TS2023

Current status of LA/ER Cabotegravir (CAB) and Rilpivirine (RPV)
including pipeline report on novel CAB formulations

Speaker: William Spreen, Cabotegravir Medicine Development Leader, ViiV Healthcare

Progress in CAB LA for HIV PrEP

  • Four regulatory approvals (US, Australia, Zimbabwe, and S Africa) and multiple submissions under active review (European Medicines Agency [EMA], Brazil, and sub-Saharan African countries).
  • The WHO has issued guidelines for use.
  • Indication – at-risk individuals >35kg, optional OLI, no contraindication in pregnancy or lactation, HIV testing via RNA-based test at initiation in US or per national guidelines elsewhere.

Data from HPTN-083 (MSM/TGW) and HPTN-084 (cis-women) illustrate the staying power of LA HIV prevention.

  • CAB LA maintains efficacy advantage over oral TDF/FTC with consistent hazards reductions in incident HIV infection across blinded and unblinded phases – 66% risk reduction in HPTN-083 (CROI 2022) and 89% risk reduction in HPTN-084 (AIDS 2022).
  • ViiV and Medicines Patent Pool signed a voluntary licensing agreement in July 2022.
    • Selected generic manufacturers can supply generic CAB LA for PrEP in 90 countries.
  • Multiple oral presentations at CROI 2023.
    • Susan H Eshleman et al. The LEVI syndrome: characteristics of early HIV infection with cabotegravir for PrEP.​
    • Mark A Marzinke et al. Cabotegravir pharmacology in the background of delayed injections in HPTN 084.
    • Hyman Scott et al. Cabotegravir for HIV PrEP in US Black men and transgender women who have sex with men​.
    • Sybil Hosek et al. CAB LA for HIV prevention in African cisgender female adolescents (HPTN 084-01).

Bi-monthly CAB + RPV LAI for HIV treatment.

  • CROI 2023 presentations.
    • SOLAR Study 12-month results.
    • Moti N. Ramgopal et al. Randomized switch trial of CAB + RPV LA vs oral B/FTC/TAF​.
    • Darrell HS Tan et al. Weight and metabolic changes with cabotegravir + rilpivirine long-acting or bictegravir.​
    • ATLAS-2M Study​. Franco Felizarta et al. Thigh Injections of Cabotegravir + Rilpivirine in Virally Supressed Adults with HIV-1​.
  • ​SOLAR Study design.


    Metabolic endpoints include change (Day 1 to Month 12) in: BMI category; waist and hip circumferences; waist-to-height ratio; waist-to-hip ratio;
    and proportion with insulin resistance or metabolic syndrome.
     

  • ATLAS-2M Study – Phase 3b sub-study evaluating CAB + RPV via IM thigh injections in virologically suppressed PLWH.

New opportunities to extend dosing intervals using a novel double-concentrated CAB400 mg/mL formulation and rHuPH20-facilitated administration.

  • Phase I healthy volunteer study (212482) of CAB400 (multiple doses and routes of administration) vs approved CAB200 (AIDS 2022).


     

    • Similar safety profile – Grade 1-2 ISRs common and short-lived.
    • Unexpectedly higher CAB400 absorption rate– higher Cmax and shorter terminal half-life. Plasma concentrations within the range of CAB200 regimens, regardless of route.
    • CAB400 practical for Q1M dosing, but dose/volume impractical for longer intervals.
  • Studies evaluating hyaluronidase-facilitated administration to allow larger injection volumes with potential to achieve ≥Q3M dosing intervals.
    • Halozyme’s recombinant hyaluronidase Ph20 enzyme (rHuPH20) temporarily expands the SC space (permeability barrier restored in 24 to 48 hours).
    • ViiV-Halozyme studies are evaluating rHuPH20 administration with HIV therapeutics across multiple targets (INSTIs, NRTIs, Capsid Inhibitors, bNAbs).
    • Study 218012 is ongoing – safety and PK of approved CAB200 and novel CAB400 formulations (multiple doses and routes of administration) with and without rHuPH20; no OLI required (NCT05418868).

Other LA initiatives.

  • Self-administration – FLAIR sub-study of sub-cutaneous dosing of CAB + RPV LA to assess safety, tolerability, and PK in participants experienced with CAB+RPV LA via gluteal IM dosing (NCT02938520).
  • Longer SC dosing intervals – CAB + RPV LA SC in healthy participants (with Janssen).
  • Other LA regimens.
  • ACTG 5357 Study of CAB LA + VRC07-523LS for HIV suppression (NCT03739996).
  • Upcoming study of CAB LA + bNAb N6-LS (VHC3810109).

Summary

  • Additional regulatory approvals and expansion of datasets for HIV PrEP with CAB LA and HIV treatment with CAB + RPV LA.
  • Novel CAB formulations are in clinical trials.
  • ViiV-Janssen collaboration evaluating additional LA opportunities with CAB + RPV LA regimen.
  • ViiV-Halozyme collaboration with rHuPH20 may enable new 2-drug regimens with other clinical candidates.
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