PAS-004 Has Tolerable Safety Profile and Preliminary Efficacy in MAPK-Driven Solid Tumors

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The next-generation macrocyclic MEK inhibitor PAS-004 is safe, tolerable, and generated early efficacy signals in patients with MAPK pathway–driven advanced cancers, according to preliminary findings from 2 cohorts of patients enrolled in a phase 1 trial (NCT06299839).¹

In the first 2 dosing cohorts (n = 6), in which patients received PAS-004 at 2 mg or 4 mg, the agent was well tolerated with a favorable safety profile. No patients required drug-related dose interruptions, reductions, or discontinuations. No drug-related serious adverse effects (AEs) were observed at any dose, and no protocol-defined stopping criteria were met. At the 2-mg and 4-mg dose levels, investigators have reported no rash or skin toxicity, gastrointestinal toxicity, or ocular toxicity to date.

Based on these favorable safety outcomes at the 2-mg and 4-mg dose levels, Pasithea Therapeutics, the manufacturer of PAS-004, has initiated cohort 3 of the trial, which will administer the agent at 8 mg. The company has also filed a protocol amendment to increase the dosing schedule of PAS-004.

“We believe these data demonstrate a pharmacokinetic and safety profile that differentiates PAS-004 as a next-generation MEK inhibitor,” Dr Tiago Reis Marques, chief executive officer of Pasithea Therapeutics, stated in a news release. “The long half-life at approximately 70 hours and the ability to achieve a flat pharmacokinetic curve at steady-state, aim to provide a constant target inhibition while avoiding peak plasma toxicities, which is a unique pharmacokinetic profile among MEK inhibitors used for the treatment of NF1[-mutated cancers].”

The multicenter, open-label, dose-escalation, 3+3 trial is investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PAS-004 in patients with MAPK pathway–driven advanced solid tumors harboring a documented NF1, RAF, or RAS mutation or those who have progressed on BRAF/MEK inhibitors. Eligible patients include those at least 18 years of age with histologically or cytologically diagnosed disease who have progressed on or are ineligible for standard-of-care therapy.² Patients must have 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.

Pharmacokinetic findings showed that plasma exposure increased with increased doses of PAS-004.1 The mean half-life of the agent was 67.9 hours, and patients experienced prolonged systemic exposure with minimal fluctuation in PAS-004 plasma concentration at steady-state, with 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.

“PAS-004 has demonstrated distinct properties that we believe are significant advantages for an oral MEK inhibitor. PAS-004 has a significantly longer half-life compared to early-generation MEK inhibitors, particularly those used for the treatment of NF1[-mutated cancers], which have half-lives of less than 8 hours,” Marques added.

“In addition, we are encouraged to see early potential signs of efficacy, with a heavily pretreated patient with colorectal cancer [CRC] showing prolonged stable disease. CRC is known to not provide a RECIST response when treated with single-agent MEK inhibitors. This patient has a BRAF K601E mutation, a mutational status with no approved therapies. We are encouraged that this patient has been treated continuously into the 6th 28-day dosing cycle with no toxicities or AEs observed. While still early in clinical development, we believe PAS-004 is showing early signs of differentiation, indicating PAS-004 has the potential to outperform current MEK inhibitors in terms of safety, reduced administration frequency, and potentially efficacy. Our goal is to provide a once-daily or less frequent dosing treatment with broader application, not only for NF1[-mutated cancers] but also for other indications,” Marques concluded.

References

1. Pasithea Therapeutics announces positive initial safety, tolerability, pharmacokinetic (PK), and preliminary efficacy data from its phase 1 clinical trial of PAS-004 in advanced cancer. News release. Pasithea Therapeutics Corp. September 26, 2024. Accessed September 27, 2024. https://ir.pasithea.com/news-events/press-releases/detail/108/pasithea-therapeutics-announces-positive-initial-safety
2. PAS-004 in patients with advanced solid tumors. ClinicalTrials.gov. Updated September 4, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT06299839