Drug Database: Leronlimab

Pharmacology

Pharmacology

Mechanism of Action

HIV-1 CCR5 antagonist. Leronlimab, a humanized IgG4 monoclonal antibody (mAb), binds to hydrophilic extracellular domains on CCR5 and competitively inhibits CCR5-mediated HIV-1 viral entry. At antiviral concentrations, leronlimab does not prevent CC-chemokine signaling.^7–9 Leronlimab is not active against CXCR4-using viruses.¹⁰

Half-life (T_½)

In a study of multiple subcutaneous (SC) doses of leronlimab in adults with HIV, the mean terminal half-lives were 3.4 days (162 mg dose) and 3.7 days (324 mg dose).⁸ In a study of single intravenous (IV) doses of leronlimab in adults with HIV, the mean terminal half-lives were 3.13 days (5 mg/kg dose) and 3.33 days (10 mg/kg dose).¹¹

Metabolism/Elimination

Leronlimab is eliminated via a saturable, antigen-mediated clearance process.⁸

Resistance

In a Phase 2b study (PRO 140_CD 01; NCT02175680), leronlimab monotherapy was evaluated for the maintenance of viral suppression in participants on ART. Eighteen out of 41 participants experienced viral rebound during a 12 week treatment phase. During an extension study (PRO 140_CD 01-Extension; NCT02355184), five out of 16 participants experienced viral rebound. In both studies, all participants who had viral rebound restarted their baseline ART regimen and were able to achieve viral resuppression. At the time of viral rebound, only two participants were found to have dual/mixed tropism; however, investigators concluded that the emergence of CXCR4-tropic virus was likely due to pre-existing virus at baseline. There was no evidence of significant changes in viral susceptibility to leronlimab in both participants who had viral rebound and in participants who did not have viral rebound.^12-14

In a Phase 2b/3 study (PRO 140_CD 02; NCT02483078), investigators evaluated leronlimab added to a failing ART regimen followed by optimized background therapy. Among participants who experienced viral rebound, no changes in co-receptor tropism were detected at the time of rebound.^15,16

Preliminary data from an ongoing Phase 2b/3 trial (PRO 140_CD03; NCT02859961) evaluating leronlimab monotherapy at three different dose levels has shown no evidence of treatment-emergent resistance to leronlimab. Participants who experienced virologic failure (VF) were able to achieve viral resuppression after reinitiating their baseline ART regimens. No changes in tropism were seen in participants experiencing virologic failure.^4,17

Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT00642707

Sponsor: CytoDyn, Inc.
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the antiviral activity, safety, and pharmacokinetics of multiple subcutaneous (SC) doses of leronlimab monotherapy.
Study Population:

• Participants were adults with R5-tropic HIV at screening and were treatment-naive or -experienced (with no ART for at least 12 weeks).
• Participants had HIV RNA ≥5,000 copies/mL and CD4 counts ≥300 cells/mm³, with no documented counts ≤250 cells/mm³.^10,18

Selected Study Results: Results published in The Journal of Infectious Diseases (2010) showed that leronlimab had substantial and prolonged dose-dependent activity against HIV. The greatest antiviral effect was seen with leronlimab 324 mg weekly, producing an average maximum reduction in viral load of 1.65 log₁₀ copies/mL.¹⁰

Study Identifiers: (1) PRO 140_CD 01; NCT02175680 and (2) PRO 140_CD 01-Extension; NCT02355184

Sponsor: CytoDyn, Inc.
Phase: 2b
Status: PRO 140_CD 01 has been completed. The status of PRO 140_CD 01-Extension is unknown.
Study Purpose: The purpose of the PRO 140_CD 01 open-label, treatment-substitution study was to evaluate the safety and efficacy of SC leronlimab monotherapy for the maintenance of viral suppression in patients who are stable on ART. The PRO 140_CD 01-Extension study is evaluating the long-term efficacy, safety, and tolerability of leronlimab monotherapy.
Study Population:

PRO 140_CD 01:

• Participants were treatment-experienced adults with R5-tropic HIV. Participants were on stable ART for the last 12 months, had no changes to their ART regimen in the 4 weeks prior to screening, and had no prior use of maraviroc.
• Participants had HIV RNA <50 copies/mL and CD4 counts >350 cells/mm³ at screening.

