Pasithea Therapeutics (NASDAQ:KTTA) outlined the rationale, early clinical profile and market opportunity for its lead MEK inhibitor candidate, PAS-004, during a virtual key opinion leader event focused on neurofibromatosis type 1, or NF1.
Chief Executive Officer Tiago Reis Marques said the company is developing PAS-004 for two NF1 manifestations: plexiform neurofibromas, or PNs, and cutaneous neurofibromas, or cNFs. NF1 is a genetic disorder associated with dysregulation of the RAS signaling pathway, which can lead to growth of tumors affecting nerves and skin.
PAS-004 Designed for Chronic Dosing
Chief Medical Officer Kartik Krishnan said PAS-004 is a macrocyclic MEK inhibitor designed to combine activity, tolerability and once-daily dosing for chronic use. He said the molecule’s structure is intended to support bioavailability and a long half-life while avoiding reactive primary alcohols that could be converted into toxic metabolites.
Pasithea initially evaluated PAS-004 in a Phase I study in advanced solid tumors. Krishnan reported no dose-limiting toxicities, no treatment-related grade 3, 4 or 5 adverse events, and no discontinuations attributed to treatment-related adverse events among patients discussed in the presentation. The company also reported low rates of rash and diarrhea, known risks associated with MEK inhibitors.
Of 34 patients included in a treatment-duration analysis, four had received treatment for more than 300 days, although three were described as too newly enrolled for inclusion in the longer-duration assessment. Two patients with BRAF V600E-mutant recurrent metastatic melanoma remained on treatment for more than 500 days after previously failing a combination of BRAF and MEK inhibitors, according to Krishnan.
He also cited a half-life of nearly 60 hours and a steady-state pharmacokinetic profile in which the ratio of minimum to maximum concentration was less than 1.5. Krishnan said the company believes sustained pathway suppression, rather than brief and complete pathway shutdown, may be important for genetic conditions such as NF1.
Challenges in Plexiform Neurofibromas
Rebecca Brown, director of the Neurofibromatosis and Schwannomatosis Program at the University of Alabama at Birmingham, said approximately half of people with NF1 develop PNs. Based on 2021 U.S. census estimates, she cited roughly 137,000 people in the U.S. with NF1, including about 68,000 with PNs and an estimated 51,000 with symptomatic PNs.
Brown said PNs can be painful, disfiguring, progressive and difficult to remove surgically because they are infiltrative and fed by large blood vessels. She said approximately 13% of patients with PNs are at risk of malignant sarcoma.
While MEK inhibitors are approved for PNs, Brown said only about 5% of patients with PNs are taking one. She attributed the gap in part to adverse effects, treatment complexity and the challenges of managing patients over potentially long treatment durations. She said the goal of treatment is often about two years, though patients may remain on therapy indefinitely because benefit generally continues only while treatment continues.
Brown noted that side effects of currently available MEK inhibitors can include rash, nail infections, gastrointestinal symptoms, fluid retention, fatigue, musculoskeletal pain, cardiac effects and vision-related risks. She said dermatologic adverse events are particularly common and that tolerability is a critical consideration for patients who may already face pain, deformity and gastrointestinal issues related to NF1.
“Safety” should rank highly alongside efficacy for chronic treatment, Brown said during the question-and-answer session. She added that some parents and clinicians may defer treatment in children because of concerns about toxicity.
Cutaneous Neurofibromas and Quality of Life
Kavita Sarin, a dermatologist at Stanford who directs the Skin Cancer Genetics Clinic at the Stanford Cancer Institute, said cNFs affect more than 95% of adults with NF1. These benign nerve-sheath tumors can begin appearing in childhood and puberty and may continue to accumulate throughout life.
In a Stanford cohort of 583 adults aged 40 and older, two-thirds had more than 100 cNFs visible in submitted photographs and one-third had more than 500, Sarin said. Facial involvement was present in nearly 90% of participants. She said quality of life worsened with greater tumor number and size, as well as facial involvement, with emotional effects particularly prominent.
Current cNF treatment is primarily procedural, including excision, laser ablation, electrodesiccation and radiofrequency treatment, Sarin said. While these options can remove individual lesions or treat multiple lesions, they can leave scars, do not prevent new tumors and may not be practical for patients with hundreds of lesions.
Sarin said published data from an 11-patient oral selumetinib pilot study showed a median best tumor-volume reduction of 28.5%, with six of eight evaluable participants achieving at least 20% shrinkage. However, all participants experienced a treatment-related side effect and only four of the 11 enrolled patients completed the study, she said.
She also discussed a topical nedometinib gel trial in 199 adults. In that study, 44% of patients receiving the high-dose gel met the study’s volume-responder definition, compared with 24% receiving vehicle. Local reactions led about one-quarter of patients in the high-dose group to discontinue treatment, she said.
NF1 Study Design and Commercial Estimates
Marques said Pasithea’s Study 103 is a Phase I/Ib, open-label, 3+3 dose-escalation study in adults with NF1 and symptomatic PNs. Six once-daily dose cohorts ranging from 4 milligrams to 24 milligrams are open. The study includes six months of treatment followed by an extension of up to 12 months.
The trial assesses both PNs and cNFs. Up to seven cNFs per patient are measured using digital calipers, while PN assessments use MRI at specified intervals. Pasithea also plans to resect a target cNF at cycle one and cycle six for pharmacodynamic analysis.
Marques said lower-dose cohorts have passed cycle 12, while higher-dose cohorts have had less exposure. He cautioned that PN responses may deepen over time and said timing should be considered when interpreting initial data.
The company said it expects to present initial PN and cNF data at the European Neurofibromatosis Conference scheduled for Nov. 12-14. Marques also said Pasithea’s second investigational new drug application in NF1, covering a cNF trial, is active with the FDA’s dermatology division.
Pasithea estimates that more than 80,000 U.S. patients with cNFs have more than 50 lesions and could represent the primary target population for systemic treatment. For PNs, the company estimates about 16,000 U.S. patients have symptomatic, unresectable disease, where MEK inhibitors are the approved systemic treatment option. The company said it holds FDA fast-track and rare pediatric disease designations for its NF1 PN program.
About Pasithea Therapeutics (NASDAQ:KTTA)
Pasithea Therapeutics Corp. is a biotechnology company focused on developing treatments for central nervous system (CNS) disorders. Its research has centered on novel therapies for conditions such as depression and other neuropsychiatric diseases, areas in which existing treatments may not provide adequate results for all patients.
The company has also pursued psychedelic-based therapeutic approaches and related clinical-development programs. In addition to drug discovery, Pasithea has explored treatment-delivery activities, including ketamine-assisted therapy services through operations associated with its business.
