Drugs

Romidepsin

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 2 development as a latency-reversing agent for HIV treatment.

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

What is romidepsin?

What is romidepsin?

Romidepsin (brand name: Istodax) is a drug that has been approved by the U.S. Food and Drug Administration for the treatment of certain types of cancer.5 It is also being studied as an investigational drug as part of a strategy to cure HIV infection.6–10 As an HIV investigational drug, romidepsin belongs to a group of drugs called latency-reversing agents.2

To learn about how investigational drugs are tested during clinical trials, read the AIDSinfo What is an Investigational HIV Drug? and HIV/AIDS Clinical Trials fact sheets.

How do latency-reversing agents work?

How do latency-reversing agents work?

Currently, there is no cure for HIV infection. One of the main obstacles to curing HIV infection is that the virus can remain hidden and inactive (latent) inside certain cells of the immune system (such as resting CD4 cells) for many months or even years. The cells where latent HIV hides are known as the latent HIV reservoir. Because HIV in this latent state is inactive, the immune system cannot detect the virus, and the antiretroviral (ARV) drugs that are used to treat HIV have no effect on it.11–13

Latency-reversing agents work by drawing HIV out of its latent state within resting CD4 cells. Once the latent HIV is reactivated, the CD4 cells that harbor the virus are more likely to be recognized and killed by the body’s immune system or may be killed by certain HIV therapies, such as those that can enhance the body’s immune response to HIV. Researchers hope that the combined use of romidepsin and other HIV-fighting strategies, including ongoing antiretroviral therapy (ART), may fully eliminate HIV from the body.11–13 To learn more, see the AIDSinfo What is a Latent HIV Reservoir? fact sheet.

Which clinical trials are studying romidepsin?

Which clinical trials are studying romidepsin?

Study Names: REDUC; NCT02092116
Phase: 1b/2a
Status: This study has been completed.
Location: Denmark
Purpose: The REDUC trial was a two-part study. Part A was designed to find a safe and effective dose of romidepsin to use in the second part of the study. Part B was designed to evaluate the effect of the investigational therapeutic vaccine Vacc-4x when combined with romidepsin on the amount of latent HIV in the body and viral load levels during a planned break from ART.6

Study Names: ACTG 5315; NCT01933594
Phase: 1/2
Status: This study has been completed.
Location: United States
Purpose: The purpose of this study was to look at the safety of single and multiple doses of romidepsin and to determine the effectiveness of these different doses in reactivating latent HIV within resting CD4 T cells.7

Study Names: HIVACAR; NCT03619278
Phase: 1/2a
Status: See the ClinicalTrials.gov record for this study's status.
Location: Not available
Purpose: The purpose of this study is to evaluate the safety and effectiveness 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 combinations can control participants’ viral load levels during a planned break from ART.14

Study Names: ROADMAP; NCT02850016
Phase: 1b/2a
Status: This study is ongoing, but not recruiting participants.
Locations: Denmark, Germany, United States
Purpose: The purpose of this study is to compare the effectiveness of romidepsin plus the investigational drug 3BNC117 to the effectiveness of romidepsin administered alone in controlling viral load during a treatment interruption.9,15

Study Names: BIOSKILL; EudraCT 2015-003186-28
Phase: 2
Status: This study has been completed.
Locations: Australia, Europe, United States
Purpose: The purpose of this study was to evaluate the safety and effectiveness of the combined use of Vacc-4x and romidepsin. The researchers measured the effects of Vacc-4x and romidepsin on viral load, latent HIV, and the body’s immune responses.10

Study Names: eCLEAR; NCT03041012
Phase: 2
Status: This study is currently recruiting participants.
Locations: Denmark
Purpose: The purpose of this study is to evaluate the effect of romidepsin, 3BNC117, or both on the latent HIV reservoir size when given soon after ART is started in adults who have never previously taken ART.16

For more details on the studies listed above, see the Health Professional version of this drug summary.

Another study, the BCN02-Romi trial (NCT02616874), is a Phase 1 trial that has been completed. This study evaluated the use of an investigational therapeutic vaccine called MVA.HIVconsv in combination with romidepsin in participants who already received investigational therapeutic vaccines during a separate trial.8

What side effects might romidepsin cause?

