A Clinical Study to Determine the Safety, Tolerability and Effect of RLS-0071 Doses When Given to Healthy Adults After Inhaling LPS

A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Dose Range Finding Study to Assess the Safety, Tolerability, PD and PK of RLS-0071 in Healthy Adult Subjects After Challenge With Inhaled Lipopolysaccharide (LPS)

This is a Phase 1b, randomized, double-blind, placebo-controlled, dose range finding study to assess the safety, tolerability, pharmacodynamics (PK) and pharmacokinetics (PD) of RLS-0071 in healthy adult subjects after challenge with inhaled lipopolysaccharide (LPS).

Clinical data are required to determine the potential benefit of RLS-0071, a novel drug that specifically inhibits multiple inflammatory pathways, for the treatment of severe asthma. This study has been designed to evaluate the efficacy of IV administered RLS-0071 to reduce inflammation symptoms in healthy subjects challenged with inhaled LPS, a well-known agent that produces a safe and well-controlled inflammatory response in the lung. This is a critical proof-of-concept study and dose-optimization study for future studies in severe asthma patients.

A total of 48 healthy adult subjects are planned to be enrolled in this study. Subjects will be randomly allocated to either of the treatment arms (Arm A or Arm B) with RLS-0071 or the placebo arm (Arm C) in a 1:1:1 ratio. Subjects will either receive intravenous infusion of RLS-0071 at a lower dose every 8 hours for a total of 3 doses (Arm A), RLS-0071 at a higher dose every 8 hours for a total of 3 doses (Arm B) or placebo dosed every 8 hours for a total of 3 doses (Arm C). Each subject completing the study will be evaluated for up to a total of 7 days. Subjects will be permitted to participate in only 1 arm of the study. Subjects discontinuing the study before data was collected at 6 hours post LPS challenge will be considered dropouts and will be replaced.

The inclusion of a double-blind design allows a comparison between subjects receiving RLS-0071 and placebo subjects who are experiencing the same procedures and restrictions in an unbiased manner. The inclusion of a placebo control group will facilitate the distinction between efficacy signals and possible procedural/environmental events.

Eligibility criteria have been included to mitigate the risk to study subjects. Vulnerable populations such as children are excluded, as well as subjects whose medical history suggest a higher risk of experiencing adverse effects.

LPS inhalation is used in this study to be able to evaluate proof-of-concept efficacy of RLS-0071 in otherwise healthy subjects. Thus, PD assessments will be conducted to provide evidence of target engagement and guide the design of future severe asthma studies.

Inclusion criteria:

1. Age 18 to 55 years, inclusive, at the time of Screening

2. Female subjects of childbearing potential must agree to use a highly effective contraceptive method from Screening until 30 days after the last investigational medicinal product (IMP) intake and have a negative pregnancy test at Screening (blood test). The following contraceptive measures can achieve a failure rate of less than 1% per year when used consistently and correctly and are considered highly effective measures:

   1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral / intravaginal / transdermal)
   2. progestogen-only hormonal contraception associated with inhibition of ovulation (oral / injectable / implantable)
   3. intrauterine device
   4. intrauterine hormone-releasing system
   5. bilateral tubal occlusion
   6. vasectomized partner (provided that the partner is the sole sexual partner of the woman of childbearing potential and has received medical assessment of the surgical success)
   7. sexual abstinence (only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment). Abstinence is only accepted as true abstinence when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods and withdrawal] is not an acceptable method of contraception).

   Female subjects who are not of childbearing potential are exempt from contraceptive requirements. To be considered of non-childbearing potential female subjects must meet the following requirements: Must be permanently sterile (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at least 3 months before first dosing with the investigational medicinal product) or postmenopausal (defined as no menses for 12 months without an alternative medical cause).

