UB-421 for Multi-Drug Resistant HIV

Overseen By Michael C Sneller, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Antiretrovirals

Must not be taking: Immunotherapy, Enfuvirtide, Ibalizumab, Maraviroc

Disqualifiers: Hepatitis B, Hepatitis C, AIDS, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 26 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether UB-421, an experimental drug, effectively treats people with HIV that no longer responds to standard anti-HIV medications. The focus is on helping those whose infections continue to spread despite taking multiple HIV drugs. Individuals with HIV who have experienced resistance to at least three classes of HIV medications and are currently on a failing treatment plan may be eligible to join. Participants will receive UB-421 weekly for 26 weeks, with follow-ups to monitor its effectiveness. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires participants to either continue their current failing HIV regimen or stay off HIV medications until day 21 of the treatment phase. Some specific medications like enfuvirtide, ibalizumab, or maraviroc must be stopped for a certain period before starting the trial.

Is there any evidence suggesting that UB-421 is likely to be safe for humans?

Research shows that UB-421 may help treat HIV that resists multiple drugs. Although detailed safety information on UB-421 is limited, similar treatments using lab-made proteins called monoclonal antibodies have been studied. These studies suggest that such treatments are usually well-tolerated.

Since this trial is in the early stages, specific safety data on UB-421 is limited. Early trials often focus on safety, so researchers closely monitor participants for any side effects. This monitoring helps determine if the treatment is safe for further study. Participants in this trial can expect close medical supervision to ensure safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for multi-drug resistant HIV, which typically involves a combination of antiretroviral drugs like reverse transcriptase inhibitors and protease inhibitors, UB-421 offers a new approach. UB-421 is a monoclonal antibody that targets the CD4 receptor on immune cells, blocking the HIV virus from entering and infecting these cells. This mechanism is different from most current treatments that focus on inhibiting viral replication rather than preventing the virus from attaching to and entering cells. Researchers are excited about UB-421 because it has the potential to be effective in patients whose virus has developed resistance to multiple classes of existing drugs, providing a new hope for those with limited treatment options.

What evidence suggests that UB-421 might be an effective treatment for drug-resistant HIV?

Research has shown that UB-421, the investigational treatment in this trial, might help combat drug-resistant HIV. Studies have found that UB-421 can control the virus in individuals whose HIV does not respond to other treatments. This means it helps manage the virus even when other medicines fail. UB-421 prevents the virus from entering cells, which is crucial to stopping its spread. These early results suggest UB-421 could be a promising option for those facing resistant forms of HIV. ^{3 4 6 7 8}

Who Is on the Research Team?

Michael C Sneller, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

Adults over 18 with HIV resistant to standard treatments, CD4+ T cell counts above 350 cells/mm3, and a life expectancy greater than 6 months. Participants must have documented resistance to drugs in at least three classes of antiretroviral medications but sensitivity to at least one FDA-approved drug. They should not be on certain other HIV treatments and must use effective contraception if of reproductive potential.

Inclusion Criteria

Ability to provide informed consent

I have been on antiretroviral therapy for at least 6 months.

Willingness to remain on treatment without changes to the OBT regimen

Exclusion Criteria

Treatment with another investigational drug or other intervention within 28 days of Screening

Pregnancy or lactation

I have not had radiation therapy in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 months

2 visits (in-person)

Baseline

Participants undergo baseline assessments including apheresis

1 week

1 visit (in-person)

Treatment

Participants receive UB-421 in combination with optimized background antiretroviral therapy

26 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• UB-421

Trial Overview The trial is testing UB-421, an anti-CD4 antibody, combined with optimized background antiretroviral therapy (OBT) for people with multi-drug resistant HIV-1 infection. Over the course of 35 weeks, participants will receive weekly infusions of UB-421 and undergo regular health checks including blood tests and apheresis.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 1 Intervention

10 adults (\>18 years of age) with human immunodeficiency virus (HIV) who demonstrate evidence of HIV-1 replication despite ongoing ART with documented genotypic and/or phenotypic resistance to multiple classes of HIV drugs (3 classes or more)

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

In a study of 57 patients with various stages of multiple myeloma, CD44v6 was found to be expressed in 43% of cases with advanced disease (stage II/III MM or plasma cell leukemia), indicating its potential as a target for treatment.

