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 Apricitabine?
Apricitabine is an investigational drug that is being studied for the treatment of HIV infection.
Apricitabine belongs to a class (group) of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs).2 NRTIs block an HIV enzyme called reverse transcriptase. (An enzyme is a protein that starts or increases the speed of a chemical reaction.) By blocking reverse transcriptase, NRTIs prevent HIV from multiplying and can reduce the amount of HIV in the body.
In vitro studies have shown that apricitabine appears to work on certain HIV strains against which other FDA-approved NRTIs, such as lamivudine (brand name: Epivir), may no longer work.3 (In vitro studies are studies done in test tubes or other laboratory equipment and not on animals or humans.)
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.4
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.4
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.4
In what phase of testing is Apricitabine?
Apricitabine has been studied in a Phase III clinical trial.2
What are some studies on Apricitabine?
Study Names: Not available
Location: Argentina, South Africa, Thailand
Participants: HIV-infected adults who had never taken HIV medicines before entering the study (also called treatment-naive).
Purpose: The purpose of this study was to look at the safety and effectiveness of different doses of apricitabine.
Study Design: Participants were randomly assigned to one of four different daily doses of apricitabine or placebo, given orally over 10 days. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.) In this study, apricitabine was given alone without any other HIV medicines (also called monotherapy).
- All daily doses of apricitabine resulted in significant reductions in participants’ viral loads (the amount of HIV in a blood sample) when compared to placebo.
- In terms of safety, no serious side effects occurred. No participants dropped out of the study because of a side effect.5,6
Study Names: (1) AVX-201; NCT00126880 and (2) AVX-201E; NCT00367952
Location: Argentina and Australia
- HIV-infected adults who had taken HIV medicines before entering the study (also called treatment-experienced). Participants were receiving a three-drug antiretroviral therapy (ART) regimen that contained either lamivudine (brand name: Epivir) or emtricitabine (brand name: Emtriva).
- Participants were experiencing treatment failure. (Treatment failure is when an ART regimen is unable to control HIV infection.)
- All participants had HIV that contained a mutation called M184V. (The M184V HIV mutation is a mutation that is known to cause lamivudine and emtricitabine to not work well.)
- About half the participants had HIV that had at least three thymidine analogue mutations (TAMs). (TAMs are HIV mutations that are known to cause resistance to certain HIV medicines, such as zidovudine [brand name: Retrovir] and stavudine [brand name: Zerit].)
Purpose: The purpose of this study was to look at the safety and effectiveness of apricitabine in treatment-experienced adults who had HIV that contained the M184V mutation.
Study Design: All doses of apricitabine were given orally and twice daily. The AVX-201 study was divided into the following three treatment periods:
- Period 1: At the beginning of the study, all participants stopped taking their existing lamivudine or emtricitabine treatment and were randomly assigned to one of the following three groups: 600 mg of apricitabine twice daily, 800 mg of apricitabine twice daily, or 150 mg of lamivudine twice daily. No changes were made to the other HIV medicines in participants’ original ART regimens (called background therapy).
- Period 2: On Day 21, participants’ background therapy could be optimized. (Optimized background therapy is a combination of drugs, chosen on the basis of a person’s resistance test results and treatment history, that are not being studied as the investigational drug[s] in the clinical trial, but are given to help control a participant’s HIV infection.)
During Periods 1 and 2, participants in each group also took matching apricitabine or lamivudine placebos so that all participants took similar-looking tablets and the same number of tablets daily. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.)
- Period 3: From Week 24 through Week 48, all participants switched to 800 mg of apricitabine twice daily plus optimized background therapy.
AVX-201E was an extension of the AVX-201 study. AVX-201E offered participants who completed AVX-201 the option to continue receiving apricitabine twice daily plus optimized background therapy for an additional 96 weeks.
- Analysis at Day 21 showed that significantly greater reductions in viral load occurred in the apricitabine group participants than in the lamivudine group participants. Overall, throughout the 48-week study, apricitabine appeared to have substantial antiviral activity in treatment-experienced participants with the M184V HIV mutation.
- Among the participants who continued with apricitabine treatment during the extension study, the majority were able to maintain control of their viral load levels up to Week 144.
- Among participants who entered the extension study and had more than two TAMs, most were able to achieve an undetectable viral load.
- Investigators reported that no drug resistance to apricitabine was seen during the study. (Drug resistance is when HIV mutates [changes form] and becomes insensitive to a drug that was previously effective.)
- In terms of safety, no serious side effects related to apricitabine occurred during AVX-201 or the extension study.7-12
Study Names: AVX-301; NCT00612898
Location: Multiple countries (worldwide)
- HIV-infected, treatment-experienced adults. Participants were experiencing treatment failure on an ART regimen that contained either lamivudine or emtricitabine.
- All participants had HIV that contained either the M184V or M184I mutation (both known to cause drug resistance to lamivudine and emtricitabine). Many participants had HIV containing TAMs.
Purpose: The purpose of this study was to look at the safety and effectiveness of apricitabine in treatment-experienced adults who had HIV that contained either the M184V or M184I mutation.
Study Design: Participants were randomly assigned to receive 800 mg of apricitabine, 1200 mg of apricitabine, or 150 mg of lamivudine, each given twice daily and orally. All participants also received optimized background therapy. This study was originally designed to last 48 weeks, but was stopped early.
- At Week 16 of the study, the 1200-mg apricitabine group was discontinued because it showed no benefit over the 800-mg apricitabine dose. The 800-mg dose was selected as the preferred apricitabine dose to be used in future study.
