A Study to Evaluate the Safety and Activity of SAR448501/DR-0201 in Patients With Autoimmune Rheumatic Diseases

A Phase 1, Open-label, Multiple Ascending Dose Basket Study to Evaluate the Safety and Activity of SAR448501/DR-0201 in Patients With Select Autoimmune Rheumatic Diseases

This is an open-label, multi-ascending dose (MAD) phase 1 study, with dose expansion at selected doses, in adult patients with select autoimmune rheumatic diseases including systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). The purpose of the study is to identify possible optimal dose(s) by assessing the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary clinical response of SAR448501/DR-0201.

The study duration per participant will be a minimum of approximately 13 months, including a screening period of up to 28 days, a treatment period of 71 days, and a follow-up period of 42 weeks. If necessary, participants will continue to have visits after End of Study (EOS) every 4 weeks until peripheral blood B cells return to at least 80% of either the lower limit of normal (LLN) or the participant's baseline value.

Inclusion Criteria:

• Diagnosis of SLE and/or RA. American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria should be used.

• Contraception during the study intervention period and for at least 140 days after the last administration of study intervention: Male participants must agree to refrain from donating or cryopreserving sperm, and either be abstinent or use contraception/barrier. Female participants must use of a highly effective contraceptive measure for all females of childbearing potential. Females of childbearing potential need to have a negative serum pregnancy test within 7 days prior to the first dose.

• Specific to Systemic Lupus Erythematosus (SLE):

  • Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score ≥8 at screening with at least 4 points from clinical features at screening.
  • At least 1 British Isles Lupus Assessment (BILAG) A score or 1 BILAG B score at screening
  • Positive ANA (titer ≥1:80) as documented in the participant's medical history
  • Positive for any of the following as documented in the participant's medical history: antidsDNA, anti-Ro (anti-SS-A), anti-La (anti-SS-B), or anti-Sm antibodies
  • Inadequate response to systemic glucocorticoids and to at least 1 therapy other than antimalarials for at least 12 weeks including: cyclophosphamide, mycophenolate mofetil or its derivatives, belimumab, azathioprine, anifrolumab, methotrexate, rituximab, obinutuzumab, cyclosporin, tacrolimus, or voclosporin.

• Specific to Rheumatoid Arthritis (RA):

  -- Moderate-to-severe disease activity as defined by a 28-joint disease activity score using C reactive protein (DAS28-CRP) >3.2 at screening.

• Inadequate response or intolerance to at least 2 disease-modifying antirheumatic drugs (DMARDs, at least 1 biologic [bDMARD] or targeted synthetic [tsDMARD]) after a minimum of 12 weeks treatment duration.

• At least 6 tender joints at screening.

• At least 6 swollen joints at screening.

• Methotrexate (MTX) for at least 12 consecutive weeks, and at a stable dose of ≤25 mg/week oral or SC since at least 4 weeks prior to randomization, OR - in case of MTX intolerance - conventional DMARDs at a stable dose for at least 28 days.

• If taking MTX, compliant with folic acid 1 mg daily or 5 mg weekly or greater in combination with MTX.

Exclusion Criteria:

• Severe manifestation of the selected autoimmune rheumatic diseases under study that could impact participant safety, or is likely to require interventions that will affect investigational drug PD.

• Receipt of super-high potency (eg, clobetasol propionate, betamethasone dipropionate) or high potency (eg, fluocinonide, methylprednisolone aceponate) topical corticosteroids within 28 days prior to screening, had dose changes in other topical corticosteroids within 14 days prior to Day 1, or had dose changes in nonsteroidal topical immunosuppressants within 28 days prior to Day 1.

• Received dose changes of mycophenolate mofetil, methotrexate, leflunomide, calcineurin inhibitors, JAK inhibitors, or azathioprine within 28 days prior to Day 1.

• Receipt of any of the following medications within 6 months of Day 1: cyclophosphamide, leflunomide >20 mg/day, abatacept.

• Receipt of any mAb or experimental immunomodulator within 28 days or 5 published half-lives prior to Day 1, whichever is longer.

• Receipt of rituximab or other B cell depleting biologics within 6 months of Day 1.

• Receipt of rituximab or other B cell depleting biologics without return of CD19 or CD20 count to above the LLN.

• Receipt of alemtuzumab, bone marrow transplantation, stem cell transplantation, total lymphoid irradiation, CAR-T or T cell vaccination therapy.

• Known history of a primary immunodeficiency or an underlying condition such as known human immunodeficiency virus (HIV) infection, positive result for HIV infection, splenectomy, or any underlying condition that predisposes the participant to infection.

• History of a hypersensitivity reaction or anaphylaxis to a previous mAb or human immunoglobulin therapy.

• Active infection or a history of serious infections as defined in the protocol.

• Surgery within 28 days prior to Day 1.

• 12-lead ECG parameters after 10 minutes resting in supine position NOT in the defined normal ranges.

• Evidence of significant, uncontrolled concurrent disease that could affect compliance with the study (eg, chronic obstructive pulmonary disease).

• Diagnosis or history of malignant disease within 5 years prior to baseline, with the exceptions of basal cell or squamous epithelial carcinomas of the skin that have been resected or cervical carcinoma in situ, with no evidence of recurrence within the 5 years prior to baseline.

• High dose of antimalarial or a change in dose within 28 days prior to Day 1.

• Receipt of systemic corticosteroids >20 mg/day (prednisone or equivalent) or had dose changes of systemic corticosteroids within 28 days prior to Day 1.

• Documented liver disease including documented diagnosis of cirrhosis.

• Participants with a history of hypercoagulation event or thrombosis (such as venous thromboembolism, pulmonary embolism, or stroke), or participants who have known hypercoagulation risk factors (including antiphospholipid syndrome), or participants currently on anticoagulation will be excluded.

• Specific to SLE:

  • Active severe or unstable neuropsychiatric SLE including but not limited to seizures, psychosis, acute confusional state, transverse myelitis, central nervous system vasculitis and optic neuritis at screening.
  • Known biopsy-proven diagnosis of lupus nephritis (any class) or otherwise unexplained proteinuria (0.5g protein/24h; or urine protein/creatinine ratio >0.5g/g) at screening.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.