A Study to Assess the Safety and Tolerability of SR-878 in Patients With Rheumatoid Arthritis

Phase 1b Study to Assess the Safety and Tolerability of SR-878 in Patients With Rheumatoid Arthritis

SR-878 is a newly developed medicine that aims to treat autoimmune disorders. It inhibits a protein (iRhom2), that regulates enzymes that are involved in the production of cytokines (small proteins that are crucial in controlling the activity of immune system cells). The aim of this clinical trial is to find a suitable safe and effective SR-878 dose for patients with rheumatoid arthritis. The study will include a screening period, an inpatient treatment period, and an outpatient follow-up period. The study duration for an individual participant is up to 113 days (about 16 weeks).

Rationale: SR-878 is an investigational medicine that targets a specific protein, called iRhom2, which is involved in inflammation in autoimmune diseases like rheumatic arthritis (RA). SR 878 blocks multiple inflammatory pathways without affecting normal body functions such as skin and gut barrier protection. This could offer broader anti-inflammatory effects with fewer side effects compared to existing therapies that block only one pathway. In a previous study with healthy volunteers, SR-878 caused a temporary increase in inflammation markers in the blood. Because this was completely unexpected, the study was stopped early. However, animal studies showed that this reaction did not occur in animals already suffering from an inflammatory condition like RA. Therefore, this new study is testing SR-878 directly in RA patients, to see if it is safe and to find the right dose to use in future studies.

Main objective: To see if SR-878 is safe and well tolerated in RA patients and to find the safest effective dose.

Additional objectives: To understand how the drug is absorbed, distributed, and cleared from the body, assess blood biomarkers (markers that indicate how the drug acts in the body), monitor additional safety parameters, and whether the body develops any immune reaction to it.

Study endpoints: The main endpoints include the percentage of patients who experienced adverse events during the study, including serious events, events linked to SR-878, and events which were so severe that the treatment dose had to be reduced or stopped. Further endpoints assess how long the drug stays in the body, how much of it is present in the blood over time (up to Day 85 and beyond), and the highest level of the drug found in the blood by Day 85. The percentage of patients who have important changes in laboratory values, electrocardiograms (ECGs), and vital signs (blood pressure, pulse and temperature) will also be evaluated as well as changes in blood biomarkers. And finally, the percentage of patients who develop an immune reaction against SR-878 will be assessed.

Study design: The study consists of a screening period (up to 28 days prior to treatment), an inpatient treatment period (3 days), and a follow-up of 82 days, thus, each patient will be in the study for up to 113 days.

Study population: Adults (18 to 60 years) diagnosed with active RA for at least 3 months who have tried and not responded well to at least one approved standard RA medication will be included. Patients must have used a molecule called methotrexate at a stable dose for at least 4 weeks before study start and must use that dose during the entire study. Individuals with any contraindication for SR-878, a diagnosis of other autoimmune diseases, active infections, or arthritis, using certain RA medications including so-called biologic treatments like tumor necrosis factor alpha blockers or interleukin-6 blockers, or with a medical history that could increase their risk during the study will not be included.

Methodology: This is a single dose escalation study, meaning that patients will receive one intravenous infusion of SR-878 at increasing doses to find the highest safe dose. Up to 9 different doses are planned to be tested. The gradual dose increases from one dose group to the next will be decided after a safety evaluation committee has carefully reviewed all data from previously treated patients, and no signals of concern had been observed. It starts with one patient at the lowest dose, then continues with groups of three patients per dose level. In addition, within a dose group, a patient will only be treated if the previous patient had no safety problems within 72 hours of dosing. Up to 27 patients may be included. Eligibility of patients will be assessed at a screening visit. Eligible patients will receive their SR-878 infusion on Day 1 and be hospitalized for at least 72 hours to closely monitor safety. After discharge from hospital patients will be further followed up at several clinic visits till the end of the study (Day 85).

Study-related procedures Screening: Written informed consent prior to any study-specific procedures, questions about demography, medical history, medication history, and on how patients assess disease activity (on a visual scale of 0 to 10), check of swollen and tender joints, physical examination which includes height and weight, ECG, vital signs, clinical laboratory tests, confirmation of RA diagnosis, recording of adverse events.

Treatment and follow-up: Some of the same assessments performed at Screening, infusion of SR-878, blood draws to measure SR-878 in the blood, safety laboratory, biomarkers (markers that indicate how the study medication acts in the body), and immune reaction, urine collections, recording of adverse events, and of new or changed medications.

