Pasithea Therapeutics Reports Positive Pharmacodynamic Results Demonstrating Robust Target Engagement from its Ongoing Phase 1 Clinical Trial of PAS-004

Rhea-AI Summary

Pasithea Therapeutics (NASDAQ: KTTA) reported positive interim pharmacodynamic data from its Phase 1 trial of PAS-004, a next-generation macrocyclic MEK inhibitor. The trial evaluated doses of 8mg, 15mg capsules, and 4mg tablets in advanced cancer patients. Key findings include up to 91% inhibition of pERK, demonstrating robust target engagement. Notably, a stage 4 pancreatic cancer patient with KRAS G12R mutation achieved tumor volume reduction of -9.8% over 5 months of treatment. The drug shows a favorable safety profile with no rash observed. PAS-004 aims to treat neurofibromatosis type 1 (NF1) and other MAPK pathway driven cancers. The ongoing Phase 1 trial (NCT06299839) is designed to evaluate safety, tolerability, and preliminary efficacy in patients with MAPK pathway driven advanced solid tumors.

Positive

• Achieved up to 91% inhibition of pERK, demonstrating strong target engagement
• Stage 4 pancreatic cancer patient showed -9.8% tumor volume reduction over 5 months
• Drug demonstrates favorable safety profile with no rash observed
• Shows clinically meaningful reductions in pERK at well-tolerated dose levels

Negative

• None.

Insights

Oncology Expert

PAS-004 shows impressive target engagement (91% pERK inhibition) and promising activity in pancreatic cancer patient with favorable safety profile.

Pasithea's Phase 1 data for PAS-004 reveals compelling pharmacodynamic evidence with up to 91% inhibition of phosphorylated ERK (pERK) - a critical biomarker for MEK inhibitor efficacy. This robust target engagement was observed even at the 8mg dose level, suggesting effective MAPK pathway modulation at lower doses than might typically be required.

The drug's pharmacokinetic profile with a Cmax/Cmin ratio below 2 indicates relatively stable drug exposure over time. This is particularly important for targeted therapies as it potentially provides more consistent pathway inhibition without the problematic peaks that often drive toxicity or the troughs that might allow for tumor escape.

The clinical observation of a patient with KRAS G12R-mutated pancreatic cancer achieving a 9.8% tumor volume reduction and maintaining stable disease beyond 5 months is noteworthy. This patient had previously progressed on three prior lines of therapy, making the response more significant. KRAS-mutated pancreatic cancer is among the most treatment-resistant malignancies, with very limited effective options.

From a safety perspective, the absence of rash is particularly important. Dermatologic toxicity is a class effect of MEK inhibitors and often dose-limiting. If this favorable skin profile holds up in expanded cohorts, it could potentially allow for more optimal dosing and better treatment adherence compared to other MEK inhibitors.

While these early signals are encouraging, they come from a limited number of patients in a Phase 1 study. The true efficacy profile will need validation in larger, more definitive trials across multiple MAPK-driven tumor types including the company's target indication of neurofibromatosis type 1.

Biotechnology Investment Analyst

Strong early clinical validation for PAS-004 with robust target engagement and promising activity in difficult-to-treat pancreatic cancer.

The pharmacodynamic data reported by Pasithea represents a meaningful technical validation of PAS-004's mechanism of action. Demonstrating up to 91% inhibition of pERK confirms the drug is effectively engaging its target in humans, which materially derisks one critical aspect of the development program.

What stands out is the preliminary efficacy signal - the 9.8% tumor volume reduction in a KRAS G12R-mutated pancreatic cancer patient after failing three prior therapies. Pancreatic cancer represents a significant market opportunity with inadequate treatment options, and KRAS mutations have been notoriously difficult to target effectively. This early signal, while from just one patient, hints at potential clinical utility in a high-unmet-need indication.

The reported favorable safety profile, particularly the absence of rash, could differentiate PAS-004 from other MEK inhibitors where dermatologic toxicity frequently limits dosing. The drug's pharmacokinetic properties with minimal peak-to-trough fluctuation (Cmax/Cmin ratio below 2) suggest a potential therapeutic advantage that could translate to better clinical outcomes if maintained in larger studies.

Pasithea is positioning PAS-004 for both neurofibromatosis type 1 (NF1) and MAPK pathway-driven cancers - a strategic approach that provides multiple paths to potential market approval. NF1 represents an attractive orphan indication with limited competition, while the MAPK pathway is implicated in approximately 30% of all human cancers.

The company's development strategy appears sound, though investors should recognize these are still early results from a dose-finding study. The next key catalysts will include complete Phase 1 results and the initiation of indication-specific Phase 2 studies that will more definitively test the drug's efficacy profile.

