Single and Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of NM-101

Study Overview
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Brief Summary
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This is a Phase I, double-blind, randomised, two-part, single-ascending dose (Part 1) and multiple-ascending dose (Part 2) study of NM-101 in healthy males and healthy females of non-childbearing potential

Detailed Description
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NM-101 is an anti-TLR2 antibody which may have clinical efficacy in Parkinson's disease patients. This Phase I study aims to assess the safety, tolerability and pharmacokinetics (PK) of single and multiple ascending doses of NM-101 in healthy males and healthy females of non-childbearing potential. A total of 56 subjects (8 per cohort) are planned to be enrolled. Subjects will be randomly assigned to recieve NM-101 or placebo in a 3:1 ratio. The study will be in 2 parts: Part 1 will consist of 3 single-dose cohorts; Part 2 will consist of 4 multiple-dose cohorts. In Part 1, sentinel dosing will be applied. In each cohort, 1 subject will be randomised to receive NM-101 and 1 subject will be randomised to receive placebo ahead of dosing in the remaining 6 subjects. The dose for Cohort 1 is 20 mg/kg NN-101. The predicted doses for Cohorts 2 and 3 are 40 mg/kg and 60 mg/kg NM-101, respectively (dependent on a blinded interim review of the safety, tolerability and PK data). Blood samples will be collected at regular intervals for PK analysis and safety from Day 1 until Day 42. In Part 2, sentinel dosing will not be applied. Each subject will receive 4 doses of NM-101 or placebo over the course of 3 months. Dosing may occur in parallel to the conduct of Part 1. The doses administered will be selected based on emerging safety, tolerability and PK data from preceding groups in Part 1. The predicted NM-101 doses are: 10 mg/kg for Cohort 4; 20 mg/kg for Cohort 5; 40 mg/kg for Cohort 6; 60 mg/kg for Cohort 7. In Cohorts 5 to 7, subjects will undergo a lumbar puncture to assess NM-101 concentrations in the cerebrospinal fluid. Blood samples will be collected at regular intervals for PK analysis and safety from Day 1 until Day 127.

Official Title
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A Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of NM-101 in Healthy Male and Female Subjects

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: NM-101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent and Compliance Must provide written informed consent Must be willing and able to communicate and participate in the whole study Demographics and Contraception Aged 18 to 65 years inclusive at the time of signing informed consent Must agree to adhere to the contraception requirements Baseline Characteristics Healthy males or WONCBP Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening Other Must have received at least 2 doses of a COVID-19 vaccine Exclusion Criteria: Medical/Surgical History and Mental Health Serious adverse reaction or serious hypersensitivity to any drug or formulation excipients History of allergic or anaphylactic reactions to humanised or other therapeutic monoclonal antibodies or to any of the excipients of NM-101 Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator Undergone a lumbar puncture within 6 weeks before Day 1 (Part 2 only) Medical history or evidence of mass occupying lesion in brain or spinal cord or history of spinal cord injury, which could preclude the procedure of lumbar puncture and CSF collection (Part 2 only) Evidence or history of clinically significant back pain, back pathology and/or back injury (e.g. degenerative disease, spinal deformity or spinal surgery) that may predispose to complications or technical difficulties in the conduct of a lumbar puncture (Part 2 only) Physical Examination Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening Diagnostic Assessments Evidence of current SARS-CoV-2 infection History of an infection requiring treatment within 14 days of first dose of the IMP A history of any ongoing, chronic or recurrent infectious disease, herpes, or evidence of tuberculosis infection as defined by a positive QuantiFERON® TB Gold test at screening Clinically significant abnormal clinical chemistry, haematology or urinalysis as judged by the investigator Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) 1 and 2 antibody results Females of childbearing potential including those who are pregnant or lactating (all female subjects must have a negative highly sensitive serum pregnancy test) Prior Study Participation Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, whichever is longer Subjects who have previously been administered IMP in this study. Subjects who have taken part in Part 1 are not permitted to take part in Part 2 and vice versa Subjects who report to have previously received NM-101 (formerly known as OPN-305) Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood Prior and Concomitant Medication Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 4 g of paracetamol per day or HRT) in the 14 days before first IMP administration. Exceptions may apply, as determined by the investigator Subjects who have had a vaccine (including COVID-19 vaccine) within 28 days before first dose Have taken non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet function within 14 days prior to scheduled lumbar puncture (Part 2 only) Lifestyle Characteristics History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption in males >21 units per week and in females >14 units per week A confirmed positive alcohol breath test at screening or admission Current smokers and those who have smoked within the last 12 months A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months Confirmed positive drugs of abuse test result Other Male subjects with pregnant or lactating partners Travelled to an area where there is risk of malaria within the past year unless adequate precautions were taken Subjects who are, or are immediate family members of, a study site or sponsor employee Failure to satisfy the investigator of fitness to participate for any other reason

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 56
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NM-101<br>Ascending doses of NM-101. IV infusion over 2 hours | Drug: NM-101<br>* In Part 1, each cohort will receive a single dose at one of three dose levels (3 cohorts). In Part 2, each cohort will receive multiple doses at one of four dose levels (4 cohorts).<br>* Other names: OPN-305 (formerly);|
| Placebo Comparator: Placebo<br>IV infusion over 2 hours | Drug: Placebo<br>* Placebo solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of NM-101: Incidence of Treatment-Related Adverse Events by Severity | A treatment related adverse event is defined as a clinical event with plausible time relationship to NM-101 administration and that cannot be explained by concurrent disease or other drugs or chemicals | up to 4 months | 
| PK Parameter | maximum concentration (Cmax) | up to 4 months | 
| PK Parameter | time of the maximum measured concentration (Tmax) | up to 4 months | 
| PK Parameter | area under the concentration-time curve from time (AUC) | up to 4 months | 
| PK Parameter | First order rate constant associated with the terminal portion of the curve (Lambda-z) | up to 4 months | 
| PK Parameter | terminal elimination half life (t1/2) | up to 4 months | 
| PK Parameter | clearance (CL) | up to 4 months | 
| PK Parameter | Volume of distribution based on the terminal phase (Vz) | up to 4 months | 
| PK Parameter | Volume of distribution at steady state (Vss) | up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebrospinal Fluid (CSF) Concentrations of NM-101 | Quantification of NM-101 24 h after the dose only in Cohorts 5 to 7 | Day 2 or Day 86 | 
| Immunogenicity of NM-101 | Quantification of NM-101 anti-drug antibodies pre-dose and after each dose of NM 101 Quantification of NM-101 anti-drug antibodies pre-dose and after each dose of NM 101 Quantification of NM-101 anti-drug antibodies pre-dose and after each dose of NM 101 | up to 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NM-101, Anti-TLR2 antibody, Blood-brain barrier, Ascending dose