Antibody therapies effective at preventing HIV from invading CD4 cells
What could be the next big break in HIV therapy?
Monoclonal antibodies, which are biologic therapies that in some cases can block HIV from infecting cells in our immune system, are currently being studied as a new HIV treatment option. At the Conference on Retroviruses and Opportunistic Infections (CROI 2017) held this month in Seattle, two new monoclonal antibodies demonstrated success in helping people living with HIV suppress their viral loads to undetectable levels.
An antibody named ibalizumab, which was given as an infusion every two weeks, was modestly effective in helping people with highly drug-resistant HIV suppress their viral loads. A second antibody named PRO 140, when given as a weekly injection, helped study participants maintain viral suppression for more than two years. Other types of antibodies are being studied for HIV prevention and cure research.
If approved in the next couple years, these therapies will offer new options for treatment-experienced people with highly resistant HIV. In the future, they may also play a role in long-acting therapy for people at any stage of HIV disease who prefer less frequent injections over daily pills.
Most people living with HIV can suppress their viral load to an undetectable level using modern combination antiretroviral therapy (ART). But a small proportion of people with extensive drug resistance are unable to maintain viral suppression using available treatments and could benefit from therapy that works in an entirely different way.
Ibalizumab (formerly known as TMB-355 and TNX-355) is a humanized monoclonal antibody that protects immune cells from HIV rather than attacking HIV directly. It binds to the CD4 receptor on the surface of T-cells and prevents the virus from entering them. Early studies showed that it was well tolerated and active against HIV that is resistant to other antiretrovirals.
Brinda Emu, MD, from Yale University presented findings from a Phase 3 trial testing ibalizumab in people who cannot maintain viral suppression on their current antiretroviral regimen (abstract 449LB).
The study enrolled 40 heavily treatment-experienced participants, mostly men, who had had HIV for over 20 years on average. At baseline they had an mean CD4 count of just 150 cells/mm3—and a dozen of them had less than 10 cells/mm3—indicating very advanced immune suppression. Half had exhausted all available drugs in at least three antiretroviral classes and 15% were resistant to all approved HIV meds.
“These were highly treatment-experienced, highly drug-resistant patients with very limited options,” Emu said.
All participants in this study received a 2,000 mg “loading dose” of ibalizumab as an intravenous infusion while remaining on their failing ART regimen, meaning the antibody was essentially used as monotherapy. As reported last fall, after seven days 83% had at least a 0.5 log drop in HIV RNA and 60% had at least a 1 log decrease.
At that point participants switched to an optimized background ART regimen determined by resistance testing. This required having at least one other active drug available, and to do so more than 40% had to include the experimental HIV attachment inhibitor fostemsavir. They received an 800 mg ibalizumab infusion on day 21 and then every other week until week 24.
At 24 weeks, 43% of study participants achieved viral suppression below 50 copies/mL. People with higher baseline CD4 counts were more likely to reach an undetectable viral load. Just over half had at least a 1 log HIV RNA decrease and 48% had at least a 2 log decrease.
In addition, participants gained an average of 48 CD4 cells/mm3. Again, improvement was greater for people with higher starting levels. People with under 50 cells/mm3 at baseline gained only 9 cells, but Emu stressed that even this small increase could make a big difference for people with such low levels.
Ibalizumab was generally safe and well tolerated, and most adverse events were mild or moderate.
Having to receive IV infusions at a healthcare facility every other week would make ibalizumab difficult to use. But researchers are studying a new formulation administered by intramuscular injection (abstract 437). Both tested doses—800 mg every two weeks and 2,000 mg every four weeks—were well tolerated and reduced viral load when used as monotherapy for seven days.
During a CROI discussion of new drugs further back in the development pipeline, Kush Dhody, MBBS, from Amarex Clinical Research presented two-year findings from a study looking at another long-acting monoclonal antibody, PRO 140 (abstract 437).
PRO 140 blocks CCR5, one of the two co-receptors HIV uses to enter cells, working like the oral antiretroviral maraviroc (Selzentry). An estimated 70% of people with HIV in the U.S.—and up to 90% of newly diagnosed people—have CCR5-using or “CCR5-tropic” virus.
An early study showed that a single IV infusion of PRO 140 had potent antiviral activity, and a follow-up study found that more convenient weekly subcutaneous injections reduced viral load significantly more than placebo.
Dhody presented the latest results from a Phase 2b trial of PRO 140 as maintenance therapy for people who achieved viral suppression on standard combination ART.
The full study included 42 people on stable ART with undetectable viral load (<40 copies/mL). They started receiving weekly 350 mg injections of PRO 140 while still on their ART regimen. After a week they stopped their current antiretrovirals and continued on PRO 140 alone. People who experienced viral rebound immediately restarted combination ART.
The researchers initially intended to continue PRO 140 monotherapy for 12 weeks, but at the end of this period some participants still had suppressed viral load, so follow-up was extended.
Sixteen participants with sustained viral suppression rolled over into the extension study and were trained to administer their injections at home. Unlike people in the ibalizumab study, this group was generally in good health with a median CD4 count of nearly 600 cells/mm3.
Dhody reported that 13 of the 16 participants (81%) maintained viral suppression for more than 40 weeks. And 10 of these (63%) had undetectable viral load for more than two years and were still being followed on PRO 140 monotherapy. An ultra-sensitive single-copy test showed that seven of them had HIV RNA below 1 copy/mL, while the other three had very low levels (4, 10, and 19 copies/mL).
Here too, PRO 140 was generally safe and well tolerated, with no serious adverse events or discontinuations due to side effects. Injection site reactions were mild and transient.
PRO 140 maintenance monotherapy is being studied in a larger ongoing trial and researchers are trying to identify factors that predict which individuals will have a good response. In addition, PRO 140 plus other antiretrovirals is being tested for treatment-experienced people with extensive drug resistance and unsuppressed viral load despite ART—more like the population in the ibalizumab study.
Taken together, these studies show that monoclonal antibodies hold promise as long-acting therapies for people with limited treatment options due to drug resistance. PRO 140 is more potent than ibalizumab, but ibalizumab is effective against HIV that uses either CCR5 or CXCR4 co-receptors.
Emu predicted that ibalizumab might be the first long-acting HIV drug to complete Phase 3 clinical trials. Researchers are working on long-acting formulations of standard antiretrovirals, including a combination of injectable cabotegravir and rilpivirine. But monoclonal antibodies represent a new type of drug that could work as “rescue” therapy for people who have been left behind by recent advances in treatment.
Liz Highleyman is a freelance medical writer and editor of HIVandHepatitis.com.