A study of safety and tolerability (acceptability of potential side effects) of exidavnemab, at 2 different doses, in patients with Parkinson’s disease and in Patients with Multiple System Atrophy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BioArctic AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

22 Oct 2024 → ongoing

Decision date (initial)

2024-09-30

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

BioArctic AB

External identifiers

EU CT number

2024-511222-30-00

WHO UTN

U1111-1307-3505

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Pharmacokinetic, Dose response

To assess the safety and tolerability of exidavnemab after multiple dosing versus placebo

Secondary objectives 3

1. To establish an appropriate dose range for a proof-of-concept trial.
2. To assess the PK of exidavnemab after multiple ascending dosing.
3. To assess and describe the systemic immunogenicity effects of exidavnemab

Conditions and MedDRA coding

Multiple System Atrophy

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 24

1. Inclusion Criteria for Cohorts 1 and 2a (Parkinson’s Disease): 1. Male and female participants 40 to 85 years of age.
2. Negative urine or serum pregnancy test at the Screening Visit and Baseline for premenopausal women, and for women who have experienced menopause onset less than 12 months prior to the first planned dose of trial medication.
3. Males and persons of childbearing potential (POCBP) must agree to practice an effective means of birth control during their participation in the trial and until 3 months after their last dose of the trial medication.
4. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and trial procedures.
5. Participants must understand their daily medication regimen and must agree that they will not change their daily medication doses during the trial.
6. The participant is capable of providing informed consent and has signed and dated the ICF before any trial specific procedures are performed.
7. Body weight more than or equal to 50 kg and less than or equal to 120 kg.
8. Have idiopathic PD (i.e., not induced by drugs or other diseases) as defined by bradykinesia combined with at least 1 of resting tremor and rigidity, as per the Movement Disorder Society Criteria for PD
9. Classified as Stage 1 to 2.5 on the modified Hoehn and Yahr scale for the staging of PD severity.
10. Participants must have cognition inconsistent with dementia as confirmed by a score of more than or equal to 22 on the MoCA.
11. Stable and optimized symptomatic PD medication, defined as the same list of medications for at least 3 months prior to the Screening Visit with no change in the dose for at least 1 month prior to the Baseline Visit, and no planned changes in dose-regimen during trial participation.
12. Prior (any time; i.e., no time limit) or current DaT-SPECT or DaT-PET consistent with dopamine transporter deficit, as per the Movement Disorder Society Criteria for PD. For participants who have not undergone DaT-SPECT or DaT-PET prior to Screening, or who have previously undergone DaT-SPECT or DaT-PET scan(s) but without results consistent with dopamine transporter deficit, DaT-SPECT or DaT-PET should be performed and read locally as part of the Screening procedures.
13. Positive smell test showing hyposmia, as defined by UPSIT scores of around or below the 15% percentile for their relevant sex and age group.
14. Ability to use tablet device to measure cognitive function, as per Investigator judgment.
15. Inclusion Criteria for Cohort 2b (Multiple System Atrophy): Male and female participants 40 to 85 years of age.
16. Body weight more than or equal to 50 kg and less than or equal to 120 kg.
17. Have clinically established or clinically probable MSA (either MSA-P or MSA-C), as per the Movement Disorder Society criteria for the diagnosis of MSA
18. Classified as Stage 1 to 3 on the modified Hoehn and Yahr scale for the staging of MSA severity.
19. Participants must have cognition inconsistent with dementia as confirmed by a score of more than or equal to 22 on the MoCA.
20. Negative urine or serum pregnancy test at the Screening Visit and Baseline for premenopausal women, and for women who have experienced menopause onset less than 12 months prior to the first planned dose of trial medication.
21. Males and POCBP must agree to practice an effective means of birth control during their participation in the trial and until 3 months after their last dose of the trial medication.
22. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and trial procedures.
23. The participant is capable of providing informed consent and has signed and dated the ICF before any trial-specific procedures are performed.
24. In the opinion of the Investigator, the participant has an expected survival of at least 6 months beyond the end of their participation in the trial.

