Drugs

Leronlimab

Other Names: PA14, PRO-140 Drug Class: CCR5 Antagonist
Molecular Formula: C6534 H10036 N1720 O2040 S42 (non glycosylated)
Registry Number: 674782-26-4 (CAS) Chemical Name: Immunoglobulin G4, anti-(human Chemokine receptor CCR5) (humanized monoclonal PRO 140 γ4-chain), disulfide with humanized monoclonal PRO 140 κ-chain, dimer Organization: CytoDyn, Inc. Phase of Development: Leronlimab is in Phase IIb/III development for HIV treatment.

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 American Medical Association website,3 and ClinicalTrials.gov4)

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.5–7 Leronlimab is not active against CXCR4-using viruses.8

Half-life (T½): 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).9

Metabolism/Elimination: Leronlimab is eliminated via a saturable, antigen-mediated clearance process.6

Resistance: In vitro, leronlimab has exhibited activity against viruses resistant to maraviroc.10

In single-dose IV or multiple-dose SC studies of leronlimab, tropism shifts were observed in five out of 84 leronlimab-treated participants. Three of the five participants with tropism shifts were classified as having pre-existing minor variants of CXCR4-using HIV-1, while analysis of the pretreatment viruses of the other two participants was still being done at the time this data was presented. No emergence of viral resistance to leronlimab was observed in these studies.11

In a Phase IIb extension study (NCT02355184) evaluating the ability of 16 eligible participants to maintain long-term viral suppression on leronlimab monotherapy, virologic failure (VF) occurred in five participants. The mean time to VF was 329 days (106–691 days). At VF, there was no detected change in co-receptor tropism. Also, there was no significant change in virus susceptibility to leronlimab, maraviroc, and AMD3100 (post-treatment compared with baseline) in both VF and non-VF participants.12,13


Select Clinical Trials


Study Identifier: NCT00642707
Sponsor: CytoDyn, Inc.
Phase: IIa
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the antiviral activity, safety, and pharmacokinetics of multiple 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/mm3.8,14
Selected Study Results:


Study Identifiers: (1) PRO 140_CD 01; NCT02175680 and (2) PRO 140_CD 01-Extension; NCT02355184
Sponsor: CytoDyn, Inc.
Phase: IIb
Status: (1) PRO 140_CD 01 has been completed and (2) PRO 140_CD 01-Extension is ongoing, but not recruiting participants.
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 two or more alternative ART regimen options to consider.
  • Participants had HIV RNA <100 copies/mL at screening. In the 12 months prior to screening, participants had undetectable viral load levels. Participants had CD4 counts >350 cells/mm3 at screening and had nadir CD4 counts >200 cells/mm3.

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, which is ongoing.12,13,15
Selected Study Results:


Study Identifiers: (1) PRO 140_CD 02; NCT02483078 and (2) PRO 140_CD 02 Extension; NCT02990858
Sponsor: CytoDyn, Inc.
Phase: IIb/III
Status: (1) PRO 140_CD 02 has been completed and (2) PRO 140_CD 02 Extension is enrolling participants by invitation.
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.
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.4,16
Selected Study Results:

 

Study Identifiers: PRO 140_CD03; NCT02859961
Sponsor: CytoDyn, Inc.
Phase: IIb/III
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this 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.
Study Population

  • 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.17
Selected Study Results:


Adverse Events


NCT00642707:

In this Phase IIa 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.8


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

Safety results of leronlimab monotherapy from 40 participants in the CD 01 study and 16 participants in the CD 01-Extension were presented in June 2016. No drug-related SAEs and no study discontinuations due to an AE occurred. In the CD 01 study, there were a total of 86 reported AEs, 25 of which were definitely, probably, or possibly related to leronlimab. In the extension study, there were 72 reported AEs, all of which were classified as either unlikely related to leronlimab or unrelated to leronlimab. Mild or moderate local injection site reactions accounted for all the AEs that were definitely or probably study-drug related. The majority of reported AEs in both the CD 01 study and extension study were of mild or moderate intensity, with only one severe AE occurring in each study.12,15,18

Study results from the 16 participants enrolled in the ongoing CD 01-Extension were updated in February 2017. At the time of the update, 10 participants were still receiving leronlimab monotherapy, with nine participants close to completing 2 years of treatment. Leronlimab continued to be generally well tolerated, with no drug-related SAEs and no discontinuations due to an AE.13,19


