Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in GBA-PD

Inclusion Criteria:

Subjects who satisfy all of the following criteria will be eligible for Part A (Genetic Screening) of the study:

• The subject is ≥35 and ≤80 years of age at the time of informed consent.

• The subject has a clinical diagnosis of PD for at least 1 year and for no longerthan 7 years before initiation of screening (for Part A), as confirmed by aneurologist using the MDS Criteria for Parkinson's Disease.

• The subject has a modified Hoehn and Yahr score ≤2.5.

• The subject is receiving symptomatic treatment for PD.

• The subject is capable of giving signed informed consent.

Subjects who satisfy all the following criteria will be eligible for Part B (Double-Blind Treatment) of the study:

• Informed Consent - The subject is capable of giving signed informed consent.

• The subject has a known GBA-PD risk-associated variant (as determined in Part A [Genetic Screening] of this study).

• The subject has a score ≥22 on the Montreal Cognitive Assessment (MoCA) scale.

• The subject does not have severe motor fluctuations or disabling dyskinesias in theclinical judgment of the investigator.

• The subject has been on stable doses of PD medications for at least 30 days (atleast 60 days for rasagiline) before initiation of screening in Part B (Double-BlindTreatment).

• The subject is able to comply with the study restrictions.

• The subject has a body mass index (BMI) of 18 to 40 kg/m2.

• If a sexually active man or a women of childbearing potential, the subject agrees touse highly effective birth control or to remain abstinent during the trial and for 30 days after the last dose of IMP. Complete abstinence from sexual intercourse ifthis is the subject's usual and preferred lifestyle; or sexual partner with surgicalsterilization (e.g., tubal ligation, hysterectomy and/or bilateral oophorectomy,vasectomy).

Exclusion Criteria:

• Individuals who do not satisfy the inclusion criteria for Part A (Genetic Screening) will be excluded.

Subjects who meet any of the following criteria for Part B (Double-Blind Treatment) are not eligible for the study.

• The subject has Gaucher's disease (GD), as defined by clinical signs and symptoms (i.e., hepatosplenomegaly, cytopenia, skeletal disease), and/or a medical history ofmarked deficiency of GCase activity compatible with GD.

• The subject is homozygous for a GBA1 pathogenic variant that is known to beassociated with GD or compound heterozygous for 2 alleles that are known to beassociated with GD.

• The subject carries a known PD-associated LRRK2 pathogenic variant.

• The subject has atypical or secondary parkinsonism by medical history or in theopinion of the investigator. Atypical parkinsonism includes, but is not limited to,diagnoses of progressive supranuclear palsy, cortico-basal syndrome, and multiplesystem atrophy. Secondary parkinsonism includes drug-induced, toxin-induced,postinfectious, posttraumatic, or vascular parkinsonism.

• The subject has a history of (within 60 days before initiation of screening) or hasplanned upcoming major surgery that could interfere with, or for which the treatmentmight interfere with, the conduct of the study or that would pose an unacceptablerisk to the subject in the opinion of the investigator.

• The subject has any active or chronic disease or condition other than PD that couldinterfere with, or for which the treatment might interfere with, the conduct of thestudy or pose an unacceptable risk to the subject in the opinion of the investigatorbased on medical history, physical examination, vital signs, 12-lead ECG, orclinical laboratory tests. Minor deviations of laboratory values from the normalrange may be acceptable if judged by the investigator to have no/minor clinicalrelevance.

• The subject has a recent history (last 6 months) of abuse of addictive substances (alcohol, illegal substances), currently uses >21 units of alcohol per week, or is aregular recreational user of sedatives, hypnotics, tranquillizers, or any otheraddictive agent in the opinion of the investigator.

• The subject has a positive test for drugs of abuse at screening or beforeadministration of the first dose of investigational medicinal product (IMP) that theinvestigator judges as clinically relevant. A positive test for tetrahydrocannabinol (THC) is exclusionary. A positive test for cannabinoids (not containing THC) is notexclusionary if the subject is a recreational user (not an abuser) of cannabinoids,in the opinion of the investigator, and agrees to abstain from using cannabinoidswithin 12 hours before study visits. A positive drug screen that is attributed to anallowed prescription drug is not exclusionary but should be agreed with the medicalmonitor.

• The subject is currently pregnant, is planning pregnancy within the timeframe of thestudy, or is breastfeeding.

• The subject is using a strong inhibitors and inducers CYP3A4 at the time ofscreening for Part B (Double-Blind Treatment).

• The subject is using a breast cancer resistance protein (BCRP) substrate (e.g.,pravastatin, rosuvastatin, glyburide) at the time of screening for Part B (Double-Blind Treatment).

• The subject has used any of the following medications within 60 days beforeBaseline: typical or atypical antipsychotics (including, but not limited to,clozapine, pimavanserin, olanzapine, risperidone, and aripiprazole), metoclopramide,prochlorperazine, methyldopa, tetrabenazine, deutetrabenazine, valbenazine, orreserpine.

• The subject has received a vaccination within 14 days before administration of thefirst dose of IMP.

• The subject has a prior history of or there is a plan to conduct deep brainstimulation (DBS), lesional procedures, (i.e., thalamotomy), or focused ultrasound;to initiate gene therapy treatment for PD; or to initiate use of any formulation ofintestinal infusion or continuous subcutaneous infusion of PD medications.

• The subject is currently participating in or has participated in an investigationaldrug study within 3 months or 5 half-lives, whichever is longer; in a therapeuticdevice study within 3 months before the first dose of IMP; or has previouslyparticipated in a gene therapy trial. Concurrent participation in an observationalstudy is acceptable.

• The subject has a positive test result for hepatitis B surface antigen (HBsAg),hepatitis C virus antibody (anti-HCV), or human immunodeficiency virus 1 (HIV-1) or 2 (HIV-2) at screening. If reflex testing for hepatitis B or HCV DNA is negative,the subject may be eligible for the study.

• The subject has renal insufficiency as defined by an estimated glomerular filtrationrate (eGFR) of <60 mL/min at screening.

• The subject has cirrhosis (Child-Pugh A, B, or C) or any of the following laboratoryvalues at screening: serum alanine aminotransferase (ALT) or aspartateaminotransferase (AST) >2 times the upper limit of normal (ULN) or bilirubin >2 ×ULN except if the subject has known or suspected Gilbert's disease.

• The subject has a QT interval corrected for heart rate by Fridericia's method (QTcF)value >450 msec if male or >470 msec if female at screening.

• The subject provides a positive response on Question 4 or 5 of the Columbia-SuicideSeverity Rating Scale (C-SSRS) based on the last 6 months or, in the opinion of theinvestigator, presents a serious risk of suicide at screening.

• The subject had a positive severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) test (any type) result within the 30 days before signing informedconsent for Part B (Double-Blind Treatment) or has 2 or more current symptoms (e.g.,sore throat, cough, fever) at the same time that are consistent with the Coronavirusdisease 2019 (COVID-19) infection (not tested) in the opinion of the investigator.

• The subject has a clinical history that is consistent with a previous COVID-19infection and has not recovered fully, maintaining nonspecific symptoms like, forexample, fatigue, shortness of breath, difficulty concentrating, sleep disorders,fever, anxiety, and depression.

• The subject has previously received BIA 28-6156 or has a known allergy orhypersensitivity to BIA 28-6156 or any components of the formulation.

• The subject is an unsuitable candidate to receive BIA 28-6156 or is unable orunlikely to comply with the dosing schedule or study evaluations in the judgment ofthe investigator.