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