PRO 140_CD 01-Extension:

• Participants who have completed 12 weeks of treatment in PRO 140_CD 01 without experiencing VF are allowed to enroll in the PRO 140_CD 01-Extension study.^12-14

Selected Study Results: Results published in HIV Clinical Trials (2018) showed that in the CD01 study, 23 out of 41 participants (56.1%) maintained virologic suppression throughout the 12 week monotherapy treatment phase. Eighteen participants did not maintain suppression during the treatment phase, with a mean time to viral rebound of 51.3 days since the initiation of leronlimab monotherapy.¹⁴ Results published in PLoS Pathogens (2022) showed that in the CD01 Extension study, five participants have maintained virologic suppression on leronlimab monotherapy for over 7 years.¹⁹

Study Identifiers: (1) PRO 140_CD 02; NCT02483078 (2) PRO 140_CD 02 Extension; NCT02990858 and (3) PRO 140_CD02_OpenLabel; NCT03902522

Sponsor: CytoDyn, Inc.
Phase: 2b/3
Status: PRO 140_CD 02 has been completed. The status of the PRO 140_CD 02 Extension and PRO 140_CD02_OpenLabel trails are unknown.
Study Purpose: The purpose of the PRO 140_CD 02 study was to evaluate the safety and efficacy of leronlimab when used in conjunction with existing failing ART and then when used in conjunction with optimized background therapy. PRO 140_CD 02 Extension is designed to provide eligible participants with continued access to leronlimab. PRO 140_CD02_OpenLabel is a single-arm open-label trial.
Study Population:

PRO 140_CD 02:

• Participants were treatment-experienced adults with R5-tropic HIV.
• Participants had been on their current ART regimen for at least 3 months and were experiencing treatment failure on their current ART regimen. Participants had documented resistance to at least one drug within three different ARV drug classes or they had documented resistance to at least one drug within two different ARV drug classes and had limited treatment options available.
• Participants had HIV RNA ≥400 copies/mL at screening and detectable HIV RNA >50 copies/mL within the 3 months prior to screening.

PRO 140_CD 02 Extension:

• Participants have successfully completed 24 weeks of treatment in the PRO 140_CD 02 trial and require continued access to leronlimab to maintain viral suppression.

PRO 140_CD 02_OpenLabel:

• Participant inclusion criteria is the same as in the PRO 140_CD02 study. (Please see the PRO 140_CD 02 study population description above.)^15,20,21

Selected Study Results: Results from the CD 02 trial presented at ASM Microbe 2019 showed that 64% of participants who received a single SC dose of leronlimab had a significant reduction in viral load levels from baseline after 1 week, as compared to 23% of participants who received placebo.¹⁶

Study Identifiers: (1) PRO 140_CD03; NCT02859961 and (2) PRO 140_CD03 Extension; NCT05271370

Sponsor: CytoDyn, Inc.
Phase: 2b/3
Status: The status of the PRO 140_CD03 and PRO 140_CD03 Extension trials are unknown.
Study Purpose: The purpose of the PRO 140_CD03 open-label, treatment-substitution study is to evaluate the safety and efficacy of SC leronlimab monotherapy for the maintenance of viral suppression in patients who are clinically stable on ART. PRO 140_CD03 Extension is evaluating the long-term efficacy, safety, and tolerability of leronlimab monotherapy.
Study Population:

PRO140_CD03:

• Participants are treatment-experienced adults with R5-tropic HIV. Participants have been receiving ART for the past 24 Participants are treatment-experienced adults with R5-tropic HIV. Participants have been receiving ART for the past 24 weeks, have had no changes to their ART regimen in the 4 weeks prior to screening, and have at least two potential approved ART options to consider.
• Participants have HIV RNA <50 copies/mL at screening. Participants have CD4 counts >350 cells/mm³ in the last 24 weeks prior to screening and at screening and have had nadir CD4 counts >200 cells/mm³ while on ART.

