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Drugs

PRO-140

Other Names: PA14 Drug Class: Entry Inhibitor Registry Number: 674782-26-4 (CAS) Organization: CytoDyn, Inc. Phase of Development: Phase 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 entry inhibitor. PRO-140, a humanized IgG4 monoclonal antibody (mAb), binds to hydrophilic extracellular domains on CCR5, and via competitive mechanisms it inhibits CCR5-mediated HIV-1 viral entry, without preventing CC-chemokine signaling at antiviral concentrations.5-7 PRO-140 does not inhibit CXCR4-using viruses.8

Half-life (T½): In a study of multiple subcutaneous (SC) doses of PRO-140 (162 mg and 324 mg) in HIV-infected adults, the mean terminal half-lives were 3.4 days (162 mg) and 3.7 days (324 mg).8 In a study of single intravenous (IV) doses of PRO-140 (5 mg/kg and 10 mg/kg) in HIV-infected adults, the mean terminal half-lives were 3.13 days (5 mg/kg) and 3.33 days (10 mg/kg).9

Metabolism/Elimination: PRO-140 pharmacokinetic characteristics are consistent with a saturable, antigen-mediated clearance pathway.6

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

Tropism shifts were observed in 5 out of 84 PRO-140-treated participants in single-dose IV or multiple-dose SC studies. Three of the 5 participants with tropism shifts were classified as having pre-existing minor variants of CXCR4-using HIV-1 (based on ES Trofile assay results), while analysis of the pre-treatment 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, as indicated by Monogram assay results.11

In a Phase IIb extension study (NCT02355184) evaluating the ability of 15 eligible participants to maintain long-term viral suppression on PRO-140 monotherapy, virologic failure (VF) occurred in 3 participants. The median time to VF was 169 days. At VF, there was no detected change in co-receptor tropism. There was also no significant change in post-treatment IC50, IC90, and fold-change values for PRO-140, maraviroc, and AMD3100 when compared with baseline results in VF and non-VF participants. All participants with VF restarted ART and experienced virologic resuppression. The median time to resuppresion was 29 days after restarting ART.12,13


Clinical Trials



Study Identifier: NCT00642707
Sponsor: CytoDyn, Inc.
Phase: IIa
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 CCR5-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
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 stable on ART.
Study Population:

PRO 140_CD 01: 

  • Participants were treatment-experienced adults with CCR5-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 was completed.
  • 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.)
    *The extension study is ongoing, but not recruiting participants.12,13,16-18
Selected Study Results:


Study Identifiers: (1) PRO 140_CD 02; NCT02483078 and (2) PRO140 CD02_EA; NCT02759042
Sponsor: CytoDyn, Inc.
Phase: IIb/III
Study Purpose: The purpose of this 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.
Study Population:

PRO 140_CD 02: 

  • Participants are treatment-experienced adults with CCR5-tropic HIV. 
  • Participants have been on their current ART regimen for at least 3 months and are failing 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.

PRO140 CD02_EA:

  • A participant who completes 24 weeks of treatment in the PRO 140_CD 02 trial and derives clinical benefits from PRO-140 may be recruited to receive continued access to PRO-140 treatment.

Dosing:

  • 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.4,19

* PRO 140_CD 02 is currently recruiting participants.
* PRO140 CD02_EA (the expanded access program) is temporarily not available for this treatment. 

Note: The company developing PRO-140 has submitted a roll-over study protocol to allow for all ongoing and future participants who successfully complete the PRO 140_CD 02 study to receive continued access to PRO-140.20

Study Identifiers: PRO 140_CD03; NCT02859961
Sponsor: CytoDyn, Inc.
Phase: IIb/III
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 CCR5-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.)21
* This study is currently recruiting participants.