Exclusion criteria 55

1. Exclusion Criteria for Cohorts 1 and 2a (Parkinson’s Disease): 1. Known hypersensitivity to trial medication, the infusion solution, or excipients.
2. Abnormal ECG that is or may be clinically significant in the Investigator’s opinion and after consultation with the Medical Monitor, including left bundle branch block, atrial fibrillation, QTcF interval (Fredericia’s correction factor) more than 450 milliseconds (msec) for males and more than 470 milliseconds (msec) for females at the Screening Visit or Baseline.
3. Systolic blood pressure (SBP) of more than 160 mmHg or diastolic blood pressure (DBP) of more than 95 mmHg on 3 separate determinations 5 minutes apart, taken at same arm, after the participant feels comfortable and relaxed at the research facility to minimize or avoid “white coat hypertension.”
4. A history of clinically significant orthostatic hypotension or syncope, or orthostatic hypotension at the Screening Visit or Baseline, defined as a SBP decrease more than or equal to 20 mmHg or DBP decrease more than or equal to 10 mmHg when standing up from sitting or lying down, and/or use of medications to treat orthostatic hypotension (e.g., droxidopa, fludrocortisone) and/or presence of severe dysautonomia.
5. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening.
6. Abnormal liver function tests: gamma-glutamyl transferase (GGT), total bilirubin (TBil), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) higher than the upper limits of normal (ULN) and regarded as potentially clinically significant by the Investigator. Note: Gilbert’s syndrome is not exclusionary.
7. Poorly controlled diabetes as defined by hemoglobin A1C more than 8%.
8. Contraindication, condition, or concomitant medication incompatible with lumbar puncture (e.g., lumbar scoliosis, coagulopathy, and infected skin at needle puncture site), 1.5T or 3T MRI (e.g., aneurysm clip, metal fragments [e.g., in-skull and cardiac devices other than those approved as safe for use in MRI scanners], and internal electrical devices such as a cochlear implant, spinal cord stimulator, or cardiac pacemaker/defibrillator), or DaT-SPECT.
9. Taking prohibited medications, use of immunomodulatory or immunosuppressive therapy (immunoglobulins, systemic mAbs [or derivatives of mAbs], systemic immunosuppressant drugs [including azathioprine, methotrexate, mycophenolate mofetil], or plasmapheresis); use of dopaminergic antagonist therapy. Note: Use of low-dose cortisones derivative for orthostatic hypotension is permitted, as are topical corticosteroids is permitted. Use of anticoagulants (including coumarins, heparin, and derivatives) and antiplatelet drugs is permitted but must be temporarily suspended prior to and after execution of lumbar puncture according to the prescribing information.
10. Severe visual or hearing impairment that, in the Investigator’s opinion, would prevent the participant from accurately completing cognitive testing assessments.
11. Participation in any other clinical trial, being treated with an investigational product less than or equal to 4 weeks prior to the Screening Visit, and less than or equal to 8 weeks if treated with mAbs prior to the Screening Visit.
12. More than 5 years of symptomatic treatment for PD.
13. Any concurrent illness or condition, including but not limited to mental illness, substance abuse, metabolic dysfunction, immunological disease, physical or neurological examination finding or clinical laboratory finding which, in the opinion of the Investigator, would make the participant unable to cooperate or participate in the trial or would represent a potential safety concern. Note: An active or recent (within 3 days) respiratory infection will not disqualify a participant from enrolling in the trial; however, all symptoms should be resolved for at least 5 days prior to the Screening Visit. The Screening Period may be extended for up to 2 weeks to accommodate this recovery.
14. Current significant compulsive behaviors or impaired impulse control in response to a dopaminergic Parkinson’s Disease medication. Any major psychiatric diagnosis, including schizophrenia, bipolar disorder, and current major depressive disorder as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).
15. Renal impairment as defined by a calculated creatinine clearance (CLcr) of less than or equal to 60 mL/min.
16. Positive serology test (hepatitis B virus surface antigen, hepatitis C virus antibody, human immunodeficiency virus 1 and 2 antibodies).
17. Participant has cancer with the exception of the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years.
18. Drug or alcohol abuse in the past 1 year (criteria for alcohol abuse as per the DSM-V).
19. Positive urine screen for drugs of abuse that include opiates, cannabis, cocaine, amphetamines, or barbiturates.
20. Suicide attempt within 1 year prior to the Screening Visit, or severe suicidal ideation within 6 months prior to the Screening Visit (i.e., the participant answers “Yes” to Questions 4 or 5 in the Baseline-Screening Columbia-Suicide Severity Rating Scale [C-SSRS]), or participant is at significant risk of suicidal behavior in the opinion of the Investigator.
21. Any condition that, in the Investigator’s opinion, would make the participant unable to comply with trial procedures or make them unsuitable for participation in the trial.
22. Participation in any prior exidavnemab study, regardless of treatment group assignment.
23. History of neurosurgical intervention for PD including implantation of brain stimulation.
24. Blood or plasma donation within 3 months prior to Screening.
25. Diagnosis of PD dementia or another dementia.
26. Any psychiatric diagnosis or symptoms (e.g., hallucinations, major depression, or delusions) that could interfere with trial procedures.
27. Freezing episodes occurring on a weekly basis or more frequently.
28. Motor fluctuations occurring on a weekly basis or more frequently.
29. Levodopa-induced troublesome dyskinesia of a severity that would significantly interfere with the participant’s ability to participate or perform trial procedures as determined by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Subscale IV.
30. History of significant cardiovascular disease or arrhythmia within 6 months of Screening.
