A Clinical Overview of INCB-9471
May 22, 2013
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
Molecular Weight: 559.673
(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)
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
T½: 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
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
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
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
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- United States National Library of Medicine. ChemIDplus Advanced.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development.
- Brown KC, Paul S, Kashuba AD. Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet. 2009;48(4):211-41.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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