Evaluation of Safety and Pharmacodynamics of BIIB122 in LRRK2-Associated Parkinson's Disease: A Phase 2a Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-513384-15-00
- Protocol
- DNLI-C-0009
- Sponsor
- Denali Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of BIIB122 in participants with LRRK2-associated Parkinson's disease (LRRK2-PD) during the double-blind period. This is clinically relevant as it aims to ensure that the investigational drug, BIIB122, is safe for use in this specific patient population, which is crucial for the development of effective treatments for Parkinson's disease.
Secondary objectives include:
- To evaluate target engagement and pathway engagement of BIIB122 in participants with LRRK2-PD. This objective is important for understanding the mechanism of action of BIIB122 and its potential therapeutic effects on the disease pathway.
Participants
The clinical trial involves a total of **23 participants** diagnosed with **Parkinson’s disease**. The study population includes both male and female subjects, with an age range of 30 to 80 years for heterozygous pathogenic LRRK2 mutation carriers, and 30 years and older for homozygous carriers. Participants were selected based on their clinical diagnosis of Parkinson’s disease, meeting the Movement Disorder Society Clinical Diagnostic Criteria, and having screening genetic test results verifying the presence of a pathogenic LRRK2 variant. The trial does not include a vulnerable population. No specific lifestyle considerations such as diet or physical activity are mentioned for this study.
Plans and Procedures
The clinical trial is a **Phase 2a**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and pharmacodynamic effects of BIIB122 in participants with LRRK2-associated **Parkinson's disease**. The trial aims to assess the safety and tolerability of BIIB122 during a 12-week double-blind period. Participants will be randomly assigned to receive either BIIB122 or a placebo, with the primary endpoint being the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) compared to placebo. Secondary endpoints include changes from baseline in whole-blood pS935 LRRK2 and urine BMP at Week 12.
The trial is expected to commence recruitment on December 1, 2024, and conclude by February 15, 2028. The study will involve several visits, beginning with an inclusion (screening) visit to verify eligibility based on criteria such as age, clinical diagnosis of Parkinson's disease, and genetic test results confirming a pathogenic LRRK2 variant. Participants will then undergo regular follow-up visits throughout the 12-week treatment period to monitor safety and efficacy outcomes. The end-of-study visit will occur at the conclusion of the treatment period to assess final outcomes and gather data for analysis.
Participant involvement is anticipated to last approximately 12 weeks, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The study will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity. The trial's design and methodology are structured to provide robust and reliable data on the effects of BIIB122 in the target population, contributing valuable insights into the management of LRRK2-associated Parkinson's disease.
Treatment
The clinical trial involves the administration of **BIIB122**, an investigational medication, in participants with LRRK2-associated Parkinson's Disease. **BIIB122** is formulated as a tablet and is intended for **oral use**. The active substance in **BIIB122** is 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, which is of chemical origin. The maximum daily dose of **BIIB122** is 225 mg, with a total maximum dose of 264.6 g over the treatment period. The maximum treatment period is 168 days. The medication is provided by Biogen Idec Research Limited.
In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind study. The placebo is designed to match the **BIIB122** tablet in appearance but does not contain the active substance. The placebo is also administered orally. The use of a placebo allows for the assessment of the safety and pharmacodynamic effects of **BIIB122** by providing a control for comparison. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
Efficacy
Efficacy in the clinical trial evaluating BIIB122 for **LRRK2-associated Parkinson's Disease** will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) with BIIB122 compared to placebo over a 12-week double-blind period. This will provide insights into the safety profile of the investigational product.
Secondary endpoints include the change from baseline in whole-blood phosphorylated serine 935 LRRK2 (pS935 LRRK2) and urine bis(monoacylglycerol)phosphate (BMP) levels with BIIB122 compared to placebo at Week 12. These biomarkers are critical for understanding the pharmacodynamic effects of BIIB122. Measurements will be collected at baseline and at the 12-week mark, utilizing laboratory tests to ensure accuracy and reliability of the data. The analysis will compare the changes in these biomarkers between the treatment and placebo groups to evaluate the efficacy of BIIB122 in modulating disease-related pathways.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Be able to provide informed consent and to authorize the use of confidential health information in accordance with national and local privacy regulations
- Be able to communicate with the investigator and clinical study staff
- 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
- Have a clinical diagnosis of PD meeting the Movement Disorder Society Clinical Diagnostic Criteria.
- 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.
- 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.
- 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
- 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
- Have abnormal PFT results at screening.
- Have clinical evidence of atypical parkinsonism (eg, multiple-system atrophy or progressive supranuclear palsy) or evidence of drug-induced parkinsonism.
- Are currently participating in the BIIB122 LUMA study (Study 283PD201)
- Have previously participated or are currently participating in a gene therapy study for PD.
- Have a history of brain surgical intervention for PD (eg, deep-brain stimulation, pallidotomy).
- 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)
- Have clinically significant abnormal laboratory test results during screening, as determined by the investigator.
- 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.
- Have vital sign abnormalities or symptomatic orthostasis at screening or baseline.
- 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.
- 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.
- 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
- Have a history of, or positive test result at screening for, human immunodeficiency virus.
- 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.
- 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.
- Have had unstable psychiatric illness, including psychosis, suicidal ideation, or untreated major depression, within 90 days before screening, as determined by the investigator.
- 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.
- 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.
- Are unable or unwilling to comply with study requirements.
- 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.
- Have other unspecified reasons that, in the opinion of the investigator or Sponsor, make the participant unsuitable for enrollment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Dec 2024 | 6 |
 Spain | Not Recruiting | 01 Dec 2024 | 21 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BIIB122 | Test | TABLET | ORAL USE | 225 | 168 | PRD10968886 |
Placebo to BIIB122 | Placebo | N/A | — | — | — | N/A |