31. Females who intend to breastfeed during the trial and for up to 3 months after the last dose of trial medication.
32. Exclusion Criteria for Cohort 2b (Multiple System Atrophy): 1. Known hypersensitivity to the trial medication, the infusion solution, or excipients.
33. Any psychiatric diagnosis or symptoms (e.g., hallucinations, major depression, or delusions) that could interfere with trial procedures.
34. History of significant cardiovascular disease or arrhythmia within 6 months of Screening.
35. Abnormal ECG that is or may be clinically significant in the Investigator’s opinion and after consultation with the Medical Monitor, including left bundle branch block, atrial fibrillation, QTcF more than 450 msec for males and more than 470 msec for females at the Screening Visit or Baseline.
36. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening.
37. Abnormal liver function tests: GGT, TBil, ALP, ALT, and AST higher than the ULN and regarded as potentially clinically significant by the Investigator. Note: Gilbert’s syndrome is not exclusionary.
38. Poorly controlled diabetes as defined by hemoglobin A1C of more than 8%.
39. Contraindication, condition, or concomitant medication incompatible with lumbar puncture (e.g., lumbar scoliosis, coagulopathy, and infected skin at needle puncture site), 1.5T or 3T MRI (e.g., aneurysm clip, metal fragments [e.g., in-skull and cardiac devices other than those approved as safe for use in MRI scanners], and internal electrical devices such as a cochlear implant, spinal cord stimulator, or cardiac pacemaker/defibrillator).
40. Taking prohibited medications; use of immunomodulatory or immunosuppressive therapy (immunoglobulins, systemic mAbs [or derivatives of mAbs], systemic immunosuppressant drugs [including azathioprine, methotrexate, mycophenolate mofetil], or plasmapheresis); use of dopaminergic antagonist therapy. Note: Use of low-dose cortisone derivatives for orthostatic hypotension is permitted, as are topical corticosteroids. Use of anticoagulants (including coumarins, heparin, and derivatives) and antiplatelet drugs is permitted but must be temporarily suspended prior to and after execution of lumbar puncture, according to the prescribing information.
41. Participation in any other clinical trial, being treated with an investigational product less than or equal to 4 weeks prior to the Screening Visit, and less than or equal to 8 weeks if treated with mAbs prior to the Screening Visit.
42. Any concurrent illness or condition, including but not limited to mental illness, substance abuse, metabolic dysfunction, immunological disease, physical or neurological examination finding, or clinical laboratory finding which, in the opinion of the Investigator, would make the participant unable to cooperate or participate in the trial or would represent a potential safety concern. Note: An active or recent (within 3 days) respiratory infection will not disqualify a participant from enrolling in the trial; however, all symptoms should be resolved at least 5 days prior to the Screening Visit. The Screening Period may be extended for up to 2 weeks to accommodate this recovery.
43. Any major psychiatric diagnosis, including schizophrenia, bipolar disorder, and current major depressive disorder as per DSM-V.
44. Renal impairment as defined by a calculated CLcr of less than or equal to 60 mL/min.
45. Positive serology test (hepatitis B virus surface antigen, hepatitis C virus antibody, human immunodeficiency virus 1 and 2 antibodies).
46. Participant has cancer with the exception of the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years.
47. Drug or alcohol abuse in the past 1 year (criteria for alcohol abuse as per the DSM-V).
48. Positive urine screen for drugs of abuse that include opiates, cannabis, cocaine, amphetamines, or barbiturates.
49. Suicide attempt within 1 year prior to the Screening Visit, or severe suicidal ideation within 6 months prior to the Screening Visit (i.e., the participant answers “Yes” to Questions 4 or 5 in the Baseline-Screening C-SSRS), or the participant is at significant risk of suicidal behavior in the opinion of the Investigator.
50. Any condition that, in the Investigator’s opinion, would make the participant unable to comply with trial procedures or make them unsuitable for participation in the trial.
51. Participation in any prior exidavnemab study, regardless of treatment group assignment.
52. Blood or plasma donation within 3 months prior to Screening.
53. Females who intend to breastfeed during the trial and for up to 3 months after the last dose of trial medication.
54. Unable to ambulate without the assistance of another person, defined as the ability to take at least 10 steps. The use of assistive devices (e.g., a walker or cane) is permitted.
55. Primary (e.g., spinocerebellar ataxia) or secondary (e.g., autoimmune neuropathy) cause of ataxia.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To determine the occurrence of AEs and SAEs after 4 treatment cycles by assessing the frequency, severity, causality, and nature of AEs and SAEs; also changes in ECG, vital signs (arterial blood pressure, heart rate, and temperature), and laboratory tests (hematology, serum chemistry, and urine) will be assessed for tolerability. The severity of the AEs and SAEs will be determined by CTCAE v5.0.

Secondary endpoints 3

1. The recommended maximal dose will be defined by the safety and tolerability profile and PK data.
2. Exposure levels of exidavnemab in serum (i.e., PK parameters of exidavnemab).
3. Immunogenicity; determination of ADAs in serum by using a tier-based approach followed by determination of NAbs if relevant.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BioArctic AB

Sponsor organisation

BioArctic AB

Address

Warfvinges Vag 35, Vastermalm Vastermalm

City

Stockholm

Postcode

112 51

Country

Sweden

Scientific contact point

Organisation

BioArctic AB

Contact name

Tomas Odergren

Public contact point

Organisation

BioArctic AB

Contact name

Olga Björklund

Third parties 10

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 29 files

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

Application history

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