First-In-Human Clinical Study of the C3 Complement Inhibitor AMY- 101 in Healthy Male Volunteers

Study Overview
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Brief Summary
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Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a Single Ascending Dose (SAD) and a Multiple Dose (MD) of the complement inhibitor AMY-101. A prospective, single-center, open-label, First-In-Human (FIH) clinical study in healthy male volunteers.

Detailed Description
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AMYNDAS is developing a novel peptidic complement inhibitor AMY-101, based on the third-generation compstatin analogue Cp40. AMY-101 is a selective inhibitor of complement activation in humans and in NHP. It binds to the complement component C3, the central functional hub that controls the upstream activation/amplification and downstream effector functions of complement. By binding to C3, AMY-101 inhibits the cleavage of native C3 to its active fragments C3a and C3b. As a consequence, the deposition of C3b, amplification via the alternative pathway and all downstream complement responses are prevented. AMY-101 is being developed to treat complement-mediated diseases, which are largely driven by aberrant C3 activation. This first-in-human study of the C3-targeting complement inhibitor AMY-101 investigates the safety and PK/PD profile of AMY-101 in healthy male volunteers after Single Ascending Dose (SAD) and Multiple Doses (MD) using subcutaneous (SQ) or intravenous (IV) administration. The study is a prospective, single-center, open-label evaluation in healthy male volunteers.

Official Title
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Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of a Single Ascending Dose (SAD) and a Multiple Dose (MD) of the Complement Inhibitor AMY-101. A Prospective, Single-center, Open-label, First-In-Human (FIH) Clinical Study in Healthy Male Volunteers

Conditions
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Complement Mediated Diseases

Intervention / Treatment
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* Drug: AMY-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the study. Healthy male subject aged 18-60 years, inclusive at the time of signing the informed consent. Body Mass Index (BMI) ≥ 18 and ≤ 30 kg/m2 and weight at least 50 kg. Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. Willing to use condom and contraceptive methods with a failure rate of < 1% to prevent pregnancy and drug exposure of a partner and to refrain from donating sperm from the date of dosing until three (3) months after dosing of the IMP. Willing and able to complete all procedures according to the Protocol. Exclusion Criteria: History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. History of any Neisseria meningitidis infection History of unexplained, recurrent infection, or infection requiring treatment with systemic antibiotics within the last 60 days prior to dosing. History of latent or active tuberculosis, as assessed by the investigator based on chest X-ray and positive Quantiferon-TB Gold test. History of complement deficiency. History of any type of malignancy. However, completely resolved minor malignancies, at the discretion of the Investigator, may not be an exclusion criterion (for example: Non-Melanoma Skin Cancer). Diagnosis of autoimmune, immunologic or rheumatologic disease (eg, systemic lupus erythematosus, rheumatoid arthritis). Any clinically significant illness, medical/surgical procedure or trauma within four (4) weeks of the administration of IMP. High CRP at screening (> 0.5 mg/dL). Current evidence or history of bacterial, viral or fungal infection within 14 days prior to (first) dosing or longer according to the judgment of the investigator for e.g. viral infections including herpes simplex or herpes zoster. Any current condition or risk, which, in the opinion of the Investigator, may interfere with the subject's participation in the study, poses an added risk for the subject, or confounds the assessment of the subject or outcome of the study Any clinically significant abnormality in clinical chemistry, hematology, or urinalysis results at the time of screening, as judged by the Investigator. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and/or Human Immunodeficiency Virus (HIV). After 10 minutes supine rest abnormal vital signs defined as any of the following: Systolic BP > 140 mm Hg Diastolic BP > 95 mm Hg HR < 40 or > 90 beats per minute Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormality in the resting ECG, as judged by the Investigator. Any history of any allergy/hypersensitivity or anaphylactic reaction or on-going allergy/hypersensitivity. History of hypersensitivity to antibiotics or drugs with a similar chemical structure or class to AMY-101. Use of any prescribed or non-prescribed medication including antacids, analgesics, herbal remedies, vitamins and minerals within two (2) weeks prior to the administration of IMP, except the occasional intake of paracetamol/acetominophen (maximum 2000 mg/day; and not exceeding 3000 mg/week) or nasal decongestant without cortisone or antihistamine, at the discretion of the Investigator. Administration of another new chemical entity (defined as a compound that has not been approved for marketing) or having participated in any other clinical study that included drug treatment within 30 day or 5 half lives of the last administration of the other IMP. Subjects consented and screened but not dosed in previous phase I studies are not excluded. Immunization with a live-attenuated vaccine one (1) month prior to the first administration of IMP. Current smokers or users of nicotine products. Irregular use of nicotine (e.g. smoking, snuffing, chewing tobacco) less than three (3) times per week is allowed before screening visit. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator. Positive screen for drugs of abuse at screening or on admission to the unit or positive screen for alcohol at screening or on admission to the unit prior to administration of the IMP. Use of anabolic steroids. Plasma donation within one (1) month of screening or any blood donation/blood loss > 450 mL during the three (3) months prior to screening. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

