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Investigational

INCB-9471  Audio icon

Other Names: INCB-009471, INCB 9471, INCB-9471 dihydrochloride
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. (In 2008, the company developing INCB-9471 announced that it was no longer actively studying INCB-9471 and was seeking a partner company to develop the drug.)
Chemical Image:
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INCB 9471
INCB 9471
Molecular Weight: 559.673
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Incyte Corporation press release3)
Patent Version Content

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

Half-life (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 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 28.7

In a separate 14-day monotherapy study (known as INCB 9471-201), 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.5



Dosing in Clinical Trials


Study Identifier: None provided
Phase: IIa
Study Purpose: Study to evaluate the safety, pharmacokinetics, and antiviral activity of INCB-9471 monotherapy over 14 days
Study Population: HIV-infected, treatment-naive or –experienced adults (no antiretroviral therapy [ART] for at least 3 months) with CCR5-tropic HIV
Dosing: INCB-9471 200 mg administered as monotherapy once daily and orally versus placebo.7-9 
(See references cited above for information on study results.)

Study Identifiers: NCT00393120; INCB 9471-20110
Phase: II
Study Purpose: Study to evaluate the safety, pharmacokinetics, and antiviral activity of INCB-9471 monotherapy over 14 days
Study Population: HIV-infected, treatment-naive or –experienced adults (no ART for at least 3 months) with CCR5-tropic HIV
Dosing: INCB-9471 100 or 200 mg (immediate-release formulation tablet) or 300 mg (slow-release formulation tablet) administered as monotherapy once daily and orally versus placebo.5,10
(See references cited above for information on 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 or study discontinuations occurred. Four out of 19 INCB-9471-treated participants (21.1%) reported an overall total of six adverse events that were considered at least possibly related to treatment. These adverse events 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 electrocardiogram (ECG) changes reported.7,8

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.11

In a pharmacokinetic study of ritonavir’s effects on INCB-9471 in healthy adults, treatment-emergent adverse events occurred in 9 of 18 participants receiving INCB-9471 with ritonavir and in 2 of 5 participants 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 cytochrome P450 3A4 (CYP3A4) in human liver microsomes.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 area under the curve (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. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/925701-76-4. Last accessed on October 26, 2014.
  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 October 26, 2014.
  3. 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 October 26, 2014.
  4. 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 October 26, 2014.
  5. 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 October 26, 2014.
  6. 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 October 26, 2014.
  7. 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 October 26, 2014.
  8. 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 October 26, 2014.
  9. 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.iasociety.org/Default.aspx?pageId=11&abstractId=200700303. Last accessed on October 26, 2014.
  10. 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 October 26, 2014.
  11. 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 October 26, 2014.
  12. 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 October 26, 2014.
     
 


Last Reviewed: October 26, 2014

Last Updated: October 26, 2014


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