Intervention: single infusion of SR-878 over 1 hour; patients are asked to continue methotrexate during the entire study at the dose already used 4 weeks before study start.

Ethical considerations: The study will be performed in accordance with the applicable version of the Declaration of Helsinki and in line with appropriate national regulations.

Risks: In a previous clinical study that tested SR-878 in 13 healthy people, most people with adverse events had mild events like cold symptoms, sore throat, headaches, and nausea. A few showed increased blood levels of an inflammatory marker (C-reactive protein), and one person had a pro inflammatory reaction called CRS (see above). CRS occur with different severities, and the reaction in this person belonged to the lowest severity grade, Grade 1 (the scale ranges from 1-5). As with other similar treatments, SR-878 may cause allergic reactions ranging from mild rashes to serious breathing issues and life-threatening reactions. To prevent this, SR-878 is given very slowly. If this happens anyway, emergency medications and equipment are readily available at the site. There is also a chance that it could increase the risk of infections and because this is a new drug, there may be unknown side effects. To protect patients a safety committee regularly reviews data and can stop the study if necessary.

Benefits: This study might help find a new and better treatment for RA. While patients may not directly benefit, the knowledge gained could help many others in the future.

Inclusion Criteria:

1. Written informed consent

2. Men and women aged 18 to 60 years inclusive

3. Body weight ≥45 kg and body mass index ≤32 kg/m²

4. Diagnosis of RA according to the 2010 ACR/EULAR classification criteria, for at least 3 months before Screening

5. Stable dose of MTX for at least 4 weeks before Day 1

6. Ability to comply with the study protocol for the duration of the study, including inpatient confinement for about 3 days

7. Adequate venous access for blood collection

8. Women must not be pregnant or breastfeeding and

   1. be of non-childbearing potential (postmenopausal [no menses for 12 months without an alternative medical cause] or surgically sterilized [documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy]) or
   2. if of childbearing potential, must use a highly effective contraceptive method for the duration of the study and have a negative pregnancy test at Screening (blood test) Note: Acceptable highly effective methods of contraception include the intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion (must be documented); oral, intravaginal, transdermal, injectable, and implantable methods of hormonal contraception associated with inhibition of ovulation, vasectomized partner (must be documented); or sexual abstinence (only when it is the usual and preferred lifestyle of the participant)

9. Men must agree, from start of SR-878 administration until 90 days after SR-878 administration, to refrain from donating sperm and use a male condom when having sexual intercourse with a woman of childbearing potential, who is not currently pregnant, and advise her to use a highly effective contraceptive method

10. Disease status appropriate to be included in this exploratory safety study according to the investigator

Exclusion Criteria:

1. Abnormal findings in medical history and physical examination considered to be clinically relevant by the investigator
2. Clinically significant abnormal screening laboratory tests
3. Known active infection with human immunodeficiency virus (HIV), hepatitis B virus, tuberculosis, and/or hepatitis C virus (HCV)
4. Clinically relevant ECG (12 leads) abnormalities
5. Acute infectious diseases within 2 weeks before Screening
6. History or presence of any autoimmune disease other than RA, chronic inflammatory condition, or clinically significant (in the opinion of the Investigator) atopic allergy (eg, asthma, urticaria, eczematous dermatitis, allergic rhinitis)
7. Relevant history of other renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, hematological, endocrine, inflammatory, chronic infectious, or neurological diseases
8. History of anaphylaxis to drugs or major allergic reactions in general, which in the view of the investigator may compromise the safety of the participant
9. Malignancy in the last 5 years before Screening (except basal or squamous cell skin cancer)
10. History of any chronic inflammatory arthritis with onset prior to the age of 18 or history of acute inflammatory joint disease of a different origin than RA
11. Current or previous (within 30 days or, if applicable, 5 half-lives of the investigational medicinal product (IMP), whatever is longer, before Screening) participation in another clinical study with an investigational drug and/or medical device
12. Known hypersensitivity to the active substance or to any of the excipients of the IMP and auxiliary medicinal products
13. Drug and alcohol abuse
14. Prohibited medication as outlined below
15. Plans to undergo elective procedures or surgeries at any time after signing the informed consent form until end of the study
16. Employees of the sponsor, or employees or relatives of the investigator
17. Individuals committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
18. Legal incapacity or limited legal capacity