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

25 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment UB-421 for multi-drug resistant HIV?

Research on similar treatments, like ibalizumab, shows promise in reducing HIV levels in patients with drug-resistant HIV. Ibalizumab, a monoclonal antibody (a type of protein made in the lab to fight infections), has been effective in lowering the virus in patients who have resistance to many other HIV drugs. ^{1 2 3 4 5}

What safety data is available for UB-421 or similar treatments for HIV?

There is no specific safety data available for UB-421 in the provided research articles. ^{2 4 6 7 8}

What makes the drug UB-421 unique for treating multi-drug resistant HIV?

UB-421 is a monoclonal antibody (a type of protein made in the lab) that targets the CD4 receptor on immune cells, which is different from traditional HIV drugs that usually target the virus itself. This unique approach may help in cases where the virus has become resistant to other treatments. ^{9 10 11 12 13}

What is the purpose of this trial?

Background: People with HIV usually take a combination of 2 or more anti-HIV drugs daily to help manage their infection. Sometimes, however, HIV becomes resistant to these drugs, and the infection cannot be treated. Untreated HIV infection can make people more vulnerable to other infections as well as some cancers. 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. Eligibility: People aged 18 years and older with HIV that is resistant to anti-HIV drugs. Design: Participants will be in the study for 35 weeks. Participants will have separate screening and baseline visits within 2 months of each other. They will have a physical exam with blood and urine tests both times. On the second visit, they will undergo apheresis: Blood will be drawn from a needle in one arm. The blood will pass through a machine that separates out the white blood cells. The remaining blood will be given back through a second needle in the other arm. Participants will begin receiving the study drug 1 week after their baseline visit. UB-421 is given through a tube attached to a needle placed in a vein in the arm. They will return for UB-421 treatments every week for 26 weeks. Each visit will take 3 to 6 hours. Participants will have 2 follow-up visits 4 and 8 weeks after their last treatment with UB-421. Apheresis will be repeated at 1 of these visits.

Research Team

Michael C Sneller, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Ibalizumab. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Antibody-based inhibitors of HIV infection. [2019]

6. Spain pubmed.ncbi.nlm.nih.gov

Ibalizumab for the treatment of multidrug-resistant HIV-1 infection. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition. [2023]

8. United States 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. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Marketed therapeutic antibodies compendium. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. [2022]

11. Italy 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. [2017]

12. United States pubmed.ncbi.nlm.nih.gov

Advances and practical use of monoclonal antibodies in multiple myeloma therapy. [2018]

13. United States 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. [2021]