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FDA-approved

Investigational

Vorinostat  Audio icon

Other Names: MK-0683, VOR, Zolinza, suberoylanilide hydroxamic acid (SAHA)
Drug Class: Latency-Reversing Agents
Molecular Formula: C14 H20 N2 O3
Registry Number: 149647-78-9 (CAS)
Chemical Name: 8-(hydroxyamino)-8-oxo-N-phenyl-octanamide
Chemical Class: Other Carboxylic Acid Derivatives
Company: Merck & Co., Inc.
Phase of Development: II
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Chemical Image:
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vorinostat
vorinostat
Molecular Weight: 264.323
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Treatment Action Group website3)
Patent Version Content

Pharmacology


Mechanism of Action: Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).3 Vorinostat, a hydroxamic acid, is a pan-HDACi of class I and II histone deacetylases (HDACs).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.4,5 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 proteins, such as release of free positive transcription elongation factor b (P-TEFb) from the inhibitory 7SK small nuclear ribonucleoprotein (snRNP).6,7

Half-life (T½): As an FDA-approved treatment for cutaneous T-cell lymphoma, vorinostat half-life properties have been previously described. After oral administration of vorinostat in patients with advanced cancer, the mean terminal half-life of vorinostat was approximately 2 hours, and the mean terminal half-lives of vorinostat’s two inactive metabolites, O-glucuronide and 4-anilino-4-oxobutanoic acid, were approximately 2 hours and 11 hours, respectively.8

Metabolism/Elimination: Vorinostat is eliminated primarily through metabolism via glucuronidation and hydrolysis (major pathways), followed by β-oxidation. CYP enzymes have a negligible role in vorinostat metabolism. Less than 1% of a total vorinostat dose is recovered as unchanged drug in urine, indicating that vorinostat is not excreted renally. Urinary recovery of a vorinostat dose at steady state was approximately 16% as the inactive metabolite O-glucuronide and approximately 36% as the inactive metabolite 4-anilino-4-oxobutanoic acid.8

Resistance: Resistance to vorinostat in the context of HIV infection has not been described.


Clinical Trials


Study Identifier: NCT01319383
Sponsor: University of North Carolina, Chapel Hill
Phase: I/II
Study Purpose: Study to determine the efficacy of vorinostat in inducing HIV RNA expression within resting CD4 T cells after single and multiple short-interval vorinostat doses
Study Population: HIV-infected adults receiving stable ART, with plasma HIV-1 RNA <50 copies/mL and CD4 cell count >300 cells/mm3 for at least 6 months before study entry
Dosing:

  • Initially, vorinostat 400 mg was administered as single oral doses at two different times.
  • Five participants in whom resting CD4 T cell-associated HIV RNA increased after the single dose proceeded to multiple weekly cycles of vorinostat in combination with ART. The weekly cycles consisted of vorinostat 400 mg once daily for 3 consecutive days a week. A total of 8 weekly dosing cycles were given, for a total of 22 vorinostat doses. (Between the dosing cycles, there were 4-day rest periods. A 4- to 8-week interval followed the fourth dosing cycle.)9-11
Selected Study Results:

 

Study Identifier: SEARCH 019; NCT02475915
Sponsor: South East Asia Research Collaboration with Hawaii
Phase: I/II
Study Purpose: Study to compare the safety and effectiveness of vorinostat + hydroxychloroquine + maraviroc (VHM) in combination with ART versus ART alone in controlling HIV RNA during a treatment interruption that followed
Study Population: Participants were HIV-infected, treatment-experienced adults who initiated ART during acute HIV infection. Participants had HIV RNA <50 copies/mL for more than 48 weeks and CD4 counts ≥450 cells/mm3. (Participants were recruited from RV254/SEARCH 010, a study of an acute HIV infection cohort.)
Dosing: Participants were randomly assigned to one of the following two groups to receive treatment over a period of 10 weeks:

