CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: NM4DTG dimeric prodrug formulation sustained plasma DTG levels ≥ 4XPAIC 90 for 4 months following a single dose. Linkage of two DTG molecules to the optimal C18 lipid for NM4DTG consistently maintains DTG concentrations at levels ≥ 4XPAIC 90 for an extended period of time at lower dosages with the potential to reduce injection volumes.

rapid drug decay after 7 months, demonstrating a short PK tail (Figure A-B). In contrast, the monomeric BIC prodrug formulation (NM2BIC) exhibited a much slower BIC plasma decay curve after 7 months post-dosing in RM. An equivalent booster dose of NM2BIC (50 mg. BIC eq./kg) in RM on day 217 resulted in higher plasma BIC levels than the corresponding time points after the first injection. Conclusion: The dimeric NMXBIC formulation exhibits high plasma BIC exposure and a shorter PK tail with the potential for dosing at 6-month intervals.

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Cabotegravir Stearate (XVIR-110), an InSTI Prodrug, Provides Ultra-Long Acting Cabotegravir Exposure Brian P Kearney 1 , Brady Sillman 2 , Howard E. Gendelman 2 , Benson Edagwa 2 , Leigh Ann Burns-Naas 3 , Alborz Yazdi 1 1 Exavir Therapeutics, Omaha, NE, USA, 2 University of Nebraska Medical Center, Omaha, NE, USA, 3 Magnolia Toxicology Consulting, LLC, Traverse City, MI, USA Background: Cabotegravir stearate (M2CAB) is a novel prodrug of the INSTI cabotegravir (CAB) that forms local and macrophage-distributed M2CAB depots, resulting in "flip-flop" plasma pharmacokinetics (PK) yielding a protracted apparent elimination half-life. M2CAB is formulated as an extended-release injectable suspension (XVIR-110) for intramuscular (IM) administration that may achieve ultra-long-acting therapeutic CAB exposures with infrequent administration. Methods: We evaluated the PK profile of M2CAB and/or CAB in following a single IM (thigh muscle(s) of hind limb; 28 ga. syringe) administration of XVIR-110 to male SD rats and male beagle dogs. XVIR-110 was dosed at target M2CAB doses of 75, 185 (single and (2)-split injections) and 638 mpk (split injections) in rats and at 40 and 151 mpk in dogs. PK were assessed at multiple timepoints over up to 12 months until CAB concentrations fell to less than the protein binding-adjusted IC 90 (PB-IC 90 ) of 166 ng/mL. Drug concentrations were measured using validated UPLC-MS/MS methods. Additionally, a separate study of injection site reactions (ISR) with histopathologic evaluation of head-to-head administration of XVIR-110 and commercial cabotegravir was conducted in rats. Results: Concentration-time profiles are presented in Figure 1 for CAB in rats (Panel A) and for M2CAB and CAB in dogs (Panel B) below. A single IM administration XVIR-110 resulted in low exposures of the prodrug M2CAB but yielded high and persistent exposures of active CAB in both rats and dogs over the period of study to date, 7 and 5 months, respectively. The study is ongoing and based on the projected apparent terminal-elimination half-life of CAB, concentrations above the PB-IC 90 of CAB are expected to remain for more than 12 months. Based upon modelling, these data suggest that XVIR-110 could be dosed once- or twice-yearly in humans. XVIR-110 was well tolerated without evidence for dose-limiting ISRs and demonstrated less pronounced early post injection microscopic changes, including tissue necrosis, inflammation, and immune cell infiltration vs. commercial cabotegravir at equivalent doses. Conclusion: XVIR-110 demonstrated sustained CAB exposures and a favorable ISR profile in nonclinical species. As such, XVIR-110 may be ideally suited where daily, self-directed, or more frequent IM or SQ may be less desirable or feasible, particularly where inconsistent and/or ad hoc adherence is a risk, such as pre exposure prophylaxis (PrEP) or in patients with known adherence challenges.

Poster Abstracts

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WITHDRAWNA Third-Generation Long-Acting Dolutegravir Homodimer Prodrug Bhoomika Suresh Gowda , Suyash Deodhar, Nam Thai Hoang Le, Mohammad Ullah Nayan, Brandon Hanson, Manish K. Sharma, Brady Sillman, Howard E. Gendelman, Benson Edagwa University of Nebraska Medical Center, Omaha, NE, USA Background: Dolutegravir (DTG) is a widely used integrase inhibitor with a high barrier to resistance & effective viral suppression. It is recommended as a part of first-line treatment for HIV-1. However, challenges center on the need for life-long daily use. Lack of adherence due to side effects, pill fatigue, & stigma underscore need for long-acting formulations. Thus, our research has focused on the development & translation of ultra-long acting monomeric prodrugs, including NM2DTG. NM2DTG safely extended DTG's apparent half-life [Nat Comm (2022)]. To reduce injection volumes & extend DTG plasma concentrations without dose adjustments, novel chemical modifications were created. A library of DTG homodimer prodrugs were made where two DTG molecules are linked to a lipid carrier. The goal was to extend DTG plasma levels ≥ 4XPAIC 90 for > 4 months after single IM or SC dosing. Methods: DTG homodimers were synthesized by covalently linking two DTG molecules to 18, 20, or 22-carbon fatty diacids to form M4, M7, & M8DTG respectively. An ionizable DTG prodrug monomer (M6DTG) was made by esterifying one of the two carboxylate groups in the optimal C18 fatty diacid. The prodrugs were nanoformulated by high-pressure homogenization. Native DTG formulations (NDTG) were also prepared. Cellular uptake, retention, antiretroviral efficacy, & cytotoxicity were evaluated in primary human MDM. Following a single IM or SC dose, PK profiles were examined in Balb/cJ mice & SD rats at 45 & 50 mg DTG eq/kg respectively. Results: Chemical characterizations confirmed DTG derivatization. The dimer prodrug nanoformulations were retained by MDM & protected against HIV-1ADA challenge. PK tests of DTG dimer prodrug formulations identified NM4DTG as the lead candidate, with DTG plasma levels > 4XPAIC 90 in initial mouse studies (Fig 1A). NM7- & NM8DTG were hydrolyzed slowly & plasma DTG levels dropped below 4XPAIC 90 within 3 days. A single IM dose of NM4DTG to SD rats sustained plasma DTG levels ≥ 4XPAIC 90 for 4 months. SC treated animals exhibited a similar plasma decay curve (Fig 1B). However, plasma DTG levels for NDTG & NM6DTG dropped < 4XPAIC 90 within 4 weeks.

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