What side effects might romidepsin cause?

One goal of HIV research is to identify new drugs that have fewer side effects. The following side effects were observed in some of the studies of romidepsin listed above.

REDUC (NCT02092116):

In Part A of the REDUC trial, all romidepsin-related side effects were mild in severity and resolved within a few days. The most common side effects related to romidepsin were abdominal symptoms (such as nausea, stomach growling, and abdominal pain) and fatigue. Some mild changes in white blood cell counts and T cell counts were seen.17

In Part B of the REDUC trial, the majority of side effects were mild in severity. Side effects associated with romidepsin included fatigue and nausea. One side effect associated with romidepsin—mild hair loss—did not resolve by the end of the study. Side effects related to Vacc-4x plus the adjuvant and to the treatment interruption also occurred.18

ACTG 5315 (NCT01933594):

Participants who received single doses of romidepsin tolerated the drug well and had no treatment-related serious side effects.7,19

Among 16 total participants enrolled to receive multiple-dose romidepsin or placebo, no life-threatening side effects were reported. One participant experienced severe neutropenia that was possibly related to treatment. Four participants experienced moderate side effects that were possibly or probably related to treatment; these included blurred vision, neutropenia, nausea, and headache.7,20

ROADMAP (NCT02850016):

In the ROADMAP trial, most of the side effects reported during the study were mild. About 27% of the side effects that occurred were at least possibly related to romidepsin or 3BNC117. The most common side effects were nausea, headache, fatigue, general discomfort, chills, and vomiting. Two participants experienced a heart rhythm abnormality after receiving romidepsin, but this abnormality went away by 1 week after the romidepsin dose.9,15,21

Because romidepsin is still being studied, information on possible side effects of the drug is not complete. As testing of romidepsin continues, additional information on possible side effects will be gathered.

Additional information on side effects known to be associated with romidepsin can be found in the FDA-approved Full Prescribing Information for Istodax.5

Where can I get more information about clinical trials studying romidepsin?

Where can I get more information about clinical trials studying romidepsin?

More information about romidepsin-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.

Some clinical trials may be looking for volunteer participants. Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

References

References

  1. United States National Library of Medicine. ChemIDplus Advanced: Romidepsin. https://chem.nlm.nih.gov/chemidplus/rn/128517-07-7. Accessed April 1, 2020
  2. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed April 1, 2020
  3. Celgene Corporation website. Therapies. https://www.celgene.com/therapies/. Accessed April 1, 2020
  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 April 1, 2020
  6. 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 April 1, 2020
  7. 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 April 1, 2020
  8. 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 April 1, 2020
  9. 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 April 1, 2020
  10. 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 April 1, 2020
  11. Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096.
  12. 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.
  13. National Institute of Allergy and Infectious Diseases (NIAID). HIV viral eradication. https://www.niaid.nih.gov/diseases-conditions/hiv-viral-eradication. Accessed April 1, 2020
  14. 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 April 1, 2020
  15. Gruell H, Cohen YZ, Gunst JD, et al. A randomized trial of the impact of 3BNC117 and romidepsin on the HIV-1 reservoir. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, MA. Abstract 38. http://www.croiconference.org/sessions/randomized-trial-impact-3bnc117-and-romidepsin-hiv-1-reservoir. Accessed April 1, 2020
  16. 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 April 1, 2020
  17. 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
  18. 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
  19. 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 April 1, 2020
  20. McMahon D. Effect of multidose romidepsin on HIV-1 expression in persons on ART: ACTG A5315. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2019; Seattle, WA. http://www.croiwebcasts.org/console/player/41062?mediaType=slideVideo&&crd_fl=0&ssmsrq=1574118674788&ctms=5000&csmsrq=5074. Accessed April 1, 2020
  21. Søgaard OS. A randomized trial of the impact of 3BNC117 and romidepsin on the HIV-1 reservoir. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Boston, MA. http://www.croiwebcasts.org/console/player/44589?mediaType=slideVideo&. Accessed April 1, 2020

Last Reviewed: April 1, 2020

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