In the JournalsPerspective

Monoclonal antibody demonstrates ‘unprecedented’ virologic suppression in HIV study

Photo of Chang-Yi Wang
Chang-Yi Wang

The monoclonal antibody UB-421 “demonstrated unprecedented and sustained” virologic suppression in the absence of ART among people with HIV during a nonrandomized, open-label, phase 2 clinical study, according to findings published today by The New England Journal of Medicine.

UB-421 blocks the virus-binding site on CD4+ cells, Chang-Yi Wang, PhD, cofounder and chief scientific officer for United Biomedical — which is developing the treatment — and colleagues explained.

In their study, Wang and colleagues gave participants eight IV infusions of UB-421 following analytic treatment interruption (ATI) of their ART regimen.

“As we all know, an HIV diagnosis is not the death sentence it once was. Current treatments require a daily cocktail of ART drugs to keep the infection in check,” Wang told Infectious Disease News. “To minimize the spread of HIV, patients are required to take a combo regimen selected from six different classes of HIV drugs. Therefore, the patients’ greatest struggle is contending with the daily regimen of pills, unappreciated long-term toxicity and stigma. These can impact a patient’s quality of life.”

Wang said there are several benefits to antibody drugs.

“One, antibodies have long half-lives and can be administered with less a frequent dosing schedule, such as ... weekly, semi-monthly or even monthly,” Wang said. “Two, biological protein drugs have lower toxicities to the liver, kidneys, etc. And three, certain antibody drugs, such as UB-421, can exhibit beneficial immunomodulatory effects that cannot be achieved by small molecule drugs.”

Last year, researchers at the National Institute of Allergy and Infectious Diseases found that short-term ATI did not increase the HIV reservoir size or cause irreversible damage to the immune system, supporting its use to determine the efficacy of ART-free novel therapeutics on virologic suppression.

The UB-421 study enrolled 29 HIV-infected adults in Taiwan, all with undetectable viral loads (less than 20 copies/mL) at screening, and separated them into two cohorts. The first cohort included 14 participants who received a dose of 10 mg/kg of body weight every week for 8 weeks, whereas the 15 participants in the second cohort received a dose of 25 mg/kg of body weight every 2 weeks for 16 weeks. The primary outcome was time to viral rebound.

According to the study findings, all patients in both cohorts maintained virologic suppression during ATI. Wang and colleagues observed what they called “intermittent viral blips” in 28% of participants, although these “did not result in additional treatment.” No participants had a viral rebound more than 400 copies/mL, CD4+ counts remained stable and there was a decrease in CD4+ regulatory T cells during UB-421 monotherapy, they reported.

The most common adverse event was rash, with 52% of all participants experiencing a mild transitory rash. Some 41% reported a grade 1 rash and 10% reported a grade 2 rash, which contributed to one participant discontinuing the study.

“When UB-421 was used as a monotherapy, our antibody reduced the levels of plasma HIV RNA to undetectable levels in a patient's system, the same low levels as antiretroviral treatment,” Wang said. “Over the 2- to 4-month course of treatment, the disease was suppressed in all patients with no generation of treatment-resistant mutated HIV. We have demonstrated unprecedented and sustained suppression of the virus in all patients and achieved a 100% success rate in this study.” – by Marley Ghizzone

Disclosures: Wang is employed by United Biomedical and reports having several U.S. patents pending for antibodies against HIV, issued or licensed. Please see the study for all other authors’ relevant financial disclosures.

Photo of Chang-Yi Wang
Chang-Yi Wang

The monoclonal antibody UB-421 “demonstrated unprecedented and sustained” virologic suppression in the absence of ART among people with HIV during a nonrandomized, open-label, phase 2 clinical study, according to findings published today by The New England Journal of Medicine.

UB-421 blocks the virus-binding site on CD4+ cells, Chang-Yi Wang, PhD, cofounder and chief scientific officer for United Biomedical — which is developing the treatment — and colleagues explained.

In their study, Wang and colleagues gave participants eight IV infusions of UB-421 following analytic treatment interruption (ATI) of their ART regimen.

“As we all know, an HIV diagnosis is not the death sentence it once was. Current treatments require a daily cocktail of ART drugs to keep the infection in check,” Wang told Infectious Disease News. “To minimize the spread of HIV, patients are required to take a combo regimen selected from six different classes of HIV drugs. Therefore, the patients’ greatest struggle is contending with the daily regimen of pills, unappreciated long-term toxicity and stigma. These can impact a patient’s quality of life.”

Wang said there are several benefits to antibody drugs.

“One, antibodies have long half-lives and can be administered with less a frequent dosing schedule, such as ... weekly, semi-monthly or even monthly,” Wang said. “Two, biological protein drugs have lower toxicities to the liver, kidneys, etc. And three, certain antibody drugs, such as UB-421, can exhibit beneficial immunomodulatory effects that cannot be achieved by small molecule drugs.”

Last year, researchers at the National Institute of Allergy and Infectious Diseases found that short-term ATI did not increase the HIV reservoir size or cause irreversible damage to the immune system, supporting its use to determine the efficacy of ART-free novel therapeutics on virologic suppression.

