GluN2B modulators(Janssen R&D)

- Results will be presented at the London International Cough Symposium on July 18, 2024 - Dose dependent cough suppression to >90% in vivo with no effect on basal respiratory rates - Multiple doses shows statistically significant reductions in coughs well below the NOAEL - Design of SILINDA Phase 2b clinical trial in refractory chronic cough unveiled - First patient expected to be enrolled in early 2025 CAMBRIDGE, Mass., July 16, 2024 (GLOBE NEWSWIRE) -- Seyltx, Inc. (“Seyltx” or the “Company”), a clinical-stage biopharmaceutical company developing a novel therapy for the treatment of refractory chronic cough (“RCC”) and other neuronal hypersensitivity indications including cough associated with idiopathic pulmonary fibrosis (“IPF”), today announced positive pre-clinical data describing near-complete cough suppression in a dose-dependent manner below the no observed adverse effect level dose (“NOAEL”). Based on this data, the Company unveiled details and timing of the SILINDA Phase 2b program for its highly selective GluN2B allosteric antagonist product candidate for the treatment of RCC. “A subunit of NMDA receptor, GluN2B, appears to be the gatekeeper of the cough reflex in the deep brain. Our orally delivered small molecule selectively targets GluN2B and deflects the sustained high-frequency firing coming from the lungs in response to diverse triggers to stop the cough reflex. The successful completion of this pre-clinical dose-ranging study, together with our human Phase 2a efficacy data, validates the target as a central node in this pathogenic process and informs our dosing regimen for our upcoming Phase 2b trial in RCC,” commented Dietrich A. Stephan, Ph.D., President and Chief Executive Officer of Seyltx. “We are now well positioned to execute our SILINDA Phase 2b program, and we look forward enrolling our first patient in 2025.” The dose-ranging study was designed as follows: 5-9 Guinea pigs (“GPs”) per dose group were injected intraperitoneally with either a vehicle control or ifenprodil at 1, 3, 10 and 30 mg/kg followed 30 minutes later by 0.1M aerosolized citric acid for 10 minutes and 5 minutes later by 0.3M citric acid for 10 minutes followed by a 5-minute washout. Cumulative cough counts and bouts were measured across the exposure and washout periods. The key results are as follows: Increasing the dose of ifenprodil reduced cough bouts in the GP model in a dose-responsive manner with the median number of bouts evoked totaling 12, 9, 8, 6 and 1 in animals treated with vehicle, 1, 3, 10 and 30 mg/kg ifenprodil, respectively.Statistically significant reductions in bouts of p<0.05 were seen at 3, 10 and 30 mg/kg. There was no respiratory depression observed at any dose, a concern clinically with other antitussives and an issue seen preclinically with both codeine and baclofen.Effect sizes of cumulative cough count reductions and associated statistical significance were high in lower cough count animals, consistent with the Phase 2a data, bolstering the opportunity for a broad label to include patients with both high and low cough counts if subsequent trials are successful.The GP-equivalent NOAEL dose is 37 mg/kg based on 52-week rat GLP toxicology data, defining a significant therapeutic index within which to work to likely achieve statistically significant cough count reductions above placebo in the clinic. “The dramatic cough suppression effects observed occur below the NOAEL dose and with no apparent impact on overall respiration,” commented Brendan Canning, Ph.D., Professor of Medicine at Johns Hopkins University School of Medicine, and a member of the Seyltx Scientific Advisory Board. “These data give us confidence in ifenprodil’s potential to be a best-in-class treatment option for RCC patients.” Based on the FDA's feedback, the SILINDA program is currently structured to include three dose arms and a placebo arm, evaluating the efficacy, safety and tolerability of ifenprodil in approximately 240 adults with RCC. SILINDA is planned to be a placebo-controlled, parallel-arm trial randomized 1:1:1:1 with expected treatment arms of 40 mg TID, 80 mg TID, 120 mg TID, and placebo. The primary endpoint of 24-hour cough frequency will be measured at 12 weeks. The SILINDA Phase 2b program’s primary endpoint will be assessed using the VitaloJAK® cough monitoring system in a patient population that is not stratified for baseline 24-hour cough frequency given the uniform efficacy seen in the Phase 2a open label study across both low and high cough count patients. Key exploratory efficacy endpoints include the Cough Severity using Visual Analogue Scale (“CS-VAS”), the Leicester Cough Questionnaire (“LCQ”) and real-time longitudinal cough monitoring. Topline data from SILINDA are expected approximately at the end of 2026. “We believe that the preclinical and clinical data to date are compelling and look forward to working with the broader clinical community on our Phase 2b trial,” commented Jacky Smith, MB, ChB, FRCP, PhD, professor of respiratory medicine at the University of Manchester and a member of the Seyltx Scientific Advisory Board. “We plan to incorporate all the recent learnings related to topics such as optimal placebo run-in and clinical endpoints to maximize SILINDA’s probability of success. Given the effect sizes we are seeing, the potential to work across a broad patient population, and the uniqueness of the target, this product candidate could benefit millions of patients suffering with this untreatable disorder.” The results of this study will be presented on July 18, 2024, at the London International Cough Symposium and published in the Journal of Thoracic Disease. About Ifenprodil Ifenprodil, a highly selective GluN2B allosteric antagonist, is in development for RCC and other neuronal hypersensitivity indications, including cough associated with IPF. An open-label Phase 2a trial was performed that showed a ~40% reduction in geometric mean cough counts (p<0.01) from baseline at a 20mg TID dose, with 80% of patients responding as measured by 24 hour counts by the VitaloJAK® device. Individual patient data in this Phase 2a trial illustrated that 90% of patients responded as measured by reductions in CS-VAS scores (p<0.001). Improvements were also seen on the LCQ (p<0.05). Reductions in 24-hour cough counts were equally seen in high and low cough count patients, and the mean and median responses were similar further illustrating that a few outliers did not drive the overall therapeutic effect of the trial cohort. The GluN2B receptor, which is implicated in transmission of sustained high-frequency firing from the vagal afferent neurons to cough centers