FosdevirineOther Names: 2248761, FDV, GSK2248761, GSK2248761A, GSK761, IDX12899, IDX899 Drug Class: Non-nucleoside Reverse Transcriptase Inhibitors
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Current Opinion in Investigational Drugs article3 )
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
Mechanism of Action: Non-nucleoside reverse transcriptase inhibitor (NNRTI). Fosdevirine is a second-generation NNRTI with in vitro activity against common NNRTI-resistant mutant viruses and against efavirenz-resistant clinical isolates. NNRTIs are noncompetitive inhibitors of HIV-1 reverse transcriptase that work by binding to a hydrophobic pocket in the HIV-1 p66 subunit of reverse transcriptase. NNRTI binding causes inhibition of reverse transcription via an allosteric mechanism of action.3,6-8
Half-life (T½): In an evaluation of single-dose fosdevirine (50 to 1200 mg) in healthy participants under fed and/or fasted conditions, the half-life ranged from 6.2 hours to 14.6 hours. During the single-dose phase, both a 50-mg capsule and 200-mg capsule formulation (having different drug-to-excipient ratios) were used. The 200-mg formulation was found to result in a longer mean half-life (11.9 to 14.6 hours in the 200- and 400-mg fasted dose groups) than the 50-mg formulation (6.2 to 6.8 hours in the 50- and 100-mg fasted dose groups). In the multiple-dose phase, participants received either fosdevirine 800 mg once daily or 400 mg twice daily over 7 days under fed conditions. The half-life at steady-state was 12.3 hours in the 400-mg twice-daily group and 13.6 hours in the 800-mg once-daily group.8
Metabolism/Elimination: Fosdevirine undergoes hepatic metabolism via cytochrome P450 3A4 (CYP3A4) oxidation and via conjugation. Following single-dose administration of oral fosdevirine (200, 400, and 800 mg) under fed and/or fasted conditions, urinary excretion of unchanged drug was undetectable for the 200- and 400-mg doses under fasted conditions and was extremely low (less than 0.001% of the total dose administered) for the 400- and 800-mg doses under fed conditions.3,8
Resistance: In vitro, fosdevirine exhibits a high genetic barrier to resistance and retains activity against common NNRTI-resistant mutants containing single mutations (K103N and Y181C) and some double mutations, as well as against clinical isolates resistant to efavirenz. Fosdevirine loses activity against Y181C double and triple mutations.8,9
During in vitro selection studies with fosdevirine, the following mutations have emerged: E138K, V90I, Y181C/I, S134I, I135R, G190E, M230L, and 138K/Y181I. Two distinct pathways to fosdevirine resistance, initiated by mutations at E138K or V90I/Y181C, were identified. Tested among NNRTI mutant virus pools (selected by fosdevirine, etravirine, efavirenz, and rilpivirine), fosdevirine showed the greatest activity against both etravirine- and efavirenz-selected resistant viruses. Fosdevirine retained greater overall activity against the NNRTI-selected virus pools than did etravirine, efavirenz, and rilpivirine; efavirenz retained the greatest activity against fosdevirine-selected virus pools.10-13
Two Phase I/IIa studies (NV-05A-002 and NCT00945282) investigated once-daily fosdevirine monotherapy (30 mg up to 800 mg) in treatment-naive participants for 7 days. At baseline, most participants (28 out of 38) had no reverse transcriptase (RT) mutations, while 10 participants had baseline RT substitutions, including K103R, V179I, V106I, K101R, and V179D/E. Participants’ HIV-1 RNA response to fosdevirine monotherapy was not affected by baseline RT substitutions. Among the 36 participants who had genotypic analysis performed on Day 8, no NNRTI resistance mutations arose during the course of treatment with fosdevirine. An L100V substitution emerged in one participant receiving fosdevirine 200 mg, but the mutant virus was fully susceptible to fosdevirine.9,14
Select Clinical Trials
Study Identifiers: NV-05A-0029
Study Purpose: The purpose of this proof-of-concept study was to evaluate the safety and antiviral activity of fosdevirine monotherapy at various dose levels.
Study Population: Treatment-naive adults with no pre-existing major NNRTI mutations at screening.
