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.
What is vorinostat?
Vorinostat (brand name: Zolinza) is a drug that has been approved by FDA for the treatment of cancer and is currently being studied as part of a possible strategy to cure HIV infection.3-7
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.)8-10
Vorinostat belongs to a class (group) of HIV drugs called histone deacetylase (HDAC) inhibitors.2 HDAC inhibitors reactivate (turn back on) latent HIV within resting CD4 T cells.10,11
How do histone deacetylase (HDAC) inhibitors work?
HDAC inhibitors 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 HDAC inhibitors, 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 safe and effective 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 vorinostat?
Vorinostat is currently being studied in Phase II clinical trials.2
What are some studies on vorinostat?
Study Name: NCT01319383
Location: United States (North Carolina)
Participants: HIV-infected adults on a stable antiretroviral therapy (ART) regimen for at least 18 months and with a suppressed viral load (the amount of HIV in the blood) and normal immune system (as measured by CD4 count) for at least 6 months.
Purpose: The purpose of this study was to determine the effectiveness of vorinostat in activating latent HIV in resting CD4 T cells when given as a single, one-time dose versus multiple doses.
- First, vorinostat was given orally as a single, one-time dose to eight participants.
- Next, more than 6 months after the single dose, five participants who showed increased activation of latent HIV after the single dose were given once-daily vorinostat a few days per week for a total of 8 weeks of dosing. (Between each week of dosing, there was a 4-day rest period when vorinostat was not given. After the fourth week of dosing, there was a 4- to 8-week period during which vorinostat was not given.)
- All participants remained on ART throughout the study.
- A single, one-time vorinostat dose increased activation of latent HIV in resting CD4 T cells in all eight participants.
- With multiple dosing of vorinostat, increased activation of latent HIV in resting CD4 T cells was seen in three out of five participants at two specific time points.
- Multiple dosing of vorinostat did not have as much of an effect on activating latent HIV as a single, one-time dose of vorinostat.
- In terms of safety, no side effects associated with vorinostat were reported in participants receiving a single vorinostat dose. During multiple vorinostat dosing, mild gastrointestinal symptoms (symptoms associated with the stomach or intestines) and headache occurred.5,13,14
Study Name: NCT01365065
Location: Australia (Victoria)
Participants: HIV-infected adults on a stable ART regimen and with a suppressed viral load for at least 3 years before the study and a normal immune system.
Purpose: The purpose of this study was to determine whether vorinostat could activate latent HIV in resting CD4 T cells.
Study Design: Twenty HIV-infected participants were given vorinostat once daily for 14 days, in combination with ART.
- Vorinostat reactivated HIV in latently infected resting CD4 T cells. However, the amount of latent HIV in the body did not appear to decrease.
- Additional therapies together with HDAC inhibitors may be needed to fully eliminate latent HIV in the body.
- In terms of safety, the majority of study participants experienced a mild or moderate side effect.
- Researchers also noted long-term gene changes in cells, even after participants were off vorinostat for 70 days. These changes will need to be studied because they may be a safety concern.4,15-17
Two Phase II studies will be looking at vorinostat combined with other therapies as a way to reduce latent HIV in resting cells.
- In one study, investigators will look at a combination approach that includes an ongoing 4-drug ART regimen (which will always include the HIV medicine raltegravir) plus two anti-HIV vaccines followed by 10 doses of vorinostat. This combination approach will be compared with ART given alone.6
- In the other study, investigators will look at combining vorinostat with AGS-004, an investigational HIV immunotherapy designed to boost the immune system's response to eliminating HIV.7
What side effects might vorinostat cause?
In the Phase I/II study discussed under the previous question, side effects during multiple vorinostat dosing included mild, temporary gastrointestinal symptoms; headache; and low platelet counts.14
In the 14-day Phase II study, most of the side effects that occurred were not serious. The most common side effects were nausea, diarrhea, fatigue, and low platelet counts.15
Because vorinostat is still being studied, information on possible side effects of the drug is not complete. As testing of vorinostat continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying vorinostat?
More information about vorinostat-related research studies is available from the AIDSinfo database of HIV/AIDS-related 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 vorinostat. 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/149647-78-9. Last accessed on July 5, 2015.
- 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 July 5, 2015.
- Merck Sharp & Dohme Corp. Zolinza: Full Prescribing Information, April 2013. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092. Last accessed on July 5, 2015.
- 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 July 5, 2015.
- 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/study/NCT01319383. Last accessed on July 5, 2015.
- 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 July 5, 2015.
- 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 July 5, 2015.
- 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 July 5, 2015.
- National Institute of Allergy and Infectious Diseases (NIAID). HIV Hides From the Immune System. Available at: http://www.niaid.nih.gov/topics/HIVAIDS/Understanding/Biology/pages/hidesimmunesystem.aspx. Last accessed on April 7, 2014.
- 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 July 5, 2015.
- 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 July 5, 2015.
- National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: http://nih.gov/health/clinicaltrials/index.htm. Last accessed on July 5, 2015.
- 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 July 5, 2015.
- 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 July 5, 2015.
- 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 at: http://napwha.org.au/sites/default/files/CROI%202013%20vorinostat%20final%202.pdf. Last accessed on July 5, 2015.
- 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 July 5, 2015.
- Margolis D. HIV Pathogenesis, Innate Defense against HIV, and HIV Cure at CROI 2014, Boston. Conference Reports for National AIDS Treatment Advocacy Project (NATAP): 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Available at: http://www.natap.org/2014/CROI/croi_150.htm. Last accessed on July 5, 2015.
Last Reviewed: July 5, 2015