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Tucidinostat

Other Names: CS-055, Chidamide, Epidaza, HBI-8000
Drug Class: Latency-Reversing Agents
Molecular Formula: C22 H19 F N4 O2
Registry Number: 1616493-44-7 (CAS)
Chemical Name: Benzamide, N-(2-amino-4-fluorophenyl)-4-(((1-oxo-3-(3-pyridinyl)-2-propen-1-yl)amino)methyl)-Benzamide, N-(2-amino-4-fluorophenyl)-4-((((2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl)amino)methyl)-
Chemical Class: Benzamide
Company: HUYA Bioscience International; Shenzhen Chipscreen Biosciences Ltd.
Phase of Development: Tucidinostat is in Phase II/III development as a latency-reversing agent for HIV.
Patent Version Content

Pharmacology


Mechanism of Action: Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).3 Tucidinostat, a benzamide derivative, is an HDACi that selectively targets the class I HDAC enzymes HDAC-1, -2, and -3, which are important in the disruption of HIV latency.4,5 Additionally, tucidinostat is active against the class II HDAC-10 enzyme. Tucidinostat is currently approved for use in China for the treatment of peripheral T-cell lymphoma.4

In HIV-1 latency, HDACs are recruited to the proviral 5' long terminal repeat (LTR), where they catalyze deacetylation of lysine residues on histones, resulting in chromatin condensation on nucleosome 1 (nuc-1) and preventing HIV transcription. Inhibition of HDAC activity promotes histone acetylation (hyperacetylation) of lysine residues by histone acetyltransferases (HATs), leading to chromatin relaxation and transcriptional activation.5,6 Some research suggests that the activity of HDACis in inducing HIV transcription may not be caused by direct effects on histone acetylation, but may be caused by effects on other non-histone proteins.7,8

Half-life (T1/2): In a Phase Ib/IIa trial (NCT02513901) of tucidinostat in adults with HIV, the elimination half-life of tucidinostat after a single oral 10-mg dose was approximately 11.5 hours. After multiple oral 10-mg doses of tucidinostat, the half-life was approximately 15.5 hours.9


Select Clinical Trials


Study Identifiers: CHARTER; NCT02513901
Sponsor: Tang-Du Hospital
Phase: Ib/IIa
Status: This study has been completed.
Study Purpose: The purpose of this open-label trial was to evaluate the safety of tucidinostat plus ART and the efficacy of tucidinostat plus ART in reactivating HIV transcription in latently infected cells and reducing latent HIV reservoir size.
Study Population:
  • Participants were adults with HIV who were on ART and who had been receiving ART for at least 18 months.
  • Participants had HIV RNA <50 copies/mL for at least 1 year and had CD4 counts >350 cells/mm3.
Dosing: Participants received tucidinostat 10 mg administered orally twice a week for 4 weeks (on Tuesday and Friday) and continued on their baseline ART regimen throughout the study.9,10
Selected Study Results:
Study Identifiers: NCT02902185
Sponsor: Tang-Du Hospital
Phase: II/III
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose this study is to confirm the efficacy of tucidinostat plus ART in reactivating HIV transcription in latently infected cells and reducing latent HIV reservoir size.
Study Population:
  • Participants are adults with HIV who are currently on ART and have been receiving ART for at least 24 months.
  • Participants have had HIV RNA <20 copies/mL for at least 1.5 years and have CD4 counts >350 cells/mm3.
Dosing: Participants will be randomized to receive either tucidinostat 10 mg or placebo, each administered twice a week (given at least 3 days apart each week) for 12 weeks. Participants will continue on their current ART regimens throughout the study.11


Adverse Events


CHARTER (NCT02513901):

In this Phase Ib/IIa trial, 7 participants completed treatment with 8 oral doses of tucidinostat. No significant adverse events (AEs) occurred, and all AEs were of Grade 1 severity. Rash and fatigue/somnolence were each reported in 1 participant. A small decrease in complete blood cell counts, most notably red blood cell counts and hemoglobin values, were seen with tucidinostat treatment, but these cases were all below Grade 1 and returned to baseline levels by Day 56. CD4 counts remained unchanged throughout the study.9,12


Drug Interactions


Information about drug-drug interactions between tucidinostat and HIV-related drugs is currently unavailable.


References


  1. United States National Library of Medicine. ChemIDplus Advanced: tucidinostat. https://chem.nlm.nih.gov/chemidplus/rn/1616493-44-7. Accessed September 5, 2018.
  2. Huya Bioscience International: Press Release, dated March 6, 2007. HUYA Bioscience licenses chidamide cancer compound from Chipscreen Biosciences. https://www.huyabio.com/huya-bioscience-licenses-chidamide-cancer-compound-chipscreen-biosciences/. Accessed September 5, 2018.
  3. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed September 5, 2018.
  4. Lu X, Ning Z, Li Z, Cao H, Wang X. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis Res. 2016;5(3):185-191. doi:10.5582/irdr.2016.01024
  5. Matalon S, Rasmussen TA, Dinarello CA. Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med. 2011;17(5-6):466-472. doi:10.2119/molmed.2011.00076
  6. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013;9(4):790-799. doi:10.4161/hv.23202
  7. Shirakawa K, Chavez L, Hakre S, Calvanese V, Verdin E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 2013;21(6):277-285. doi:10.1016/j.tim.2013.02.005
  8. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(11). doi:10.1371/journal.ppat.1004473
  9. Sun Y, Li J, Ma C. Chidamide disrupts and reduces HIV-1 latency in patients on suppressive antiretroviral therapy. Slides presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands. https://programme.aids2018.org/PAGMaterial/PPT/3643_2431/2018-IAS-Chidamide.pptx. Accessed September 5, 2018.
  10. Tang-Du Hospital. Safety and efficacy of the histone deacetylase inhibitor chidamide in combination with antiretroviral therapy for eradication of the latent HIV-1 reservoir (CHARTER). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 30, 2015. NLM Identifier: NCT02513901. https://clinicaltrials.gov/ct2/show/NCT02513901. Accessed September 5, 2018.
  11. Tang-Du Hospital. Efficacy of the histone deacetylase inhibitor chidamide in combination with antiretroviral therapy for reactivation of the latent HIV-1 reservoir: a randomized controlled clinical trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 6, 2016. NLM Identifier: NCT02902185. https://clinicaltrials.gov/ct2/show/NCT02902185. Accessed September 5, 2018.
  12. Sun Y, Li J, Ma J. Chidamide reactivates and diminishes latent HIV-1 DNA in patients on suppressive antiretroviral therapy. Abstract presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands. Abstract WEAA0101. http://programme.aids2018.org/Abstract/Abstract/9294. Accessed September 5, 2018.


Last Reviewed: September 5, 2018