), a lower peak viral load or viral control (HIV RNA maintained below 1000). The median time to viral rebound was 29 days in the budigalimab group vs 21 days in the placebo group. “A one-week difference is not that big, but there seems to be some effect,” Routy said.
Six out of nine budigalimab recipients who completed the second stage were considered good responders. In this subgroup, the peak viral load after rebound was around 10,000 copies compared with around 100,000 in the placebo group.
Two budigalimab recipients were deemed controllers. In one individual from Montreal, viral load remained undetectable for about 50 days after ART interruption, then rose to about 350 copies, followed by a decline and sustained suppression below 100 for 19 months, having had their latest blood test three weeks ago, Routy reported. A second individual from the United States experienced a viral load spike around 20 days after ART interruption, reaching about 700 copies, followed by a rapid decline and sustained suppression below 200 for 18 months.
Based on these findings, the researchers concluded that further studies of budigalimab using the 10mg dose are warranted. A phase II trial aims to enrol 140 participants in Europe, the United, Canada, Brazil and South Africa, according to Routy. Study M19-965 (NCT06032546) will test budigalimab and another investigational monoclonal antibody (ABBV-382) that blocks the alpha-4 beta-7 integrin receptor, used alone or in combination.
Researchers and advocates have debated the ethics of treatment interruption trials, recognising that it is necessary to stop antiretrovirals to see if an intervention works. As expected, no placebo recipients in this study were able to control HIV after stopping ART. While a majority of budigalimab responders had a viral load below 1000 during much of the treatment interruption period, even low-level persistent viraemia can lead to health problems, and 1000 is around the level where HIV transmission can occur.
Long-time advocate Simon Collins of HIV i-Base suggested that it would be useful to follow a combined cohort of participants who undergo ART interruption in multiple trials in order to amass sufficient numbers of people to understand long-term outcomes.
Collins also brought up community concerns about the importance of including people of all demographic groups in HIV cure studies, which to date have mostly enrolled White gay men. He urged researchers not to impose upper age cut-offs that would exclude long-term survivors. Professor Sarah Fidler of Imperial College London noted that regulatory requirements regarding contraception and pregnancy can be a barrier to enrolling more women. While advocates urge the inclusion of people from low- and middle-income countries in cure research, she stressed the importance of safety in areas where frequent monitoring is not easily available.
Routy J-P et al. Safety, pharmacokinetics, and exploratory efficacy of the PD-1 inhibitor budigalimab in antiretroviral treatment-suppressed people living with HIV-1: preliminary analysis of 2 Phase 1b studies including an analytical treatment interruption. 19th European AIDS Conference, Warsaw, abstract PS10.O3, 2023.