  • ART + three 14-day cycles of vorinostat 400 mg daily + hydroxychloroquine 200 mg twice daily + maraviroc 150 mg to 600 mg twice daily (maraviroc dose depended on participant’s ART regimen)
  • ART alone
Treatment interruption was initiated at Week 10, and ART was resumed if HIV RNA >1,000 copies/mL. (For participants who were on NNRTI-based therapy, the NNRTI was interrupted at Week 8. In order to prevent NNRTI resistance, PI replacement therapy with darunavir/ritonavir was given between Weeks 8 and 10, and the maraviroc dose was reduced from 1200 mg daily to 300 mg daily.) Participants were followed through Week 34.12-14

* An observational sub-study (SEARCH 026; NCT02470351) was conducted to assess the central nervous system (CNS) effects, CNS HIV reservoir, and CNS viral rebound in consenting SEARCH 019 participants.15,16
Selected Study Results:

 

Study Identifier: NCT01365065
Sponsor: Bayside Health
Phase: II
Study Purpose: Study to determine the ability of vorinostat to induce HIV RNA expression within resting CD4 T cells after 14 days of daily vorinostat dosing
Study Population: HIV-infected adults receiving suppressive ART, with HIV-1 plasma RNA <50 copies/mL for at least 3 years and CD4 count >500 cells/mm3
Dosing: Vorinostat 400 mg once daily for 14 days, in combination with ART6,17-19
Selected Study Results:

 

Study Identifier: RIVER trial; NCT02336074 
Sponsor: Imperial College London
Phase: II
Study Purpose: Proof-of-concept study to determine whether a combined approach using 4-drug ART + HDACi + 2 anti-HIV vaccines can lead to greater reductions in the size of the latent HIV reservoir when compared to 4-drug ART alone
Study Population: HIV-infected, treatment-naive adults. Participants will be enrolled within 4 weeks of a diagnosis of primary HIV infection.
Dosing: All participants will begin receiving 4-drug ART (which will include raltegravir) at Week 0. At Week 22, participants who meet eligibility requirements (which will include achieving viral suppression) will be randomized to either:

  • Continue on 4-drug ART, or 
  • Continue on 4-drug ART and receive ChAdV63.HIVconsv (ChAd) prime vaccine at Week 24 + MVA.HIVconsv (MVA) boost vaccine at Week 32. This will be followed by 10 doses of the HDACi vorinostat given over 28 days.20

* This study is currently recruiting participants.

In addition, a Phase I/IIa eradication study (VORVAX trial; NCT02707900) will examine the use of AGS-004, an investigational HIV immunotherapy, plus the HDACi vorinostat to eliminate the latent HIV reservoir in patients on suppressive ART.21,22


Adverse Events


In the Phase I/II study (NCT01319383), no vorinostat-associated adverse events (AEs) were reported during single limited exposures to vorinostat in eight HIV-infected participants on suppressive ART. No AEs greater than Grade I severity occurred.9 During multiple short-interval vorinostat dosing in five participants, some mild, transient gastrointestinal symptoms and headache occurred (all below Grade I severity). Transient thrombocytopenia occurred in all participants, with only one participant on a single study visit developing thrombocytopenia reaching Grade I toxicity.10 A neurocognitive assessment performed on all five participants at baseline and study end found no significant change in neurocognitive functioning.23

In the SEARCH 019 study (NCT02475915), serious adverse events (SAEs) occurred in 2 out of 10 participants in the VHM arm. One of the 2 participants discontinued the study because of renal insufficiency plus low platelets (VHM-related), and the other participant had diarrhea (possibly due to food poisoning/VHM). In terms of non-serious AEs, 81 events occurred in 10 ART + VHM participants, and 37 events occurred in 5 ART-only participants. Significantly more participants in the ART + VHM group than in the ART-only group experienced non-serious thrombocytopenia and elevated creatinine levels. There were no reports of acute retroviral syndrome following treatment interruption (TI). Additionally, following TI, there were no new resistance mutations detected and no reports of virological failure after participants resumed ART.12,13 The CNS sub-study (NCT02470351) found that VHM treatment did not result in detectable CSF HIV RNA or in persistent adverse outcomes—this was based on CSF inflammatory measures, neuropsychological testing, and magnetic resonance spectroscopy (MRS). TI was found to be associated with CNS immune activation and detectable HIV RNA in CSF.15,16

In the Phase II study (NCT01365065) of 20 HIV-infected adults on suppressive ART, during which oral vorinostat 400 mg was administered once daily for 14 days, 90% of study participants experienced a Grade 1 or 2 AE, with nausea, diarrhea, fatigue, and thrombocytopenia being the most common AEs. There was no occurrence of AEs of a higher grade, dose modifications, or drug discontinuations. Significant and prolonged changes in host gene expression were observed at Day 84, which investigators said warranted long-term follow-up.6,13

Additional AEs known to be associated with vorinostat use are described in the FDA-approved Zolinza Full Prescribing Information.


