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INCB-9471  Audio icon

Other Names: INCB 9471, INCB-009471
Drug Class: Entry and Fusion Inhibitors
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: Phase II
Chemical Image:
Click image to enlarge
INCB 9471
INCB 9471
Molecular Weight: 559.673
(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)

Pharmacology


Mechanism of Action: HIV-1 entry inhibitor. INCB-9471 is a selective, reversible, small-molecule CCR5 coreceptor 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.3,4

: Approximately 60 hours.5

Metabolism/Elimination: INCB-9471 is eliminated primarily by CYP3A-mediated metabolism.6

Resistance: In a 14-day monotherapy study of once-daily INCB-9471 (100, 200, or 300 mg) in R5-tropic HIV-infected adults, dual/mixed tropic virus emerged in 4 subjects out of 39 who completed INCB-9471 treatment (2 subjects in the 200-mg group and 2 subjects in the 300-mg group). Analysis on the 2 subjects receiving the daily 200-mg dose suggested that emergence of CXCR4-using viral variants reflected outgrowth from pretreatment viral reservoirs.5


Dosing


INCB-9471 is administered once daily.5,7

Two Phase II studies (adults who were treatment-naive or –experienced—but off antiretroviral therapy for at least 3 months—and with CCR5-tropic virus):

  • INCB-9471 200 mg versus placebo.7,8
  • INCB-9471 100 mg or 200 mg of an immediate-release formulation or 300 mg of a slow-release formulation versus placebo.5,9


Adverse Events


In a Phase II 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.7

In two 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 adverse event 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.10

In a pharmacokinetic study of ritonavir’s effects on INCB-9471 in healthy adults, treatment emergent adverse events occurred in 9 of 18 subjects receiving INCB-9471 with ritonavir and in 2 of 5 subjects receiving placebo with ritonavir. The most common adverse events were headache, diarrhea, sore throat, and cold symptoms.6


Drug Interactions


INCB-9471 is metabolized predominantly by CYP3A4 in human liver microsomes.6 INCB-9471 is a weak inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activity and has low potential for CYP3A4 enzyme induction.3,6

When co-administered with ritonavir versus administration alone, the single-dose INCB-9471 pharmacokinetic profile is significantly altered, with INCB-9471 clearance reduced by 93% and AUC, t½, and Cmax increasing by 14-fold, 7.3-fold, and 55%, respectively. INCB-9471 dose reductions will likely be required when co-administered with ritonavir.3,6


References


1. United States National Library of Medicine. ChemIDplus Advanced.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development.

3. Brown KC, Paul S, Kashuba AD. Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet. 2009;48(4):211-41.

4. 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.

5. 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. Poster presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Poster 862.

6. 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. Accessed from Incyte Corporation Event Details webpage on May 19, 2013.

7. 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.

8. Incyte Corporation: Press Releases. Phase IIa Study Results Demonstrate that Once-Daily 200 mg Dosing of INCB9471 Provided Potent and Prolonged Antiviral Activity in HIV-Infected Patients. Accessed May 19, 2013.

9. 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. Last Accessed: May 19, 2013.

10. 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. Accessed from Incyte Corporation Event Details webpage on May 19, 2013.


Last Reviewed: May 22, 2013

Last Updated: May 22, 2013