NOTE: The development of fosdevirine for HIV treatment has been discontinued.
The study of fosdevirine as a non-nucleoside reverse transcriptase inhibitor (NNRTI) was discontinued. In 2011, the US Food and Drug Administration halted all studies of fosdevirine because of seizures that occurred in five participants in a Phase IIb study. It has since been reported that fosdevirine is no longer being developed.4,5
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 fosdevirine?
Fosdevirine is an investigational drug that was being studied for the treatment of HIV infection.
Fosdevirine belongs to a class (group) of HIV drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs).2 NNRTIs attach to and 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, NNRTIs prevent HIV from multiplying and can reduce the amount of HIV in the body.
In vitro, fosdevirine appears to work on certain HIV strains against which other FDA-approved NNRTIs, such as efavirenz (brand name: Sustiva), may no longer work.6 (In vitro refers to 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.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 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.7
In what phase of testing is fosdevirine?
Fosdevirine has been studied in Phase II clinical trials.2 The development of fosdevirine for the treatment of HIV infection was discontinued.5
What are some studies on fosdevirine?
Study Names: 1) NV-05A-002 and 2) SGN113020; NCT00945282
Participants: HIV-1-infected adults who have never taken HIV medicines before entering the study (also called treatment-naive). At the time of study entry, participants did not have any major HIV mutations that would cause NNRTI medicines to not work well.
Purpose: The purpose of these studies was to evaluate the safety and antiviral activity of fosdevirine.
Study Design: The two studies NV-05A-002 and SGN113020 looked at the effect of fosdevirine given alone without any other HIV medicines (also called monotherapy) over 7 days.
- In NV-05A-002, investigators looked at four different dose levels of once-daily fosdevirine, starting with the highest dose level; the dose levels were 800 mg, 400 mg, 200 mg, and 100 mg. Within each dose group, participants were given either fosdevirine or placebo. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.)
- SGN113020 was an extension of the NV-05A-002 study. In SGN113020, investigators evaluated a much lower dose of once-daily fosdevirine. Participants in the SGN113020 study were given either 30 mg of fosdevirine or placebo.
In both studies, participants started either antiretroviral treatment (ART) or the HIV medicine lopinavir/ritonavir (brand name: Kaletra) after their last dose of fosdevirine.
- In the NV-05A-002 study, all dose levels of fosdevirine (100 mg to 800 mg) proved capable of significantly reducing participants’ viral load (the amount of HIV in a blood samples) after 7 days of treatment. The time it took to achieve viral load reductions was rapid, with substantial reductions occurring by Day 4.
- In the SGN113020 study, which evaluated a much lower dose of fosdevirine (30 mg), significant viral load reductions were also achieved, but the extent of reduction was smaller than what was seen in the NV-05A-002 study.
- In terms of safety, no serious side effects were reported in either the NV-05A-002 or the SGN113020 study. None of the side effects that occurred during treatment resulted in a participant dropping out of the study.8-10
The following two Phase IIb studies of fosdevirine were also started, but were never completed: (1) the SIGNET study (NCT01231555) looked at fosdevirine in treatment-naive adults, and (2) the SONNET study (NCT01199731) looked at fosdevirine in participants who had taken HIV medicines before entering the study (also called treatment-experienced) and whose HIV did not respond to certain approved NNRTI medicines.5,11,12
Because of seizures that occurred in some participants in the SONNET study, all fosdevirine studies were stopped in 2011. Since then, the development of fosdevirine has been discontinued.4,5
What side effects might fosdevirine cause?
In the Phase I/IIa studies discussed under the previous question (NV-05A-002 and SGN113020), the most common side effects reported across all groups were headache, upset stomach, and nausea. All side effects were mild to moderate in intensity.9
The Phase IIb SIGNET (NCT01231555) and SONNET (NCT01199731) studies were not completed, but 35 participants were given at least one dose of fosdevirine, and a safety analysis was done on these participants. The most common side effects occurring in participants in the SIGNET study while taking fosdevirine were drowsiness and nightmares. The most common side effects occurring in participants in the SONNET study while taking fosdevirine were seizure, diarrhea, itchiness, and inflamed sinuses.5
Information on possible side effects of the drug is not complete. If testing of fosdevirine begins again, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying fosdevirine?