The expression of CD44v6 was significantly associated with deletions in chromosome 13q14, a known risk factor in multiple myeloma, suggesting that targeting CD44v6 with therapies like bivatuzumab mertansine could be beneficial for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD44v6, a target for novel antibody treatment approaches, is frequently expressed in multiple myeloma and associated with deletion of chromosome arm 13q. Liebisch, P., Eppinger, S., Schöpflin, C., et al.[2017]

Proteasome inhibitors and immunomodulatory agents have significantly improved outcomes for myeloma patients, but drug resistance remains a major challenge, necessitating the exploration of new treatment strategies.

Recent approvals of monoclonal antibodies like daratumumab and elotuzumab, which target specific proteins on myeloma cells, represent a promising advancement in antibody-based therapies for myeloma, with several other mAbs currently in clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances and practical use of monoclonal antibodies in multiple myeloma therapy. Lee, HC., Weber, DM.[2018]

In a phase 1 study involving 232 patients with heavily pretreated relapsed or refractory multiple myeloma, talquetamab showed a substantial response rate of 70% and 64% for two recommended subcutaneous doses, indicating its efficacy in this challenging patient population.

Common side effects included cytokine release syndrome, skin-related events, and dysgeusia, but these were mostly low-grade, suggesting that talquetamab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. Chari, A., Minnema, MC., Berdeja, JG., et al.[2022]

Ibalizumab, a new CD4 postattachment inhibitor, has shown significant efficacy in treating HIV-1, with 83% of participants experiencing a decline in plasma HIV-1 RNA by more than 0.5 log within one week during a phase III trial.

The drug was well-tolerated with low-grade adverse effects and led to 43% of participants achieving undetectable HIV-1 levels after 24 weeks when used alongside an optimized antiretroviral regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibalizumab. Bettiker, RL., Koren, DE., Jacobson, JM.[2019]

Ibalizumab is a newly approved monoclonal antibody for treating multidrug-resistant HIV-1 in heavily treatment-experienced adults, marking it as the first drug in the post-attachment inhibitor class.

It works by blocking essential changes in the CD4-gp120 complex needed for the virus to enter cells, showing significant antiviral activity in patients with limited treatment options, although it can cause side effects like diarrhea and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibalizumab for the treatment of multidrug-resistant HIV-1 infection. Rizza, SA., Bhatia, R., Zeuli, J., et al.[2019]

Ibalizumab, an investigational monoclonal antibody, showed significant efficacy in reducing viral load by approximately 4.0 log(10) in a patient with advanced HIV-1 and high-level resistance to multiple antiretroviral classes.

Despite the development of resistance to ibalizumab after a missed infusion, the patient's HIV-1 RNA levels stabilized at about 2.0 log(10) copies/ml, highlighting the potential of monoclonal antibodies in managing treatment-experienced HIV patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment. Fessel, WJ., Anderson, B., Follansbee, SE., et al.[2021]

ABBV-838, an antibody-drug conjugate targeting multiple myeloma cells, was found to be safe and well-tolerated in a phase I/Ib study involving 75 patients, with the most common side effects being neutropenia and anemia.

Despite its safety profile, ABBV-838 showed limited efficacy, with an overall response rate of only 10.7%, indicating that while it can be administered safely, it may not be effective for treating relapsed and refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Phase I Study of ABBV-838, an Antibody-Drug Conjugate Targeting SLAMF7/CS1 in Patients with Relapsed and Refractory Multiple Myeloma. Vij, R., Nath, R., Afar, DEH., et al.[2021]

Ibalizumab, a monoclonal antibody approved for HIV-1 treatment, significantly reduced viral load in HIV-infected adults compared to placebo, with reductions of 1.07 log10 and 1.33 log10 in two treatment arms at week 16.

The treatment was well-tolerated with no serious adverse events reported, and it also led to significant increases in CD4+ T cell counts, indicating its potential effectiveness for patients with multidrug-resistant HIV-1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Pharmacokinetics, and Safety Over 48 Weeks With Ibalizumab-Based Therapy in Treatment-Experienced Adults Infected With HIV-1: A Phase 2a Study. Gathe, JC., Hardwicke, RL., Garcia, F., et al.[2023]

As of March 2012, 34 therapeutic monoclonal antibodies (mAbs) have been approved for use in Europe and the US, with 28 currently available on the market, highlighting the growing role of mAbs in treatment options.