-- PAS-004 shows up to 91% inhibition of pERK, confirming substantial target engagement --

-- One patient in cohort 4A with stage 4 KRAS G12R mutated pancreatic cancer achieves over 5 months of stable disease with tumor volume reduction of -9.8% --

MIAMI, May 06, 2025 (GLOBE NEWSWIRE) -- Pasithea Therapeutics Corp. (NASDAQ: KTTA) (“Pasithea” or the “Company”), a clinical-stage biotechnology company developing PAS-004, a next-generation macrocyclic MEK inhibitor for the treatment of neurofibromatosis type 1 (NF1) and other MAPK pathway driven cancer indications, today announced positive interim pharmacodynamic (PD) data from its ongoing Phase 1 trial of PAS-004 in advanced cancer patients. The data includes results from cohorts 3 and 4A, evaluating 8mg and 15mg capsules, as well as cohort 4B evaluating 4mg tablets, and demonstrates strong target engagement consistent with PAS-004’s favorable pharmacological profile.

Inhibition of ERK phosphorylation (pERK) is widely recognized as a gold-standard PD biomarker for assessing MEK inhibitor activity. To evaluate target engagement, pERK levels were measured in peripheral blood mononuclear cells (PBMCs) collected from patients at baseline and steady-state at day 22.

Preliminary results demonstrate robust pERK inhibition, with reductions in pERK levels of up to 91% even at the 8mg dose level, in line with a previous developed PK/PD model, confirming substantial target engagement in patients receiving PAS-004.

Pharmacodynamic activity is supported by encouraging preliminary clinical observations, with several patients achieving stable disease and tumor shrinkage while on PAS-004 treament. Notably, one patient in cohort 4A (15mg capsule) with stage 4 KRAS G12R-mutated pancreatic cancer, having progressive disease while on three prior lines of therapy, achieved a tumor volume reduction of -9.8% over 5 months of PAS-004 treatment and currently remains on study.

“With today’s update, 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 (PK) profile with a Cmax/Cmin ratio below 2. We’re also 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.”

The ongoing Phase 1 clinical trial is a multi-center, open-label, dose escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of PAS-004 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 or RAF mutation or patients who have failed BRAF/MEK inhibition (NCT06299839).

About Pasithea Therapeutics Corp.

Pasithea is a clinical-stage biotechnology company focused on the discovery, research and development of innovative treatments for central nervous system (CNS) disorders, RASopathies and MAPK pathway driven tumors.

Forward Looking Statements

This press release contains statements that constitute “forward-looking statements” made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include statements regarding the Company’s ongoing Phase 1 clinical trial of PAS-004 in advanced cancer patients, the Company’s planned Phase 1/1b clinical trial of PAS-004 in adult NF1 patients, and the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD) and preliminary efficacy of PAS-004, as well as all other statements, other than statements of historical fact, regarding the Company’s current views and assumptions with respect to future events regarding its business, as well as other statements with respect to the Company’s plans, assumptions, expectations, beliefs and objectives, the success of the Company’s current and future business strategies, product development, pre-clinical studies, clinical studies, clinical and regulatory timelines, market opportunity, competitive position, business strategies, potential growth opportunities and other statements that are predictive in nature. Forward-looking statements are subject to numerous conditions, many of which are beyond the control of the Company. While the Company believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements, which are based on information available to the Company on the date of this release. These forward-looking statements are based upon current estimates and assumptions and are subject to various risks and uncertainties, including risks that future clinical trial results may not match results observed to date, may be negative or ambiguous, or may not reach the level of statistical significance required for regulatory approval, as well as other factors set forth in the Company’s most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q and other filings made with the U.S. Securities and Exchange Commission (SEC). Thus, actual results could be materially different. The Company undertakes no obligation to update these statements whether as a result of new information, future events or otherwise, after the date of this release, except as required by law.

Pasithea Therapeutics Contact

Patrick Gaynes
Corporate Communications
pgaynes@pasithea.com

FAQ

What are the key findings from KTTA's Phase 1 trial of PAS-004?

The trial showed up to 91% inhibition of pERK, demonstrating strong target engagement. A stage 4 pancreatic cancer patient achieved -9.8% tumor volume reduction over 5 months of treatment.

What types of cancer is Pasithea Therapeutics' PAS-004 targeting?

PAS-004 is being developed for neurofibromatosis type 1 (NF1) and other MAPK pathway driven cancer indications, targeting patients with RAS, NF1 or RAF mutations.

What is the safety profile of KTTA's PAS-004 in the Phase 1 trial?

PAS-004 demonstrated a favorable safety profile, with no rash observed and doses being well-tolerated at the tested levels (8mg, 15mg capsules, and 4mg tablets).

What is the design of Pasithea's Phase 1 trial for PAS-004?

The trial is a multi-center, open-label, dose escalation 3+3 study evaluating safety, tolerability, pharmacokinetic, pharmacodynamic, and preliminary efficacy in patients with MAPK pathway driven advanced solid tumors.