Drugs

PRO-140

Other Names: PA14 Drug Class: CCR5 Antagonist Registry Number: 674782-26-4 (CAS) Organization: CytoDyn, Inc. Phase of Development: IIb/III

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

Pharmacology


Mechanism of Action: HIV-1 CCR5 antagonist. PRO-140, 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, PRO-140 does not prevent CC-chemokine signaling.5-7 PRO-140 is not active against CXCR4-using viruses.8

Half-life (T½): In a study of multiple subcutaneous (SC) doses of PRO-140 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 PRO-140 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: PRO-140 is eliminated via a saturable, antigen-mediated clearance process.6

Resistance: In vitro, PRO-140 has exhibited activity against viruses resistant to maraviroc.10

In single-dose IV or multiple-dose SC studies of PRO-140, tropism shifts were observed in 5 out of 84 PRO-140-treated participants. Three of the 5 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 2 participants was still being done at the time this data was presented. No emergence of viral resistance to PRO-140 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 PRO-140 monotherapy, virologic failure (VF) occurred in 5 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 PRO-140, maraviroc, and AMD3100 (post-treatment compared with baseline) in both VF and non-VF participants.12,13


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 PRO-140.
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.
Dosing: PRO-140 doses were administered as monotherapy and via SC infusion. Participants were randomized to 1 of the following 4 groups:
  • PRO-140 162 mg weekly on Days 1, 8, and 15
  • PRO-140 324 mg every 2 weeks on Days 1 and 15; placebo on Day 8
  • PRO-140 324 mg weekly on Days 1, 8, and 15
  • Placebo weekly on Days 1, 8, and 158,14,15
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 PRO-140 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 PRO-140 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 2 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.

Dosing:

  • PRO 140_CD 01: PRO-140 350 mg monotherapy was administered weekly via SC injection for 12 weeks. (The total treatment duration with PRO-140 was 14 weeks, with a 1-week overlap of existing ART and PRO-140 at the beginning of the study treatment and then another similar 1-week overlap at the end of treatment in participants who did not experience VF.)
  • PRO 140_CD 01-Extension: Participants will receive an additional 160 weeks of PRO-140 monotherapy. (The total treatment duration during the extension study will be 161 weeks, with a 1-week overlap of existing ART and PRO-140 at the end of treatment in participants who do not experience VF.)12,16-19
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 is currently recruiting participants and (2) PRO 140_CD 02 Extension is enrolling participants by invitation.
Study Purpose: The purpose of the PRO 140_CD 02 study is to evaluate the safety and efficacy of PRO-140 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 PRO-140.
Study Population:

PRO 140_CD 02:

  • Participants are treatment-experienced adults with R5-tropic HIV. 
  • Participants have been on their current ART regimen for at least 3 months and are experiencing treatment failure on their current ART regimen. Participants have documented resistance to at least 1 drug within 3 different ARV drug classes or they have documented resistance to at least 1 drug within 2 different ARV drug classes and have limited treatment options available.
  • Participants have 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 PRO-140 to maintain viral suppression.

Dosing:

PRO 140_CD 02:

  • Part 1 (1-week blinded phase): Participants will receive either PRO-140 350 mg or placebo, each administered weekly via SC injection and each in combination with existing ART.
  • Part 2 (24-week, open-label phase): All participants will receive PRO-140 350 mg administered weekly via SC injection and in combination with optimized background therapy.
  • A follow-up phase will last 4 weeks or will continue until viral suppression is achieved. Follow-up may last up to a maximum of 6 months after a participant has experienced treatment failure.

PRO 140_CD 02 Extension:

  • All eligible participants will continue to receive SC injections of PRO-140.4,20,21
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 PRO-140 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 2 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.

Dosing: Participants will substitute weekly SC PRO-140 mg monotherapy for their existing ART regimen. (The total treatment duration with PRO-140 will be 48 weeks, with a 1-week overlap of existing ART and PRO-140 at the beginning of the study treatment and then another similar 1-week overlap at the end of treatment in participants who do not experience VF.)22


Adverse Events


NCT00642707:
In this Phase IIa trial, 44 total participants were treated with either PRO-140 or placebo. The most frequent systemic adverse events (AEs), which were associated with either placebo or SC PRO-140, 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 PRO-140 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 PRO-140. In the extension study, there were 72 reported AEs, all of which were classified as either unlikely related to PRO-140 or unrelated to PRO-140. 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 1 severe AE occurring in each study.12,16,18

