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FDA-approved

Investigational

PRO-140  Audio icon

Other Names: PA14
Drug Class: Entry Inhibitor
Registry Number: 674782-26-4 (CAS)
Company: CytoDyn, Inc.
Phase of Development: Phase IIb/III
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(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 CytoDyn, Inc. website,3 and ClinicalTrials.gov4)
Patent Version Content

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): 3.4 and 3.7 days (multiple subcutaneous [SC] doses, 162 mg and 324 mg, in HIV-infected adults)8; 3.13 and 3.33 days (single intravenous [IV] dose, 5 mg/kg and 10 mg/kg, in HIV-infected adults).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 is being investigated. 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: Multiple-dose study to evaluate the antiviral activity, safety, and pharmacokinetics of subcutaneous (SC) PRO-140
Study Population: HIV-infected, treatment-naive or -experienced adults (with no antiretroviral therapy [ART] for at least 12 weeks); CCR5-tropic HIV at screening
Dosing: PRO-140 doses were administered as monotherapy and via SC infusion. Participants were randomized to one of the following four 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 Identifier: NCT00613379
Sponsor: CytoDyn, Inc.
Phase: IIa
Study Purpose: Single-dose study to evaluate the antiviral activity, safety, and pharmacokinetics of intravenous (IV) PRO-140
Study Population: HIV-infected, treatment-naive or -experienced adults (no ART for at least 12 weeks); CCR5-tropic HIV at screening
Dosing: PRO-140 5 mg/kg or 10 mg/kg monotherapy administered as a single dose via IV infusion versus placebo9,16,17
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: Treatment substitution study 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: HIV-infected, treatment-experienced adults (on stable ART for the last 12 months); CCR5-tropic HIV at screening; no detectable viral loads within the last 12 months
Dosing:
  • PRO 140_CD 01: PRO-140 350 mg monotherapy 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 a 1-week overlap at the end of the treatment in participants who did not experience virologic failure.)
  • PRO 140_CD 01-Extension: Participants who completed 12 weeks of treatment without experiencing virologic failure could enroll in an extension study in which participants are receiving an additional 108 weeks of PRO 140 monotherapy. (The total treatment duration during the extension study will be 109 weeks, with a 1-week overlap of existing ART and PRO-140 at the end of treatment in participants who did not experience virologic failure.) The extension study is ongoing and may be extended further.12,13,18-20
Selected Study Results:


Study Identifiers: PRO 140_CD 02; NCT02483078
Sponsor: CytoDyn, Inc.
Phase: IIb/III
Study Purpose: Study to evaluate the safety and efficacy of PRO-140 used in conjunction with existing failing ART and then used in conjunction with optimized background therapy
Study Population: HIV-infected treatment-experienced adults with CCR5-tropic HIV. Participants are failing their current ARV therapy, have documented resistance to at least two ARV drug classes, and have limited treatment options available.
Dosing:
  • Part 1 (1-week blinded phase): PRO-140 350 mg administered weekly via SC injection or placebo, each in combination with existing ART.
  • Part 2 (24-week open-label phase): PRO-140 350 mg administered weekly via SC injection or placebo, each in combination with optimized background therapy.4
* This study is currently ongoing.

Additionally, another Phase IIb study (PRO 140 2102; NCT02438345) is ongoing. 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.21


Adverse Events


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

Adverse events associated with IV PRO-140 and occurring in more than two participants in a Phase IIa trial (NCT00613379) were headache and nasal congestion. There were no clinically relevant changes in ECG parameters, including QTc intervals, or laboratory or vital sign abnormalities among the study participants.9,16

In the Phase IIb CD 01 study (NCT02175680) and CD 01-extension study (NCT02355184) evaluating SC PRO-140 monotherapy, no drug-related serious adverse events and no study discontinuations due to an adverse event (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.12,13,18


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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 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 July 26, 2016.
  16. CytoDyn, Inc. A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of PRO 140 by Intravenous Administration in Adult Subjects With Human Immunodeficiency Virus Type 1 Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 30, 2008. NLM Identifier: NCT00613379. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00613379. Last accessed on July 26, 2016.
  17. Jacobson J, Thompson M, Fischl M, et al. Phase 2a Study of PRO 140 in HIV-Infected Adults. Abstract presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Abstract H-1229. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=30cfb0e3-06f8-42ba-b4fb-47507d251418&cKey=178c6776-c5f4-4c4b-bcfd-d4c0a753891a&mKey=%7b14EBFE7E-6F65-4D97-8CB6-F64F4347C38A%7d. Last accessed on July 26, 2016.
  18. 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 July 26, 2016.
  19. 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 July 26, 2016.
  20. CytoDyn, Inc.: News, dated September 21, 2015. HIV Patients Successfully Reach One Year of Virologic Suppression in PRO 140 Monotherapy Study. Available at: http://content.equisolve.net/cytodyn/news/2015-09-21_HIV_Patients_Successfully_Reach_One_Year_of_211.pdf. Last accessed on July 26, 2016.
  21. 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. Last accessed on July 26, 2016.


Last Reviewed: July 26, 2016

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