More information about fosdevirine-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.
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/1018450-26-4. Last accessed on October 26, 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 October 26, 2015.
- Klibanov OM, Kaczor RL. IDX-899, an aryl phosphinate-indole non-nucleoside reverse transcriptase inhibitor for the potential treatment of HIV infection. Curr Opin Investig Drugs. 2010 Feb; 11(2):237-45. Available at: http://www.researchgate.net/publication/41175431_IDX-899_an_aryl_phosphinate-indole_non-nucleoside_reverse_transcriptase_inhibitor_for_the_potential_treatment_of_HIV_infection. Last accessed on October 26, 2015.
- National AIDS Treatment Advocacy Project (NATAP). The FDA places GSK2248761 ('761', formerly IDX899) a NNRTI on clinical hold. News Updates; 2011. Available at: http://www.natap.org/2011/newsUpdates/021111_04.htm. Last accessed on October 26, 2015.
- Margolis DA, Eron JJ, DeJesus E, et al. Unexpected finding of delayed-onset seizures in HIV-positive, treatment-experienced subjects in the Phase IIb evaluation of fosdevirine (GSK2248761). Antivir Ther. 2014;19(1):69-78. doi: 10.3851/IMP2689. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=dfd06a18-9c71-49d4-b3c8-8f982a56a403. Last accessed on October 26, 2015.
- Zhou X-J, Pietropaolo K, Damphousse D, et al. Single-Dose Escalation and Multiple-Dose Safety, Tolerability, and Pharmacokinetics of IDX899, a Candidate Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Subjects. Antimicrob Agents Chemother. 2009 May; 53(5): 1739–1746. Available at: http://aac.asm.org/content/53/5/1739.full. Last accessed on October 26, 2015.
- National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: http://nih.gov/health/clinicaltrials/index.htm. Last accessed on October 26, 2015.
- St. Clair M, Dudas K, Lou Y, Zala C, Mayers D, Dumont E. GSK2248761, an NNRTI with Activity Against Common NNRTI Resistance Mutants, Did Not Select for NNRTI Resistance Mutations in Two 7-Day Monotherapy Studies. 50th Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2010; Boston, MA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2010. Available at: http://www.natap.org/2010/ICAAC/ICAAC_23.htm. Last accessed on October 26, 2015.
- Zala C, St. Clair M, Dudas K, et al. Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects. Antimicrob Agents Chemother. 2012 May; 56(5): 2570–2575. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346662/. Last accessed on October 26, 2015.
- ViiV Healthcare. A Proof of Concept Study for GSK2248761 (An Extension of NV-05A-002: A Phase I/IIa Double-Blind Study to Evaluate the Safety and Tolerability, Antiretroviral Activity, Pharmacokinetics and Pharmacodynamics of IDX12899 in Antiretroviral Treatment-Naive HIV-1 Infected Subjects, Completed by Idenix). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 23, 2009. NLM Identifier: NCT00945282. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00945282. Last accessed on October 26, 2015.
- ViiV Healthcare. Phase 2b Study to Select a Once Daily Oral Dose of GSK2248761 Administered With Tenofovir/Emtricitabine or Abacavir/Lamivudine in HIV-1 Infected Antiretroviral Therapy Naive Adult Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 14, 2010. NLM Identifier: NCT01231555. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01231555. Last accessed on October 26, 2015.
- ViiV Healthcare. A Phase 2b Study to Select a Once Daily Oral Dose of GSK2248761 in HIV-1 Infected Antiretroviral Therapy Experienced Adults With Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) Resistance. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 9, 2010. NLM Identifier: NCT01199731. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01199731. Last accessed on October 26, 2015.
Last Reviewed: October 26, 2015