The review also notes that some mAbs, such as muromonab-CD3 and gemtuzumab ozogamicin, have been withdrawn from the market, indicating that not all approved therapies remain available, which is important for physicians and patients to consider.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Marketed therapeutic antibodies compendium. Reichert, JM.[2021]

Vedolizumab (VDZ) effectively blocks the binding of MAdCAM-1 to α4β7+ memory CD4+ T cells in vitro, but it does not prevent or control HIV-1 infection in humanized mice, indicating limited efficacy against the virus.

In settings where combined antiretroviral therapy (cART) is withdrawn, VDZ does not prevent HIV-1 rebound, suggesting that it may not be a viable option for HIV-1 prevention or treatment in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice. Ling, L., Wu, T., To, KKW., et al.[2020]

In a study involving 107 HIV-1 infected and 82 non-infected recipients of the VRC01 antibody, higher serum concentrations of VRC01 were associated with a lower risk of HIV-1 acquisition, indicating that VRC01 concentration is a potential marker for effective dosing.

The research suggests that fixed dosing of VRC01 may be as effective as body weight-based dosing for preventing HIV-1, which could simplify future treatment regimens in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition. Seaton, KE., Huang, Y., Karuna, S., et al.[2023]

Monoclonal antibodies targeting HIV show potential as new treatment options, especially against drug-resistant strains, as recent trials and lab studies indicate their clinical promise.

The main challenge remains in developing antibody therapies that provide long-lasting effectiveness, low toxicity, and a reduced risk of the virus developing resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-based inhibitors of HIV infection. Choudhry, V., Zhang, MY., Dimitrova, D., et al.[2019]

In a phase 1b clinical trial involving seven HIV-1 viremic individuals, a combination of two potent broadly neutralizing antibodies (bNAbs) was well-tolerated and led to a significant average reduction in HIV-1 viral load by 2.05 log10 copies per ml for three months in those with sensitive viruses.

Importantly, none of the participants developed resistance to both antibodies, suggesting that this combination therapy may effectively limit the emergence of drug-resistant viral variants, warranting further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Bar-On, Y., Gruell, H., Schoofs, T., et al.[2022]

Citations

1. niaid.nih.gov niaid.nih.gov/news-events/novel-treatment-mdr-hiv

NIAID Study Describes Successful Treatment Regimen for ... UB-421 was included in the regimen because prior studies have shown that it may be effective against drug-resistant HIV variants. The ...

2. clinicalinfo.hiv.gov clinicalinfo.hiv.gov/en/drugs/ub-421/patient

Semzuvolimab Patient Drug Record | NIH Purpose: The purpose of this study is to evaluate the efficacy of semzuvolimab plus optimized background therapy in reducing viral load levels in participants ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39753965/

Sustained virologic suppression of multidrug-resistant HIV in ... Our data demonstrate that combination therapy with UB-421 could provide sustained virologic suppression in people harboring MDR HIV with limited therapeutic ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03743376

The HIV Functional Cure Potential of UB-421 in ART ... A way for patients with serious diseases or conditions who cannot participate in a clinical trial to gain access to a medical product that has not been approved ...

5. withpower.com withpower.com/trial/phase-2-hiv-infections-9-2022-adc11

UB-421 for Multi-Drug Resistant HIV · Info for Participants Better treatments are needed for people with drug-resistant HIV.Objective:To see if a study drug (UB-421) is effective in people with drug-resistant HIV.

6. reporter.nih.gov reporter.nih.gov/search/JWotWEW9JU-283iSwMz7Yg/project-details/11010806

RePORT ⟩ RePORTER We're sorry but RePORTER doesn't work properly without JavaScript enabled. Please enable it to continue.

7. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT03743376

The HIV Functional Cure Potential of UB-421 in ART ... These trials gather additional information about a drug's safety, efficacy, or optimal use. Phase Not Applicable. Describes trials without FDA-defined phases ...

8. patents.google.com patents.google.com/patent/WO2016043788A1/en

Treatment and functional cure of hiv infection by ... As discussed in previous Examples, mAb dB4 antibodies, including mAb dB4C7 (the main component in the UB-421 drug candidate), demonstrate high biding ...