Drugs

Elsulfavirine

Other Names: Elpida, VM-1500, prodrug of VM-1500A Drug Class: Non-nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C24 H17 Br Cl2 F N3 OS
Registry Number: 868046-19-9 (CAS) Chemical Name: N-(4-((2-(4-Bromo-3-(3-chloro-5-cyano-phenoxy)-2-fluoro-phenyl)acetyl)amino)-3-chloro-phenyl)sulfonylpropanamide
Organization: Viriom Phase of Development: Elsulfavirine is in Phase II/III study for HIV treatment. In June 2017, elsulfavirine received marketing approval in Russia for the treatment of HIV.

Chemical Image:

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Elsulfavirine

Elsulfavirine

Molecular Weight: 629.2823

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Viriom press release,3 and ClinicalTrials.gov4)

Pharmacology


Mechanism of Action: Non-nucleoside reverse transcriptase inhibitor (NNRTI). Elsulfavirine (brand name: Elpida) is a prodrug of VM-1500A, a selective NNRTI with potent activity against HIV-1.5,6 NNRTIs generally function by inhibiting HIV-1 reverse transcriptase and preventing the conversion of viral RNA to DNA.7,8 Elsulfavirine is being developed as a once-daily oral treatment for HIV and has been studied in a Phase II/III trial. In June 2017, elsulfavirine was granted marketing approval in Russia for treating HIV.3,4,9

Investigators are also examining once-weekly oral dosing of elsulfavirine for HIV treatment. Fixed-dose combinations (FDCs) containing elsulfavirine and a long-acting injectable formulation of VM-1500A are also in development for HIV treatment. In addition, the long-acting injectable formulation of VM-1500A will be looked at as a potential agent for HIV pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).9

Half-life (T½): Following single oral doses of elsulfavirine in healthy participants without HIV, the mean half-life of elsulfavirine was 1.7 hours (20-mg dose) and 2.6 hours (40-mg dose). The half-life of VM-1500A, the active metabolite, was 8.9 days (20-mg dose) and 8.8 days (40-mg dose).10

In a study of treatment-naive participants with HIV, the half-life of elsulfavirine following a single oral dose was 1.9 hours (20-mg dose) and 2.1 hours (40-mg dose). After 7 days of once-daily administration, the half-life of elsulfavirine was 2.4 hours (40-mg dose). The half-life of the VM-1500A metabolite after 7 days was 7.4 days (20-mg dose) and 5.4 days (40-mg dose).10


Select Clinical Trials


Study Identifier: NCT02485509
Sponsor: Viriom
Phase: Ib/IIa
Status: This study has been completed.
Study Purpose: The purpose of this two-part study was to 1) assess the safety and pharmacokinetics of elsulfavirine in healthy participants without HIV, and 2) evaluate the pharmacokinetics, safety, and antiviral activity of elsulfavirine in participants with HIV.
Study Population:
  • Part 1: Participants were healthy adults without HIV.
  • Part 2: Participants were treatment-naive adults with HIV.11
Selected Study Results:
Study Identifier: NCT02489461
Sponsor: Viriom
Phase: II/III
Status: This study has been completed.
Study Purpose: The purpose of this study was to 1) select an optimal dose of elsulfavirine and 2) compare the safety and effectiveness of the optimal elsulfavirine dose to efavirenz (EFV).
Study Population:
  • Participants were treatment-naive adults with clinically stable (World Health Organization [WHO] clinical stage 1 or 2) HIV infection.
  • Participants had HIV RNA ≥5,000 copies/mL and CD4 counts >200 cells/mm3 at screening.4,5
Selected Study Results:

Additional clinical trials of elsulfavirine have also been completed or are planned, including a Phase Ib trial (NCT03730311) that is investigating the safety and pharmacokinetics of once-weekly oral elsulfavirine in healthy adults without HIV.12


Adverse Events


NCT02485509:

In Part 2 of this Phase Ib/IIa trial, eight total participants were randomized to the 20-mg group (n=7 elsulfavirine; n=1 placebo). Three of the eight participants experienced mild dry mouth and polyuria and one participant had mild headache. No adverse events (AEs) were reported among participants receiving elsulfavirine 40 mg.11,13


NCT02489461:

In Part 1 of this Phase II/III trial, a safety analysis was performed on data from 30 participants receiving elsulfavirine 20 mg, 29 participants receiving elsulfavirine 40 mg, and 28 participants receiving EFV. Overall, drug-related AEs occurred in 3.3% of participants on elsulfavirine 20 mg, 13.8% of participants on elsulfavirine 40 mg, and 46.4% of participants on EFV. Three participants experienced a serious adverse event (SAE), but none of the events were likely related to study treatment. Neurologic and psychiatric AEs that were definitely associated with the study drugs occurred in a greater proportion of participants receiving EFV than in participants receiving elsulfavirine. More types of neurologic and psychiatric events commonly occurred in the EFV group compared to either of the elsulfavirine groups. Commonly occurring neurologic events in the elsulfavirine groups were headache (seen in both the 20- and 40-mg groups) along with unusual dreams, dizziness, sleep disturbance, and drowsiness (seen in the 40-mg group). Common psychiatric events in the elsulfavirine groups included sleep disturbances (seen in both the 20-mg and 40-mg groups) plus depression and nightmares (seen in the 20-mg group).4,6