Dosing: Four sequentially descending dose cohorts received 800, 400, 200, and 100 mg of fosdevirine monotherapy administered once daily and orally for 7 days or placebo for 7 days. (All doses were administered under fed conditions.) Following their last dose of fosdevirine, participants started highly active antiretroviral treatment (HAART). Participants who did not meet the criteria for HAART or who were not willing to receive HAART received 28 days of lopinavir/ritonavir monotherapy.9,14
(See references cited above for information on study results.)
Study Identifiers: SGN113020;9 NCT0094528215
Study Purpose: The purpose of this proof-of-concept extension study was to evaluate the safety and antiviral activity of fosdevirine monotherapy at a single 30-mg dose level. (SGN113020 was an extension study of NV-05A-002.)
Study Population: Treatment-naive adults with no pre-existing major NNRTI mutations at screening.
Dosing: Participants received either 30 mg of fosdevirine monotherapy administered once daily and orally for 7 days or placebo for 7 days. Following their last dose of fosdevirine, participants started HAART. Participants who did not meet the criteria for HAART or who were not willing to receive HAART received 28 days of lopinavir/ritonavir monotherapy.9,14,15
(See references cited above for information on study results.)
The following two Phase IIb studies of fosdevirine were also undertaken, but were not completed: (1) the SIGNET study (NCT01231555) was investigating fosdevirine 100 mg or 200 mg versus efavirenz, each given in combination with background ART in treatment-naive adults; (2) the SONNET study (NCT01199731) was designed to evaluate fosdevirine 100 mg or 200 mg versus etravirine, each given in combination with background ART in treatment-experienced adults with NNRTI-resistant HIV. Because of new-onset seizures that occurred in five treatment-experienced participants in the SONNET study, all fosdevirine studies were put on clinical hold in 2011. Both the SIGNET and SONNET studies have since been terminated, and fosdevirine is no longer in clinical development.5,16,17
(A drug exposure registry was created to collect clinical and safety data from all participants who had received fosdevirine in either of the Phase IIb studies.)18
In a combined safety analysis of both Phase I/IIa proof-of-concept studies (NV-05A-002 and SGN113020), 67% of total participants experienced an adverse event (AE). All AEs that occurred were mild to moderate in intensity. No serious AEs, deaths, or discontinuations due to an AE were reported. The most common AEs reported across all groups were headache, dyspepsia, and nausea. No specific pattern of AEs with fosdevirine or placebo was seen. There were no Grade 3 or 4 laboratory abnormalities.14
In the Phase IIb SIGNET (NCT01231555; SGN113404) and SONNET (NCT01199731; SGN113399) studies, which were terminated prior to completion, 35 participants received at least one dose of fosdevirine. The duration of exposure to fosdevirine ranged from 7 to 56 days in treatment-naive participants (mean duration of exposure was 23.6 days) and from 6 to 81 days in treatment-experienced participants (mean duration of exposure was 44 days). Forty percent of SIGNET participants and 65% of SONNET participants were exposed to fosdevirine for 4 weeks or more. The most common AEs occurring in participants in the SIGNET study while on fosdevirine were somnolence (13%) and nightmares (13%). Two serious AEs occurred but were unrelated to fosdevirine. The most common AEs occurring in participants in the SONNET study while on fosdevirine included seizure (20%), diarrhea (20%), pruritus (10%), and sinusitis (10%).