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: Sequential Assignment
Interventional Model Description: This is a prospective, single-center, open-label FIH study investigating the safety, tolerability, PK and PD after single and multiple doses of AMY-101 in healthy male volunteers. In the SAD part of the study, a single dose at ascending dose levels of AMY-101 will be administered to different cohorts, following a careful dose-escalation strategy. In the MD part of the study, multiple doses will be administered using different dosing intervals; the cohorts will include a minimum of four (4) subjects each. Additional subjects may be added in the cohorts if necessary.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Dose (SAD)<br>In the SAD arm subjects will be sequentially included in one of up to six cohorts (dose levels). All cohorts will include at least four subjects each. Additional subjects may be added in any cohort if necessary. AMY-101 will be administered as a SQ or IV injection. Subjects in each cohort will be dosed sequentially, to allow for close safety monitoring. Between each cohort, safety data will be analyzed, evaluated and reviewed by the internal Safety Review Committee. Subsequent dose levels will be administered until either the maximum tolerated dose (MTD) or the study maximum dose (SMD) is reached based on specified dose escalation criteria. | Drug: AMY-101<br>* AMY-101 is a selective inhibitor of complement activation, which binds to the complement component C3.<br>|
| Experimental: Multiple Dose (MD)<br>Depending on the results of the SAD, multiple doses of AMY-101 will be administered at the dose which has been identified as the dose which saturates target C3, for a duration that results to an exposure level equivalent to the maximum exposure achieved in the SAD. The dose and dosing interval will be determined based on the PK data obtained in the SAD part of the study. Each MD cohort will include at least four subjects and may be expanded with additional subjects if necessary. Between each cohort, safety data will be analyzed, evaluated and reviewed by the internal Safety Review Committee. | Drug: AMY-101<br>* AMY-101 is a selective inhibitor of complement activation, which binds to the complement component C3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | Up to 21 days after treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration time curve (AUCt) after a single dose |  | Up to 14 days after treatment. | 
| Area under the plasma concentration time curve from zero to infinity (AUC 0->∞) after a single dose |  | Up to 14 days after treatment. | 
| Peak Plasma Concentration (Cmax) after single and multiple doses |  | Up to 14 days after treatment. | 
| Time to Cmax (Tmax) after single and multiple doses |  | Up to 14 days after treatment. | 
| Terminal elimination rate constant (lambdaz) after single and multiple doses |  | Up to 14 days after treatment. | 
| Terminal half-life (T1/2) after single and multiple doses |  | Up to 14 days after treatment. | 
| Total apparent clearance of drug from plasma/serum (CL/F) after single and multiple doses |  | Up to 14 days after treatment. | 
| Volume of distribution (Vz) / fraction of drug absorbed (F) after single and multiple doses |  | Up to 14 days after treatment. | 
| Area under the curve at steady state (AUCss) after multiple doses |  | Up to 14 days after treatment. | 
| Activation of the classical complement pathway | CH50 | Up to 14 days after treatment. | 
| Activation of the alternative complement pathway | AP50 | Up to 14 days after treatment. | 
| Complement protein C3 plasma levels |  | Up to 14 days after treatment. | 
| Complement protein C4 plasma levels |  | Up to 14 days after treatment. | 
| Measurement of immune response (plasma protein electrophoresis - IgG,IgA, IgM) after single and multiple administrations of AMY-101. |  | Up to 14 days after treatment. | 
| Investigation for anti-drug antibodies after single and multiple administrations of AMY-101. |  | Up to 14 days after treatment. | 
| Measurement of lymphocyte subsets after multiple administrations of AMY-101. |  | Up to 14 days after treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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complement inhibition, C3 complement inhibitor, AMY-101, Compstatin Cp40, Paroxysmal Nocturnal Hemoglobinuria (PNH), C3 glomerulopathy (C3G), Periodontal disease, Age-related macular degeneration (AMD), ABO incompatible kidney transplantation