Comparative Safety, Tolerability, Pharmacokinetic Study of AVT02 (100MG/ML) and Humira (100MG/ML) in Healthy Volunteers

Study Overview
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Brief Summary
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Adalimumab is an immunosuppressive drug that belongs to the family of anti-TNF agents. It contains a monoclonal antibody produced by biotechnology. It is designed to bind to tumor necrosis factor (TNF), a substance that is involved in several auto-immune processes. By binding to TNF, adalimumab blocks its activity, reducing the severity of various chronic inflammatory diseases including Rheumatoid Arthritis, Plaque Psoriasis and others. Often, the high cost of biologic products may preclude access to the treatment to a big portion of the population worldwide. A biosimilar product that provides comparable safety and efficacy at more affordable cost would fulfill a broader medical need. Humira has been available on the market for several years. Recently, a higher concentration (100 mg/mL) formulation has been introduced in major markets. Alvotech is developing AVT02, that is a proposed biosimilar of adalimumab containing high concentration (100 mg/mL) of active ingredient. The objective of this clinical trial is to assess the similarity of AVT02 (100 mg/mL) with Humira (100 mg/mL), in terms of tolerability, safety (including immunogenicity) and compare the pharmacokinetics in healthy volunteers.

Official Title
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Single Centre, Randomised, Single-Blind, Pilot Study to Compare the Safety, Tolerability and Pharmacokinetics of AVT02 to EU-approved Humira® as a Single Dose (40 mg) Subcutaneous Injection in Healthy Adult Subjects (ALVOPAD)

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Adalimumab 100 MG/ML [Humira]
* Drug: AVT02 100MG/ML


