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 elvucitabine?
Elvucitabine is an investigational drug that is being studied for the treatment of HIV infection.
Elvucitabine 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.
Elvucitabine is similar in chemical structure to the FDA-approved NRTIs lamivudine (brand name: Epivir) and emtricitabine (brand name: Emtriva).5 However, in vitro studies have suggested that elvucitabine may work on certain HIV strains against which other NRTIs, such as lamivudine and emtricitabine, no longer work.6 (In vitro studies are studies done in test tubes or other laboratory equipment and not on animals or humans.)
Studies have also suggested that elvucitabine may be effective against hepatitis B virus (HBV).6-8
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.9
- 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.9
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.9
In what phase of testing is elvucitabine?
Elvucitabine has been studied in Phase II clinical trials.2 (The company developing elvucitabine has reported that it is out-licensing elvucitabine and looking to work with partner companies to focus elvucitabine’s development in regions outside the United States. Through a partner company, elvucitabine is being developed in China, Hong Kong, and Taiwan.)3,4
What are some studies on elvucitabine?
Study Names: (1) ACH443-015; NCT00350272 and (2) ACH443-904; NCT00675844
Location: United States and India
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 elvucitabine and to compare elvucitabine to lamivudine.
Study Design: ACH443-015 was a 96-week study in which participants were randomly assigned to receive either 10 mg of elvucitabine once daily or 300 mg of lamivudine once daily. All participants also received the HIV medicines tenofovir disoproxil fumarate (brand name: Viread) and efavirenz (brand name: Sustiva) as part of their background regimens. (A background regimen is a combination of drugs that are not being studied as the investigational drug[s] in the clinical trial, but are being given to help control a participant’s HIV infection.)
A 48-week extension study (ACH443-904) was offered to participants who completed 96 weeks of treatment with elvucitabine and whose viral load (the amount of HIV in a blood sample) was at a level that meant their HIV infection was being controlled with the HIV medicines (called viral control).
- In an “as-treated” analysis (looking at data from the participants who completed the full length of the study), elvucitabine proved as effective as lamivudine, with similar numbers of participants in both treatment groups having reductions in viral load after 96 weeks.
- However, in an “intention-to-treat” analysis (looking at data from all study participants, including those who discontinued the study), fewer participants in the elvucitabine treatment group had a virologic response than in the lamivudine group. This difference is because the elvucitabine group had a higher proportion of study drop-outs than the lamivudine group did.
- All serious side effects that occurred during the 96 weeks were unrelated to the study drugs. One participant discontinued elvucitabine because of a drug-related side effect.10-13
Study Names: (1) ACH443-014A; NCT00312039 (2) ACH443-018; NCT00380159 and (3) ACH443-904; NCT00675844
Location: United States
- HIV-infected adults who had taken HIV medicines before entering the study (also called treatment-experienced). Participants were taking an antiretroviral therapy (ART) regimen containing either lamivudine or emtricitabine.
- 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 known to cause lamivudine and emtricitabine to not work well.)
Purpose: The purpose of this study was to look at the safety and effectiveness of elvucitabine in treatment-experienced adults with the M184V HIV mutation.
Study Design: At the beginning of the study, all participants stopped taking their existing lamivudine or emtricitabine treatment, but continued with any other HIV medicines they were taking. Participants were then randomly assigned to one of two groups to receive either 10 mg of elvucitabine once daily or 300 mg of lamivudine once daily. Background regimens remained the same. This study lasted 14 days.
A 48-week extension study (ACH443-018) was offered to participants who completed 14 days of treatment with elvucitabine. Beyond the initial 48-week extension, a second extension was also offered to allow participants who maintained viral control to continue elvucitabine treatment.
- The company developing elvucitabine has reported some results on the effectiveness of elvucitabine in ACH443-014A and its initial extension study. Details about these results can be seen in the company’s press release (see Reference 16).13-16
What side effects might elvucitabine cause?
In the 96-week Phase II study (ACH443-015) discussed under the previous question, the number, types, and severity of side effects that occurred were similar between the elvucitabine and lamivudine groups. Some drug-related side effects that were reported included the following: nausea, dizziness, fatigue, diarrhea, vomiting, indigestion, and weakness.10-12
Because elvucitabine is still being studied, information on possible side effects of the drug is not complete. As testing of elvucitabine continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying elvucitabine?
More information about elvucitabine-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 elvucitabine. 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.9
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/181785-84-2. Last accessed on December 3, 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 3, 2015.
