Drugs

Romidepsin

Other Names: FK228, Istodax, RMD Drug Class: Latency-Reversing Agents
Molecular Formula: C24 H36 N4 O6 S2
Registry Number: 128517-07-7 (CAS) Chemical Name: (1S,4S,7Z,10S,16E,21R)-7-Ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo(8.7.6)tricos-16-ene-3,6,9,19,22-pentone Chemical Class: Cyclic tetrapeptide Organization: Celgene Corporation Phase of Development: Romidepsin is in Phase II development as a latency-reversing agent for HIV treatment.

Chemical Image:

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romidepsin

romidepsin

Molecular Weight: 540.7024

(Compound details obtained from ChemIDplus Advanced,1 Treatment Action Group website,2 Celgene Corporation website,3 and Journal of Biomedicine and Biotechnology article4)

Pharmacology


Mechanism of Action: Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).2 Romidepsin, a bicyclic depsipeptide, is an HDACi targeting the Class I HDAC enzymes HDAC1 and HDAC2.5–7 Romidepsin is an FDA-approved drug indicated for the treatment of cutaneous and peripheral T-cell lymphoma. As an HIV therapeutic, romidepsin is currently being investigated as an agent for reactivating latent HIV expression.2,5,8 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.7,9 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.6,10

Half-life (T½): In a study of participants with T-cell lymphomas who were receiving intravenous (IV) romidepsin 14 mg/m2 over 4 hours on days 1, 8, and 15 of a 28-day cycle, the terminal half-life of romidepsin was approximately 3 hours.5

Metabolism/Elimination: In vitro, romidepsin is extensively metabolized. The primary metabolic enzyme is CYP3A4. The CYP3A5, CYP1A1, CYP2B6, and CYP2C19 enzymes also contribute to romidepsin metabolism, but to a lesser extent. Therapeutic concentrations of romidepsin used to treat T-cell lymphomas did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and did not cause significant induction of CYP1A2, CYP2B6, and CYP3A4 in vitro.5


Select Clinical Trials


Study Identifiers: REDUC; NCT02092116
Sponsor: Bionor Immuno AS
Phase: Ib/IIa
Status: This study has been completed.
Study Purpose: The REDUC trial was a two-part open-label study. The purpose of Part A was to verify a safe and effective dose of romidepsin for latency reversal prior to use in the second part of the study. The purpose of Part B was to evaluate the effect of the therapeutic HIV vaccine Vacc-4x plus adjuvant combined with romidepsin on the latent HIV reservoir and on viral load control during an analytical treatment interruption of ART.
Study Population:
  • Participants were adults with HIV who were on ART at the time of enrollment and who had been on ART for at least 1 year.
  • Participants had HIV-1 RNA <50 copies/mL for at least 1 year and had CD4 counts ≥500 cells/mm3. Participants’ nadir CD4 counts in the past 2 years were ≥200 cells/mm3.11–13
Selected Study Results:

 

Study Identifiers: ACTG 5315; NCT01933594
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: I/II
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety of single and multiple doses of romidepsin and the effectiveness of single and multiple doses of romidepsin in inducing HIV-1 expression in latently infected CD4 T cells.
Study Population:

  • Participants were adults with HIV who were on an ART regimen containing two or more NRTIs in combination with raltegravir, dolutegravir, or efavirenz for at least the past 90 days prior to study entry.
  • Participants had HIV RNA <50 copies/mL for at least the past 365 days prior to study entry.
  • Participants had CD4 counts ≥300 cells/mm3 prior to study entry.14
Selected Study Results:

 

Study Identifiers: HIVACAR; NCT03619278
Sponsor: David Garcia Cinca
Phase: I/IIa
Status: This study is not yet open for participant recruitment.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of different therapeutic HIV vaccines (HIVARNA01.3 with and without MVA-vectored vaccine boosts or HIVACAR01), each in combination with the broadly neutralizing antibody (bNAb) 10-1074 and romidepsin. Researchers will assess whether these combination strategies can control participants’ viral load levels during an analytical treatment interruption of ART.
Study Population:

  • Participants are adults with HIV who have been on a stable ART regimen for at least 18 months.
  • Participants have had HIV RNA <50 copies/mL for the past 12 months prior to study entry and have current CD4 counts >450 cells/mm3. Participants’ nadir CD4 counts are ≥350 cells/mm3.15

 

Study Identifiers: ROADMAP; NCT02850016
Sponsor: Rockefeller University
Phase: IIa
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to compare the efficacy of romidepsin plus the investigational bNAb 3BNC117 to the efficacy of romidepsin administered alone on delaying or preventing viral rebound during an analytical treatment interruption of ART.
Study Population:

  • Participants are adults with HIV who have been receiving ART for at least 24 months.
  • Participants on a PI- or NNRTI-based ART regimen or on a cobicistat-containing regimen must be willing to switch to an INI-based regimen prior to enrollment.
  • Participants have had HIV RNA <50 copies/mL for at least 18 months and have CD4 counts >500 cells/mm3 at screening.16

