A Phase 2/3, Double-Blind, Placebo-Controlled Study of BHV-8000 in Participants with Early Parkinson’s Disease

The primary objective is to evaluate the efficacy of two dose levels of BHV-8000 compared to placebo in delaying the time to the first qualifying worsening event on the Movement Disorder Society – Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II in patients with early Parkinson's disease. This endpoint assesses the progression of motor experiences of daily living, providing clinically relevant information on disease modification and functional decline.

The secondary objectives include:

• Evaluation of BHV-8000 efficacy compared to placebo on the change from baseline to Week 48 on the MDS-UPDRS Part III, which measures motor examination findings and represents a key indicator of motor symptom severity.

• Assessment of efficacy on the change from baseline to Week 48 on the Clinician Global Impression of Severity (CGI-S) score, providing an overall clinical assessment of disease severity.

• Evaluation of efficacy on the change from baseline to Week 48 in dopamine transporter single photon emission computed tomography (DaT-SPECT) scan Striatal Binding Ratio (SBR) in the putamen ipsilateral to the clinically most affected side, serving as a biomarker of dopaminergic neuronal integrity.

• Assessment of efficacy on the change from baseline to Week 48 on the Parkinson's Disease Composite Score – Function (PARCOMS-Function), which evaluates multiple domains of functional capacity.

• Evaluation of the safety and tolerability profile of BHV-8000 throughout the treatment period.

This clinical trial enrolled a total of **112 participants** diagnosed with **early Parkinson's disease**. The study population included both **male and female** individuals aged **40 to 85 years** at the time of informed consent. Participants were required to meet the diagnostic criteria for probable Parkinson's disease as assessed by the **Movement Disorder Society Clinical Diagnostic Criteria**. A key selection requirement was a clinician-documented diagnosis of **idiopathic Parkinson's disease** with symptom onset within **2 years** prior to the screening visit. The trial included adults and elderly individuals, with a vulnerable population component identified in the study design. The sponsor did not provide specific information regarding lifestyle considerations such as diet, physical activity, or habits of the participants.

This is a Phase 2/3, double-blind, placebo-controlled clinical trial evaluating the efficacy, safety, and tolerability of **BHV-8000** in participants with **early Parkinson's disease**. BHV-8000 is a brain-penetrant, selective dual inhibitor of **TYK2** and **JAK1**, administered as a **prolonged-release tablet** via the **oral** route. The study employs a **randomized** design in which participants will receive either one of two dose levels of BHV-8000 (10 mg or 20 mg daily) or matching **placebo**. The maximum treatment period is **48 weeks**. The trial also includes **DaTSCAN** (ioflupane 123I), a **solution for injection** administered via **intravenous** route, which will be used as an auxiliary medicinal product for imaging purposes to assess **dopamine transporter** activity through **DaT-SPECT** scanning. The estimated recruitment start date is September 2025, with an estimated end date of September 2027.

The primary objective of the trial is to evaluate the efficacy of two dose levels of BHV-8000 compared to placebo by delaying the time to the first qualifying worsening event on the **Movement Disorder Society – Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II**. Secondary objectives include assessing changes in **MDS-UPDRS Part III** (motor examination), **Clinical Global Impression of Severity (CGI-S)**, **DaT-SPECT** scan **striatal binding ratio (SBR)** in the **putamen**, and **Parkinson's Disease Composite Score - Function (PARCOMS-Function)** from baseline to Week 48. Safety and tolerability will be evaluated by monitoring the number of participants with deaths, **serious adverse events (SAEs)**, adverse events leading to study drug discontinuation, moderate or severe adverse events, and clinically significant laboratory abnormalities.

Eligible participants include male or female individuals aged 40 to 85 years at the time of informed consent who meet the diagnostic criteria for "Probable PD" as assessed by the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease. Participants must have a clinician-documented diagnosis of **idiopathic Parkinson's disease** with an onset within 2 years of the screening visit. The screening visit will serve as the inclusion visit during which eligibility criteria will be confirmed and baseline assessments will be conducted. Follow-up visits will occur at regular intervals throughout the 48-week treatment period to monitor efficacy, safety, and disease progression. An end-of-study visit will be conducted at Week 48 or upon early termination. Participant involvement is expected to last approximately 48 weeks, although the exact duration may vary depending on individual circumstances. Early termination from the study may occur due to adverse events, lack of efficacy, participant withdrawal of consent, protocol violations, or at the discretion of the investigator if continued participation is not in the participant's best interest.

The experimental medication **BHV-8000** is formulated as a **prolonged-release tablet** for **oral administration**. BHV-8000 is a brain-penetrant, selective dual inhibitor of **TYK2** and **JAK1**, containing the active substance **(2R,5S)-tetrahydro-5-(2-methyl-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)-2H-pyran-2-acetonitrile**. Two dosage regimens are evaluated in this clinical trial: a lower dose of **10 mg** administered once daily with a maximum total daily dose of 20 mg, and a higher dose of **20 mg** administered once daily with a maximum total daily dose of 20 mg. The maximum treatment period for both dosage regimens is **48 weeks**.

A matching **placebo** for BHV-8000 is utilized as the comparator treatment in this double-blind, placebo-controlled study. The placebo is designed to be indistinguishable from the active medication to maintain blinding integrity throughout the trial.

**DaTSCAN** 74 MBq/ml **solution for injection** serves as an auxiliary medicinal product in this trial. DaTSCAN contains the active substance **ioflupane (123I)** and is administered via **intravenous** route. The maximum daily dose is **0.13 micrograms**, with a maximum total dose of 0.13 micrograms administered as a single dose. The maximum treatment period for DaTSCAN is **1 day**. This radiopharmaceutical agent is utilized for diagnostic imaging purposes to support trial assessments.

The primary efficacy endpoint is the time to first qualifying worsening event on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II, assessed up to 48 weeks. The MDS-UPDRS Part II evaluates motor experiences of daily living through a self-administered questionnaire and is scored on a 52-point scale, where higher scores indicate more severe disability. This endpoint will be used to evaluate the efficacy of BHV-8000 compared to placebo by measuring the delay in prespecified worsening.

Secondary efficacy endpoints include the change in MDS-UPDRS Part III from baseline to week 48, which assesses motor examination conducted by a rater using a 132-point scale, with higher scores representing greater motor impairment. The change in Clinical Global Impression of Severity (CGI-S) from baseline to week 48 will be evaluated, using a 7-point scale where 7 represents the most extremely ill participants, as determined by the managing clinician. Changes in dopamine transporter single-photon emission computed tomography (DaT-SPECT) scan from baseline to week 48 will be measured by assessing the Striatal Binding Ratio in the putamen, where reduced uptake of the radiotracer indicates decreased dopamine-secreting cells and suggests disease progression. The change in Parkinson's Disease Composite Score-Function (PARCOMS-Function) from baseline to week 48 will be assessed using a composite measure derived from select items of the MDS-UPDRS Part II and the PDQ-39, scored on a 100-point scale with higher scores indicating greater dysfunction.