- Achillion Pharmaceuticals. Achillion Pharmaceuticals 2009 Annual Report. Available at: http://files.shareholder.com/downloads/ACHN/3406700524x0x368900/1A85086D-BD5F-4384-B5F9-960A5E379C48/ACHL_09AR_4.26.10.pdf. Last accessed on December 3, 2015.
- Achillion Pharmaceuticals website. Achillion Pharmaceuticals May 2015 Quarterly Report. Available at: http://files.shareholder.com/downloads/ACHN/1050979136x0xS1193125-15-175915/1070336/filing.pdf. Last accessed on December 3, 2015.
- Shi J, Mathew JS, Tharnish PM, et al. N4-acyl-modified D-2',3'-dideoxy-5-fluorocytidine nucleoside analogues with improved antiviral activity. Antivir Chem Chemother. 2003 Mar;14(2):81-90. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12856919. Last accessed on December 3, 2015.
- Colucci P, Pottage JC, Robison H, Turgeon J, Ducharme MP. Effect of a Single Dose of Ritonavir on the Pharmacokinetic Behavior of Elvucitabine, a Nucleoside Reverse Transcriptase Inhibitor, Administered in Healthy Volunteers. Antimicrob Agents Chemother. 2009 Feb;53(2):646-50. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630647/. Last accessed on December 3, 2015.
- Zhu YL, Dutschman DE, Liu SH, Bridges EG, Cheng YC. Anti-Hepatitis B Virus Activity and Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta-L(-)-5-Fluorocytidine. Antimicrob Agents Chemother. 1998 Jul;42(7):1805-10. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC105687/. Last accessed on December 3, 2015.
- DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine Phase II 48 Week Interim Results Show Safety and Efficacy Profiles Similar to Lamivudine in Treatment Naive HIV-1 Infected Patients with a Unique Pharmacokinetic Profile. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/46th Infectious Diseases Society of America (IDSA) Meeting; October 25-28. 2008; Washington DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2008. Available at: http://www.natap.org/2008/ICAAC/ICAAC_22.htm. Last accessed on December 3, 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 3, 2015.
- DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine vs Lamivudine with Tenofovir and Efavirenz in Antiretroviral-Treatment-Naïve HIV-1 Infected Patients: 96 Week Final Results. Poster presented at: 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Paper 511. Available at: http://www.retroconference.org/2010/PDFs/511.pdf. Last accessed on May 29, 2013.
- Mascolini M. Elvucitabine Versus 3TC in First-Line Regimens for 96 Weeks - see slides from poster below. Conference Reports for National AIDS Treatment Advocacy Project (NATAP): 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Available at: http://www.natap.org/2010/CROI/croi_60.htm. Last accessed on December 3, 2015.
- Achillion Pharmaceuticals. A Randomized, Blinded, 12-week Comparison of Elvucitabine/Efavirenz/Tenofovir Versus Lamivudine/Efavirenz/Tenofovir in HIV-1 Infected, Treatment Naive Subjects. There is a 36 Week, Open Label, Extension Phase for Eligible Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 6, 2006. NLM Identifier: NCT00350272. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00350272. Last accessed on December 3, 2015.
- Achillion Pharmaceuticals. An Open Label Treatment Protocol to Provide Continued Elvucitabine Treatment for 48-Weeks in Subjects Who Have Completed 96 -Weeks of Elvucitabine Therapy in Protocol ACH443-015 or 48 Weeks of Therapy in Protocol ACH443-018. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 8, 2008. NLM Identifier: NCT00675844. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00675844. Last accessed on December 3, 2015.
- Achillion Pharmaceuticals. A 14 Day Randomized, Double Blind, Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 5, 2006. NLM Identifier: NCT00312039. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00312039. Last accessed on December 3, 2015.
- Achillion Pharmaceuticals. An Open-Label,48 Week Extension Study of Elvucitabine Administered In Combination With Background Antiretroviral Agents in Subjects Who Have Completed 14 Days of Treatment in Protocol ACH443-014A. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 21, 2006. NLM Identifier: NCT00380159. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00380159. Last accessed on December 3, 2015.
- Achillion Pharmaceuticals: Press Release, dated January 31, 2008. New Data for Achillion's Elvucitabine Demonstrate Drug's Safety, Efficacy and Suitability for Combination Therapy in HIV-Infected Patients. Available at: http://ir.achillion.com/releasedetail.cfm?releaseid=291181. Last accessed on December 3, 2015.
Last Reviewed: December 3, 2015