N2-(3-(2-(2H-1,2,3-TRIAZOL-2-YL)PROPAN-2-YL)-1-CYCLOPROPYL-1H-PYRAZOL-5-YL)-N4-ETHYL-5-(TRIFLUOROMETHYL)PYRIMIDINE-2,4-DIAMINE for Parkinson's disease | LRRK2-associated Parkinson's disease

Inclusion criteria

• {"criterion_text":"- Be able to provide informed consent and to authorize the use of confidential health information in accordance with national and local privacy regulations\n- Be able to communicate with the investigator and clinical study staff\n- Men and women must be aged as follows at screening: - For heterozygous pathogenic LRRK2 mutation carriers: ≥30 to ≤80 years - For homozygous pathogenic LRRK2 mutation carriers: ≥30 years\n- Have a clinical diagnosis of PD meeting the Movement Disorder Society Clinical Diagnostic Criteria.\n- During the screening period produce genetic test results verifying the presence of a pathogenic LRRK2 variant (eg, G2019S, N1437H, R1441G, R1441C, R1441H, Y1699C, or I2020T). Participants with additional LRRK2 variants may be included if data emerge to convincingly support an association between the variants and LRRK2-PD pathogenicity. Confirmation of this eligibility requirement may be provided by an accredited genetic test that includes all inclusionary LRRK2 genetic variants as approved by the Sponsor.\n- Have screening or historical DaT/SPECT or historical F-DOPA (scan and/or report) consistent with neurodegenerative Parkinsonism, unless any of the following applies: - The ioflupane I-123 (DaTScan™) radioligand is not regionally available or scanning cannot be practically performed - The participant has a history of severe allergic or anaphylactic reactions, or history of hypersensitivity to the ioflupane I-123 (DaTScan) radioligand - The participant is taking a medication that may interfere with DaT/SPECT imaging, including, but not limited to, the following: amoxapine, amphetamine, armodafinil, benztropine, bupropion, cocaine, mazindol, methylphenidate, modafinil, phentermine, and sertraline.\n- Female participants of childbearing potential must meet all of the following criteria: - Must not be pregnant or breastfeeding AND - For at least 3 months before the first dose of study intervention and at least 90 days after the last dose of study intervention, must use effective contraceptive AND - Must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at baseline, and must also agree to take urine pregnancy tests during treatment with study intervention as indicated in the SOA. A positive urine pregnancy test result must be confirmed with a serum pregnancy test. If the pregnancy test result is positive, the participant must be excluded from the study. AND - Should not donate eggs for the duration of the study and for at least 3 months after their last dose of study intervention"}