PRO 140_CD03 Extension:

• Participants have successfully completed 48 weeks of treatment in the PRO 140_CD03 trial.^4,22

Selected Study Results: Preliminary results presented at CROI 2019 indicated that the majority of participants who received higher weekly SC doses of leronlimab (525 mg and 700 mg) were able to maintain virologic suppression.¹⁷

Adverse Events

Adverse Events

NCT00642707

In this Phase 2a trial, 44 total participants were treated with either leronlimab or placebo. The most frequent systemic adverse events (AEs), which were associated with either placebo or SC leronlimab, included diarrhea, headache, lymphadenopathy, and hypertension. No drug-related serious AEs (SAEs) or dose-limiting toxicities among participants were reported. There were also no clinically relevant drug-related effects on ECG among participants. AEs related to administration-site reactions were infrequent and described as mild, transient, and self-resolving. Administration-site reactions occurring in more than 5% of participants were induration, pain, and irritation.¹⁰

PRO 140_CD 01 (NCT02175680); PRO 140_CD 01-Extension (NCT02355184)

Safety data from 41 participants in the CD 01 study and 16 participants in the CD 01-Extension study found no SAEs related to leronlimab treatment or study discontinuations due to an AE. In both studies, mild and transient local injection site reactions accounted for all the AEs that were definitely or probably study-drug related.^12–14

PRO 140_CD 02 (NCT02483078); PRO 140_CD 02 Extension (NCT02990858)

In the CD 02 study, 52 participants were randomized to either the leronlimab or placebo group. Final results from this study showed that 65.4% of participants experienced at least one AE and 19.23% of participants had at least one treatment-related AE. One participant discontinued treatment because of an AE. No treatment-related SAEs were reported. Injection site reactions that occurred during the study were mostly mild and self-resolving. Forty participants have enrolled into the CD 02 Extension study.^15,16,20

PRO 140_CD03 (NCT02859961)

In the CD03 trial of leronlimab monotherapy, preliminary data was presented on 226 participants in the 350-mg dose group, 115 participants in the 525-mg dose group, and 43 participants in the 700-mg dose group. Thus far, the incidence and severity of AEs have not been dose-proportional. Most AEs were mild in intensity and no AE pattern was observed. None of the SAEs that occurred were definitely or probably related to leronlimab. The majority of injection site reactions were mild and self-resolving.^4,17

Drug Interactions

Drug Interactions

Drug-drug interactions associated with leronlimab are currently unknown.

