None listed
Conditions
Brief summary
Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organ involvement characterized by chronic immune activation, severe inflammation and organ damage. Although multiple genetic and environmental factors act synergistically to promote immunopathology and tissue damage in SLE patients, dysregulation of cytokines plays an important role in SLE patients. Interleukin 2 (IL-2) deficiency has been implicated in SLE progression and immunopathology in SLE patients. RS2102 is PEG-modified, N88R-mutated IL-2. N88R mutation reduces the affinity of RS2102 for Interleukin-2 Receptor beta and gamma chains and further improves the selectivity of RS2102 binding to Interleukin-2 Receptor alpha, beta and gamma chains, allowing it specifically activate Treg cells. Meanwhile, PEG modification can prolong the half-life of RS2102 in vivo and maintain the efficacy duration. Therefore, RS2102 can be used for the treatment of autoimmune diseases such as SLE by specifically binding Interleukin-2 Receptor alpha, beta and gamma chains and activating Treg cells, which are expected to be administered once every 2 weeks in clinical settings.
Interventions
Part 1 (Single Ascending Dose Study, SAD):
Part 1 (Single Ascending Dose Study, SAD) will be conducted in Australia, as a single-center, randomized, double-blind and placebo-controlled single ascending subcutaneous dose study. Seven cohorts will be included as a tentative plan, the order of cohorts may be adjusted based on the safety of the previous cohort (s), and additional cohort (s) may be added to obtain additional safety and Pharmacokinetics (PK)/ Pharmacodynamics (PD) data based on the a
Part 1 (Single Ascending Dose Study, SAD): Part 1 (Single Ascending Dose Study, SAD) will be conducted in Australia, as a single-center, randomized, double-blind and placebo-controlled single ascending subcutaneous dose study. Seven cohorts will be included as a tentative plan, the order of cohorts may be adjusted based on the safety of the previous cohort (s), and additional cohort (s) may be added to obtain additional safety and Pharmacokinetics (PK)/ Pharmacodynamics (PD) data based on the approval from Safety Review Committee (SRC). In Part 1 of the study, each cohort follows the principle of sentinel administration (i.e., 2 subjects are enrolled and dosed first in each cohort, 1 is randomly assigned to the active drug and 1 to the placebo). If no significant safety risk is observed within 48 hours after dose administration, the remaining 6 subjects can be dosed. Cohorts 1 to 7 are sequential. After all subjects of the cohort reach D15 post-dose, the safety data will be thoroughly assessed, and the Safety Review Committee (SRC) will determine whether it is appropriate to escalate to the next dose level. The dose levels for subsequent cohorts may be adjusted based on the SRC review. Cohorts Planned Dose Levels* & Dose Frequency Subjects 1) 0.16 µg/ - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo 2) 0.5 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo 3) 1.5 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo 4) 5 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo 5) 15 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo 6) 30 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo 7) 60 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo * The dose levels are tentative. Dose cohorts/levels adjustment were allowed based on the SRC review. The dosing will be supervised by the Principal Investigator, sub-investigator along with experienced and trained site staff (which would include but limited to study nurse, study pharmacist, study coordinators). Part 1 includes a screening period (D-28 to D-1) and an observation period (D1 to D29). Eligible subjects should be admitted no later than Day -1, receiving abdominal subcutaneous injection of RS2102 in the morning on Day 1, and are suggested to discharge after completing all sampling and lab tests on Day 7 (the discharge time can be adjusted according to the site decision, but should be based on the safety of subjects). Subjects then complete all other on-site visits. All subjects should receive safety monitoring and sampling for pharmacokinetics, pharmacodynamics and immunogenicity at scheduled timepoints. Part 2 (Multiple-ascending-dose study, MAD): Part 2 (Multiple Ascending Dose Study, MAD) will be conducted in China, as a single-center, randomized, double-blind, and placebo-controlled multiple ascending subcutaneous dose study. The tentative plan for this second part includes four cohorts (the dose cohorts and frequency/treatment duration are tentative until data from Part 1 are available), with 8 subjects in each cohort. Each subject receives medication once a week for 4 weeks (i.e., QW, 4 times in total) as a tentative plan. After all subjects of the cohort reach 2 weeks after the last administration, the safety data will be thoroughly assessed, and the Safety Review Committee (SRC) will determine whether it is appropriate to escalate to the next dose level. The dose levels/frequency for subsequent cohorts may be adjusted based on the SRC review. Part 2 includes a screening period (D-28 to -1) and an observation period (D1 to D50). Eligible subjects should be admitted no later than Day -1, receiving the first dose on Day 1 and suggested to be discharged after completing sampling and safety tests on Day 8 (the discharge time can be adjusted according to the site decision, but should be based on the safety of subjects); be admitted again no later than Day 21, receive the last dose on Day 22 and suggested to be discharged after completing sampling and safety tests on Day 28 (the discharge time can be adjusted according to the site decision, but should be based on the safety of subjects); all subjects should complete all other on-site visits. On the morning of the dosing date, all subjects will be administered the abdominal subcutaneous injection. Before and after dosing, safety monitoring will be conducted, and sampling for pharmacokinetics, pharmacodynamics and immunogenicity will be completed. Note: based on results from SAD, if the risk-benefit didn’t support MAD in healthy volunteers, the sponsor may decide to close this Part 2 study and open another protocol for MAD study in patients.