 

Study Identifiers: BIOSKILL; EudraCT 2015-003186-28
Sponsor: Bionor Pharma ASA
Phase: II
Status: This study is ongoing.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of Vacc-4x plus adjuvant when given prior to romidepsin. Effects on viral load, latent HIV reservoir size, and immune responses will be measured.8,17

Study Identifiers: eCLEAR; NCT03041012
Sponsor: Aarhus University Hospital
Phase: II
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the impact of early administration of romidepsin and/or 3BNC117 on the latent HIV reservoir size in treatment-naive individuals who are initiating ART.
Study Population:

  • Participants are treatment-naive adults with HIV.
  • Participants have CD4 counts >200 cells/mm3 prior to study entry.18

 

A Phase I trial (BCN02-Romi; NCT02616874) has also been completed. The BCN02-Romi trial enrolled participants from the BCN01 vaccine trial in which two viral vector-based therapeutic HIV vaccines (ChAdV63.HIVconsv and MVA.HIVconsv prime/boost regimen) were evaluated. In the BCN02-Romi trial, participants were given booster immunizations with MVA.HIVconsv in combination with romidepsin and underwent a treatment interruption of ART.19,20


Adverse Events


REDUC (NCT02092116):

In Part A of this Phase Ib/IIa trial, no severe adverse events (AEs) or suspected unexpected serious adverse reactions (SUSARs) occurred in the six participants enrolled in the study. Among 41 reported AEs, 35 were considered related to romidepsin. All romidepsin-related AEs were Grade 1 and resolved within a few days. The most common romidepsin-related AEs were abdominal symptoms (such as nausea, borborygmia, abdominal pain) and fatigue. Changes in white blood cell counts and T cell counts that occurred during the study were considered modest. After the second romidepsin infusion, the lowest counts were seen, and after the third infusion, no further decline in counts occurred. The following were not observed: neutrophil counts below 1000 cells/μL, CD4 T cell counts below 350 cells/μL, or platelet counts below 100,000 cells/μL.12

In Part B of the REDUC trial, 20 participants were enrolled. Only one of three participants who discontinued the study during the immunization phase dropped out because of AEs that were potentially related to Vacc-4x. One hundred forty-one total AEs were reported. Of the drug-related AEs, 42 (31%) were Grade 1 AEs related to Vacc-4x and adjuvant, one was a Grade 2 AE related to Vacc-4x and adjuvant, and 57 (40%) were Grade 1 AEs related to romidepsin. The most common AEs associated with Vacc-4x and adjuvant were transient redness and itching at the injection site. Fatigue and nausea were the most frequently reported AEs associated with romidepsin. Only one romidepsin-related AE, Grade 1 hair loss, was not resolved at the end of the study. During the treatment interruption, six Grade 1 AEs and three Grade 2-3 AEs were reported. Four of the Grade 1 events were considered related to the treatment interruption. No drug-related serious adverse events (SAEs) occurred during the study.13

ACTG 5315 (NCT01933594):

In this Phase I/II study, 43 participants were enrolled in one of the three single-dose cohorts and received one infusion of either romidepsin or placebo. Romidepsin was reported as being well-tolerated by participants. No treatment-related Grade 3 AEs occurred.14,21

Additional AEs known to be associated with romidepsin use are described in the FDA-approved Full Prescribing Information for Istodax.5


Drug Interactions


Studies have indicated that therapeutic concentrations of romidepsin used to treat T-cell lymphomas did not competitively inhibit the following CYP enzymes in vitro: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Also, romidepsin did not cause any significant induction of CYP1A2, CYP2B6, and CYP3A4 in vitro. Therefore, when CYP substrates are coadministered with romidepsin, drug-drug interactions resulting from CYP induction or inhibition by romidepsin are not expected to occur.5

Romidepsin is extensively metabolized by CYP3A4, and strong CYP3A4 inhibitors can increase romidepsin concentrations. Initial coadministration of romidepsin with strong CYP3A4 inhibitors should include monitoring for toxicities associated with increased romidepsin exposure. A drug interaction study with coadministered rifampin (a strong CYP3A4 inducer) found that romidepsin exposure was increased significantly; therefore, coadministration of romidepsin with rifampin should be avoided. Coadministration of romidepsin with other potent CYP3A4 inducers should be avoided.5

Romidepsin is a substrate of P-gp, and coadministration of romidepsin with drugs that inhibit P-gp may increase concentrations of romidepsin.5

Additional drug-drug interactions between romidepsin and coadministered drugs are described in the FDA-approved Full Prescribing Information for Istodax.5


