(M1430-09-61) Preclinical Development of Long-Acting Injectable Formulations of Glecaprevir and Pibrentasvir for Curative Treatment of Hepatitis C in Low- and Middle-Income Countries

Purpose: A long-acting form of Hepatitis C treatment has the potential to cure infection in a single administration at the point of diagnosis. Although effective oral therapies are available, uptake of, and adherence to treatment is often compromised, particularly in low- and middle-income countries, which carry a disproportionate burden of Hepatitis C case numbers and costs. An oral fixed dose combination (FDC) of glecaprevir (GLE) and pibrentasvir (PIB), both pangenotypic active pharmaceutical ingredients (APIs), can cure hepatitis C infection in as little as 8 weeks. Oral GLE+PIB is administered daily; an administration form that offers longer dosing intervals could improve adherence, and Hepatitis C cure rates. Recent patient engagement studies have reported that long-acting injectable (LAI) options are desirable for patients and clinicians, and have demonstrated effective therapeutic and prophylactic effects in the infectious disease space.1, 2 As part of a multidisciplinary collaborative programme, we have developed LAI formulations of GLE+PIB through leveraging solid drug nanoparticle (SDN) generation and reconstituting the dried material at high concentration. Dry powder products can offer longer shelf life compared to liquid formulations, which may in turn reduce infrastructural requirements that increase cost, such as cold chain storage.

Methods: Powder SDN materials containing 80 wt% API, stabilised by 15 wt% polyvinylpyrrolidone and 5 wt% docusate sodium, were prepared using a dichloromethane (DCM)-in-water emulsion spray drying methodology. Dried materials were characterised using Dynamic Light Scattering (DLS), powder X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM), High Performance Liquid Chromatography (HPLC) and Karl Fischer titration. Osmolality of the suspended forms was also investigated. In vivo pharmacokinetic (PK) studies investigated whether sustained release of GLE and PIB administered as single dose LAI suspensions was possible, and the effect on PK of 4 different GLE and PIB FDCs.

Results: Powder XRD showed materials to be amorphous in nature, and SEM micrographs confirmed this. Powder materials contained ≤1% residual water and unquantifiable amounts of residual DCM. Materials were characterised by DLS after reconstitution (hydrodynamic diameter 296-319 nm, polydispersity index 0.34‑0.40), and API weight loading of the powders was confirmed by HPLC (79.4-80.4 wt%). Analyses were repeated after 5 months storage at accelerated conditions; hydrodynamic diameter, polydispersity index and moisture content increased during storage. In vivo studies were carried out using SDNs reconstituted at up to ~310 mg.mL-1 API, a concentration at which the suspension could be passed through a 25G needle without excess finger force. Results of osmometric analysis of suspensions at this concentration were in the range of 106-145 mOsm.kg-1, lower than physiological levels, but generally accepted as tolerable with respect to injection site discomfort.3 Sustained release of both APIs was measured over 56 days after a single intramuscular or subcutaneous administration to Sprague Dawley rats. Administration of GLE and PIB as FDCs appeared to modulate the release of GLE, depending on the ratio of GLE:PIB in the FDC.

Conclusion: High concentration aqueous suspensions of GLE and PIB were developed and enabled sustained in vivo release of both APIs over 8 weeks, at concentrations above the troughs for daily oral dosing in humans. Administered as FDCs, PK of GLE appeared to be modified, suggesting a potential modulating effect of GLE in the presence of PIB. Further pharmacodynamic studies would be beneficial to elucidate a mechanism. Translation to a contract development and manufacturing organisation is underway, successful completion of which is intended to lead to a Good Laboratory Practice toxicology study and Phase 1 clinical trial.

References: 1. R. Furl, K. K. Scarsi, H. Sayles, M. Anderson, J. D. Ofimboudem, E. D. Weld, I. Waked, A. Gomaa, A. Al-Khatib, F. M. Elshobary, H. Desalegn, H. Fisseha, S. Solomon, S. Mehta, A. Owen, S. Rannard, D. L. Thomas and S. Swindells, J. Viral Hepatitis, 2025, 32, 12.
2. J. E. Johnson, A. L. Brotherton, M. R. Rossi, M. C. Sanchez and C. G. Beckwith, Curr. HIV/AIDS Rep., 2025, 22, 14.
3. W. Wang, Int. J. Pharm., 2015, 490, 308-315.

Acknowledgements: This work was supported through global health agency Unitaid project LONGEVITY (2020-38-LONGEVITY)