Exclusion criteria

• {"criterion_text":"- Have a history of any clinically significant neurological disorder other than PD, including, but not limited to, stroke and dementia, in the opinion of the investigator, within 5 years of the screening visit\n- Have abnormal PFT results at screening.\n- Have clinical evidence of atypical parkinsonism (eg, multiple-system atrophy or progressive supranuclear palsy) or evidence of drug-induced parkinsonism.\n- Are currently participating in the BIIB122 LUMA study (Study 283PD201)\n- Have previously participated or are currently participating in a gene therapy study for PD.\n- Have a history of brain surgical intervention for PD (eg, deep-brain stimulation, pallidotomy).\n- Have any physical condition that may confound the motor assessment (MDS-UPDRS) over time (eg, severe arthritis, severe dyskinesias, traumatic injuries with permanent physical disability)\n- Have clinically significant abnormal laboratory test results during screening, as determined by the investigator.\n- Were hospitalized as an inpatient for any reason during the 4 weeks before screening Note: Rescreening may occur, if medically stable, following 4 weeks posthospitalization.\n- Have vital sign abnormalities or symptomatic orthostasis at screening or baseline.\n- Have a current HCV infection (defined as positive anti-HCV and detectable HCV RNA). Participants with positive anti-HCV and undetectable HCV RNA are eligible for the study.\n- Have a current HBV infection (defined as positive HBsAg). Participants with immunity to HBV from previous natural infection (defined as negative HbsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HbsAg, negative anti-HBc, and positive anti-HBs) are eligible for the study.\n- Have evidence of acute or chronic viral, autoimmune, alcoholic, cirrhotic, or other types of hepatitis or clinically significant hepatic impairment or hepatobiliary disease at screening, including ALT, AST, or total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome based on bilirubin fractionation) within 6 months of screening\n- Have a history of, or positive test result at screening for, human immunodeficiency virus.\n- Have a history of, or ongoing, malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell carcinomas and squamous cell carcinomas of the skin that have been completely excised and considered cured  1 year prior to baseline). Participants with cancers in remission for > 5 years prior to baseline may be enrolled after discussion with the Sponsor.\n- Have a history of, or current, clinically significant cardiovascular disease or abnormal assessments, including any of the following: - Myocardial infarction or unstable angina within 6 months prior to screening - Ventricular tachycardia, family or personal history of long QT syndrome, atrial fibrillation or flutter, or other significant arrhythmias - New York Heart Association Class III or IV congestive heart failure - History of cardiac syncope or syncope/near syncope of unknown etiology within the past 6 years or any syncope/near syncope within the last 3 years prior to screening that is deemed clinically significant as assessed by the investigator - Clinically significant 12-lead ECG abnormalities, as determined by the investigator at baseline - Confirmed demonstration of QTcF of >450 ms for male participants and >460 ms for female participants at baseline. See Section 5.3.2 for guidance on retesting.\n- Have had unstable psychiatric illness, including psychosis, suicidal ideation, or untreated major depression, within 90 days before screening, as determined by the investigator.\n- Have a history of drug or alcohol abuse within the past 5 years (as defined by the investigator), a positive urine drug test result at screening (exception: participants who test positive for benzodiazepines or other narcotics that are prescribed and monitored by a physician may be included in the study, at the discretion of the investigator), or an unwillingness to abstain from these substances during clinic visit days. Participants who test positive for cannabinoids due to occasional marijuana use (as determined by the investigator) and who agree to refrain from using marijuana for the duration of the study may be enrolled at the investigator’s discretion, after consultation with the Sponsor. The use of cannabinoids other than marijuana (eg, cannabinoid cream or gel) is acceptable, unless the use is considered to be drug abuse by the investigator.\n- Have a history of systemic hypersensitivity reaction to BIIB122, the excipients contained in the formulation, or, if appropriate, any diagnostic agents to be administered during the study.\n- Are unable or unwilling to comply with study requirements.\n- Have participated in a clinical study involving administration of an investigational drug (new chemical entity), device, or surgery within 90 days or 5 half-lives (whichever is longer) of screening Note: Participants may be rescreened after an appropriate interval, rather than being excluded.\n- Have other unspecified reasons that, in the opinion of the investigator or Sponsor, make the participant unsuitable for enrollment."}

Primary endpoints

• {"endpoint_text":"- Incidence of TEAEs and SAEs with BIIB122 compared with placebo over the 12-week double-blind period","definition_or_measurement_approach":"Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will be compared between BIIB122 and placebo during the 12-week double-blind period (as stated)."}

Secondary endpoints

• {"endpoint_text":"- Change from baseline in whole-blood pS935 LRRK2 with BIIB122 compared with placebo at Week 12","definition_or_measurement_approach":"Change from baseline in whole-blood pS935 LRRK2 measured at Week 12 and compared between BIIB122 and placebo."}
• {"endpoint_text":"- Change from baseline in urine BMP with BIIB122 compared with placebo at Week 12","definition_or_measurement_approach":"Change from baseline in urine BMP measured at Week 12 and compared between BIIB122 and placebo."}

Spain

Earliest CTIS Part Ii Submission Date

03-12-2024

Latest Decision Or Authorization Date

01-04-2026

Processing Time Days

484

Number Of Sites

7

Number Of Participants

21

Germany

Earliest CTIS Part Ii Submission Date

21-11-2024

Latest Decision Or Authorization Date

31-03-2026

Processing Time Days

495

Number Of Sites

3

Number Of Participants

6

Primary sponsor

Full Name

Denali Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

4g Clinical LLC

Responsibilities

3

Name

Medidata Solutions Inc.

Responsibilities

6

Name

Bioclinica Inc.

Responsibilities

Respiratory, Cardiac, eCOA

Name

WCG Clinical Inc.

Responsibilities

PI Safety Letter Portal

Name

Primevigilance Limited

Responsibilities

Safety Vendor

Name

Invicro LLC

Responsibilities

DaT/SPECT

Third parties

• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"3","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"G1 Therapeutics Inc.","duties_or_roles":"Sample Management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Mlm Medical Labs LLC","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Amprion Inc.","duties_or_roles":"alpha-synuclein testing","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Respiratory, Cardiac, eCOA","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"6","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Early Development Laboratories Inc.","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"Safety Vendor","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Invicro LLC","duties_or_roles":"DaT/SPECT","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"PI Safety Letter Portal","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient Reimbursement","organisation_type":"Non-Pharmaceutical company"}