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Romidepsin. https://chem.nlm.nih.gov/chemidplus/rn/128517-07-7. Accessed March 7, 2019.
  2. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed March 7, 2019.
  3. Celgene Corporation website. Therapies. https://www.celgene.com/therapies/. Accessed March 7, 2019.
  4. Masetti R, Serravalle S, Biagi C, Pession A. The role of HDACs inhibitors in childhood and adolescence acute leukemias. J Biomed Biotechnol. Article ID 148046 2011. doi:10.1155/2011/148046
  5. Celgene Corporation. Istodax: full prescribing information, August 2016. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=03b39d40-90fe-11df-9de6-0002a5d5c51b. Accessed March 7, 2019.
  6. 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
  7. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccines Immunother. 2013;9(4):790–799.
  8. EU Clinical Trials Register. EudraCT Number: 2015-003186-28; BIOSKILL: studying Vacc-4x, an HIV therapeutic vaccine, an assessment of immune-mediated anti-viral effects, when administered with adjuvant GM-CSF prior to HIV latent reservoir activation by the HDAC inhibitor, romidepsin. https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003186-28/DK#E. Accessed March 7, 2019.
  9. 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
  10. 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;13(10(11)):e1004473. doi: 10.1371/journal.ppat.1004473. doi:10.1371/journal.ppat.1004473
  11. Bionor Immuno AS. An open Phase I/IIa study to evaluate the safety and effect of therapeutic HIV-1 immunization using Vacc-4x + rhuGM-CSF, and HIV-1 reactivation using romidepsin, on the viral reservoir in virologically suppressed HIV-1 infected adults on cART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2014. NLM Identifier: NCT02092116. https://clinicaltrials.gov/ct2/show/NCT02092116. Accessed March 7, 2019.
  12. Søgaard OS, Graversen ME, Leth S, et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015;11(9). doi:10.1371/journal.ppat.1005142
  13. Leth S, Schleimann MH, Nissen SK, et al. Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial. Lancet HIV. 2016;3(10):e463-e472. doi:10.1016/S2352-3018(16)30055-8
  14. National Institute of Allergy and Infectious Diseases (NIAID). A Phase I/II study of romidepsin in HIV-infected adults with suppressed viremia on antiretroviral therapy to assess safety, tolerability, and activation of HIV-1 expression. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 28, 2013. NLM Identifier: NCT01933594. https://clinicaltrials.gov/ct2/show/NCT01933594. Accessed March 7, 2019.
  15. David Garcia Cinca. A Phase I/IIa, randomised study to evaluate the safety and the effectiveness of a combination of therapeutic vaccine, broadly neutralising antibody (10-1074), and the latency reversing agent romidepsin to achieve a remission of HIV infection in chronically HIV-infected participants under stable combined antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 14, 2018. NLM Identifier: NCT03619278. https://clinicaltrials.gov/ct2/show/NCT03619278. Accessed March 7, 2019.
  16. Rockefeller University. A Phase 2a, randomized study of romidepsin with or without 3BNC117 to evaluate the effects on the HIV-1 reservoir (ROADMAP). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 26, 2016. NLM Identifier: NCT02850016. https://clinicaltrials.gov/ct2/show/NCT02850016. Accessed March 7, 2019.
  17. Bionor Pharma: Press release, dated December 21, 2015. Bionor announces that the HIV ’Shock & Kill’ trial REDUC with Vacc-4x and romidepsin meets its primary endpoint by significantly reducing latent HIV reservoir and demonstrates control of viral load. http://globenewswire.com/news-release/2015/12/21/797102/10158683/en/Bionor-announces-that-the-HIV-Shock-Kill-trial-REDUC-with-Vacc-4x-and-romidepsin-meets-its-primary-endpoint-by-significantly-reducing-latent-HIV-reservoir-and-demonstrates-control-.html. Accessed March 7, 2019.
  18. Aarhus University Hospital. Early administration of latency reversing therapy and broadly neutralizing antibodies to limit the establishment of the HIV-1 reservoir during initiation of antiretroviral treatment - a randomized controlled trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 20, 2017. NLM Identifier: NCT03041012. https://clinicaltrials.gov/ct2/show/NCT03041012. Accessed March 7, 2019.
  19. IrsiCaixa. An open label Phase I trial to evaluate the safety and effect of HIVconsv vaccines in combination with histone deacetylase inhibitor romidepsin on the viral rebound kinetic after treatment interruption in early treated HIV-1 infected individuals (BCN02-Romi). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered November 9, 2015. NLM Identifier: NCT02616874. https://clinicaltrials.gov/ct2/show/NCT02616874. Accessed March 7, 2019.
  20. Mothe B. Viral control induced by HIVconsv vaccines & romidepsin in early treated individuals. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, Washington. http://www.croiwebcasts.org/console/player/33576?mediaType=slideVideo&. Accessed March 7, 2019.
  21. McMahon D, Zheng L, Cyktor JC, et al. Single romidepsin infusions do not increase HIV expression in persons on ART (A5315). Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4–7, 2018; Boston, MA. Abstract 72. http://www.croiconference.org/sessions/single-romidepsin-infusions-do-not-increase-hiv-expression-persons-art-a5315. Accessed March 7, 2019.


Last Reviewed: March 7, 2019