Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first-in-human study

Abstract

Aims: PTC518 is an orally administered, centrally and peripherally distributed huntingtin (HTT) pre-mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease-modifying treatments. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers.

Methods: This phase 1, single-centre, randomized study in 77 healthy male and female volunteers evaluated the safety and tolerability and PK of PTC518 following single ascending doses and multiple ascending doses, PD as assessed by HTT mRNA and HTT protein levels after single and multiple doses, and food effects.

Results: PTC518 demonstrated a favourable safety profile. The majority of treatment-emergent adverse events were mild and transient. PTC518 T_max was reached at 6-7 h and the terminal T_1/2 was 54.0-75.3 h following a single oral dose. Exposure increased with dose though less than dose proportionally. The PTC518 concentrations in cerebrospinal fluid were approximately 2.6-fold higher than the unbound free-drug concentrations in plasma. A significant dose-dependent reduction of up to approximately 60% in HTT mRNA and a significant dose-dependent, time-dependent and sustained reduction in HTT protein levels of up to 35% were observed after PTC518 treatment.

Conclusions: PTC518 was well tolerated, and proof of mechanism of this novel splicing modifier was demonstrated by the dose-dependent decrease in systemic HTT mRNA and HTT protein levels. Results from this first-in-human study support further studies in patients with HD and demonstrate the potential for PTC518 as a breakthrough treatment for HD.

Keywords: genetic diseases; neuroscience; pharmacokinetics–pharmacodynamics; phase 1.

FIGURE 1

HTT pre‐mRNA splicing and PTC518 mechanism of action. HTT, huntingtin; psiExon, pseudoexon; ss, splice site.

FIGURE 2

Mean plasma PTC518 concentration–time profiles following a single oral dose of 5, 15, 45, 90 and 135 mg PTC518 under fasted conditions in healthy subjects (semi‐log scale).

FIGURE 3

Mean (±SD) plasma (free‐drug concentration) and CSF PTC518 concentration–time profiles on Day 7 following multiple daily oral doses of 30 mg PTC518 under fasted conditions in healthy subjects (linear scale). CSF, cerebrospinal fluid; LD, loading dose; QD, once daily; SD, standard deviation. Subjects received an LD of 90 mg PTC518 on Days 1 and 2, followed by 30 mg PTC518 QD on Days 3 to 7 (cohort 3.1: n = 3). Note: plasma free‐drug concentrations were derived from the measured plasma total concentration using the percentage of unbound drug concentration in plasma from in vitro assays (18.5%).

FIGURE 4

Dose‐dependent decrease in full‐length HTT mRNA at 24 h following single ascending doses (panel A) and following multiple ascending doses for 14 days (panel B) of PTC518. HTT, huntingtin. Figures show the mean (± standard deviation) percent of baseline (predose level prior to the first dose) full‐length HTT mRNA at the time of maximum effect, 24 h postdose. The horizontal dotted lines show reductions from baseline of 30% and 50%. Single ascending doses (panel A): placebo (n = 10 [all five cohorts combined]), cohort 1.1 (5 mg: n = 6), cohort 1.2 (15 mg: n = 6), cohort 1.3 (45 mg: n = 6), cohort 1.4 (90 mg: n = 5), cohort 1.5 (135 mg: n = 6). Multiple ascending doses (panel B): placebo (n = 4 [cohorts 2.1 and 2.2 combined]), 15 mg for 14 days (cohort 2.1: n = 5), and 30 mg for 14 days (cohort 2.2: n = 6).

FIGURE 5

Decrease in total HTT protein in subjects (30 mg group) receiving PTC518 once daily for 21 days. HTT, huntingtin. Figure shows the mean (± standard deviation) percent of baseline (predose level prior to the first dose) HTT protein. The horizontal dotted lines show reductions from baseline of 30% and 50%. * P = .0068 calculated using two sample t‐test. Figure shows placebo (cohort 2.3: n = 2) and PTC518 30 mg for 21 days with 100 mg loading dose for 2 days (cohort 2.3: n = 6).