in the brain, is a rational target for treating chronic cough. Non-selective NMDA receptor antagonists have been evaluated in multiple pre-clinical and clinical trials and have been shown to be antitussive, but these non-selective NMDA channel blockers have associated dose-limiting adverse events (“AEs”). These AEs are linked to the broad expression of NMDA receptors throughout the brain which are responsible for a myriad number of functions. The Company was founded on research led by Johns Hopkins University researchers, where expression profiling of NMDA receptor subunit types in the nucleus of the solitary tract in the medulla, where the vagal afferent neurons terminate, identified GluN2B as a target of interest. Ifenprodil is an approved drug in Japan and South Korea but is considered a new chemical entity (“NCE”) in the major global markets, allowing the Company to de-risk development due to extensive safety data which includes a lack of AEs typically associated with non-selective NMDA receptor blockers, while simultaneously obtaining maximum exclusivity and intellectual property protection. Seyltx believes that its highly selective GluN2B antagonist has the potential to reduce cough frequency in patients with RCC and improve quality of life while limiting the AEs associated with non-selective NMDA receptor blockade by focusing on mitigation of the relatively unique sustained high-frequency firing of the vagal afferent neurons. The Company is evaluating potential opportunities to study ifenprodil in additional cough indications where vagal afferent neuronal hypersensitivity plays an important role such as cough associated with IPF. About Seyltx (www.seyltx.com) Seyltx is a clinical-stage biopharmaceutical company developing novel therapeutics for the treatment of RCC and other neuronal hypersensitivity indications. The Company's product candidate ifenprodil, recently acquired from Algernon Pharmaceutical Corporation, has successfully completed a Phase 2a trial in cough associated with IPF. Seyltx is planning a Phase 2b program, named SILINDA (Selective IfenprodiL INhibition of NMDA), which is expected to have the first patient enrolled in early 2025. Chronic cough is a cough lasting longer than eight weeks. When the cause of chronic cough cannot be identified or the cough persists despite treatment of all identified associated causes, the condition is referred to as RCC. Based on the Company’s real-world evidence analysis, it is estimated that there are at least 5.9 million adult patients in the United States suffering from RCC. RCC is associated with significant adverse physical, social, and psychological effects on health and quality of life. Currently, there is no specific therapy approved for RCC and treatment options are limited. The Company is exploring the potential use of ifenprodil in other patient populations experiencing cough hypersensitivity as well as other neuronal hypersensitization conditions. 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. Such statements include, but are not limited to, the potential of ifenprodil to successfully treat RCC and other hypersensitization-related disorders and benefit such patients, Seyltx’s expectations related to its preclinical studies and clinical trials, including the timing of initiation of and the design of its Phase 2b clinical trial of ifenprodil in RCC, the timing and outcome of interactions with regulatory agencies, the potential activity and tolerability profile, selectivity, potency and other characteristics of ifenprodil, including as compared to other competitor candidates, especially where head-to-head studies have not been conducted and cross-trial comparisons may not be directly comparable due to differences in study protocols, conditions and patient populations, the commercial potential of ifenprodil, including with respect to patient population, pricing and labeling, Seyltx’s financial position and sufficiency of cash resources to bring through topline results with SILINDA, and the potential applicability of ifenprodil and Seyltx’s GlunN2B platform to treat other disorders. Risk factors that may affect Seyltx’s future results include but are not limited to: the benefits and impact on label of its non-enrichment strategy, estimates and projections regarding the size and opportunity of the addressable RCC market for ifenprodil, the ability to expand and develop its project pipeline, the ability to obtain adequate financing, the ability of Seyltx to maintain its rights to intellectual property and obtain adequate protection of future products through such intellectual property, the impact of general economic conditions, general conditions in the pharmaceutical industry, the impact of the ongoing COVID-19 pandemic on Seyltx’s operations, plans and prospects, including to the initiation and completion of clinical trials in a timely manner or at all, changes in the regulatory environment in the jurisdictions in which Seyltx does business, supply chain impacts, stock market volatility, fluctuations in costs, changes to the competitive environment due to consolidation, achievement of forecasted burn rate, achievement of forecasted preclinical study and clinical trial milestones, reliance on third parties to conduct preclinical studies and clinical trials for ifenprodil and that actual results may differ from topline results once the final and quality-controlled verification of data and analyses has been completed. In addition, the length of Seyltx’s product candidate’s development process and its market size and commercial value are dependent upon a number of factors. Moreover, Seyltx’s growth and future prospects are mainly dependent on the successful development, patient tolerability, regulatory approval, commercialization and market acceptance of its product candidate ifenprodil and other products. Consequently, actual future results and events may differ materially from the anticipated results and events expressed in the forward-looking statements. Seyltx believes that expectations represented by forward-looking statements are reasonable, yet there can be no assurance that such expectations will prove to be correct. The reader should not place undue reliance, if any, on any forward-looking statements included in this news release. These forward-looking statements speak only as of the date made, and Seyltx is under no obligation and disavows any intention to update publicly or revise such statements as a result of any new information, future event, circumstances or otherwise, unless required by applicable legislation or regulation. CONTACT Matt LaneInvestor RelationsMilestone Advisors, LLCmatt@milestone-advisorsllc.com