References

References

1. National Center for Biotechnology Information. PubChem Substance Record for SID 135308456, Leronlimab [USAN], Source: ChemIDplus. Accessed April 29, 2024
2. Jefferys R. The antiretroviral therapy pipeline 2023. Treatment Action Group Pipeline Report 2023. Accessed April 29, 2024
3. American Medical Association website. Statement on a nonproprietary name adopted by the USAN Council: Leronlimab. Accessed April 29, 2024
4. CytoDyn, Inc. A Phase 2b/3, multicenter study to assess the treatment strategy of using PRO 140 SC as long-acting single-agent maintenance therapy for 48 weeks in virologically suppressed subjects with CCR5-tropic HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 13, 2016. NLM Identifier: NCT02859961. Accessed April 29, 2024
5. CytoDyn Inc.: Press release, dated March 30, 2022. CytoDyn announces partial clinical hold of HIV program and full clinical hold of COVID-19 program. Accessed April 29, 2024
6. CytoDyn Inc.: Press release, dated February 29, 2024. CytoDyn announces FDA has lifted clinical hold. Accessed April 29, 2024
7. Olson WC, Doshan H, Zhan C, et al. Prolonged coating of CCR5 lymphocytes by PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy. Conference on Retroviruses and Opportunistic Infections (CROI); February 5-8, 2006; Denver, CO. National AIDS Treatment Advocacy Project (NATAP): HIV Articles. Accessed April 29, 2024
8. Jacobson JM, Saag MS, Thompson MA, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J Infect Dis. 2008;198(9):1345-1352. Accessed April 29, 2024
9. Trkola A, Ketas TJ, Nagashima KA, et al. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J Virol. 2001;75(2):579-588. doi:10.1128/JVI.75.2.579-588.2001. Accessed April 29, 2024
10. Jacobson JM, Thompson MA, Lalezari JP, et al. Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody. J Infect Dis. 2010;201(10):1481-1487. doi:10.1086/652190. Accessed April 29, 2024
11. Jacobson JM, Lalezari JP, Thompson MA, et al. Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults. Antimicrob Agents Chemother. 2010;54(10):4137-4142. doi:10.1128/AAC.00086-10. Accessed April 29, 2024
12. CytoDyn, Inc. A Phase 2b study to assess suppression of HIV-1 replication following substitution of stable combination antiretroviral therapy with a PRO 140 (monoclonal CCR5 antibody) monotherapy in adult subjects with HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 24, 2014. NLM Identifier: NCT02175680. Accessed April 29, 2024
13. CytoDyn, Inc. Extension of protocol PRO140_CD01 to evaluate long-term suppression of HIV-1 replication following substitution of stable combination ART with PRO 140 (monoclonal CCR5 antibody) monotherapy for additional 160 weeks in adult subjects w/ HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 30, 2015. NLM Identifier: NCT02355184. Accessed April 29, 2024
14. Dhody K, Pourhassan N, Kazempour K, et al. PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection. HIV Clin Trials. 2018;19(3):85-93. doi:10.1080/15284336.2018.1452842. Accessed April 29, 2024
15. CytoDyn, Inc. A multi-center, randomized, double-blind, placebo-controlled trial, followed by single-arm treatment of PRO 140 in combination with optimized background therapy in treatment-experienced HIV-1 subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 24, 2015. NLM Identifier: NCT02483078. Accessed April 29, 2024
16. Dhody K, Kazempour K, Pourhassan N, Maddon PJ. Final results of the pivotal study of PRO 140 SC in heavily treatment-experienced HIV patients. Poster presented at: American Society for Microbiology (ASM) Microbe; June 20-24, 2019; San Francisco, CA. Poster AAR-713. Accessed April 29, 2024
17. Dhody K, Kazempour K, Pourhassan N, Maddon PJ. PRO 140 (leronlimab) SC: long-acting single-agent maintenance therapy (SAMT) for HIV-1 infection. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2019; Seattle, WA. Poster 486. Accessed April 29, 2024
18. CytoDyn, Inc. A Phase 2a, randomized, double-blind, placebo controlled study of PRO 140 by subcutaneous administration in adult subjects with human immunodeficiency virus type 1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 21, 2008. NLM Identifier: NCT00642707. Accessed April 29, 2024
19. Chang XL, Reed JS, Webb GM, et al. Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody leronlimab in two species. PLoS Pathog. 2022;18(3). Accessed April 29, 2024
20. CytoDyn, Inc. An extension protocol for subjects who successfully completed PRO140_CD02 study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 17, 2016. NLM Identifier: NCT02990858. Accessed April 29, 2024
21. CytoDyn, Inc. A multi-center, two-part, single-arm, open label, 25-week trial with PRO 140 in treatment-experienced HIV-1 subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 2, 2019. NLM Identifier: NCT03902522. Accessed April 29, 2024
22. CytoDyn, Inc. An extension protocol for virologically suppressed subjects who successfully completed PRO140_CD03 study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 13, 2022. NLM Identifier: NCT05271370. Accessed April 29, 2024

Last Reviewed: April 29, 2024