Drug Interactions


As an FDA-approved treatment for cutaneous T-cell lymphoma, vorinostat drug interactions have been previously described. In this context, previous studies have indicated that vorinostat at the 400-mg dose level does not inhibit CYP-drug-metabolizing enzymes. Because vorinostat is not eliminated via CYP pathways, drug-drug interactions between vorinostat and agents that are known CYP inhibitors or inducers are not anticipated. Vorinostat is not a substrate of human P-gp and is not likely to inhibit P-gp at a serum concentration of 2 µM (Cmax) in humans.8

An in vitro study investigating the interaction of CYP modulators (nevirapine, cobicistat, rifampin, and ketoconazole) on vorinostat in human hepatocytes found that vorinostat metabolism was affected by CYP modulators; however, there was no meaningful change in the clearance of vorinostat.24

During the Phase II study (NCT01365065) involving 20 participants who received at least three ARV agents and once-daily vorinostat over 14 days, there were no significant interactions between vorinostat and ART.6

Additional drug-drug interactions between vorinostat and co-administered drugs are described in the FDA-approved Zolinza Full Prescribing Information.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/149647-78-9. Last accessed on August 16, 2016.
  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 August 16, 2016.
  3. Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on August 16, 2016.
  4. Rasmussen TA, Tolstrup M, Winckelmann A, Ostergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013 Apr 1;9(4):790-799. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903897/. Last accessed on August 16, 2016.
  5. Matalon S, Rasmussen TA, Dinarello CA. Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir. Mol Med. 2011 May-Jun;17(5-6):466-72. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105138/. Last accessed on August 16, 2016.
  6. 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 Nov 13;10(11):e1004473. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231123/. Last accessed on August 16, 2016.
  7. Bartholomeeusen K, Fujinaga K, Xiang Y, Peterlin BM. Histone deacetylase inhibitors (HDACis) that release the positive transcription elongation factor b (P-TEFb) from its inhibitory complex also activate HIV transcription. J Biol Chem. 2013 May 17;288(20):14400-7. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656295/. Last accessed on August 16, 2016.
  8. Merck Sharp & Dohme Corp. Zolinza-vorinostat capsule: Full Prescribing Information, December 2015. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092. Last accessed on August 16, 2016.
  9. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704185/. Last accessed on August 16, 2016.
  10. Archin NM, Bateson R, Tripathy M, et al. HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat. J Infect Dis. 2014 Sep 1;210(5):728-35. Available from National AIDS Treatment Advocacy Project (NATAP): http://www.natap.org/2014/HIV/JInfectDis.2014Archin-728-35.pdf. Last accessed on August 16, 2016.
  11. University of North Carolina, Chapel Hill. A Phase I/II Investigation of the Effect of Vorinostat (VOR) on HIV RNA Expression in the Resting CD4+ T Cells of HIV-Infected Patients Receiving Stable Antiretroviral Therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 17, 2011. NLM Identifier: NCT01319383. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01319383. Last accessed on August 16, 2016.
  12. South East Asia Research Collaboration with Hawaii. A Randomized Study to Compare the Efficacy of Vorinostat/Hydroxychloroquine/Maraviroc (VHM) in Controlling HIV After Treatment Interruption in Subjects Who Initiated ART During Acute HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 3, 2015. NLM Identifier: NCT02475915. Available at: https://clinicaltrials.gov/ct2/show/study/NCT02475915. Last accessed on August 16, 2016.
  13. Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals treated during acute HIV infection. 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Mascolini: Vorinostat, HCQ, Maraviroc Do Not Delay Time to Rebound After Interruption. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Available at: http://www.natap.org/2016/IAC/IAC_07.htm. Last accessed on August 16, 2016.