Sponsors
Atridia Pty Ltd
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject is a healthy adult subject, male or female, 18 to 55 years of age (inclusive) at the time of informed consent. 2. Subject has a body mass index (BMI equal to weight/height squared) between 18 and 28 kg/m2 (inclusive), and weight of: male greater than or equal to 50 kg and female greater than or equal to 48 kg. 3. Good overall health judged by investigator based on the results of medical history, physical examination, vital signs, laboratory tests, 12-lead ECG, and chest radiography at screening. 4. All female or male subjects and their partners of childbearing potential must be willing to follow contraception requirements as per protocol and all female and male subjects who have egg or sperm donation plan must follow egg or sperm donation requirements. 5. Subject is willing and able to comply with the scheduled visits and treatment plan, laboratory testing and other study procedures. 6. Subject is capable of providing a signed and dated informed consent form (ICF) indicating the subject has been informed of all pertinent aspects of the study described in ICF.
Exclusion criteria
1) Suspected allergy to the study drug (including IL-2 and polyethylene glycol) or any component of the study drug, or history of anaphylaxis or severe allergic reaction to any drug, food, toxin or other contact exposure per PI discretion. 2) Subject with a history of malignant tumor (except for subjects with non-melanoma skin cancer that was cured more than 2 years ago and cervical intraepithelial neoplasia that was cured more than 5 years ago). 3) Subjects who had undergone any surgery in the previous 3 months prior to screening, or subject has not recovered from prior surgery as judged by investigators, or plan to receive the operation during the study and within 1 month after completing all study visits. 4) Subject with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine, or hematological abnormalities, which is considered by the investigator to potentially impact the study results or affect absorption, distribution, metabolism and excretion of drug or places the subjects at unnecessary risk. 5) Active tuberculosis indicated by clinical symptoms, signs, laboratory tests or chest X-ray; latent tuberculosis indicated by T-spot or Quanti-FERON TB test; 6) Subject has investigator judged clinically significant infections within 1 month prior to screening, including acute and chronic infections such as abscess, furuncle, carbuncle and other local infections, respiratory tract infections, urinary and reproductive infections, systemic infections, etc. (Minor skin or respiratory infections that have completely resolved even within 1 month are acceptable at the discretion of the investigator). 7) Subject with any autoimmune diseases or immune dysfunction at screening. 8) Subject participated in any clinical trial of drug or medical device within 2 months prior to screening (or 5 half-lives of drug, whichever is longer). Subject who is receiving or has a history of receiving any of the following medications: 9) Use of prescription drug within 14 days prior to baseline or during the study (except for hormonal contraception, topical medications at the discretion of the investigator, brief use of medications that are not expected to interfere with safety or data quality at the discretion of the Principal Investigator and Sponsor). 10) Use of over-the-counter drugs, including natural health products (brief use of a supplement in this period that is not expected to interfere with safety or data may be allowed at the discretion of the Principal Investigator and Sponsor) within 14 days prior to baseline, with the exception of occasional use of paracetamol (up to 2 g daily), ibuprofen, or regular doses of vitamins. 11) Subject who has received any live vaccine within 1 month prior to screening or need to receive live vaccine during the study (including 30 days after the last dose of study drug). Subject who meets any of the following laboratory endpoints in screening or baseline examination: 12) QTc greater than 450 ms or other significant ECG abnormalities with clinical significance as judged by the investigator. 13) White blood cell count, neutrophil count, lymphocyte count or hemoglobin in hematology out of the normal reference range and is judged as clinically significant by the investigator. 14) Alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal (ULN) and/or aspartate aminotransferase (AST) greater than 1.5 times ULN and/or bilirubin greater than 1.5 times ULN. 15) Subject who is positive for hepatitis B surface antigen, hepatitis B e antigen, anti-hepatitis C virus antibody, syphilis antibody or HIV antibody. Subject under any of the following general conditions: 16) Smoker: average daily smoking of more than 5 cigarettes (or other nicotine-containing products) at the time of screening. 17) Drinker: positive breath alcohol test (positive with greater than or equal to 0 mg/dL) at screening; or long-term fixed alcohol consumption within 3 months prior to screening, the subject drinks more than 14 units of alcohol per week [1 unit equal to 150 mL of wine, rice wine or low-alcohol liquor, 360 mL of beer, or 45 mL of high-alcohol (Alcohol by volume greater than 40 percentage) liquor]. 18) Drug abuser: positive in urine drug screening test. 19) Woman who is pregnant or breastfeeding. 20) At the discretion of the investigator and sponsor, subject is unable to complete the study or otherwise is unsuitable for this study.
Outcome results
None listed