(T1530-03-21) A First-in-Human Assessment for TQS-168, Including Safety, Tolerability, Pharmacokinetics, Formulation Selection, and Food Effect in Healthy Volunteers

Purpose: TQS-168, a first-in-class peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) inducer in development for the treatment of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease. TQS-168 is a Biopharmaceutics Classification System (BCS) Class II compound, and preclinical data have indicated solubility limited absorption, hence solubility enhancement is likely required to achieve adequate exposure in humans. The purpose of the first in human (FIH) study was to establish safety, tolerability and pharmacokinetics (PK) for TQS-168, but also to assess performance of solubility enhanced formulations, allowing selection of an appropriate technology for Phase II progression. The food effect was also assessed on the selected formulation technology.

Methods: A randomized, double blind, placebo controlled single ascending dose (SAD) and multiple ascending dose (MAD) study was conducted in healthy volunteers using the Translational Pharmaceutics^® platform (rapid manufacturing and clinical testing), allowing assessment of multiple formulations during the FIH, facilitating formulation selection. The SAD study enrolled 6 cohorts of 8 subjects (6 active and 2 placebo). All cohorts adopted a sentinel dosing design whereby 1 active and 1 placebo subject were dosed ahead of the main group, with 24 hours safety data being reviewed before progression to the main group. Three suspension formulations were developed for potential assessment in this study: a crystalline methylcellulose (MC) suspension, a spray dried dispersion (SDD) suspension and a hot melt extrusion (HME) suspension. The MC suspension was dosed in Cohorts 1 to 3, with the option to dose Cohort 3 with alternative formulations (SDD and HME suspensions) to assess performance in Periods 2 and 3. The best performing formulation was then selected for dosing the remaining SAD and MAD cohorts. All SAD cohorts were dosed in the fasted state except for Cohort 4 which assessed performance in the fed state following a high fat breakfast. The MAD study consisted of 3 cohorts of 10 subjects (8 active and 2 placebo) which were dosed with the selected formulation once a day for 7 days in either the fed or fasted state. For both parts, interim decisions occurred between dosing periods, whereby PK and safety data were reviewed for dose escalation, formulation selection (Cohort 3 SAD) and prandial state selection for subsequent dosing periods/cohorts.

Results: In SAD Cohorts 1 to 3, the MC suspension was dosed at 60, 180 and 540 mg (Figure 1). Exposure was 3-fold higher than predicted from preclinical data and displayed supra proportional kinetics over the dose range explored, with a 9-fold increase in dose resulting in a 13.5- and 22-fold increase in C_max and AUC_(0-24), respectively. After review of Cohort 3 MC suspension data, the dose for the SDD and HME suspensions was reduced to 180 mg to ensure exposure did not exceed the planned maximum exposure. The SDD and HME suspensions both showed increased exposure when compared to the MC suspension at 180 mg (Figure 2). Biorelevant dissolution data showed increased dissolution with both the SDD and HME compared to crystalline API, confirming that the in vitro dissolution method was clinically relevant. The SDD suspension was the best performing formulation showing approximately a 4-fold increase in exposure compared to the MC suspension and was therefore selected for future SAD cohorts, which tested 90 mg and 270 mg. The dose of 90 mg SDD suspension was also assessed in the fed state, and showed a delayed T_max and reduced C_max which can be attributed to a delay in gastric emptying in the fed state, but overall exposure was similar. Multiple dosing of TQS-168 SDD suspension resulted in limited accumulation of TQS-168, ranging from 1.03 to 1.74 for C_max and 1.24 to 1.66 for AUC_(0-tau) respectively. Exposure (geometric mean C_max and AUC_(0-tau)) to TQS-168, increased with an increase in dose on multiple dosing, with a supra-proportional increase on Day 1 and Day 7 for the 90 and 300 mg dose levels in the fed state. Single doses and multiple doses of TQS-168 for all formulations tested were safe and were generally well tolerated in fasted and fed states. Tolerability at the higher doses was impacted mainly by subjective hot flushes.

Conclusion: Safety, tolerability, and PK were established for TQS-168 in this FIH study. Translational Pharmaceutics allowed emerging clinical data to be used within a clinical study to assess performance of multiple formulations and select the best performing suspension formulation to progress to patient studies.

Acknowledgements:Clinical protocol reviewed and approved by the London - Riverside Research Ethics Committee, 17th August 2021).

Figure 1: Geomean plasma concentration profiles of TQS-168 following single-dose administration of MC suspension

Figure 2: Geomean plasma concentration profiles of TQS-168 following single dose administration of 180 mg MC, SDD and HME suspensions