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Investigational

INCB-9471  Audio icon

Other Names: INCB 9471, INCB-009471, INCB-9471 dihydrochloride
Drug Class: Entry Inhibitor
Molecular Formula: C30 H40 F3 N5 O2
Registry Number: 925701-76-4 (CAS)
Chemical Name: (4,6-dimethylpyrimidin-5-yl)-[4-[(3S,4R)-4-[(2R)-2-ethoxy-5-(trifluoromethyl)indan-1-yl]-3-methyl-piperazin-1-yl]-4-methyl-1-piperidyl]methanone
Company: Incyte Corporation
Phase of Development: II (discontinued)
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INCB 9471
INCB 9471
Molecular Weight: 559.673
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Treatment Action Group 2008 Pipeline Report3)
Patent Version Content

NOTE: The development of INCB-9471 for HIV treatment has been discontinued.


The study of INCB-9471 as an entry inhibitor HIV medicine was discontinued. In 2008, the company developing INCB-9471, Incyte Corporation, announced that it would no longer actively study INCB-9471 and would instead seek a partner company to develop the drug. Incyte Corporation said that stopping INCB-9471 development would allow the company to focus its resources on programs with the “greatest near-term value.”3,4


Pharmacology


Mechanism of Action: HIV-1 entry inhibitor. INCB-9471 is a selective, reversible, small-molecule CCR5 co-receptor antagonist that binds to a CCR5 binding pocket that is different from what maraviroc binds to. INCB-9471prevents viral entry by inhibiting the interaction between HIV-1 gp120 and CCR5. INCB-9471 prevents CCR5-mediated viral entry via allosteric noncompetitive mechanisms. INCB-9471 does not inhibit CXCR4-tropic or dual-tropic viruses.5,6

Half-life (T½): The half-life of INCB-9471 is approximately 60 hours.7

Metabolism/Elimination: INCB-9471 is eliminated primarily by CYP3A-mediated metabolism.8

Resistance: In a 14-day monotherapy study of INCB-9471 200 mg in R5-tropic HIV-infected, treatment-naive and -experienced adults, 2 treatment-experienced participants out of 19 INCB-9471-treated participants showed a tropism change to dual/mixed tropic virus. Preliminary analysis suggested that these X4-using viruses emerged from pre-existing viral variants. In both participants, virus reverted to R5-tropic after Day 28.9

In a separate 14-day monotherapy study (NCT00393120), in which once-daily INCB-9471 (100, 200, or 300 mg) was given to R5-tropic HIV-infected adults, dual/mixed tropic virus emerged in 4 participants out of 39 who completed INCB-9471 treatment (2 participants in the 200-mg group and 2 participants in the 300-mg group). Analysis on the 2 participants receiving the daily 200-mg dose suggested that emergence of CXCR4-using viral variants reflected outgrowth from pre-treatment viral reservoirs.7,10


Clinical Trials


Study Identifier: Not available
Organization: Incyte Corporation
Phase: IIa
Study Purpose: The purpose of this study was to evaluate the safety, pharmacokinetics, and antiviral activity of INCB-9471 monotherapy over 14 days.
Study Population

  • Participants were treatment-naive or –experienced adults (no ART for at least 3 months prior to screening) who were infected with CCR5-tropic HIV.
  • Participants had HIV RNA >10,000 copies/mL and mean CD4 counts >500 cells/mm3.

Dosing: Participants received either INCB-9471 monotherapy (200 mg) or placebo, each administered once daily and orally.9,11,12 
Selected Study Results:

Study Identifiers: INCB 9471-201; NCT00393120 
Sponsor: Incyte Corporation
Phase: II
Study Purpose: The purpose of this study was to evaluate the safety, pharmacokinetics, and antiviral activity of INCB-9471 monotherapy over 14 days.
Study Population:

  • Participants were treatment-naive or –experienced adults (no ART for at least 3 months prior to screening) who were infected with CCR5-tropic HIV.
  • Participants had HIV RNA >10,000 copies/mL and CD4 counts >350 cells/mm3.

Dosing: Participants received either INCB-9471 monotherapy (100-mg immediate-release tablet, 200-mg immediate-release tablet, or 300-mg slow-release tablet) or placebo, each administered once daily and orally.7,10
Selected Study Results:


Adverse Events


In a Phase IIa 14-day monotherapy study of once-daily INCB-9471 at a dose level of 200 mg in HIV-infected adults, study treatment was reportedly safe and well tolerated. No serious adverse events (SAEs) or study discontinuations occurred. Four out of 19 INCB-9471-treated participants (21.1%) reported an overall total of 6 adverse events (AEs) that were considered at least possibly related to treatment. These AEs were all mild in intensity and included constipation, diarrhea, nausea, headache, hiccups, and rash. Four INCB-9471-treated participants had changes on liver function tests (Grade 1). There were no clinically significant chemistry, hematology, or ECG changes reported.9,11

In 2 ascending-dose studies of INCB-9471 in healthy adults (doses ranging from 2.5 mg to 300 mg in the single-dose study; doses of 50 mg twice daily, 100 mg twice daily, 150 mg once daily, and 200 mg once daily in the repeat-dose study), no dose-limiting toxicities were identified. The most common AE occurring in the repeat-dose study was non-dose-related headache. There were no significant trends observed for changes in ECG, vital signs, or laboratory parameters in either study.13

