Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of FNP-223 in Progressive Supranuclear Palsy to Evaluate Efficacy and Safety

The primary objective of this Phase 2 study is to evaluate the **efficacy** of FNP-223 in slowing the progression of **progressive supranuclear palsy (PSP)**, as measured by the PSP Rating Scale (PSPRS) over a period of 52 weeks. Additionally, the study aims to assess the safety and tolerability of FNP-223 in participants with PSP over the same duration. This is clinically relevant as PSP is a progressive neurodegenerative disorder with limited treatment options, and slowing its progression could significantly impact patient outcomes.

Secondary objectives include:

• Assessing the effects of FNP-223 on disease severity using a clinical global scale.
• Evaluating the effects of FNP-223 on patient and caregiver perception of disease severity.
• Investigating the effects of FNP-223 on cognitive function and additional health-related quality of life parameters.
• Characterizing the pharmacokinetic profile of FNP-223 and its active metabolite in participants with PSP.

The clinical trial involves a total of **80 participants** diagnosed with **progressive supranuclear palsy (PSP)**. The study population includes both male and female subjects, aged between **50 to 80 years**. Participants were selected based on specific criteria, including the ability to understand and provide informed consent, and the presence of a caregiver or study partner. The trial population is characterized by individuals who have been diagnosed with possible or probable PSP-RS phenotypes, as per the MDS PSP clinical features criteria. Participants must have experienced PSP symptoms within three years prior to screening and have a full 28-item PSP Rating Scale score of 40 or less. They should be able to ambulate independently or with minimal assistance and have a MoCA score of 23 or higher. The body weight of participants ranges from 43 kg (95 lbs) to 120 kg (265 lbs). Participants reside outside skilled nursing or dementia care facilities, although those in assisted living facilities are included. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study aims to assess the efficacy and safety of FNP-223 in slowing disease progression over a 52-week period.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 2 study to evaluate the efficacy, safety, and pharmacokinetics of the investigational product FNP-223 in participants with **progressive supranuclear palsy (PSP)**. The trial aims to assess the ability of FNP-223 to slow disease progression over a period of 52 weeks, as measured by the PSP Rating Scale (PSPRS). The study will also evaluate the safety and tolerability of FNP-223 during this period. Participants will be randomly assigned to receive either the active treatment or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the trial.

The trial will span approximately two years, with an estimated recruitment start date in September 2024 and an anticipated end date in November 2026. Participants will be involved in the study for a total of 52 weeks, during which they will attend multiple study visits. The sequence of study visits includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis of PSP, and ability to ambulate independently. Following successful screening, participants will undergo baseline assessments before commencing the treatment phase.

Throughout the trial, participants will attend regular follow-up visits to monitor their health status, assess the efficacy of the treatment, and record any adverse events. These visits will include evaluations of vital signs, clinical laboratory tests, and assessments using various scales, such as the Clinician Global Impression of Severity scale and the Montreal Cognitive Assessment. The end-of-study visit will occur at the conclusion of the 52-week treatment period, where final assessments will be conducted to evaluate the overall impact of the treatment.

Participant involvement may be terminated early if certain conditions arise, such as the occurrence of serious adverse events, non-compliance with study procedures, or withdrawal of consent. The primary endpoints of the study include changes from baseline to Week 52 in the total score of the PSPRS and the incidence of treatment-emergent adverse events. Secondary endpoints involve changes in various clinical and quality of life scales over the same period. The trial is not classified as a low-intervention study, and it is conducted under the regulatory oversight of relevant authorities to ensure compliance with ethical and safety standards.

The clinical trial involves the administration of **FNP-223**, an experimental medication formulated as a **film-coated tablet**. The active substance in FNP-223 is **(S)-N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide, hydrochloride salt**, which is of chemical origin. The medication is administered orally, with a maximum daily dose of 900 mg and a total maximum dose of 328,500 mg over a treatment period of 365 days. The primary objective of the trial is to evaluate the efficacy of FNP-223 in slowing the progression of **progressive supranuclear palsy (PSP)**, as well as to assess its safety and tolerability over a 52-week period.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is also presented in the form of a film-coated tablet, ensuring blinding is maintained throughout the trial. The placebo does not contain any active pharmaceutical ingredients and is administered following the same oral route and dosing schedule as FNP-223. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The efficacy of FNP-223 in slowing the progression of **progressive supranuclear palsy (PSP)** will be assessed using several parameters over a 52-week period. The primary efficacy endpoint is the change from baseline to Week 52 in the total score of the full 28-item PSP Rating Scale (PSPRS) for the European regulatory authority and the mPSPRS-10 outcome for the US regulatory authority. Secondary efficacy endpoints include changes from baseline to Week 52 in various scales and assessments, such as the Clinician Global Impression of Severity scale (CGI-S), Patient Global Impression of Severity Scale (PGI-S), Caregiver Global Impression of Severity scale (CaGI-S), and the Schwab and England Activities of Daily Living Scale (SE-ADL). Additional secondary endpoints involve the slope of decline in PSPRS, changes in individual subitems of PSPRS, the Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS), the Montreal Cognitive Assessment (MoCA), and the Progressive Supranuclear Palsy Quality of Life scale (PSP-QoL). Pharmacokinetic characterization of FNP-223 and its active metabolite will also be conducted.

Safety endpoints will be evaluated over the same 52-week treatment period, focusing on the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). This includes monitoring clinically significant changes in vital signs, clinical laboratory evaluations, physical examination findings, ECG parameters, and suicidal ideation or behavior using the Columbia Suicide Severity Rating Scale (C-SSRS). The assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis.