Pasithea Therapeutics Corp. (NASDAQ: KTTA) has reported positive pharmacodynamic results from its ongoing Phase 1 clinical trial of PAS-004, demonstrating robust target engagement in patients with advanced cancers. The next-generation macrocyclic MEK inhibitor achieved up to 91% inhibition of ERK phosphorylation (pERK), a gold-standard biomarker for assessing MEK inhibitor activity, even at the 8mg dose level.
The Safety Review Committee has recommended dose escalation to the next cohort (30mg capsule) following review of safety data from the previous cohort, with no dose-limiting toxicities (DLTs) observed to date. Notably, none of the first 19 patients treated with either capsule or tablet formulations experienced rash during the DLT period, a common adverse event with competitor MEK inhibitors that often leads to treatment discontinuation.
Strong Target Engagement with Favorable Safety Profile
PAS-004 is being developed as a next-generation MEK inhibitor for neurofibromatosis type 1 (NF1) and other MAPK pathway-driven cancers. The pharmacodynamic data collected from peripheral blood mononuclear cells (PBMCs) at baseline and day 22 showed substantial reductions in pERK levels, confirming the drug's mechanism of action.
"We are pleased that PAS-004 has demonstrated clinically meaningful reductions in pERK levels at dose levels that are both well-tolerated and safe, with no rash observed," said Dr. Tiago Reis Marques, Chief Executive Officer of Pasithea. "We believe PAS-004's profile offers the potential to finely modulate MAPK pathway activity, enabled by its previously reported long half-life and favorable pharmacokinetic profile with a Cmax/Cmin ratio below 2."
The absence of rash is particularly significant as currently approved MEK inhibitors for NF1 have on-label rash rates exceeding 80%, which frequently leads to treatment discontinuation despite clinical benefit.
Encouraging Clinical Activity
Beyond the favorable safety and pharmacodynamic profile, PAS-004 is showing preliminary signs of clinical efficacy. Several patients have achieved stable disease and tumor shrinkage while on treatment. Most notably, a patient in cohort 4A (15mg capsule) with stage 4 KRAS G12R-mutated pancreatic cancer, who had progressive disease despite three prior lines of therapy, achieved a tumor volume reduction of 9.8% over five months of PAS-004 treatment and remains on study.
This early signal of activity in a notoriously difficult-to-treat cancer type with a KRAS mutation suggests PAS-004 may have potential across multiple MAPK pathway-driven tumor types.
Trial Design and Patient Population
The ongoing Phase 1 clinical trial employs a multi-center, open-label, dose escalation 3+3 study design to evaluate PAS-004 in patients with advanced solid tumors driven by the MAPK pathway. Eligible patients must have documented RAS, NF1, or RAF mutations, or have failed prior BRAF/MEK inhibition (NCT06299839).
The trial is currently progressing to Cohort 6 (30mg capsule), with strong enrollment demand reported by the company. Dr. Reis Marques noted, "We are seeing substantial enrollment demand and have already identified Cohort 6 patients."
Pharmacokinetic Advantages
PAS-004's pharmacokinetic profile appears to support the company's development strategy. The drug demonstrates substantial exposure levels that may deliver relevant pERK inhibition below the no observed adverse effect levels (NOAEL), as modeled and observed during previously conducted nine-month chronic toxicity studies.
The favorable Cmax/Cmin ratio below 2 suggests a steady drug concentration in the body, potentially allowing for effective pathway inhibition without the toxicity spikes associated with some other kinase inhibitors.
Future Development Plans
Pasithea is positioning PAS-004 for development in both oncology and NF1, a genetic disorder affecting 1 in 3,000 people worldwide that causes tumors to grow on nerves throughout the body. The company has indicated it will provide additional safety, pharmacokinetic, and pharmacodynamic data in the coming weeks and months.
The encouraging safety profile, particularly the absence of rash, combined with robust target engagement and preliminary signs of clinical activity, suggests PAS-004 may offer advantages over existing MEK inhibitors for both cancer and NF1 patients.
"We're encouraged by the emerging clinical signals we're seeing across multiple cancer types and look forward to sharing further safety, PK and PD data in the coming months," concluded Dr. Reis Marques.