During Stage 2 of the trial, the safety of elsulfavirine was assessed among 60 elsulfavirine participants and 58 EFV participants. Drug-related AEs occurred in 36.7% of elsulfavirine participants versus 77.6% of EFV participants. Three participants receiving elsulfavirine experienced three SAEs, but none of the events were drug-related; seven participants receiving EFV experienced eight SAEs, three of which were not drug-related and five of which were probably drug-related. Study discontinuations due to an AE occurred in one participant receiving elsulfavirine versus seven participants receiving EFV. CNS and skin AEs occurring in more than 5% of participants were reported in a greater proportion of EFV participants (62.1%) than elsulfavirine participants (31.7%). The most common of these AEs were headache (15.0% elsulfavirine; 24.1% EFV), dizziness (6.7% elsulfavirine; 27.6% EFV), and sleep disorders (5% elsulfavirine; 20.7% EFV). Abnormal dreams (17.2%), skin rash (17.2%), and pruritus (5.2%) occurred only in EFV-treated participants.5


Drug Interactions


Drug-drug interactions associated with elsulfavirine are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Elsulfavirine. https://chem.nlm.nih.gov/chemidplus/rn/868046-19-9. Accessed May 7, 2019.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed May 7, 2019.
  3. Viriom. Press release, dated July 25, 2017. Viriom obtains first market approval of elsulfavirine (Elpida®) for treatment of HIV-1 infection in Russia. https://www.viriom.com/news/2017/11/30/viriom-obtains-first-market-approval-of-elsulfavirine-elpida-for-treatment-of-hiv-1-infection-in-russia. Accessed May 7, 2019.
  4. Viriom. International, multicenter, randomized, partially blind clinical study to evaluate efficacy, safety and selection of the optimal dose for VM-1500 in comparison to efavirenz in combination with two NRTIs in treatment-naive, HIV-1 infected patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 18, 2015. NLM Identifier: NCT02489461. https://www.clinicaltrials.gov/ct2/show/NCT02489461. Accessed May 7, 2019.
  5. Murphy RL, Kravchenko AV, Orlova-Morozova EA, et al. Elsulfavirine as compared to efavirenz in combination with TDF/FTC: 48-week study. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, Washington. Poster 452LB. http://www.croiconference.org/sites/default/files/posters-2017/452LB_Murphy.pdf. Accessed May 7, 2019.
  6. Kravchenko AV, Orlova-Morozova EA, Nagimova FI, et al. Safety and antiviral effect of Elpida (VM-1500), a novel NNRTI (+Truvada) in treatment-naive HIV-1 infected patients. Poster presented at: European AIDS Conference (EAC); October 21-24, 2015; Barcelona, Spain. Poster PE7/4. http://rusnanonet.ru/download/documents/barcelona2015.pdf. Accessed May 7, 2019.
  7. Sluis-Cremer N, Tachedjian G. Mechanisms of inhibition of HIV replication by nonnucleoside reverse transcriptase inhibitors. Virus Res. 2008;134(1-2):147-156. doi:10.1016/j.virusres.2008.01.002
  8. Schauer G, Leuba S, Sluis-Cremer N. Biophysical insights into the inhibitory mechanism of non-nucleoside HIV-1 reverse transcriptase inhibitors. Biomolecules. 2013;3(4):889-904. doi:10.3390/biom3040889
  9. Viriom, Inc. website. Pipeline. https://www.viriom.com/pipeline/. Accessed May 7, 2019.
  10. Ratanasuwan W, Werarak P, Koryakova A, Berzins B, Bichko V, Murphy R. Pharmacokinetics of VM-1500 20 mg and 40 mg in healthy and HIV-infected patients. International AIDS Conference (AIDS); July 20-25, 2014; Melbourne, Australia. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2014. http://www.natap.org/2014/IAC/IAC_108.htm. Accessed May 7, 2019.
  11. Viriom. Phase Ib/IIa, single-centre, placebo-controlled randomized study of safety and pharmacokinetics in healthy volunteers and safety, tolerability and antiviral activity of VM-1500 in patients with human immunodeficiency virus-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 18, 2015. NLM Identifier: NCT02485509. https://clinicaltrials.gov/ct2/show/NCT02485509. Accessed May 7, 2019.
  12. Viriom. Phase Ib, single-centre, placebo-controlled randomised study of safety, tolerability and pharmacokinetics of Elpida in healthy HIV-uninfected volunteers. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 1, 2018. NLM Identifier: NCT03730311. https://clinicaltrials.gov/ct2/show/NCT03730311. Accessed May 7, 2019.
  13. Ratanasuwan W, Werarak P, Murphy RL, Bichko V. A randomized, placebo-controlled, double-blind study of VM-1500 in HIV-naive patients. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, Massachusetts. Abstract 544LB. http://www.croiconference.org/sites/default/files/abstracts/544LB.pdf. Accessed May 7, 2019.


Last Reviewed: May 7, 2019