An additional participant in the SONNET study had an initial seizure 3 days after withdrawing from fosdevirine treatment. In total, 5 treatment-experienced participants (1 receiving fosdevirine 100 mg and 4 receiving fosdevirine 200 mg) experienced seizure after exposure to fosdevirine. All participants who experienced a seizure were exposed to fosdevirine for 4 weeks or more and experienced recurrent seizures occurring 1 week to 5 months after discontinuing fosdevirine. No participants in the etravirine comparator group reported a seizure. No seizures occurred in treatment-naive participants in the SIGNET study. Study investigators have concluded that the development of seizures in the treatment-experienced participants was likely related to fosdevirine.5
In vitro studies indicate that fosdevirine inhibits CYP450 2C8, 2C9, and 2C19 enzymes and also inhibits organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3). Co-administration of midazolam and dextromethorphan with repeat doses of fosdevirine resulted in AUC(0,∞) increases of 54% for midazolam and 83% for dextromethorphan, indicating that fosdevirine is a weak CYP3A4 and CYP2D6 inhibitor. Fosdevirine did not alter flurbiprofen exposures, indicating that fosdevirine does not affect CYP2C9 activity.19
Multiple studies to characterize the drug interaction profile of fosdevirine have been completed. Data from these studies suggest that drug interactions requiring dosage adjustments are unlikely when fosdevirine is co-administered with atazanavir, tenofovir DF/emtricitabine, raltegravir, or ritonavir-boosted darunavir. In addition, no fosdevirine dose modifications are necessary when fosdevirine is co-administered with lopinavir/ritonavir. However, lopinavir/ritonavir twice daily co-administered with fosdevirine 100 mg once daily resulted in decreases in plasma lopinavir AUC(0,τ) by 23%, Cmax by 14%, and Cτ by 40% and decreases in ritonavir AUC(0,τ) by 19%, Cmax by 21%, and Cτ by 42%. Further studies will be needed to determine if lopinavir/ritonavir dose adjustments will be needed.19
Exposure of the HMG-CoA reductase inhibitors atorvastatin, rosuvastatin, and simvastatin increased significantly when co-administered with fosdevirine. Simvastatin metabolism appeared to be more affected by fosdevirine than atorvastatin and rosuvastatin metabolism were. Atorvastatin and rosuvastatin are preferable to use over simvastatin when co-administered with fosdevirine. Simvastatin doses above 40 mg should be used with caution in individuals receiving concomitant fosdevirine.19
No clinically meaningful PK changes occurred when the oral contraceptive ethinylestradiol/drospirenone was co-administered with fosdevirine, and dose adjustments are not required.19
- 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/profile/Olga_Klibanov/publication/41175431_IDX-899_an_aryl_phosphinate-indole_non-nucleoside_reverse_transcriptase_inhibitor_for_the_potential_treatment_of_HIV_infection/links/5414fb8d0cf2fa878ad3ed8a.pdf. 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.
- Seckler JM, Barkley MD, Wintrode PL. Allosteric Suppression of HIV-1 Reverse Transcriptase Structural Dynamics upon Inhibitor Binding. Biophys J. 2011 Jan 5; 100(1): 144–153. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010017/. Last accessed on October 26, 2015.
- Schauer GD, Huber KD, Leuba SH, Sluis-Cremer N. Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence. Nucleic Acids Res. 2014 Oct 13; 42(18): 11687–11696. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191400/. 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.
- 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.
- Jakubik JJ, Chapron C, Hubbard L, Seifer M, Standring DN. In Vitro Cross-Resistance Profile for a Next-Generation NNRT I: IDX899. 17th International HIV Drug Resistance Workshop; June 10-14, 2008; Sitges, Spain. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2008. Available at: http://www.natap.org/2008/ResisWksp/ResisWksp_06.htm. Last accessed on October 26, 2015.
- Murphy R, Zala C, Jakubik JJ, et al. In vitro cross-resistance profile, antiviral activity, safety and pharmacokinetics in HIV-1-infected patients of IDX899, a novel HIV-1 NNRTI with high barrier to resistance. Abstract presented at: 17th International HIV Drug Resistance Workshop; June 10-14, 2008; Sitges, Spain. Abstract 5. Available at: http://www.euresist.org/c/document_library/get_file?uuid=abfbc26e-aa26-4fda-a35f-1add3453c481&groupId=85965. Last accessed on October 26, 2015.
- Jakubik J, Seifer M, Gray L. IDX12899 anti-HIV-1 activity and resistance profile is superior to efavirenz. Abstract presented at: 16th International HIV Drug Resistance Workshop; June 12-16, 2007; Barbados, West Indies. Abstract 30. Available at: http://www.euresist.org/c/document_library/get_file?uuid=ba9d30d6-1ccb-4414-b40a-deb59a6273b4&groupId=85965. Last accessed on October 26, 2015.
- Richman DD, Jakubik J, Chapron C, et al. Genotypic Resistance and Phenotypic Cross-Resistance Profile in vitro for a Novel NNRTI: IDX899. 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2008. Available at: http://www.natap.org/2008/CROI/croi_88.htm. Last accessed on October 26, 2015.
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Last Reviewed: October 26, 2015