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Revolutionary Implants and Transdermal Drug Delivery for HIV Prevention

Explore the potential of long-acting implants and transdermal drug delivery systems for HIV prevention discussed by Dr. Charles Flexner at #IAS2019. Learn about the benefits, challenges, and advancements in drug delivery technology.

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Revolutionary Implants and Transdermal Drug Delivery for HIV Prevention

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  1. Implants and transdermal drug delivery systems for HIV prevention Charles Flexner, MD Johns Hopkins University Share your thoughts on this presentation with #IAS2019

  2. Dr. Flexner is disclosing the following potential conflicts as recommended by the Conference: • Research grants and contracts: Gilead • Consulting: Cipla, Merck, Mylan, ViiV Healthcare • Stockholder and equity: none to report. • Patents and intellectual property: none to report.

  3. Why implants?

  4. Potential advantages over injectables Removable (inert, or early bioerodable forms) More consistent and predictable drug release PK not dependent on injection site May remain in place for years (inert, non-degradable subcutaneous versions) Potential disadvantages over injectables Specialized device required for insertion Minor surgical procedure to remove Should be removed (if not bioerodable) Regulated as both a drug and a device Difficulty moving to a generic marketplace Long Acting ARV Implants

  5. Over 40 million women worldwide use injectable contraception, and nearly half (47%) of modern contraception users in sub-Saharan Africa rely on injectable contraceptives to prevent pregnancy. Returning to a health care provider for an injection every 2-3 months is considered a disadvantage of DMPA. Discontinuation rates of injectable contraceptives in sub-Saharan Africa are high, contributing to the growing popularity of longer-acting implants. Norplant-2 (levonorgestrel; JadelleTM, Levoplant, Sinoplant – 2 rods, 5-year duration) is now used by millions of women in SSA. Cost per generic implant is less than $15 USD (~$3 pppy for effective hormonal contraception). Use of LAIs in Hormonal Contraception - Fok WK. Curr Opin Obstet Gynecol. 2017;29:419-426.

  6. The Implant Quandry – Inert or Bioerodable?

  7. Example of a Bioerodable Implant - Courtesy Eric Appel, Stanford University

  8. Example of a Bioerodable Implant - Courtesy Eric Appel, Stanford University

  9. Nonerodable Implants: Tenofovir alafenamide (TAF)

  10. LA ARV Implants – Tenofovir Alafenamide M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913

  11. LA ARV Implants – Tenofovir Alafenamide M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913

  12. Implant Candidate MK-8591 (EFdA): Formulations Release Effective Drug Concentrations for >180 days • >180-day extended release from solid state implant formulations after a single injection in rats. • Data suggest the potential to provide coverage for durations up to 1 year. - Barrett SE et al. Antimicrob Agents Chemother 2018; DOI: 10.1128/AAC.01058-18

  13. Unique properties Unique mechanism of action (translocation inhibitor) Exceedingly potent (possible dose in humans of <5 mg/day) Lack of cross-resistance with most NRTI’s Minor impact of M184V More active against HIV-2 than other NRTI’s Long half-life of intracellular TP (>72 hours) in rhesus macaques Possibility of once-weekly oral dosing Possibility of implant formulation with dosing interval of >one year 4’-Ethynyl-2-fluoro-2’-deoxyadenosine (EFdA)

  14. Implants – A Note of Caution

  15. Transdermal drug delivery? Microneedles

  16. Potential advantages over injectables Removable Can be applied by the patient or family member PK not dependent on placement site (?) May remain in place for days or weeks Also appropriate for short-duration drug delivery (per day or week) Potential disadvantages over injectables Limited number of drug candidates Complex manufacturing Expensive to manufacture Regulated as both a drug and a device Difficulty moving to a generic marketplace Transcutaneous ARV Delivery Systems

  17. - Vora et al. J Contr Release 2017

  18. - Vora LK et al. J Contr Release 2017

  19. - Vora et al. J Contr Release 2017

  20. What is it like to wear a microneedle patch?

  21. Estimated cabotegravir concentrations after applying a 30-60 cm2 microneedle patch (adults) - Rajoli et al. CROI 2018

  22. Acknowledgements Johns Hopkins University Amer Al-Khouja David Meyers Caren Freel Meyers Jane McKenzie-White Stanford University Eric Appel Univ. of Liverpool Rajoth Rajoli Saye Khoo Andrew Owen Marco Siccardi FUNDING SOURCES Bill and Melinda Gates Foundation NIAID, R24 AI-118397 (LEAP) NIAID, R01 AI-114405 longactinghiv.org

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