- Results will be presented at the American Cough Conference on June 7, 2025

- NHP receptor occupancy studies indicate increasing the dose in Phase 2 from 20 mg to 40-80 mg is likely to significantly increase cough suppression before receptor saturation

- Oral administration in the Guinea pig model shows cough suppression up to 74% from baseline while staying under the NOAEL

- Durability of cough suppression over time promises cough control with TID dose regimen and opens opportunity for once daily reformulation

Seyltx, Inc. a clinical-stage biotherapeutics company focused on developing innovative therapies to treat chronic cough and other neuronal hypersensitivity indications, today announced promising preclinical results for its lead compound, Ifenprodil. These new findings, to be presented at the American Cough Conference on June 7, 2025, offer critical insights into optimal dosing strategies and therapeutic durability, which will significantly inform the design of upcoming Phase 2 crossover studies planned for 2026.

Ifenprodil, a NMDA antagonist with >200x selectivity towards the GluN2B subunit, is being developed to address refractory chronic cough (RCC), a significant unmet medical need, with a follow-on opportunity in chronic cough associated with Idiopathic Pulmonary Fibrosis (IPF-Cough). The company has already completed a Phase 2a trial in IPF-Cough at an exploratory low dose (20 mg TID) which yielded statistically significant reductions in objective cough count of 39% from baseline (at 12 weeks) and statistically significant improvement on multiple patient-reported outcomes.

A NHP receptor occupancy (RO) study, conducted in collaboration with Yale University, was performed whereby rhesus monkeys underwent 120-minute PET scans following the intravenous injection of 135 ± 64 MBq (S)-[18F]OF-NB1 (tracer molecule). Ifenprodil was administered via 10-minute intravenous infusion at doses from 0.025 to 1 mg/kg (corresponding to oral human equivalent doses (HED) of 10-400 mg), with PET acquisition commencing 15’ post-infusion.

• Dose-dependent GluN2B receptor occupancy was observed with a calculated EC50 (50% occupancy) of 0.04 mg/kg (HED of ~20 mg) and approximately 80% receptor occupancy predicted at 0.2 mg/kg (HED of ~80 mg).
• Doses between 40-80 mg TID are therefore expected to achieve 60-80% receptor occupancy, significantly enhancing therapeutic effects compared to the 20 mg TID dose used in the prior Phase 2a trial.

In vivo studies conducted in Guinea pigs (GPs; 6-16 animals per group) assessed the antitussive effect of oral doses of Ifenprodil ranging from 1.5 mg/kg to 12 mg/kg (human equivalent doses of 20 to 160 mg). Ifenprodil demonstrated statistically significant (p<0.01) cough count reduction across the dose range of 39-74% following exposure to a tussive agent (1M citric acid).

• The lowest tested dose of 1.5 mg/kg (HED of 20 mg) resulted in a 39.1% reduction in cough count from baseline, consistent with the 39% reduction seen in the Phase 2a trial.
• Doubling this dose to an HED of 40 mg TID, which is well-tolerated in humans, improved the cough suppression to 56.0% reduction from baseline.
• A maximal reduction of 74.4% from baseline was observed at 12 mg/kg (HED 160 mg), a dose under the estimated NOAEL.
• The therapeutic effect proved durable, lasting up to 8 hours, even as systemic levels of Ifenprodil were cleared. This robust target engagement at the GluN2B subunit supports durable cough control with a TID (three times daily) dose regimen and opens the door for potential once-daily reformulation.

These combined preclinical findings suggest an optimal human dose range of 40 to 80 mg for maximal therapeutic benefit, with the 80 mg dose yielding approximately 80% receptor occupancy, safely below levels that have shown adverse events in preclinical models.

"These compelling preclinical results represent a significant leap forward in our understanding of Ifenprodil’s potential to provide meaningful relief for patients suffering from chronic cough," said Dr. Dietrich Stephan, CEO of Seyltx. "The data not only confirms Ifenprodil’s robust antitussive properties but also provides invaluable guidance on optimizing our dosing strategy for future clinical trials. We are excited to integrate these learnings into the design of our upcoming Phase 2 studies, bringing us closer to delivering a truly impactful therapy for this debilitating condition."

Dr. Stephan further emphasized, "The promise of addressing GluN2B in the brain is that this target appears to be a central node in the cough reflex, likely providing significant cough control as a monotherapy without addictive potential across the population independent of etiology, if the preclinical data is translatable. The agent also has the potential to be used in combination with future peripherally acting therapies that might be approved."

Seyltx plans to incorporate these key learnings into the design of its Phase 2 crossover studies, slated to commence in 2026.

About Seyltx: Seyltx (www.seyltx.com) is a clinical stage biotherapeutics company focused on developing innovative therapies to treat chronic cough and other neuronal hypersensitivity indications. Its lead indication is refractory chronic cough, a significant unmet medical need, with a follow-on opportunity in chronic cough associated with Idiopathic Pulmonary Fibrosis (IPF-Cough). Seyltx's lead compound is Ifenprodil, an NMDA antagonist highly selective towards the GluN2B subunit, has completed a Phase 2a trial in chronic cough associated with IPF.

Forward-Looking Statements: Certain statements contained in this news release, other than statements of fact that are independently verifiable at the date hereof, may constitute "forward-looking statements" within the U.S. Private Securities Litigation Reform Act of 1995, as amended, and other applicable securities laws. Forward-looking statements are frequently, but not always, identified by words such as “expects,” “anticipates,” “believes,” “intends,” “estimates,” “potential,” “possible,” “projects,” “plans,” and similar expressions. Such statements, based as they are on the current expectations of management, inherently involve numerous important risks, uncertainties and assumptions, known and unknown, many of which are beyond Seyltx's control.

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"These compelling preclinical results represent a significant leap forward in our understanding of Ifenprodil’s potential to provide meaningful relief for patients suffering from chronic cough," said Dr. Dietrich Stephan, CEO of Seyltx.