The UB-421 study enrolled 29 HIV-infected adults in Taiwan, all with undetectable viral loads (less than 20 copies/mL) at screening, and separated them into two cohorts. The first cohort included 14 participants who received a dose of 10 mg/kg of body weight every week for 8 weeks, whereas the 15 participants in the second cohort received a dose of 25 mg/kg of body weight every 2 weeks for 16 weeks. The primary outcome was time to viral rebound.

According to the study findings, all patients in both cohorts maintained virologic suppression during ATI. Wang and colleagues observed what they called “intermittent viral blips” in 28% of participants, although these “did not result in additional treatment.” No participants had a viral rebound more than 400 copies/mL, CD4+ counts remained stable and there was a decrease in CD4+ regulatory T cells during UB-421 monotherapy, they reported.

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The most common adverse event was rash, with 52% of all participants experiencing a mild transitory rash. Some 41% reported a grade 1 rash and 10% reported a grade 2 rash, which contributed to one participant discontinuing the study.

“When UB-421 was used as a monotherapy, our antibody reduced the levels of plasma HIV RNA to undetectable levels in a patient's system, the same low levels as antiretroviral treatment,” Wang said. “Over the 2- to 4-month course of treatment, the disease was suppressed in all patients with no generation of treatment-resistant mutated HIV. We have demonstrated unprecedented and sustained suppression of the virus in all patients and achieved a 100% success rate in this study.” – by Marley Ghizzone

Disclosures: Wang is employed by United Biomedical and reports having several U.S. patents pending for antibodies against HIV, issued or licensed. Please see the study for all other authors’ relevant financial disclosures.

    Perspective

    For the last few years, there has been great excitement in the HIV field about broadly neutralizing antibodies that target the virus. However, when only a single antibody against the virus is given, HIV often mutates or changes to become resistant. For that reason, combinations of antibodies against HIV are being studied. An alternative approach is to target the human receptor for the virus, CD4. The antibody ibalizumab, does just that — by targeting CD4, ibalizumab blocks HIV from entering cells. Ibalizumab was recently approved for treatment of HIV that is resistant to other medications. Now, results of a study of a new antibody, UB-421, have been published.

    UB-421 also targets CD4, like ibalizumab, but it aims at a different part of CD4. Instead of testing it against multidrug-resistant HIV, the researchers in this study did something interesting. They focused on substituting the antibody for standard oral HIV treatment.

    They enrolled 29 people who were on oral HIV therapy and gave them the antibody by IV infusion, and then stopped oral ART a week after the first infusion was administered. This was followed by multiple doses of the antibody for 8 or 16 weeks.

    What I think is interesting and exciting about the study is that essentially all of the participants maintained viral suppression for anywhere from 8 to 16 weeks with infusions of the antibody. The reason this single antibody is working is probably because it is targeting the human CD4 receptor, which does not change or mutate like the virus does.

    Now, a couple of cautionary notes to mention. About half of the participants did have a mild rash, and it was transitory. But one person had to stop the antibody because of the rash. About a quarter of participants had low levels of detectable HIV, but it did not exceed the threshold of 200 copies. So, that is promising, but it is something that needs to be watched.

    What I took away from this study was that if you give an antibody directed against CD4, it can maintain virologic suppression, at least in the short-term. Now, what needs to be done is to see if the antibody works in a larger number of people and for a longer time. This trial should prompt bigger and longer studies.

    How this antibody might be used if larger and longer studies show it to be safe and effective, still needs to be determined. Would it be used for people whose virus has become resistant to first- and second-line therapy, and now need a third-line — like ibalizumab? Would the antibody be used to replace oral daily therapy? UB-421 is given through an IV, so it is less convenient than oral therapy because the patient must come into the office to receive an IV infusion rather than taking a pill. There are also new investigational antiretrovirals, cabotegravir plus rilpivirine, that are given by injection into a muscle, which may be easier than an IV. Those new injectable drugs are likely to be submitted to the FDA this year; we will see what the FDA says but, if approved, those injections may be another option rather than daily pills for some people.

    There are other possibilities with UB-421. If the antibody has an effect on the immune system and HIV reservoir, that would be exciting. And if they could make the antibody, or another antibody, that could be engineered to last not 1 week, not 2 weeks but for many months, that would be a major advance. We are not there yet but this is an area to explore for the future.

    What I am excited about in general is, even after decades of advances in ART, we continue to develop new approaches and new medicines. It is not like the HIV field is resting on its laurels. As we continue to make advances, however, let us not forget: We need to make sure everyone with HIV has access to the life-saving medicines that we have available right now.

    • Rajesh T. Gandhi, MD
    • Vice chair, HIV Medicine Association
      Director of HIV clinical services and education,
      Massachusetts General Hospital
      Professor of medicine, Harvard Medical School

    Disclosures: Gandhi reports receiving education grants to his institution (Massachusetts General Hospital) from Gilead Sciences, Janssen, Theratechnologies and Viiv Healthcare, and serving on scientific advisory boards for Gilead and Merck.