FDA Grants Fast Track Designation to PAS-004 for NF1-Associated Plexiform Neurofibromas

The FDA has granted fast track designation to PAS-004, a next-generation macrocyclic MEK inhibitor, for the treatment of neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PN) causing significant morbidity.¹ The designation is intended to facilitate development and expedite review of therapies that address unmet medical needs in serious or life-threatening conditions.

PAS-004 is currently under investigation in a phase 1/1b multicenter, open-label, dose-escalation trial (NCT06961565) enrolling adult patients with symptomatic, inoperable, incompletely resected, or recurrent NF1-associated PN . The agent is also being evaluated in a separate phase 1 trial (NCT06299839) in patients with advanced solid tumors harboring NF1, RAF, or RAS mutations or who have progressed on BRAF/MEK inhibitor therapy.

Fast Track Designation and Its Implications

Fast track designation is one of the FDA's expedited programs designed to facilitate the development and review of drugs that demonstrate potential to address unmet medical needs in serious or life-threatening conditions.² Products with fast track designation may also be eligible for accelerated approval and/or priority review if relevant criteria are met.

"We appreciate the FDA's decision that PAS-004 meets the criteria for fast track designation for this indication," said Tiago Reis Marques, MD, PhD, chief executive officer of Pasithea Therapeutics, in a news release.¹ "The ability to have early and frequent interactions with the FDA supports our goal to expeditiously develop PAS-004 for patients with NF1-associated PN causing significant morbidity."

Disease Background: NF1-Associated Plexiform Neurofibromas

NF1 is an autosomal dominant RASopathy caused by loss-of-function mutations in the NF1 gene, which encodes neurofibromin, a tumor suppressor that negatively regulates the RAS/MAPK signaling pathway. The condition affects approximately 1 in 2000 to 6000 individuals.³ Plexiform neurofibromas are tumors originating from the nerve sheath that grow through and around nerves and may involve multiple nerve branches. An estimated 30% to 50% of patients with NF1 harbor PN, which can undergo malignant transformation to become malignant peripheral nerve sheath tumors.^1,4 PN-related morbidities are primarily caused by the direct impact of the tumor on surrounding structures and can be life-threatening when they compress vital organs or undergo malignant transformation. Surgical outcomes for PN are often poor due to the diffuse, infiltrative nature of these tumors.⁴

Current Treatment Landscape

MEK inhibitors have become central to the treatment of NF1-associated PN, targeting the overactive RAS/MAPK pathway that drives tumor growth. Two MEK inhibitors are currently FDA-approved for symptomatic, inoperable PN: selumetinib (Koselugo) and mirdametinib (Gomekli). Selumetinib was initially approved in April 2020 for pediatric patients aged 2 years and older with NF1 and symptomatic, inoperable PN, based on data from the SPRINT trial. In November 2025, the FDA expanded the selumetinib indication to include adults, based on results from the phase 3 KOMET trial (NCT04924608), in which the confirmed overall response rate was 20% (95% CI, 11%-31%) in the selumetinib arm vs 5% (95% CI, 2%-13%) in the placebo arm (P =.011), with 86% of responders achieving a duration of response of at least 6 months.⁵ Despite these advances, the modest response rates and toxicity profile of available agents underscore the continued need for additional therapeutic options.

PAS-004: Mechanism and Early Clinical Data

PAS-004 is a next-generation macrocyclic MEK inhibitor designed to address limitations of earlier-generation agents. Its macrocyclic structure is intended to confer greater selectivity and a distinct pharmacokinetic profile compared with conventional MEK inhibitors. In the ongoing Phase 1 trial in advanced solid tumors (NCT06299839), preliminary data from the first 2 dosing cohorts (2 mg and 4 mg; n = 6) demonstrated a favorable safety profile, with no drug-related dose interruptions, reductions, or discontinuations, and no drug-related serious adverse events observed at any dose level. No rash, skin toxicity, gastrointestinal toxicity, or ocular toxicity was reported at these dose levels.6 Pharmacokinetic analyses showed dose-proportional plasma exposure with a mean half-life of approximately 67.9 hours and a Cmax/Cmin ratio of 1.2 at steady state, suggesting minimal plasma concentration fluctuation.6 This prolonged half-life—substantially longer than the sub-8-hour half-lives reported for earlier-generation MEK inhibitors used in NF1—may support once-daily or less frequent dosing and sustained target inhibition while potentially reducing peak plasma toxicities.

In the NF1-specific phase 1/1b trial (NCT06961565), PAS-004 tablets demonstrated dose-proportional, predictable pharmacokinetics with lower variability than the capsule formulation. Dose-normalized exposures following once-daily administration of PAS-004 tablets were approximately 3-fold higher than those following capsule administration, and the agent exhibited a long half-life of approximately 57 hours with a steady-state peak-to-trough ratio below 2.⁷

REFERENCES

1. Pasithea Therapeutics announces grant of fast track designation by FDA to PAS-004 for treatment of neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) causing significant morbidity. News release. Pasithea Therapeutics Corp; April 1, 2026. Accessed April 2, 2026. https://tinyurl.com/2wpb4exc

2. Fast Track. US Food and Drug Administration. Accessed April 2, 2026. https://tinyurl.com/y748ywj9

3. Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017;3:17004. doi:10.1038/nrdp.2017.4

4. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430-1442. doi:10.1056/NEJMoa1912735

5. FDA approves selumetinib for adults with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. US Food and Drug Administration. November 19, 2025. Accessed April 2, 2026. https://tinyurl.com/nydz6aja

6. 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 April 2, 2026. https://tinyurl.com/257f25pm

7. Pasithea Therapeutics announces positive PAS-004 tablet pharmacokinetic (PK) data in ongoing phase 1/1b trial in adult NF1 patients. News release. Pasithea Therapeutics Corp. November 21, 2025. Accessed April 2, 2026.https://tinyurl.com/mtr53uck