CNS penetration and target engagement of Mirivadelgat in Parkinson’s disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Helse Bergen HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2026-06-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Cure Parkinson's · Norwegian Parkinson's Association · Helse Vest Trust · Helse Bergen Trust

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Pharmacodynamic

To assess the safety and tolerability of a Mirivadelgat in participants with PD. To evaluate the central nervous system (CNS) exposure of the active Mirivadelgat metabolite AD-835 in participants with PD at steady state, following 12 weeks of treatment with Mirivadelgat (300 mg per day). To assess the effect of Mirivadelgat (300 mg/day) compared with placebo on CSF levels of 4-hydroxy-2-nonenal (4-HNE) protein adducts.

Secondary objectives 4

1. To assess the effect of Mirivadelgat (300 mg/day) compared with placebo on CSF levels of 4-hydroxy-2-nonenal (4-HNE)
2. To assess the effect of Mirivadelgat (300 mg/day) compared with placebo on aldehyde-related lipid peroxidation in CSF, as measured by thiobarbituric acid reactive substances (TBARS)
3. To assess the effect of Mirivadelgat (300 mg/day) compared with placebo on CSF levels of 4-HNE-modified α-synuclein
4. To assess the effect of Mirivadelgat (300 mg/day) compared with placebo on brain bioenergetic status after 12 weeks of treatment.

Conditions and MedDRA coding

Parkinson's Disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Participants must be 40 to 85 years of age inclusive, at the time of signing the informed consent.
2. Participants who are diagnosed with clinically established PD as defined by the MDS Clinical Diagnostic Criteria13, meeting all of the following: a. Diagnosis of PD within 10 years of enrollment b. Hoehn and Yahr score of ≤3 in the ON dopaminergic state at enrolment c. On stable anti-parkinsonian treatment (no commencement of new anti-parkinsonian medications, or changes in doses of current anti-parkinsonian medications for a period of at least 2 weeks) prior to baseline
3. Body weight within 45-120 kg (inclusive)
4. Male or female assigned at birth, inclusive of all gender identities. Contraceptive requirements apply during the entire treatment period, and following a washout period of 8 weeks after last intake of the last study intervention, or within 5 half-lives of the experimental treatment, whichever is longer. For additional details see protocol section 7.1
5. Signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
6. Presence of dopaminergic nigrostriatal denervation documented by dopamine transporter (DAT) single photon emission tomography (SPECT) or positron emission tomography (PET), or [18F]DOPA-PET
7. Lack of evidence of other neurodegenerative disorders or any severe somatic or mental illness that may interfere with the study
8. Are able to undergo MRI, blood sampling, and lumbar puncture (LP).