Additionally, another Phase IIb study (PRO 140 2102; NCT02438345 and NCT01272258) is currently recruiting participants. This study is investigating the use of SC PRO-140 as an adjunct to optimized ART in HIV-infected injection drug users with viral rebound and poor adherence to previous ART.22,23


Adverse Events


The most frequent systemic adverse events (AEs) occurring in a Phase IIa trial (NCT00642707), which were associated with either placebo or SC PRO-140, included diarrhea, headache, lymphadenopathy, and hypertension. There were no drug-related serious AEs or dose-limiting toxicities among participants. There were also no clinically relevant drug-related effects on electrocardiogram (ECG), including QTc intervals, 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

In the Phase IIb CD 01 study (NCT02175680) and CD 01-Extension study (NCT02355184) evaluating SC PRO-140 monotherapy, no drug-related serious AEs and no study discontinuations due to an AE occurred. Twenty-five out of 86 total reported AEs in the CD 01 study and none of the 72 total reported AEs in the extension study were definitely, probably, or possibly related to PRO-140. All AEs that were definitely or probably study-drug related were local injection site reactions of mild or moderate severity. The majority of reported AEs in both the CD 01 study and extension study were of mild or moderate severity, with only 1 severe AE occurring in each group.12,13,16


Drug Interactions


PRO-140 drug interactions are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/674782-26-4. Last accessed on December 6, 2016.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on December 6, 2016.
  3. CytoDyn Inc.: Press Release, dated July 30, 2012. CytoDyn Announces Entry into Agreement with Progenics Pharmaceuticals, Inc. to Acquire PRO 140. Available at: http://www.cytodyn.com/media/press-releases/detail/33/cytodyn-announces-entry-into-agreement-with-progenics. Last accessed on December 6, 2016.
  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 December 6, 2016.
  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. 13th 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 December 6, 2016.
  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: http://jid.oxfordjournals.org/content/198/9/1345.long. Last accessed on December 6, 2016.
  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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC113953/. Last accessed on December 6, 2016.
  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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856743/. Last accessed on December 6, 2016.
  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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944554/. Last accessed on December 6, 2016.
  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: 17th 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 December 6, 2016.
  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: 17th 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 24 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 December 6, 2016.
  13. 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 December 6, 2016.
  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: http://www.clinicaltrials.gov/ct2/show/NCT00642707. Last accessed on December 6, 2016.
  15. Thompson M, Lalezari J, Saag M, et al. Weekly and Biweekly Subcutaneous PRO 140 Demonstrates Potent, Sustained Antiviral Activity: 2-week study. 16th 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 December 6, 2016.
  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: http://www.clinicaltrials.gov/ct2/show/NCT02175680. Last accessed on December 6, 2016.
  17. CytoDyn, Inc.: News, 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 December 6, 2016.
  18. CytoDyn Inc.: News Release, dated August 23, 2016. Patients Approach Two Years of Complete HIV Viral Load Suppression in Phase 2b PRO 140 Monotherapy Extension Study. Available at: http://content.equisolve.net/cytodyn/news/2016-08-23_Patients_Approach_Two_Years_of_Complete_HIV_Viral__241.pdf. Last accessed on December 6, 2016.
  19. CytoDyn, Inc. An Expanded Compassionate Access Protocol for a Single Subject Who Has Completed 24-Weeks of Treatment in PRO140_CD02 Study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 19, 2016. NLM Identifier: NCT02759042. Available at: https://clinicaltrials.gov/ct2/show/NCT02759042. Last accessed on December 6, 2016.
  20. CytoDyn Inc: News Release, dated October 24, 2016. CytoDyn Files Protocol for Extended Access to PRO 140 for Patients Who Reach the End of PRO 140 Pivotal Phase 3 Trial. Available at: http://content.equisolve.net/cytodyn/news/2016-10-24_CytoDyn_Files_Protocol_for_Extended_Access_to_PRO__245.pdf. Last accessed on December 6, 2016.
  21. 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 December 6, 2016.
  22. Drexel University. A Phase 2b, Randomized, Double-blind, Placebo-controlled Clinical Trial of Observed Systemic, Long-acting, Anti-HIV Treatment With a Monoclonal CCR5 Antibody (PRO 140) as an Adjunct to a New, Optimized, Oral Antiretroviral Regimen in HIV-infected Recreational Drug Users With Viral Rebound and Poor Adherence to the Previous Antiretroviral Regimen. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 6, 2015. NLM Identifier: NCT02438345. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02438345.
  23. CytoDyn, Inc. A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Observed Systemic, Long-Acting, Anti-HIV Treatment With a Monoclonal Anti CCR5 Antibody (PRO 140) as an Adjunct to a New, Optimized, Oral Antiretroviral Regimen in HIV-Infected Injection Drug Users With Viral Rebound and Documented Poor Adherence to the Previous Antiretroviral Regimen. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 5, 2011. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01272258. Last accessed on December 6, 2016.


Last Reviewed: December 7, 2016