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

In June 2018, an analysis of safety data from 25 participants who were randomized to leronlimab and 27 participants who were randomized to placebo in the CD 02 study was presented. Fifty-six percent of participants from the leronlimab group and 51.9% of participants from the plabeo group had completed the 25-week-long treatment phase of the study. There were no study discontinuations because of an AE and no treatment-related SAEs. No notable AE pattern was seen. Injection site reactions, which were infrequent and mild, occurred in less than 10% of participants. These reactions were also temporary and resolved on their own without intervention. Thus far, 35 participants have enrolled into the CD 02 Extension study.4,16,20


Drug Interactions


Drug-drug interactions associated with leronlimab are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced: leronlimab. https://chem.nlm.nih.gov/chemidplus/rn/674782-26-4. Accessed February 11, 2019.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed February 11, 2019.
  3. American Medical Association website. Statement on a nonproprietary name adopted by the USAN Council: Leronlimab. https://searchusan.ama-assn.org/undefined/documentDownload?uri=%2Funstructured%2Fbinary%2Fusan%2Fleronlimab.pdf. Accessed February 11, 2019.
  4. 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. https://clinicaltrials.gov/ct2/show/NCT02483078. Accessed February 11, 2019.
  5. 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. http://www.natap.org/2006/HIV/022406_02.htm. Accessed February 11, 2019.
  6. 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.
  7. 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
  8. 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
  9. 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
  10. Marozsan AJ, Ketas TJ, Huang W, et al. CCR5 monoclonal antibody PRO 140 inhibited HIV-1 resistant to maraviroc, a small molecule CCR5 antagonist. Abstract presented at: International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract TUAA0305. https://library.iasociety.org/AbstractView.aspx?confID=2008&abstractId=12707. Accessed February 11, 2019.
  11. Jacobson J, Morris S, Carpenito J, et al. Co-receptor tropism and viral resistance following short-term monotherapy with the anti-CCR5 monoclonal antibody PRO 140. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Paper 531. http://www.retroconference.org/2010/Abstracts/38126.htm. Accessed May 23, 2013.
  12. 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. https://clinicaltrials.gov/ct2/show/NCT02355184. Accessed February 11, 2019.
  13. Lalezari J, Dhody K, Kowalczyk U, Kazempour K, Pourhassan N, Maddon PJ. PRO140 single-agent maintenance therapy for HIV-1 infection: a 2-year update. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Abstract 437. http://www.croiconference.org/sessions/pro140-single-agent-maintenance-therapy-hiv-1-infection-2-year-update. Accessed February 11, 2019.
  14. 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. https://clinicaltrials.gov/ct2/show/NCT00642707. Accessed February 11, 2019.
  15. 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. https://clinicaltrials.gov/ct2/show/NCT02175680. Accessed February 11, 2019.
  16. 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. https://clinicaltrials.gov/ct2/show/NCT02990858. Accessed February 11, 2019.
  17. 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. https://clinicaltrials.gov/ct2/show/NCT02859961. Accessed February 11, 2019.
  18. Lalezari J, Dhody K, Kowalczyk U, Kazempour K, Pourhassan N, Maddon PJ. PRO140 SC monotherapy (MT) provides long-term, full virologic suppression in HIV patients. American Society for Microbiology (ASM) Microbe; June 16-20, 2016; Boston, MA. Levin: National AIDS Treatment Advocacy Project (NATAP); HIV Articles; 2016. http://www.natap.org/2016/HIV/062216_03.htm. Accessed February 11, 2019.
  19. Lalezari J, Dhody K, Kowalczyk U, Kazempour K, Pourhassan N, Maddon PJ. PRO 140 single-agent maintenance therapy for HIV-1 infection: a 2-year update. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Poster 437. http://www.croiconference.org/sites/default/files/posters-2017/437_Dhody.pdf. Accessed February 11, 2019.
  20. Dhody K, Kazempour K, Pourhassan N, Maddon PJ. Primary efficacy results of PRO 140 SC in a pivotal Phase 2b/3 study in heavily treatment-experienced HIV-1 patients. American Society for Microbiology (ASM) Microbe; June 7-11, 2018; Atlanta, GA. Mascolini: ASM - Primary Efficacy Results of PRO 140 SC in a Pivotal Phase 2b/3 Study in Heavily Treatment-Experienced HIV-1 Patients; HIV Articles; 2018. http://www.natap.org/2018/HIV/061118_02.htm. Accessed February 11, 2019.


Last Reviewed: February 11, 2019