HIV clinicians who have patients in declining health due to extensive HIV drug resistance may soon have a new lifesaving option: ibalizumab. The HIV entry inhibitor in development shows highly encouraging antiretroviral activity in the days after it is first administered, according to early Phase 3 study results presented at IDWeek 2016 by Jacob Lalezari, M.D. Lalezari discussed the results at a press conference on Oct. 28 and during an oral abstract presentation on Oct. 29.
Ibalizumab is "not the most potent drug we've seen for HIV, but it's ... very good," Lalezari said. More to the point, he said, it is "maybe all we have right now" for people who have few to no HIV treatment options remaining due to the development of multidrug resistance. He described the drug as being aimed at people with HIV who have been "left behind by an otherwise amazing evolution in HIV treatment."
The Case for Ibalizumab
Antiretroviral therapy is drastically more effective and considerably less toxic today than at any point in the history of the HIV pandemic, and with an array of one-pill-per-day regimens available, it carries a lower pill burden as well. As a result, "a great majority of our patients are doing fine," Lalezari said. "This is really about the patients who got left behind, who are in trouble" -- the less than 5% of people on HIV treatment who Lalezari estimates have considerable drug resistance.
Ibalizumab is unlike any U.S. Food and Drug Administration (FDA)-approved HIV medication. Although technically part of the entry inhibitor family, the drug is a humanized monoclonal antibody. It mainly binds to the second extracellular domain on CD4 cells, Lalezari said. It does not technically prevent HIV from attaching to a CD4 cell, Lalezari noted; instead, the drug works by blocking post-attachment conformational changes, thus stopping HIV from fully binding to and entering the CD4 cells it attempts to infect. Unlike the entry inhibitor maraviroc (Selzentry, Celsentri), ibalizumab also appears to be active against "a variety of tropic viruses," including CCR5-tropic and CXCR4-tropic variants, Lalezari said.
Ibalizumab's unique mechanism of action, coupled with the small but at-need target population, may have been the driving force behind the FDA's decision to grant it orphan drug status in 2014 and to award it the "breakthrough therapy" designation in 2015, paving the way for the current Phase 3 study. That's rapid, recent advancement for a drug whose development began in 2001, according to Lalezari, who referred to its path as an "epic and heroic journey."
The Phase 3 study, named TMB-301, which Lalezari presented at IDWeek 2016, has been spearheaded by the biotechnology company TaiMed.
Study TMB-301: 14-Day Results
The baseline characteristics of the 40 study participants in TMB-301 were stark. Their mean CD4 count was just 160 cells/mm3; one-third had a CD4 count below 10 cells/mm3. Mean viral load was 10,000 copies/mL; 18% had a viral load of 10,000 copies/mL or higher. (The cohort was 85% male and 55% white.)
Given the nature of this study, it probably goes without saying that this was a highly treatment-experienced group, but baseline data revealed just how experienced. The mean duration of antiretroviral therapy was 21 years; 28% of participants reported having taken 10 or more HIV antiretrovirals in their lifetimes. Preliminary data indicated that half of the 40 volunteers had resistance to all drugs from at least three of the four major HIV drug classes. Fully 88% had phenotypic and genotypic resistance to nucleoside reverse transcriptase inhibitors (NRTIs), 88% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), 85% to protease inhibitors and 58% to integrase inhibitors.
Once enrolled in the study, volunteers moved through three distinct periods. For the first seven days (the control period), they remained on their current unsuccessful antiretroviral regimen, with their viral load tested at day 0 and day 7. On day 7, they entered the study's monotherapy period, during which they continued with their failing regimen but also received a single 2,000 mg intravenous "loading dose" of ibalizumab. Their viral load was next tested at day 14. On day 14, they entered the study's maintenance period, during which their failing antiretroviral regimen was replaced with a new optimized background regimen. One week later (on day 21) they received their second intravenous dose of ibalizumab, this time at 800 mg. They continued to receive a new 800 mg dose every two weeks. The study period ended at week 25.
At IDWeek 2016, Lalezari presented data only through the end of the study's monotherapy period on day 14 -- after volunteers had received their loading dose of ibalizumab but before their failing regimens were switched out for an optimized background regimen.
From day 7 through day 14, study participants experienced a median viral load decline of 1.1 log. Sixty percent of study participants experienced a full log or greater decline in viral load; 83% experienced a decline of at least one-half log. All findings were highly statistically significant.
Ibalizumab had "excellent short-term safety," Lalezari said. No treatment-related serious adverse events occurred among study volunteers through day 14, and nobody discontinued the therapy, Lalezari reported. Treatment-emergent adverse events included dizziness (10%), asthenia/fatigue (5%), nausea/vomiting (5%) and rash (2.5%). Lalezari noted that, due to the way it was engineered, the drug is not expected to cause immune damage or CD4 depletion, which can be a concern associated with HIV medications that target CD4 binding sites instead of HIV itself. The drug also has no significant liver or kidney metabolism, Lalezari said, reducing any overt concerns about damage to those organs.
In addition to its lack of direct, serious effects in this brief study, Lalezari noted that ibalizumab appears to play well with other HIV-related medications. "For the primary care HIV doc who is increasingly overwhelmed by drug-drug interaction considerations, the good news is that ibalizumab does not have obvious drug-drug-interactions either with antivirals or with other drugs of other classes." He also said that no evidence exists of cross-resistance with existing entry inhibitors or with approved antiretrovirals in other drug classes.
A Rare, New Tree in the Forest
TMB-301 is designed to extend out through 24 weeks, as volunteers progress through their maintenance period, receiving one ibalizumab dose every two weeks while also taking an oral optimized background regimen. In the meantime, Lalezari mentioned that an expanded access program for ibalizumab exists for HIV clinicians whose patients are running out of treatment options.
The success and continued development of ibalizumab bucks a trend that has persisted in the HIV drug pipeline for several years. The extensively drug-resistant patients who stand to benefit most from ibalizumab "are in trouble, ironically, because of the success of HIV drug development," Lalezari said. "The very success that has led to wonderful once-a-day therapies that treat almost everybody has set the bar very high and made it difficult for new companies to enter the space and bring novel agents into the clinic." From the CCR5 inhibitor vicriviroc in 2010 to the maturation inhibitor BMS-986173 this month, the HIV drug development forest is littered with fallen trees that failed to reach the sun because the space around them was too crowded with drug candidates that would reach a greater number of patients.
"These patients are not large in number, but they're extremely vulnerable," Lalezari said. "Which is why this study is really so important."
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.