(W0930-05-26) Preclinical Development of Long Acting Injectables for Delivery of Targeted Protein Degraders

Purpose: Targeted protein degraders (PROTACs) potentially enable next generation precision therapies. Long acting injectables (LAI) for either sub-cutaneous or intra-muscular administration provides a promising and effective drug delivery option for these novel PROTACs that are not orally bioavailable. The purpose of this presentation is to demonstrate the preclinical proof of concept of drug delivery of heterobifunctional PROTACs with LAI formulations.

Methods: Preclinical development with LAI has been conducted for BRD9, CBP and EP300 degraders with various formulation platforms such as aqueous nanosuspensions and microsuspensions of crystalline and/ or amorphous particles, in situ PLGA gels, phospholipid-based gels and oil/organic solvent-based solutions. The experimental details for long acting enabled injectable work in this presentation will focus on FHD-609, a potent heterobifunctional degrader of BRD9 which had previously been administered intravenously (IV) twice weekly in medical facilities during clinical trials for synovial sarcoma. Formulation development in the preclinical phase was conducted in a material sparing manner and included optimization of drug loading, excipient types/levels, and method of preparation; all to enable ease of preparation for PK studies and support clinical image drug product. Characterization of formulations included evaluation of physical and chemical stability and in-vitro release assessments to rank order formulations. The chosen formulations from various platforms were dosed in rodents to assess pharmacokinetics. In addition, to demonstrate the pharmacodynamic properties of this mode of delivery for the PROTACs, PK/PD and efficacy studies were conducted in vivo in xenograft models of different sensitivities, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX) in mice.

Results: Two formulation platforms of FHD-609 successfully provided sustained, long-acting release that met the target plasma C_min criteria for at least 3 weeks in various preclinical species as shown in Figures 1 and 2. These formulations were: (i) aqueous suspensions with nano- and micron sized particles (referred to as microsuspension), and (ii) PLGA microspheres. For pharmacological proof of concept, we compared pharmacokinetic and pharmacodynamic properties, as well as the efficacy of the LAI formulation in xenograft models of different sensitivities (including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX)) of an LAI formulation dosed once every 4 weeks versus an IV formulation dosed twice a week. Our results showed that a single dose of the injectable suspension formulation was well-tolerated in mice and exhibited a sustained and stable PK profile for up to 28 days. Moreover, it demonstrated comparable in vivo efficacy and BRD9 protein degradation to the standard IV administration (Figure 3).

Conclusion: Long-acting injectable formulations are a promising and efficient drug delivery solution for protein degraders lacking oral bioavailability. Various formulation platforms including aqueous nano/microsuspensions, PLGA microspheres and in situ gels are viable platforms depending on dose, drug loading, route of administration and stability of compound. LAI formulations provided encouraging PK /PD/ efficacy data. The LAI formulations can be as effective as IV formulation, provide a versatile option with the potential of reducing systemic side effects due to lower C_max and have the potential to provide good patient compliance, acceptance, and adherence in clinical and commercial settings.


Figure 1: FHD-609 Long-Acting Formulation PK Studies Data Using Microsuspension Formulation


Figure 2: FHD-609 Long-Acting Formulation Preclinical Studies Data Using PLGA Microsphere Formulation


Figure 3: In SYO-1 xenograft model A) BRD9 degradation levels were maintained for up to 28 days with FHD-609 LAI formulation; B) Sustainable exposure was achieved with FHD-609 LAI formulation. C) Dose-dependent BRD9 degradation at the end of the efficacy; D) FHD-609 LAI achieved comparable efficacy.