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Male and female healthy adult subjects willing to sign an Informed Consent Form and able to undergo protocol related procedures. Age: 18 to 55 years, inclusive. Body Mass Index (BMI): 19.0 to 30.0 kg per m2. Medical history without major pathology, at the discretion of Principal Investigator. Resting supine systolic blood pressure of ≤150 mmHg and diastolic blood pressure of ≤90 mmHg. Other vital signs showing no clinically relevant deviations according to the Principal Investigator's judgment. Computerised 12-lead ECG recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the Principal Investigator. Subjects who do not smoke tobacco products or use nicotine replacement therapy or e-cigarettes. Main Exclusion Criteria: Evidence of clinically relevant pathology. Unable to follow protocol instructions in the opinion of the Principal Investigator. History of relevant drug and or food allergies. History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study. Known history of previous exposure to adalimumab or other anti-TNF-alpha molecules. Any past or concurrent medical conditions potentially increasing the subject's risks, or would have interfered with the study evaluation, procedures, or study completion. Examples of these include medical history with evidence of clinically relevant pathology (e.g., malignancies, demyelinating disorders, herpes zoster, or hepatic, gallbladder or pancreatic diseases). Presence of chronic obstructive pulmonary disease. Asthma in the childhood is allowed. Evidence of a recent, within 6 months, infection requiring hospitalisation or intravenous antibiotic use. Subject has a positive test for Tuberculosis (TB) during screening or a known history of active or latent TB, except documented and complete adequate treatment of TB. Having received live vaccines during the 4 weeks before screening or have the intention to receive vaccination during the study. Positive for Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HbcAb), anti- Hepatitis C virus antibodies (HCV), or anti-human immunodeficiency virus (HIV) 1 on 2 antibodies at screening. Impaired liver function Any persons who are an employee of the Principal Investigator, clinical centre, clinical research organisation or Sponsor, a relative of an employee of the clinical centre, the Investigator, Clinical Research Organization (CRO) or the Sponsor. Other inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Single Centre, Randomised, Single-Blind, Pilot Study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AVT02 100 MG/ML<br>Single subcutaneous injection of 40 mg of AVT02 (100MG/ML) | Drug: AVT02 100MG/ML<br>* prefilled syringe at a concentration of 100MG/ML delivering 40MG of AVT02, as a single dose on day 1 day 1<br>|
| Active Comparator: Adalimumab 100 MG/ML [HUMIRA]<br>Single subcutaneous injection of 40 mg of Adalimumab (100MG/ML) [HUMIRA] | Drug: Adalimumab 100 MG/ML [Humira]<br>* prefilled syringe at a concentration of 100MG/ML and delivering 40MG of adalimumab, as a single dose on day 1 day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline blood pressure at 1, 2, 3, 4, 5, 6, 7, 8, 9, 64 days post dosing | Measurement of blood pressure (systolic and diastolic in mm Hg) | Predose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 64 days post dosing | 
| Change from baseline heart rate at 1, 2, 3, 4, 5, 6, 7, 8, 9, 64 days post dosing | Measure of heart rate (beats per minute) | Predose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 64 days post dosing | 
| Change from baseline body temperature at 1, 2, 3, 4, 5, 6, 7, 8, 9, 64 days post dosing | Measurement of oral temperature (Celsius degree) | Predose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 64 days post dosing | 
| Change from baseline electrocardiogram at 1, 2, 5, 9, 64 days post dosing | Analysis of 12-lead electrocardiogram | Predose and 1, 2, 5, 9, 64 days post dosing | 
| Change from baseline red blood cells at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure red blood cells count, (unit/mm3) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline haemoglobin at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure haemoglobin (g/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline white blood cells at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure white blood cells count, (unit/mm3) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline platelets at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure platelets count, (unit/mm3) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood gamma glutamyl transferase at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure gamma glutamyl transferase (UI/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood aspartate aminotransferase at 2, 3, 5, 9, 64 days post | Blood collection to measure aspartate aminotransferase (UI/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood alanine aminotransferase at 2, 3, 5, 9, 64 days post | Blood collection to measure alanine aminotransferase (UI/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood potassium at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure potassium (mmol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood sodium at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure sodium (mmol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood calcium at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure calcium (mmol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood phosphate at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure phosphate (mmol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood chloride at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure chloride (mmol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood bicarbonate at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure bicarbonate (mmol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood creatinine at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure creatinine (micromol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline blood bilirubin at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure Bilirubin (micromol/L) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline international normalised ratio at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure international normalised ratio | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline prothrombin time at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure prothrombin time (sec) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline partial prothrombin time at 2, 3, 5, 9, 64 days post dosing | Blood collection to measure partial prothrombin time (sec) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline activated partial thromboplastin time at 2, 3, 5, 9, 64 days post | Blood collection to measure activated partial thromboplastin time (sec) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline thrombin time at 2, 3, 5, 9, 64 days post | Blood collection to measure thrombin time (sec) | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline urine leucocytes at 2, 3, 5, 9, 64 days post dosing | Urine sample collection to measure leucocytes | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline urine glucose at 2, 3, 5, 9, 64 days post dosing | Urine sample collection to measure glucose | Predose and 2, 3, 5, 9, 64 days post dosing | 
| Change from baseline urine protein at 2, 3, 5, 9, 64 days post dosing | Urine sample collection to measure protein | Predose and 2, 3, 5, 9, 64 days post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve (AUC) | Venous blood samples will be collected for measurement of Area under the plasma concentration-time curve (AUC) of AVT02 and EU Humira | Over 64 days | 
| Maximum serum concentration | Venous blood samples will be collected for measurement of serum concentration of AVT02 and EU Humira | Over 64 days | 
| Time to maximum serum concentration | Evaluation of time to maximum plasma concentration (Tmax) of AVT02 and Humira. | Over 64 days | 
| Terminal half-life | Evaluation of terminal elimination half-life (T1/2) of AVT02 and Humira | Over 64 days | 
| Volume of distribution | Evaluation of volume of distribution during the elimination phase (Vz) of AVT02 and Humira | Over 64 days | 
| Clearance | Evaluation of total plasma clearance (CL) of AVT02 and Humira | Over 64 days | 
| Incidence and titer of anti-drug antibodies to adalimumab | A blood sample will be collected to measure antibodies to AVT02 and Humira | 15, 29 and 64 days after dosing |