3. A male study subject must agree to use a double barrier method (eg, condom and spermicide) during sexual contact with a pregnant woman or a woman of childbearing potential ,and agree to not donate sperm during the study and for at least 90 days after the last dose of the IMP

4. Medically healthy on the basis of medical history, physical examination, and clinical laboratory testing in the opinion of the Investigator

5. Nonsmokers and nonusers of nicotine-containing products, including vaping devices for at least 6 continuous months before the first dosing with the investigational medicinal product and for the duration of the study, to be confirmed by cotinine testing at Screening and a smoking history of < 5 pack years

6. Negative alcohol testing at Screening and Day 1

7. Negative cotinine and drug screen testing at Screening.

8. Vital signs (after semi-recumbent for at least 5 minutes) that are within the following ranges at Screening:

   1. Systolic blood pressure (BP): 90 to 140 mmHg, inclusive
   2. Diastolic BP: 50 to 90 mmHg, inclusive
   3. HR: > 45 to ≤ 100 bpm

9. Weight ≤ 100 kg and body mass index ≥ 18 and ≤ 32 kg/m2 at Screening

10. Normal renal function, defined as estimated creatinine clearance > 90 mL/min at Screening; an Investigator can determine based on clinical judgment whether a lower clearance rate can be accepted based on the muscle composition of the subject

11. Willing and able to understand the information on the nature, the scope, and the relevance of the clinical study, and to provide voluntary, written informed consent to participate in the study

12. Able to communicate well with the Investigator and/or study site personnel and to comply with the requirements of the entire study

Exclusion Criteria:

1. Use of any prescription or over-the-counter (OTC) medications, herbal products (eg, cannabidiol, St John's Wort, milk thistle), or supplements/vitamins within 14 days or 5 half-lives (whichever is longer) before first dosing with IMP and for the duration of the study, with the exception of those approved by the Investigator and Sponsor (eg, oral contraceptives, hormone replacement therapy, acetaminophen for pain relief).

2. Receipt of any investigational agent or treatment within 30 days or 5 half-lives, whichever is longer, before first dosing with IMP, or concurrent participation in another clinical study.

3. Receipt of any protein- or antibody-based therapeutic agents (eg, growth hormones or monoclonal antibodies) within 3 months before first dosing with IMP.

   Note: Influenza and COVID-19 vaccines will be allowed if all doses in the regimen have been administered more than 21 days before first dosing with IMP.

4. History of any major surgery within 6 months before first dosing with IMP.

5. Prior diagnosis of COVID 19 within 90 days before first dosing with IMP.

6. History of hepatic disease, or current clinically significant liver function test results, defined as ALT, AST, total bilirubin and fractionated bilirubin, or alkaline phosphatase > 1.5 × upper limit of normal (ULN) at Screening.

   Note: Isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated, and direct bilirubin is < 35%.

7. History of any clinically relevant or chronic psychiatric, renal, hepatic, pancreatic, cardiovascular, neurological, hematological, or gastrointestinal abnormality (eg, inflammatory bowel disease)

8. History of severe allergic/anaphylactic reaction

9. History of autoimmune disease including glomerulonephritis

10. Known hypersensitivity to the active substance or to any of the excipients of each IMP including lipopolysaccharide (LPS) and polyethylene glycol (PEG)

11. History of any active infection within 14 days before dosing with IMP, if deemed clinically significant by the Investigator and Sponsor

12. Any acute illness within 30 days before dosing with IMP

13. Lower respiratory tract infection within 3 months before first dosing with IMP

14. History of warfarin use or International Normalized Ratio ≥ 1.5

15. History (within 2 years before the first dosing with IMP) of moderate or severe use disorder for any substance other than caffeine (based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria)

16. Known diagnosis or active infection with Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV)-1 or HIV-2

17. Existence of any surgical or medical condition that, in the judgment of the Investigator, might interfere with the absorption, distribution, metabolism, or excretion of RLS-0071

18. Presence of clinically significant ECG finding (confirmed upon repeat testing) that, in the opinion of the Investigator and/or Sponsor, may interfere with any aspect of study conduct or interpretation of results

19. Concurrent conditions that could interfere with safety and/or tolerability measurements, as determined by the Investigator

20. Pregnant and/or lactating

21. Inability to produce sufficient amounts of induced sputum at baseline visit

22. Inability to tolerate IV administration

23. Poor venous access, as determined by the Investigator

24. Unable or unwilling to cooperate with the study site staff for any reason

25. Employees of the Sponsor or subjects who are employees or relatives of the Investigator