Pasithea Therapeutics (NASDAQ:KTTA) is advancing its oral MEK inhibitor, PAS-004, in neurofibromatosis type 1, or NF1, with initial clinical data from its ongoing study scheduled for presentation at the European Neurofibromatosis Conference next month.
Chief Executive Officer Dr. Tiago Reis Marques said NF1 is a genetic disorder caused by mutations in the NF1 gene, which produces the protein neurofibromin. Neurofibromin normally acts as a negative regulator of the RAS-RAF-MEK-ERK, or MAPK, pathway. When the protein is disrupted, the pathway becomes overactive, contributing to tumor formation.
According to Marques, NF1 affects approximately one in every 3,000 newborns, with an estimated 150,000 people in the United States living with the condition. Pasithea is pursuing two manifestations of NF1: cutaneous neurofibromas, which appear as skin lesions or bumps, and plexiform neurofibromas, which arise from deep nerves.
Cutaneous Neurofibroma Opportunity
Marques described cutaneous neurofibromas as a particularly burdensome manifestation for patients because they can number in the dozens, hundreds or thousands and may cause pain, itching, stigma and quality-of-life challenges. He said the condition affects more than 99% of patients with NF1.
He noted that lesions generally begin emerging around puberty and increase in number and volume over time. By age 50, more than 80% of participants in large cohorts have over 100 lesions, according to Marques.
There are no FDA-approved systemic therapies for cutaneous neurofibromas, he said. Current approaches can involve individually removing lesions through biopsy or laser procedures, which can leave small scars. Pasithea aims to develop what Marques said could be the first approved systemic treatment for the indication.
PAS-004 Design and Safety Focus
MEK inhibitors have expanded beyond oncology into other disease areas, but Marques said the safety profile of existing therapies has limited their use in more chronic, non-oncology settings. He cited rash, gastrointestinal toxicity, ocular toxicity and cardiac toxicity among the concerns associated with currently approved MEK inhibitors for NF1.
Pasithea designed PAS-004 as a macrocyclic MEK inhibitor intended for chronic use in non-oncology conditions, according to Marques. He said the drug has a rigid molecular structure and a roughly 60-hour half-life, which the company believes may help avoid the drug-concentration peaks and troughs associated with some existing therapies requiring twice-daily dosing.
Marques said PAS-004 is designed to enable partial pathway inhibition rather than full inhibition. He said efficacy may be achievable with approximately 50% to 60% pathway inhibition in plexiform neurofibromas and approximately 25% to 50% inhibition in cutaneous neurofibromas, potentially reducing safety liabilities.
Upcoming Clinical Data
The company is in the dose-escalation portion of its Phase Ib NF1 trial, evaluating six dose cohorts ranging from 4 milligrams to 24 milligrams. The study measures plexiform neurofibroma size using MRI scans and cutaneous neurofibroma size using digital calipers.
The planned conference presentation will include data from 18 patients and roughly 70 lesions across both manifestations, according to the discussion.
For cutaneous neurofibromas, Marques said the primary measure of success would be evidence of meaningful lesion-volume reductions. For plexiform neurofibromas, he said investors and clinicians should focus initially on the trajectory of tumor-volume change, as approved therapies selumetinib and mirdametinib have average response times of approximately seven to eight months.
Patient time on treatment varies by cohort. Some participants in lower-dose groups have been treated for more than a year, while patients in higher-dose cohorts have been enrolled for about four to six months, Marques said. He added that safety, including dose reductions, interruptions, discontinuations and serious adverse events, will be an important component of the data review.
Regulatory Paths and Next Steps
Although both conditions involve neurofibromas, Marques said plexiform and cutaneous manifestations are overseen by different FDA divisions. Plexiform neurofibroma development falls under the Division of Oncology, while cutaneous neurofibroma development would proceed through the Division of Dermatology.
For plexiform neurofibromas, he said prior MEK inhibitor approvals have followed Phase II registrational pathways, including comparisons against historical controls or placebo. For cutaneous neurofibromas, Pasithea expects a large Phase II study evaluating lesion-volume reductions alongside patient-reported outcomes or an Investigator Global Assessment tool, followed by a single Phase III registrational trial.
Over the next 12 months, Pasithea expects to present its initial data, select doses for the expansion portion of its study around the first or second quarter of next year, and seek an investigational new drug application with the FDA’s Division of Dermatology for a Phase II cutaneous neurofibroma trial, Marques said.
About Pasithea Therapeutics (NASDAQ:KTTA)
Pasithea Therapeutics Corp. is a biotechnology company focused on developing treatments for central nervous system disorders and other serious diseases. The company’s research has included novel pharmaceutical therapies as well as psychedelic- and ketamine-assisted treatment approaches for conditions such as depression and other mental health disorders.
Pasithea’s development portfolio has included PAS-004, an orally administered MEK1/2 inhibitor designed to affect the RAS/MAPK signaling pathway.
