NEW ORLEANS – Ibalizumab, the first monoclonal antibody to reach a phase III trial for multidrug resistant HIV therapy, has demonstrated efficacy, safety, and a novel mechanism of action, offering promise to many patients with few remaining options.
“The drug has now shown very significant antiretroviral activity, with 83% of patients demonstrating a half log decrease after 7 days, and a mean and median decrease of 1.1 log,” Jacob Lalezari, MD, lead author of the study and medical director of Quest Clinical Research in San Francisco, said at IDWeek 2016, the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society. “The big message here is the novel mechanism of action provides new treatment to patients with limited options, really offering hope to those left behind by an otherwise amazing evolution of HIV treatment.”
Damian McNamara/Frontline Medical News
Dr. Jacob Lalezari (left) and Dr. Daniel Kurkitzkes
Dr. Lalezari said there is currently no evidence of cross-resistance with existing antiretrovirals. “I think we got lucky with that,” he noted. “For the primary care HIV doc, who is increasingly overwhelmed by drug-drug interactions, the good news is ibalizumab does not have obvious drug-drug interactions with antiretrovirals or other [HIV] drugs in other classes.”
Daniel Kuritzkes, MD, chief of infectious diseases at Brigham and Women’s Hospital and professor at Harvard Medical School, both in Boston, announced the findings with Dr. Lalezari at an IDWeek 2016 press conference. “This study is very important, because although we have terrific therapies for initial and second line treatment, we’ve really come to need treatment for the core group of patients who have developed resistance to all the drugs in the armamentarium,” he said.
Multidrug resistance emerges in less than 5% of people with HIV, affecting up to about 10,000 people in the United States. “It’s not a huge population, but it’s the most vulnerable and in need,” Dr. Lalezari said.
The 40 treatment-experienced patients in the study had their viral load and CD4+ counts measured at day 0. At day 7, they received a 2,000 mg IV loading dose of ibalizumab. At day 14, the response to ibalizumab monotherapy was measured and participants began an optimized background regimen with at least one other agent to which HIV showed sensitivity. Unfortunately, for about 50% of the patients, there was no such agent remaining, so researchers added BMS-663068, an investigational oral attachment inhibitor.
The cohort was 85% men, 45% nonwhite, and had a mean duration of HIV infection of 21 years. At study entry, patients’ mean viral load was approximately 100,000 copies/mL and mean CD4+ T-cell count was 160/mcL. However, half of the patients had T-cell counts below 100, and one third had counts below 10, “meaning they are at the very edge of sustainability,” Dr. Lalezari said.
Efficacy and safety
“The story is pretty simple – the drug worked,” Dr. Lalezari said. In addition to the 83% who met the primary endpoint of a half-life log decrease in HIV-1 RNA, 60% had a full log decrease or more at day 14. The mean and median HIV-1 RNA decrease for the entire cohort was 1.1 log10, a significant difference, compared with the day 0 to 7 control period (P less than .0001).
Putting the findings in perspective, Dr. Lalezari said, “So 1 log is not the most potent drug we see for HIV, but it’s pretty good. And in the setting of multidrug-resistant virus, it’s very good.” Although the agent is not potent enough for monotherapy, he said it is a strong candidate for combination therapy. The goal is to “give somebody a chance, potentially their last chance, to get control of the virus and prevent the progression of disease, and importantly, prevent them from spreading it to somebody else.”
“It’s a bit of a mystery” why 7 of the 40 patients did not meet the primary endpoint, Dr. Lalezari added. None of the factors the investigators compared between responders and nonresponders were significantly different.
Ibalizumab appears safe with no discontinuations and no treatment-related serious adverse events, Dr. Lalezari said. “We have not seen anything that strikes me as concerning at all in terms of safety, and it’s in a patient population that is quite ill.”
When asked during the press conference to address cost concerns, an issue in other specialties when biologics are introduced, Dr. Lalezari responded, “The one comment I will make is that whatever this drug is, it’s not a ‘me too drug.’ It’s unique and offers a unique mechanism of action. For those patients, the patients we saw whose T cells were under 10, whose health was failing and they were getting ready to die, their viral loads got suppressed and now they’re living, so it brings great value.”
Ibalizumab’s antiretroviral activity stems from blocking post-attachment conformational changes that are required to enable the HIV virus to bind with its co-receptors and ultimately gain entry into the target T cell. “Importantly the drug is away from the binding site for MHC class II molecules, and therefore not thought to cause T-cell depletion or be immunosuppressive,” Dr. Lalezari said.
In terms of the bigger picture, unlike most HIV drugs taken daily, ibalizumab is the first of the long-acting antiretrovirals, he noted. “I do think a paradigm shift is looming for at least some patients for whom long-acting therapy might be advantageous. There is also a movement toward IM and hopefully subcutaneous therapy as well, which would be very advantageous for patient self-administration.”
Although Dr. Lalezari and Dr. Kuritzkes presented the 14-day findings, the study is ongoing and participants continue to receive 800 mg ibalizumab intravenously every two weeks.
TaiMed Biologics, the sponsor of the study, has an expanded access program. Dr. Lalezari said, “So if you [have] a patient who is in trouble, in need of rescue therapy, there is an option for you now to consider.”
Dr. Lalezari receives research funding from TaiMed Biologics. Dr. Kuritzkes had no relevant financial disclosures.