Seyltx has announced significant preclinical advances for its lead chronic cough therapy Ifenprodil, with new non-human primate and guinea pig studies providing critical dosing insights that will inform upcoming Phase 2 trials. The clinical-stage biotherapeutics company simultaneously expanded its pipeline through a strategic option agreement with NeurOp for additional GluN2B antagonist compounds.
Receptor Occupancy Studies Guide Dose Optimization
Non-human primate receptor occupancy studies conducted in collaboration with Yale University revealed dose-dependent GluN2B receptor engagement following Ifenprodil administration. Rhesus monkeys underwent 120-minute PET scans after intravenous injection of the tracer molecule (S)-[18F]OF-NB1, with Ifenprodil administered at doses from 0.025 to 1 mg/kg.
The studies calculated an EC50 of 0.04 mg/kg, corresponding to a human equivalent dose of approximately 20 mg for 50% receptor occupancy. At 0.2 mg/kg (human equivalent of ~80 mg), approximately 80% receptor occupancy was predicted. These findings suggest that doses between 40-80 mg three times daily are expected to achieve 60-80% receptor occupancy, significantly enhancing therapeutic effects compared to the 20 mg dose used in prior Phase 2a trials.
Guinea Pig Studies Demonstrate Robust Antitussive Effects
Complementary in vivo studies in guinea pigs assessed oral Ifenprodil doses ranging from 1.5 mg/kg to 12 mg/kg (human equivalent doses of 20 to 160 mg). Following exposure to 1M citric acid as a tussive agent, Ifenprodil demonstrated statistically significant cough count reductions (p<0.01) across the entire dose range.
The lowest tested dose of 1.5 mg/kg (20 mg human equivalent) resulted in a 39.1% reduction in cough count from baseline, consistent with the 39% reduction observed in the company's Phase 2a trial. Doubling the dose to a 40 mg human equivalent improved cough suppression to 56.0% reduction from baseline, while the maximal reduction of 74.4% was observed at 12 mg/kg (160 mg human equivalent), a dose remaining under the estimated no observed adverse effect level.
Notably, the therapeutic effect proved durable, lasting up to 8 hours even as systemic Ifenprodil levels were cleared, supporting potential once-daily reformulation opportunities.
Strategic Pipeline Expansion Through NeurOp Partnership
Seyltx has entered an option agreement with NeurOp for a portfolio of eight novel GluN2B negative allosteric modulators, including NP10679, which has completed Phase 1 development. This agreement provides Seyltx with potential worldwide exclusive rights to develop and commercialize these compounds for chronic cough treatment.
"We are incredibly excited about this option agreement with NeurOp, which significantly strengthens our pipeline for chronic cough therapies," said Dr. Dietrich A. Stephan, Seyltx's CEO. "Refractory chronic cough impacts approximately 6 million people in the USA alone, representing a substantial unmet medical need."
The optioned compounds demonstrate excellent potency, selectivity, pharmacokinetics, solubility, and metabolism profiles, with strong intellectual property protection across all compounds. NP10679 offers the potential for differentiated performance compared to Ifenprodil while maintaining the ability to engage the GluN2B receptor below established safety thresholds.
Addressing Significant Unmet Medical Need
Ifenprodil, an NMDA antagonist with greater than 200-fold selectivity towards the GluN2B subunit, targets refractory chronic cough and chronic cough associated with idiopathic pulmonary fibrosis. The company's completed Phase 2a trial in IPF-associated chronic cough at 20 mg three times daily yielded statistically significant reductions in objective cough count of 39% from baseline at 12 weeks, along with statistically significant improvements on multiple patient-reported outcomes.
According to the company, chronic cough associated with IPF affects up to 140,000 people in the US and represents a primary driver of deteriorated quality of life for these patients. NMDA represents a validated therapeutic target in cough, with the only FDA-approved cough therapy being a non-specific NMDA antagonist.
Clinical Development Timeline
The 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 while remaining safely below levels associated with adverse events in preclinical models. Seyltx plans to incorporate these learnings into Phase 2 crossover studies scheduled to commence in 2026.
The option agreement with NeurOp has been approved by both companies' management, with conversion to an exclusive worldwide license agreement anticipated within 12 months. Results from the preclinical studies will be presented at the American Cough Conference on June 7, 2025.
