Pasithea Therapeutics' next-generation macrocyclic MEK inhibitor, PAS-004, has shown a promising safety profile and early efficacy signals in patients with MAPK pathway-driven advanced cancers. These findings come from the initial cohorts of a phase 1 trial (NCT06299839) evaluating the drug's safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy.
Favorable Safety Profile
In the first two dosing cohorts, involving six patients receiving PAS-004 at 2 mg or 4 mg, the drug was well-tolerated. There were no drug-related dose interruptions, reductions, or discontinuations reported. Notably, no drug-related serious adverse effects (AEs) were observed at either dose level, and no protocol-defined stopping criteria were met. Investigators reported an absence of rash, skin toxicity, gastrointestinal toxicity, or ocular toxicity at these dose levels.
Based on these encouraging safety results, Pasithea Therapeutics has initiated cohort 3 of the trial, which will administer PAS-004 at 8 mg. The company has also filed a protocol amendment to explore increased dosing schedules.
Pharmacokinetic Advantages
According to Dr. Tiago Reis Marques, CEO of Pasithea Therapeutics, the data indicates a pharmacokinetic and safety profile that distinguishes PAS-004 as a next-generation MEK inhibitor. The drug's long half-life (approximately 70 hours) and ability to achieve a flat pharmacokinetic curve at steady-state aim to provide constant target inhibition while avoiding peak plasma toxicities. This pharmacokinetic profile is considered unique among MEK inhibitors, especially those used for treating NF1-mutated cancers.
Pharmacokinetic findings revealed that plasma exposure increased with higher doses of PAS-004. The mean half-life of the agent was 67.9 hours, with patients experiencing prolonged systemic exposure and minimal fluctuation in PAS-004 plasma concentration at steady-state, indicated by a Cmax/Cmin ratio of 1.2. At steady-state, PAS-004 levels peaked at approximately 5 hours, with a Cmax of 16.2 ng/mL for the 2-mg dose and 61.3 ng/mL for the 4-mg dose.
Trial Design and Endpoints
The multicenter, open-label, dose-escalation trial is designed to assess PAS-004 in patients with MAPK pathway-driven advanced solid tumors harboring documented NF1, RAF, or RAS mutations, or those who have progressed on BRAF/MEK inhibitors. Eligible patients are at least 18 years old with histologically or cytologically diagnosed disease, have progressed on or are ineligible for standard-of-care therapy, possess an ECOG performance status of 0 or 1, an estimated life expectancy of at least 12 weeks, and adequate organ function.
The study plans to evaluate PAS-004 in a sequential dose-escalation design at doses of 2 mg, 4 mg, 8 mg, 15 mg, 22 mg, 30 mg, 37 mg, and 45 mg. The primary end points include dose-limiting toxicities, AEs, hematology laboratory parameters, and clinical chemistry laboratory parameters. Secondary end points include apparent terminal elimination half-life in plasma, Cmax, Ctau/Ctrough, Tmax, area under the concentration versus time curve, apparent total plasma clearance, overall response rate, progression-free survival, and overall survival.
Early Efficacy Signals
Encouragingly, early potential signs of efficacy have been observed. One heavily pretreated patient with colorectal cancer (CRC) showed prolonged stable disease. This patient has a BRAF K601E mutation, a mutational status with no approved therapies. The patient has been treated continuously into the 6th 28-day dosing cycle without any observed toxicities or AEs.
Dr. Marques noted that PAS-004 has demonstrated distinct properties that could offer significant advantages over earlier-generation MEK inhibitors, particularly those used for treating NF1-mutated cancers, which have half-lives of less than 8 hours. The goal is to provide a less frequent dosing treatment with broader application, not only for NF1-mutated cancers but also for other indications.
