Randomized, Double-Blinded, Vehicle-Controlled, Crossover Phase 2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intranasal Cenegermin (Recombinant Human Nerve Growth Factor [rhNGF]) in Pediatric Participants with Spastic Cerebral Palsy (CP).

The primary objective is to evaluate the safety and tolerability of intranasal cenegermin in pediatric participants with spastic cerebral palsy. This assessment is clinically relevant for determining whether this recombinant human nerve growth factor (rhNGF) formulation can be safely administered via the intranasal route in this vulnerable patient population.

The secondary objectives include:

• To evaluate the long-term safety and tolerability of intranasal cenegermin in pediatric participants with spastic cerebral palsy.

• To evaluate motor outcomes of pediatric participants with spastic cerebral palsy treated with intranasal cenegermin compared to vehicle.

• To evaluate neurodevelopmental function in pediatric participants with spastic cerebral palsy treated with intranasal cenegermin compared to vehicle.

• To determine the systemic pharmacokinetic characteristics of intranasal cenegermin in pediatric participants with spastic cerebral palsy treated with intranasal cenegermin compared to vehicle.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of **pediatric participants** between **2 and 6 years of age**, including both **male** and **female** subjects. Participants have a confirmed diagnosis of predominantly **spastic cerebral palsy** with a **spasticity score** of ≥2 on the **Modified Ashworth Scale (MAS)** in at least one joint. The trial includes children classified across all **Gross Motor Function Classification System – Expanded & Revised (GMFCS-E&R)** levels I through V. Eligible participants must have a **body weight** of at least 8 kg, with those exceeding 30 kg considered on a case-by-case basis with potential dosing modifications. A key lifestyle consideration for inclusion is that participants must be currently receiving **physical therapy** and/or **occupational therapy** for a minimum of 3 months prior to enrollment and throughout the study duration. This trial involves a **vulnerable population** due to the pediatric age group and the nature of the neurological condition being studied.

This is a randomized, double-blind, vehicle-controlled, crossover Phase 2 clinical trial designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intranasal cenegermin (recombinant human nerve growth factor) in pediatric participants with spastic cerebral palsy. The primary objective is to assess the safety and tolerability of intranasal cenegermin in this patient population. The investigational product is a lyophilized rhNGF-based intranasal solution administered as a nasal spray, powder for solution, delivered via a CE-marked intranasal delivery device. The active substance, cenegermin, is a protein of non-chemical origin. The placebo formulation is identical to the active drug product except that it does not contain cenegermin. The maximum treatment period per participant is 28 days. The study is expected to begin recruitment in November 2025 and is estimated to conclude in November 2028.

Eligible participants include male and female children aged 2 to 6 years with a confirmed diagnosis of predominantly spastic cerebral palsy, demonstrating a spasticity score of at least 2 on the Modified Ashworth Scale (MAS) in at least one joint. Participants must have a Gross Motor Function Classification System – Expanded & Revised (GMFCS-E&R) level of I, II, III, IV, or V, a body weight of at least 8 kg, and must be currently receiving physical and/or occupational therapy for at least 3 months prior to informed consent and throughout the study duration. Participants weighing more than 30 kg may be included at the investigator's judgment following medical monitor review, with dosing modifications applied as necessary.

The primary endpoint is the incidence of treatment-emergent adverse events following the first administration of the investigational product. Secondary endpoints include the incidence of treatment-emergent serious adverse events (SAEs), treatment-emergent non-serious adverse events, and study discontinuation for tolerability reasons. Additional safety assessments include changes in vital signs, weight and height, physical examinations, clinical laboratory assessments, 12-lead electrocardiogram (ECG) results, and electroencephalogram (EEG) results. Pharmacodynamic endpoints include changes in the MAS score, patient-reported outcome measures (PROM), Gross Motor Function Measure-66 (GMFM-66), and GMFCS-E&R. Changes in daily activities, social and cognitive domains as assessed by the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and communication function as assessed by the Communication Function Classification System (CFCS) are also evaluated. Pharmacokinetic assessments include measurement of nerve growth factor (NGF) serum concentrations.

The trial employs a crossover design in which each participant receives both the active treatment and placebo in a randomized sequence. The screening visit serves to confirm eligibility and obtain informed consent from the participant's legally authorized representative. Following enrollment, participants undergo a series of study visits during which the investigational product is administered and safety, tolerability, pharmacokinetic, and pharmacodynamic assessments are performed. Follow-up visits are scheduled to monitor ongoing safety and evaluate treatment effects. The end-of-study visit marks the completion of participant involvement and includes final assessments. The expected length of participant involvement is determined by the treatment period and follow-up duration as specified in the protocol. Early termination from the study may occur due to tolerability issues, withdrawal of consent, protocol violations, or at the discretion of the investigator if continuation is deemed not in the participant's best interest.

The experimental medication under investigation is **cenegermin**, a **recombinant human nerve growth factor (rhNGF)** formulated as a lyophilized **nasal spray, powder for solution**. Cenegermin is classified as a protein-based active substance and is manufactured by Dompé Farmaceutici SpA. The investigational product is administered via the **intranasal route** using a CE-marked intranasal delivery device. The maximum treatment period for cenegermin administration is **28 days**. The dosage is expressed in **micrograms per kilogram (µg/kg)** body weight, though specific dose amounts are determined according to the study protocol. The pharmaceutical form requires reconstitution prior to administration to prepare the intranasal solution.

The **placebo** comparator used in this study is formulated identically to the cenegermin drug product with the exception that it does not contain the active substance cenegermin. This vehicle-controlled placebo maintains the same composition and appearance as the active treatment to ensure blinding integrity throughout the double-blinded crossover study design. The placebo is administered using the same intranasal route and delivery device as the active treatment to maintain consistency in the administration procedure and participant experience across treatment periods.

Both the experimental medication and placebo are administered according to a crossover design, whereby participants receive both treatments in sequence during separate treatment periods. The intranasal delivery device facilitates consistent and standardized administration of both the active drug product and placebo. Participant compliance monitoring and adherence to the dosing schedule are maintained throughout the study duration to ensure reliable safety, tolerability, **pharmacokinetic**, and **pharmacodynamic** assessments in the pediatric population with **spastic cerebral palsy**.

Efficacy will be assessed through multiple parameters in this clinical trial. The primary efficacy endpoint is the incidence of treatment-emergent adverse events following the first administration of investigational product. Secondary efficacy endpoints include change in the Modified Ashworth Scale (MAS) score, patient-reported outcome measures (PROM), Gross Motor Function Measure-66 (GMFM-66), and Gross Motor Function Classification System – Expanded & Revised (GMFCS-E&R). Additional secondary endpoints encompass the incidence of treatment-emergent serious adverse events, treatment-emergent nonserious adverse events, and study discontinuation for tolerability reasons. Changes in vital signs, weight and height, physical examinations, clinical laboratory assessments, 12-lead electrocardiogram results, and electroencephalogram results will also be evaluated. Further assessment will include changes in daily activities and social/cognitive domains as measured by the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and changes in communication function as assessed by the Communication Function Classification System (CFCS). Nerve growth factor (NGF) serum concentrations will be measured as part of the pharmacodynamic evaluation.