Exclusion criteria 34

1. Known or suspected cause of parkinsonism other than neurodegenerative idiopathic PD, including but not limited to atypical parkinsonian syndromes (e.g., progressive supranuclear palsy (PSP), or multiple system atrophy (MSA), corticobasal syndrome (CBS), dementia with Lewy bodies (DLB)), drug-induced parkinsonism (e.g., neuroleptics, metoclopramide, etc.), encephalitis, known monogenic disorders, etc.
2. Known or suspected neurodegenerative disorders other than neurodegenerative idiopathic PD.
3. MoCA score < 23, dementia, or other significant cognitive impairment that, in the opinion of the Investigator, would interfere with study evaluation.
4. Unable to attend the clinic visits in the practically defined OFF medication state.
5. Use of dopaminergic therapy pumps of any kind (levodopa, apomorphine, etc.).
6. History of any brain surgery for PD (e.g., pallidotomy, deep brain stimulation, or fetal tissue transplant) or history of focused ultrasound treatment at any time; or history of neuromodulation procedures, including, but not limited to, transcranial magnetic stimulation (TMS), transcranial direct or alternating current stimulation (tDCS/tACS) that have been performed within 90 days of screening.
7. A moderate or high suicide risk on the Columbia Suicide Severity Rating Scale (C-SSRS) at screening.
8. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class 3 or 4), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year before Screening.
9. Poorly controlled diabetes mellitus, as defined by having dosage adjustment of diabetic medication within 3 months before dosing (Day 1) or glycosylated hemoglobin ≥ 8% at Screening.
10. History of active malignancy. At Investigator’s discretion, participants with a history of malignancy that is considered cured can participate.
11. History of solid organ transplantation.
12. History of alcohol/substance abuse within 1 year from baseline.
13. History of any psychiatric disorder that would interfere with the participant's ability to comply with the study, as determined by the Investigator.
14. History of any somatic illness that would interfere with the participant's ability to comply with the study, as determined by the Investigator.
15. Participant is enrolled in a current clinical trial, or has been enrolled in a clinical trial of an experimental therapy within 12 weeks prior to baseline (first dose) or within 5 half-lives of the IMP (whichever is longer), or has been enrolled in a SLEIPNIR cohort within 26 weeks prior to baseline (first dose) or within 5 half-lives of the previous IMP (whichever is longer), or has participated in two SLEIPNIR cohorts already.
16. Prolonged QT-interval with QTcF > 480 ms at screening or baseline (the mean of the triplicate QTcF values will be used). QT intervals will be corrected for heart rate using Fridericia’s formula (QTcF = QT / RR^(1/3)), in accordance with ICH E14 recommendations.
17. Any ECG abnormality or rhythm disturbance that, in the opinion of the investigator, poses a significant risk of ventricular arrhythmia.
18. History or positive test result at Screening for human immunodeficiency virus (HIV).
19. History or positive test result at Screening for hepatitis C virus antibody.
20. Current hepatitis B virus (HBV) infection (defined as positive for hepatitis B surface antigen [HbsAg]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HbsAg, positive anti-HBc, and positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative HbsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
21. Currently active infection or serious infection (e.g., pneumonia, septicemia) within 8 weeks before Day 1, as determined by the Investigator.
22. Liver function test results (ALAT, ASAT, bilirubin) ≥ 1.5 times the upper limit of normal at the Screening Visit. a. Participants with previously diagnosed Gilbert’s syndrome and elevated levels of bilirubin consistent with such diagnosis may be allowed in the study.
23. Urinary albumin/creatinine ratio (ACR) ≥ 20 mg/mmol at time of enrollment.
24. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at screening, calculated using the CKD-EPI 2021 creatinine equation14: eGFR = 142 × min(Scr/K, 1)α × max(Scr/K, 1)-1.200 × 0.9938Age × (1.012 - if female) Where: - Scr is serum creatinine, - K is 0.7 for females and 0.9 for males, - α is -0.241 for females and -0.302 for males, - min indicates the minimum of Scr/K or 1, - max indicates the maximum of Scr/K or 1.
25. Screening value for hemoglobin < 12 g/dL for men or < 11 g/dL for women.
26. Platelet count < 145 x 109/L for men or < 165 x 109/L for women
27. Use of Mucuna pruriens within 90 days before baseline and for the duration of the study.
28. Use of any recreational drugs within 7 days before baseline and for the duration of the study.
29. Use of strong CYP3A inhibitors within 14 days or five half-lives (whichever is longer) prior to randomization. In addition, the use of strong CYP3A inhibitors is prohibited during the treatment period. Strong CYP3A inhibitors will be defined according to current FDA and ICH M12–aligned drug–drug interaction classifications and confirmed by medical/pharmacy review and relevant SmPC/product information. Examples include, but are not limited to: clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, ritonavir- or cobicistat-containing regimens, indinavir, and telaprevir.
30. Any contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible implants; claustrophobia that cannot be managed without general anesthesia, etc.).
31. Any contraindications to having a lumbar puncture. Contraindications as defined by institutional guidelines: a. Increased intracranial pressure and/or space-occupying lesion b. Spinal epidural abscess c. Infection in or near the puncture site d. Known spinal stenosis with myelopathy or spinal cord compression above level of puncture e. Known spinal or cranial developmental abnormalities that pose a significant risk or interfere with the procedure f. Increased risk of bleeding: • Platelet count < 40 x 109/L • INR  1.4 • Use of anticoagulants other than acetylsalicylic acid (ASA 75 mg once daily) • Use of NSAIDs that cannot be discontinued within the recommended timeframe according to institutional guidelines for each specific drug • Known increased bleeding risk from other causes, deemed clinically significant by the investigator
32. Known hypersensitivity and/or allergies to active Mirivadelgat, the placebo, or their excipients
33. Participant is currently prescribed a drug/nutraceutical known to interact with Mirivadelgat.
34. Previous participation in the SLEIPNIR 2 study arm covered by this sub-protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Incidence and severity of adverse events (AEs) and serious adverse events (SAEs); treatment adherence based on dosing compliance and study drug discontinuation rate.
2. CSF-to-plasma concentration ratio of the Mirivadelgat metabolite AD-835 at Week 12, measured by LC-MS.
3. Change from baseline to Week 12 in CSF total 4-HNE protein adduct levels, measured by validated ELISA assay.

Secondary endpoints 4

1. Change from baseline to Week 12 in CSF levels of 4-HNE, measured by ELISA, or other relevant method.
2. Change from baseline to Week 12 in CSF levels of TBARS (nmol malondialdehyde [MDA] equivalents per mL), measured using a validated thiobarbituric acid reactive substances (TBARS) spectrophotometric assay.
3. Change from baseline to Week 12 in CSF levels of 4-HNE-α-synuclein using a custom sandwich ELISA assay.
4. Change from baseline to Week 12 in the following brain bioenergetic indices: • Inorganic phosphate to ATP ratio (Pi/ATP), reflecting ATP turnover and energy consumption. • Phosphocreatine to inorganic phosphate (PCr/Pi) ratio, reflecting cellular energetic state and phosphorylation potential. • Phosphocreatine to ATP ratio (PCr/ATP), reflecting ATP resynthesis reserve and energetic state. measured by phosphorus magnetic resonance spectroscopy (31P-MRS) in the posterior brain.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Helse Bergen HF

Sponsor organisation

Helse Bergen HF

Address

Haukelandsveien 22

City

Bergen

Postcode

5021

Country

Norway

Scientific contact point

Organisation

Helse Bergen HF

Contact name

Charalampos Tzoulis

Public contact point

Organisation

Helse Bergen HF

Contact name

Charalampos Tzoulis

Third parties 2

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications