What is an investigational drug?
An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.
To learn more about investigational drugs, read the AIDSinfo What is an Investigational HIV Drug? fact sheet.
What is romidepsin?
Romidepsin (brand name: Istodax) is a drug that has been approved by FDA for the treatment of certain types of cancer. It is currently being studied to see if it could be effective as part of a strategy to cure HIV infection.5-8
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 T cells) for many months or even years. While HIV is in this latent state, the immune system cannot recognize the virus, and antiretroviral therapy (ART) has no effect on it. (ART is the recommended treatment for HIV infection and involves using a combination of different antiretroviral [ARV] drugs to prevent HIV from replicating.)9,10
Romidepsin belongs to a general class (group) of HIV drugs called latency-reversing agents.2 Latency-reversing agents reactivate (turn back on) latent HIV within resting CD4 T cells.10,11 There are different types of latency-reversing agents. Romidepsin is a type of latency-reversing agent called a histone deacetylase (HDAC) inhibitor.11
How do latency-reversing agents work?
Latency-reversing agents reactivate (turn back on) latent HIV within resting CD4 T cells. When latent HIV is reactivated, it is once again able to produce new virus and multiply (replicate). It is hoped that after latent HIV is reactivated, the CD4 T cells in which the virus was hiding are more likely to die off on their own or be recognized and killed by the body’s immune system.10,11
In addition, any new virus that is produced during reactivation can then be prevented from infecting other cells with the use of ongoing ART.10,11 Recent research has shown that additional therapies, together with latency-reversing agents, may be needed to fully eliminate latent HIV from the body.11
How are clinical trials of investigational drugs conducted?
Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.12
- Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
- Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
- Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.12
In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.12
In what phase of testing is romidepsin?
Romidepsin is being studied in Phase I/II clinical trials.2
What are some studies on romidepsin?
Study Names: REDUC trial; NCT02092116
Participants: HIV-infected adults who had taken HIV medicines before entering the study (also called treatment-experienced). Participants were all receiving antiretroviral therapy (ART) at the time of study enrollment and had received ART for at least 1 year. Participants had viral load levels (the amount of HIV in a blood sample) that were suppressed to less than 50 copies/mL.
Purpose: The purpose of this study was to evaluate a combination strategy of the HDAC inhibitor romidepsin and the investigational therapeutic vaccine Vacc-4x as a way to reduce the amount of latent HIV in the body.
Study Design: The REDUC trial was a two-part study as follows:
Part A: In Part A of the trial, the safety and effect of romidepsin on reactivating latent HIV was confirmed.
- Participants received one infusion of romidepsin per week for 3 weeks and were followed for up to 70 days after the last infusion. (An infusion is a method to deliver a drug or other fluids, typically into a vein, over a period of time.)
Part B: In Part B of the trial, researchers evaluated Vacc-4x and romidepsin as a possible combination strategy to reduce the amount of latent HIV in the body.
- Participants received six injections of the Vacc-4x therapeutic vaccine. Vacc-4x was given along with an adjuvant called rhu GM-CSF. (An adjuvant is a substance used to enhance or modify the immune-stimulating properties of a vaccine.)
- Three weeks after the last injection of Vacc-4x, participants received three infusions of romidepsin given over 3 weeks.
- After an 8-week follow-up period, participants underwent an analytical treatment interruption of ART for up to 16 weeks to evaluate the ability of the combination regimen in controlling viral load in the absence of ART. (An analytical treatment interruption is a planned break from ART to evaluate how well an investigational drug can maintain control of a participant’s viral load during a clinical trial.)
- Romidepsin caused significant reactivation of latent HIV, and this led to increases in participants’ viral loads.
- Romidepsin did not appear to negatively affect immune cell functions that are important in clearing latently infected cells from the body.
- Romidepsin had no significant effect on reducing the amount of latent HIV in the body.
- In terms of safety, no unexpected serious side effects occurred.
- Results to Part B of the study were announced in a December 2015 press release from the company studying Vacc-4x plus romidepsin. The press release indicated that the combination regimen of Vacc-4x plus romidepsin was able to significantly reduce the amount of latent HIV in the body.
- Even though romidepsin reactivated HIV production in latent cells, in the majority of participants, viral load levels stayed below detectable levels while participants were on ART. Researchers noted that this indicated that Vacc-4x appeared to help the body’s immune system control the reactivated virus.
- The average duration of the analytical treatment interruption before a participant had to restart ART was 24.5 days. Investigators reported that this was the same duration as what would be expected without treatment. Investigators suggested that a third therapy, along with Vacc-4x and an HIV latency reversing drug, is needed to achieve long-lasting control of viral load in the absence of ART.
- In terms of safety, all side effects that occurred were consistent with the known side effects of either romidepsin or Vacc-4x given with rhu GM-CSF.6,13-15
HIV-infected, treatment-experienced adults with a viral load suppressed to less than 50 copies/mL. Participants are required to be on a Department of Health and Human Services (DHHS)-recommended ART regimen containing efavirenz
(brand name: Sustiva
(brand name: Isentress
), or dolutegravir
(brand name: Tivicay
The purpose of this study is to identify single doses of romidepsin that are safe and effective in reactivating latent HIV within resting CD4 T cells.
Participants will be randomly assigned to receive a single dose
of either romidepsin or placebo
in one of three groups. The three groups will differ in terms of the romidepsin dose, with group 1 receiving the lowest dose and group 3 receiving the highest dose. The study will last 28 days and possibly up to 56 days, depending on a participant’s viral load on Day 7 or whether a participant experiences a severe side effect.7
* This study is currently recruiting participants and results are not yet available.7
Other studies involving romidepsin used in a combination strategy to reduce the amount of latent HIV in the body are either being planned or are ongoing.15,16 One study (called the BIOSKILL trial) is in planning stages and is a Phase II trial that will continue to evaluate the combined use of Vacc-4x and romidepsin.15 The other study (the BCN02-Romi trial) is a Phase I trial that is looking at the use of an investigational therapeutic vaccine called MVA.HIVconsv in combination with romidepsin in participants who have already received investigational therapeutic vaccines during a separate trial.16
What side effects might romidepsin cause?
In Part A of the REDUC trial discussed under the previous question, all romidepsin-related side effects that occurred were considered mild in severity. 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.13
In Part B of the REDUC trial, the majority of side effects that occurred were mild in severity. Side effects associated with romidepsin included fatigue, nausea, and constipation. Side effects associated with Vacc-4x administered with rhu GM-CSF included local skin reaction, fatigue, and headache.15
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.
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.
I am interested in participating in a clinical trial of romidepsin. How can I find more information about participating in a clinical trial?
Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.12
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.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/128517-07-7. Last accessed on January 28, 2016.
- Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on January 28, 2016.
- Celgene Corporation website. Therapies. Available at: https://www.celgene.com/therapies/. Last accessed on January 28, 2016.
- Masetti R, Serravalle S, Biagi C, and Pession A. The Role of HDACs Inhibitors in Childhood and Adolescence Acute Leukemias. J Biomed Biotechnol. Vol 2011; Article ID 148046. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026992/pdf/JBB2011-148046.pdf. Last accessed on January 28, 2016.
- Celgene Corporation. ISTODAX – romidepsin: Full Prescribing Information, October 2014. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=03b39d40-90fe-11df-9de6-0002a5d5c51b. Last accessed on January 28, 2016.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02092116. Last accessed on January 28, 2016.
- National Institute of Allergy and Infectious Diseases (NIAID). A Phase I/II Study of Single Dose 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01933594. Last accessed on January 28, 2016.
- 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 on November 9, 2015. NLM Identifier: NCT02616874. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02616874. Last accessed on January 28, 2016.
- National Institute of Allergy and Infectious Diseases (NIAID): Bulletin, dated June 16, 2009. NIAID Invites Applications to Conduct Basic Research on HIV Persistence: Studies Key to Search for a Cure. Available at: http://www.niaid.nih.gov/news/newsreleases/Archive/2009/Pages/HIV_persistence.aspx. Last accessed on January 28, 2016.
- Siliciano RF, Greene WC. HIV Latency. Cold Spring Harb Perspect Med. 2011 Sep;1(1):a007096. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234450/. Last accessed on January 28, 2016.
- 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 January 28, 2016.
- National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: http://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on January 28, 2016.
- Søgaard OS, Graversen ME, Leth S, et al. The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLoS Pathog. 2015 Sep; 11(9): e1005142. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575032/. Last accessed on January 28, 2016.
- Bionor Pharma: Press Release, dated May 4, 2015. Bionor announces promising results from an interim analysis of the functional cure HIV study REDUC Part B. Available at: http://www.bionorpharma.com/en/News/2015/Scientific/Bionor+announces+promising+results+from+an+interim+analysis+of+the+functional+cure+HIV+study+REDUC+P.b7C_wlzM3A.ips. Last accessed on January 28, 2016.
- 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. Available at: http://www.bionorpharma.com/en/Media/News/2015/Financial/Bionor+announces+that+the+HIV+%E2%80%99Shock+%26+Kill%E2%80%99+trial+REDUC+with+Vacc-4x+and+romidepsin+meets+its+prima.b7C_wlzW3q.ips. Last accessed on January 28, 2016.
Last Reviewed: January 28, 2016