  14. Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals initiating ART during acute HIV infection. Abstract presented at: 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Abstract TUAX0101LB. Available at: http://programme.aids2016.org/Abstract/Abstract/10535. Last accessed on August 16, 2016.
  15. South East Asia Research Collaboration with Hawaii. Study SEARCH 026Assessment of the HIV CNS Reservoir, Neurological and Neuro-cognitive Effects, and Source of Rebound HIV in CNS in Subjects Participating in Study SEARCH 019. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on: June 2, 2015. NLM Identifier: NCT02470351. Available at: https://clinicaltrials.gov/ct2/show/study/NCT02470351. Last accessed on August 16, 2016.
  16. Kroon E, Ananworanich J, Le LT, et al. Central nervous system impact of vorinostat, hydroxychloroquine and maraviroc combination therapy followed by treatment interruption in individuals treated during acute HIV infection (SEARCH 026). Poster presented at: 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Poster LBPE005. Available at: http://programme.aids2016.org/PAGMaterial/eposters/0_10588.pdf. Last accessed on August 16, 2016.
  17. Wightman F, Elliot JH, Solomon AE, et al. Multidose vorinostat in HIV-infected individuals on effective ART leads to an increase in regulatory T cells but no change in inducible virus or HIV-specific T cells. Abstract presented at: 20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia. Abstract LBPE07. Available at: http://pag.aids2014.org/abstracts.aspx?aid=11368. Last accessed on August 16, 2016.
  18. Elliott J, Solomon A, Wightman F, et al. THE SAFETY AND EFFECT OF MULTIPLE DOSES OF VORINOSTAT ON HIV TRANSCRIPTION IN HIV-INFECTED PATIENTS RECEIVING COMBINATION ANTIRETROVIRAL THERAPY. Abstract presented at: 20th Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2013; Atlanta, GA. Abstract 50LB. Available from National Association of People with HIV Australia (NAPWHA):http://napwha.org.au/sites/default/files/CROI%202013%20vorinostat%20final%202.pdf. Last accessed on August 16, 2016.
  19. Bayside Health. A Pilot Study to Assess the Safety and Effect on HIV Transcription of Vorinostat in Patients Receiving Suppressive Combination Anti-retroviral Therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 1, 2011. NLM Identifier: NCT01365065. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01365065. Last accessed on August 16, 2016.
  20. Imperial College London. Research In Viral Eradication of HIV Reservoirs. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 23, 2014. NLM Identifier: NCT02336074. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02336074. Last accessed on August 16, 2016.
  21. Argos Therapeutics: Press Release, dated April 1, 2015. NIH Funds Study of Fully Personalized Immunotherapy AGS-004 Combined With a Latency Reversing Therapy for the Treatment of HIV. Available at: http://ir.argostherapeutics.com/releasedetail.cfm?ReleaseID=904466. Last accessed on August 16, 2016.
  22. Cynthia L Gay, MD. IGHID 11424 - A Pilot Trial of the Effect of Vorinostat and AGS-004 on Persistent HIV-1 Infection (The VOR VAX Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2016. NLM Identifier: NCT02707900. Available at:  https://www.clinicaltrials.gov/ct2/show/NCT02707900. Last accessed on August 16, 2016.
  23. Robertson K, Kuruc J, Gay C, Archin N, Eron J, Margolis D. Preliminary assessment of the neurocognitive effects of vorinostat administration in HIV eradication. Abstract presented at 20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia. Abstract WEPE018. Available at: http://pag.aids2014.org/Abstracts.aspx?AID=8679. Last accessed on August 16, 2016.
  24. Shaik H, Pillai VC, Parise RA, et al. Metabolism of Vorinostat in Primary Human Hepatocytes Is Not Affected by HAART Drugs, Nevirapine and Cobicistat. Poster presented at: 2014 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition; November 2-6, 2014; San Diego, CA. Poster T2293. Available at: http://abstracts.aaps.org/Verify/AAPS2014/PosterSubmissions/T2293.pdf. Last accessed on August 16, 2016.


Last Reviewed: August 16, 2016

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