- Results at Week 24 indicated that apricitabine produced a greater reduction in participants’ viral load than lamivudine did. Investigators noted though that because AVX-301 was stopped early, study results lacked statistical significance (meaning that the differences seen between treatment groups may have occurred by chance).
- No drug resistance to apricitabine was detected.
- In terms of safety, no serious side effects related to apricitabine were reported.13,15,16
What side effects might Apricitabine cause?
In the 10-day Phase II study in treatment-naive adults discussed under the previous question, headache was the most common side effect in apricitabine-treated participants. Nasal congestion occurred more frequently in apricitabine-treated participants than in placebo-treated participants.5
In the Phase IIb study (AVX-201), the most common side effects at Week 24 (reported equally by each study group) were diarrhea, nausea, high triglyceride levels, common colds, and infections of the upper respiratory tract. Some side effects that occurred in participants that may have been related to apricitabine treatment included diarrhea, dizziness, nausea, heartburn, anorexia, weight loss, and symptoms of GI intolerance.10
In the Phase III study (AVX-301), treatment with apricitabine over 24 weeks appeared to be safe. Apricitabine appeared to have a safety profile similar to that of lamivudine.14
Because apricitabine is still being studied, information on possible side effects of the drug is not complete. As testing of apricitabine continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying Apricitabine?
More information about apricitabine-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 Apricitabine. 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.4
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/160707-69-7. Last accessed on December 1, 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 December 1, 2015.
- Cahn P, Wainberg MA. Resistance profile of the new nucleoside reverse transcriptase inhibitor apricitabine. J Antimicrob Chemother. 2010 Feb; 65(2):213-7. Available at: http://jac.oxfordjournals.org/content/65/2/213.full.pdf+html. Last accessed on December 1, 2015.
- 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 December 1, 2015.
- Cahn P, Cassetti I, Wood, R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS. 2006 June; 20(9): 1261-1268. National AIDS Treatment Advocacy Project (NATAP): HIV Articles; Efficacy and tolerability of 10-day monotherapy with SPD574 (apricitabine) in antiretroviral-naive, HIV-infected patients. Available at: http://www.natap.org/2006/HIV/081106_07.htm. Last accessed on December 1, 2015.
- Cahn P, van Leeuwen R, Sawyer J, Shiveley L. Tolerability and Anti-HIV-1 Activity of SPD754 as 10 days’ Monotherapy in Treatment-Naïve Patients. Poster presented at: 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 14-17, 2003; Chicago, IL. Poster/Abstract A-3093. Available at: http://www.avexa.com.au/sites/default/files/news/Cahn%20A-3093%2043rd%20ICAAC%202003.pdf. Last accessed on December 1, 2015.
- Avexa. A Phase II, Randomised, Double-blind, Dose-ranging Study of AVX754 Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V Mutation in Reverse Transcriptase. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 3, 2005. NLM Identifier: NCT00126880. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00126880. Last accessed on December 1, 2015.
- Avexa. An Open Label Long Term Safety Extension Study of Apricitabine in Treatment-experienced HIV-1 Infected Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 22, 2006. NLM Identifier: NCT00367952. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00367952. Last accessed on December 1, 2015.
- Cahn P, Altclas J, Martins M, et al. Antiviral activity of apricitabine in treatment-experienced HIV-1-infected patients with M184V who are failing combination therapy. HIV Med. 2011 Jul; 12(6):334-42. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2010.00887.x/pdf. Last accessed on December 1, 2015.
- Cahn P, Altclas J, Martins M, et al. 24 Week Data from Study AVX-201: A Prospective, Randomised, Double-Blind, Dose-Ranging Phase 2b Study of Apricitabine in Treatment-Experienced Patients with M184V and NRTI Resistance. Poster presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Poster 793. Available at: http://www.avexa.com.au/sites/default/files/news/CROI%20poster%20formatted%2024Jan2008.pdf. Last accessed on December 1, 2015.
- Cahn P, Altclas J, Martins M, et al. O414 48-week data from Study AVX-201 – a randomised phase IIb study of apricitabine in treatment-experienced patients with M184V and NRTI resistance. J Int AIDS Soc. 2008 Nov; 11: O41. Available at: http://library.iasociety.org/JIASArticleView.aspx?jiasid=51. Last accessed on December 1, 2015.
- Avexa Limited: Press Release, dated February 15, 2010. Avexa Reports Positive Phase IIb 144 Week Data for HIV Drug Apricitabine (ATC). Available at: http://www.avexa.com.au/sites/default/files/asx/Avexa%20reports%20positive%20phase%20IIb%20144%20week%20data%20for%20HIV%20drug%20apricitabine.pdf. Last accessed on December 1, 2015.
- Avexa. A Phase 2b/3, Randomized, Double Blind, Dose Confirming Study of the Safety, Efficacy and Tolerability of Apricitabine Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V/I Mutation in Reverse Transcriptase. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 30, 2008. NLM Identifier: NCT00612898. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00612898. Last accessed on December 1, 2015.
- Avexa. ATC: Phase 3 data from the AVX-301 study. Slides presented at: 24th International Conference on Antiviral Research (ICAR); May 8-11, 2011; Sofia, Bulgaria. Available at: http://www.avexa.com.au/sites/default/files/news/ICAR%20Sofia%20Clin%20Symp%20May%202011.pdf. Last accessed on December 1, 2015.
Last Reviewed: December 1, 2015