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 PRO-140 monotherapy, with 9 participants close to completing 2 years of treatment. PRO-140 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 2017, a brief safety analysis was presented on the Phase IIb/III CD 02 studies, as well as other ongoing trials of PRO-140 (CD 01-Extension [NCT02355184] and CD 03 [NCT02859961]). Thus far, PRO-140 has not led to any drug-related SAEs, discontinuations because of AEs, or any notable patterns of toxicity. Injection site reactions, which were described as infrequent, mild, transient, and self-resolving, have been the most common AEs reported and have occurred in less than 10% of participants.4,12,20-22


Drug Interactions


PRO-140 drug interactions are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/674782-26-4. Last accessed on January 4, 2018.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on January 4, 2018.
  3. CytoDyn Inc.: Press Release, dated July 30, 2012. CytoDyn announces entry into agreement with Progenics Pharmaceuticals, Inc. to acquire PRO 140. Available at: https://www.cytodyn.com/media/press-releases/detail/33/cytodyn-announces-entry-into-agreement-with-progenics. Last accessed on January 4, 2018. [Archived at WebCite]
  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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02483078. Last accessed on January 4, 2018.
  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. Available at: http://www.natap.org/2006/HIV/022406_02.htm. Last accessed on January 4, 2018. [Archived at WebCite]
  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 Nov 1;198(9):1345-52. Available at: https://academic.oup.com/jid/article/198/9/1345/834086. Last accessed on January 4, 2018.
  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 Jan;75(2):579-88. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC113953/. Last accessed on January 4, 2018.
  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 May 15;201(10):1481-7. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856743/. Last accessed on January 4, 2018.
  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 Oct;54(10):4137-42. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944554/. Last accessed on January 4, 2018.
  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. Available at: http://library.iasociety.org/AbstractView.aspx?confID=2008&abstractId=12707. Last accessed on January 4, 2018. [Archived at WebCite]
  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. Available at: http://www.retroconference.org/2010/Abstracts/38126.htm. Last accessed on 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02355184. Last accessed on January 4, 2018.
  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. Available at: http://www.croiconference.org/sessions/pro140-single-agent-maintenance-therapy-hiv-1-infection-2-year-update. Last accessed on January 4, 2018. [Archived at WebCite]
  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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00642707. Last accessed on January 4, 2018.
  15. Thompson M, Lalezari J, Saag M, et al. Weekly and biweekly subcutaneous PRO 140 demonstrates potent, sustained antiviral activity: 2-week study. Conference on Retroviruses and Opportunistic Infections (CROI); February 8-11, 2009; Montreal, Canada. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2009. Available at: http://www.natap.org/2009/CROI/croi_99.htm. Last accessed on January 4, 2018. [Archived at WebCite]
  16. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02175680. Last accessed on January 4, 2018.
  17. CytoDyn, Inc.: News Release, dated February 3, 2015. CytoDyn concludes Phase 2b study with 98% success with 4 weeks of monotherapy – many HIV patients in extension study with some approaching 6 months. Available at: http://content.equisolve.net/cytodyn/news/2015-02-03_CytoDyn_Concludes_Phase_2b_Study_With_98_Success_204.pdf. Last accessed on January 4, 2018. [Archived at WebCite]
  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. Available at: http://www.natap.org/2016/HIV/062216_03.htm. Last accessed on January 4, 2018. [Archived at WebCite]
  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. Available at: http://www.croiconference.org/sites/default/files/posters-2017/437_Dhody.pdf. Last accessed on January 4, 2018. [Archived at WebCite]
  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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02990858. Last accessed on January 4, 2018.
  21. Dhody K, Maddon PJ, Kazempour K, Pourhassan N, Green D, Burger D. Interim results in a Phase 2b/3 pivotal study of PRO 140 in treatment-experienced HIV-1 patients with multiple ARV class resistance. American Society for Microbiology (ASM) Microbe; June 1-5, 2017; New Orleans, LA. Mascolini: PRO 140 CCR5 monoclonal antibody strong in highly pretreated people: Week 25 - (ICAAC 2017 June 1); National AIDS Treatment Advocacy Project (NATAP): HIV Articles; 2017. Available at: http://natap.org/2017/HIV/060617_04.htm. Last accessed on January 4, 2018. [Archived at WebCite]
  22. 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. Available at: https://clinicaltrials.gov/ct2/show/NCT02859961. Last accessed on January 4, 2018.


Last Reviewed: January 4, 2018