DexelvucitabineOther Names: D-d4FC, DFC, DPC 817, Reverset Drug Class: Nucleoside Reverse Transcriptase Inhibitors Molecular Formula: C9 H10 F N3 O3 Registry Number: 134379-77-4 (CAS) Chemical Name: 4-amino-5-fluoro-1-[(2R,5S)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical Class: Pyrimidine Nucleosides Organization: Incyte Corporation; Pharmasset, Ltd. Phase of Development: Phase II (discontinued)
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Incyte Corporation website3,4)
NOTE: The development of dexelvucitabine for HIV treatment has been discontinued.
The study of dexelvucitabine as a 4(NRTI) HIV medicine was discontinued in 2006. The company developing the drug announced that this decision was based on safety concerns in a Phase IIb long-term extension study in which dexelvucitabine was associated with a high of severe hyperlipasemia. (Hyperlipasemia is a marker of pancreatic inflammation.)
What is an investigational drug?
Anis one that is under study and is not approved by the U.S. (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 dexelvucitabine?
Dexelvucitabine is an investigational drug that was studied for the treatment of HIV.
Dexelvucitabine belongs to a class (group) of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs).2 NRTIs block an HIV called reverse transcriptase. (An enzyme is a 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.
Dexelvucitabine is a prodrug, which means that it is an inactive drug. Once taken, a prodrug does not work until the body converts it into an active form. In the body, dexelvucitabine is converted to DFC-5′-triphosphate (DFC-TP).5,6
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.7
- 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.7
In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III 7to 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.
In what phase of testing is dexelvucitabine?
Dexelvucitabine has been studied in Phase II clinical trials.2
What are some studies on dexelvucitabine?
In a Phase IIb study (known as Study 203), the safety and effectiveness of three different strengths of dexelvucitabine taken once daily were compared to that of 8,9(an inactive drug that is identical in appearance to the active drug being studied). The study included HIV-infected participants who were already taking HIV medicines before entering the study (also called ). Participants had HIV mutations associated with drug resistance at the time they entered the study. For the first 2 weeks of the study, dexelvucitabine or placebo was added to a participant’s previous (ARV) therapy regimen. After 2 weeks, participants continued either dexelvucitabine or placebo and then also began an optimized background regimen. (An optimized background regimen 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 the final 8 weeks of the study, participants who had been receiving placebo were allowed to take dexelvucitabine.
In this study, dexelvucitabine taken at the highest lamivudine (brand name: Epivir) or emtricitabine (brand name: Emtriva) was more effective in reducing viral load than treatment with placebo. However, some participants taking dexelvucitabine did develop severe hyperlipasemia, which is high levels of lipase (a protein released by the ) and which may indicate a problem with the pancreas. The majority of participants who had severe hyperlipasemia were also taking the FDA-approved NRTI didanosine (brand name: Videx). (inflammation of the pancreas) also occurred in several participants.8,9reduced . (Viral load is the amount of HIV in a blood sample.) The study also found that treatment with the highest dose of dexelvucitabine and without the FDA-approved NRTIs
In a long-term extension of the study described above, dexelvucitabine taken at the two higher doses was further examined. During this study (known as Study 901), it became apparent that too many severe cases of hyperlipasemia were occurring in participants taking dexelvucitabine at the highest dose. Because of this safety issue, study investigators decided to stop the clinical development of dexelvucitabine for the treatment of HIV infection.4
What side effects might dexelvucitabine cause?
In the Phase IIb study (Study 203) discussed under the previous question, most side effects were generally mild and included headache, fatigue, and didanosine) developed severe hyperlipasemia and . Other serious side effects that may have been related to treatment included reduced number or function of red blood cells, reduced number of white blood cells, reduced number of platelets, and high levels of .8disorders. However, some participants (many of whom were also taking
Severe hyperlipasemia was also reported in Study 901, the long-term extension of Study 203.4
If testing of dexelvucitabine continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying dexelvucitabine?
More information about dexelvucitabine-related research studies is available from the AIDSinfo database of 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.
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.7
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/134379-77-4. Last accessed on November 19, 2014.
- 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 November 19, 2014.
- Incyte Corporation: Press Release, dated September 8, 2003. Incyte and Pharmasset Enter into a Collaborative Licensing Agreement for a Phase II HIV Drug. Available at: http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=446461&highlight=. Last accessed on November 19, 2014.
- Incyte Corporation: Press Release, dated April 3, 2006. Incyte to Discontinue Development of DFC as a Treatment for HIV; Conference Call Scheduled for 8:30 a.m. ET Today. Available at: http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=837677&highlight=. Last accessed on November 19, 2014.
- Schinazi RF, Mellors J, Bazmi H, et al. DPC 817: a Cytidine Nucleoside Analog with Activity against Zidovudine- and Lamivudine-Resistant Viral Variants. Antimicrob Agents Chemother. 2002 May;46(5):1394-401. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC127174/. Last accessed on November 19, 2014.
- Schinazi RF, Massud I, Rapp KL, et al. Selection and Characterization of HIV-1 with a Novel S68 Deletion in Reverse Transcriptase. Antimicrob Agents Chemother. 2011 May;55(5):2054-60. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088218/. Last accessed on November 19, 2014.
- 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 November 19, 2014.
- Cohen C, Katlama C, Murphy R, et al. Antiretroviral Activity and Tolerability of Reverset (D-d4FC), a New Fluoro-cytidine Nucleoside Analog, When Used in Combination Therapy in Treatment-Experienced Patients: Results of Phase IIb Study RVT-203. 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Levin: Reverset (d4FC), new NRTI: phase IIb data; Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2005. Available at: http://www.natap.org/2005/ias/ias_2.htm. Last accessed on November 19, 2014.
- Erickson-Viitanen S, Hou K, Lloyd R Jr, et al. Baseline Genotype/Phenotype, Virological Response, and Lack of de novo Resistance Mutation Generation during Therapy with Dexelvucitabine (Formerly Reverset) In Study RVT-203. 13th Conference on Retroviruses and Opportunistic Infections (CROI); February 5-8, 2006; Denver, CO. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2011. Available at: http://www.natap.org/2006/CROI/CROI_38.htm. Last accessed on November 19, 2014.
Last Reviewed: November 19, 2014