In a pharmacokinetic study of ritonavir’s effects on INCB-9471 in healthy adults, treatment-emergent AEs occurred in 9 of 18 participants receiving INCB-9471 with ritonavir and in 2 of 5 participants receiving placebo with ritonavir. The most common AEs were headache, diarrhea, sore throat, and cold symptoms.8


Drug Interactions


INCB-9471 is metabolized predominantly by CYP3A4 in human liver microsomes.7 INCB-9471 is a weak inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activity and has low potential for CYP3A4 enzyme induction.5,8

When coadministered with ritonavir instead of administered alone, the single-dose INCB-9471 pharmacokinetic profile was significantly altered, with INCB-9471 clearance reduced by 93%, AUC increased by 14-fold, t½ increased by 7.3-fold, and Cmax increased by 55%. INCB-9471 dose reductions will likely be required when coadministered with ritonavir.5,8


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/925701-76-4. Last accessed on January 11, 2017.
  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 11, 2017.
  3. Chou L, Harrington M, Huff B, et al. Treatment Action Group. 2008 Pipeline Report. July 2008. Available at: http://www.treatmentactiongroup.org/sites/default/files/2008%20pipeline_0.pdf. Last accessed on January 11, 2017.
  4. Incyte Corporation: Press Release, dated March 17, 2008. Incyte to Provide Update on Clinical Programs at Cowen Health Care Conference. Available at: http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=1119174&highlight. Last accessed on January 11, 2017.
  5. Brown KC, Paul S, Kashuba AD. Drug Interactions with New and Investigational Antiretrovirals. Clin Pharmacokinet. 2009;48(4):211-41. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857544/. Last accessed on January 11, 2017.
  6. Shin N, Solomon K, Zhou N, et al. Identification and Characterization of INCB9471, an Allosteric Noncompetitive Small-Molecule antagonist of C-C Chemokine Receptor 5 with Potent Inhibitory Activity against Monocyte Migration and HIV-1 Infection. J Pharmacol Exp Ther. 2011 Jul;338(1):228-39. Available at: http://jpet.aspetjournals.org/content/338/1/228.long. Last accessed on January 11, 2017.
  7. Erickson-Viitanen S, Abremski K, Solomon K, et al. Co-Receptor Tropism, ENV Genotype, and in vitro Susceptibility to CCR5 Antagonists During a 14-Day Monotherapy Study with INCB9471. 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Poster 862. Levin: Co-Receptor Tropism, ENV Genotype, and in vitro Susceptibility to CCR5 Antagonists During Monotherapy Study with INCB9471; Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2008. Available at: http://www.natap.org/2008/CROI/croi_74.htm. Last accessed on January 11, 2017.
  8. Troy S, Emm T, Yeleswaram S, et al. Effect of Ritonavir on the Pharmacokinetics of INCB9471, a Potent Antagonist of CCR5 Co-Receptor. Poster presented at: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2007; Chicago, IL. Poster H-1035. Available from Incyte Corporation at: http://library.corporate-ir.net/library/69/697/69764/items/261808/Poster%20H-1035.pdf. Last accessed on January 11, 2017.
  9. Cohen C, DeJesus E, Mills A, et al. Potent Antiretroviral Activity of the Once-Daily CCR5 Antagonist INCB009471 Over 14 Days of Monotherapy. 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Levin: New Incyte CCR5 Drug Shows Good Activity: 14 day monotherapy study; Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2007. Available at: http://www.natap.org/2007/IAS/IAS_19.htm. Last accessed on January 11, 2017.
  10. Incyte Corporation. A Randomized, Double-blind, Placebo-controlled Study Exploring the Safety, Tolerability, PK & Virological Effect of Once Daily Oral Dosing of INCB009471 as Monotherapy for 14 Days in ARV-naïve/Limited ARV-experienced, HIV-1 Infected Pts. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 24, 2006. NLM Identifier: NCT00393120. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00393120. Last accessed on January 11, 2017.
  11. Cohen C, DeJesus E, Mills A, et al. Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. Abstract presented at: 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB106. Available at: http://www.abstract-archive.org/Abstract/Share/59259. Last accessed on January 11, 2017.
  12. Incyte Corporation: Press Release, dated July 24, 2007. Phase IIa Study Results Demonstrate that Once-Daily 200 mg Dosing of INCB9471 Provided Potent and Prolonged Antiviral Activity in HIV-Infected Patients. Available at: http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=1029620&highlight=. Last accessed on January 11, 2017.
  13. Troy S, Emm T, Yeleswaram S, et al. Single and Multiple Dose Pharmacokinetics of INCB9471, a Potent Antagonist of CCR5 Co-Receptor. Poster presented at: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2007; Chicago, IL. Poster H-1034. Available from Incyte Corporation at: http://library.corporate-ir.net/library/69/697/69764/items/261807/Poster%20H-1034.pdf. Last accessed on January 11, 2017.


Last Reviewed: January 11, 2017

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