PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical in vitro anticancer activity, and its pharmacokinetic–pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma. Using X-ray crystallography, it was determined that PTC596 binds to the colchicine site of tubulin with unique key interactions. PTC596 exhibited broad-spectrum anticancer activity. PTC596 showed efficacy as monotherapy and additive or synergistic efficacy in combinations in mouse models of leiomyosarcomas and glioblastoma. PTC596 demonstrated efficacy in an orthotopic model of glioblastoma under conditions where temozolomide was inactive. In a first-in-human phase I clinical trial in patients with cancer, PTC596 monotherapy drug exposures were compared with those predicted to be efficacious based on mouse models. PTC596 is currently being tested in combination with dacarbazine in a clinical trial in adults with leiomyosarcoma and in combination with radiation in a clinical trial in children with diffuse intrinsic pontine glioma.

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.

To evaluate the potential for ethnicity‐related differences in ataluren pharmacokinetics (PK) and safety, a phase 1 single‐dose study was conducted in 48 healthy (24 Japanese and 24 Caucasian subjects), nonsmoking male volunteers who were equally divided into 3 cohorts of oral doses at 5, 10, and 20 mg/kg. Blood samples were collected until 48 hours postdose. PK results demonstrated rapid absorption of ataluren, with peak plasma levels (C_max) being attained between 0.875 and 2.5 hours after dosing. The mean C_max and area under the concentration‐time curve (AUC_(0‐last)) increased with each increasing dose level in both Japanese and Caucasian subjects. Although the C_max was similar across all subjects at each dose regardless of ethnicity, Japanese subjects had a mean AUC_(0‐last) approximately 14% to 34% lower than that of Caucasian subjects across the 3 dose levels. This difference was likely due to the higher variability of AUC values in Caucasian subjects and the relatively small study population. In conclusion, similar ataluren PK profiles were observed in healthy Japanese and Caucasian subjects following single oral administration of ataluren at all dose levels.

Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug‐induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome‐coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase elevations observed in prior emvododstat clinical trials in patients with solid tumors, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on physiologically‐based pharmacokinetic modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only eight patients experienced aminotransferase elevations, all of which were mild (grade 1), all resolving within a short period of time, and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safety. Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed.

Background: Sepiapterin is a natural precursor of tetrahydrobiopterin (BH₄), a key cofactor for phenylalanine hydroxylase. It is being developed for the treatment of patients with phenylketonuria. In this study, the ethnic differences in pharmacokinetics and safety of sepiapterin in Japanese and non-Japanese participants and food effects were evaluated. Methods: Healthy participants (n = 60) received a single oral dose of sepiapterin at either 20, 40, or 60 mg/kg with a low-fat diet. The Japanese participants received two doses at 40 mg/kg, either under fasted conditions or with a low-fat diet with a 3-day washout period in between. Results: Sepiapterin was well tolerated in all participants, with no serious adverse events. Sepiapterin was quickly absorbed (T_max 1.4–4.5 h) and rapidly and extensively converted to BH₄ (T_max ~4 h). Exposures to sepiapterin were A mutation in the Japanese population.