A Study Evaluating the Effects of GLPG3667 Administered As Oral Treatment in Adult Participants with Active Systemic Lupus Erythematosus

Key Inclusion Criteria:

1. Participant with documented diagnosis of SLE as defined by the 2019 European LeagueAgainst Rheumatism (EULAR)/American College of Rheumatology (ACR) classificationcriteria with a disease diagnosed ≥24 weeks before the screening visit.

2. Participant has a total Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≥6 points and a clinical SLEDAI-2K score ≥4 at screening andbaseline (scores must be confirmed by central review at screening).

• Lupus headache, alopecia, organic brain syndrome, and mucous membraneulceration will not count toward the score required for screening at entry.

• Clinical SLEDAI-2K excludes laboratory abnormalities such as hematuria, pyuria,urinary casts, proteinuria, positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA), decreased complement, thrombocytopenia, and leukopenia.

3. Participant is positive for 1 of the following: antinuclear antibodies (ANA) ≥1:80or positive anti-dsDNA (indeterminate values are considered positive), or positiveanti-Smith (anti-Sm), as determined by the central laboratory.

4. At least 1 of the following BILAG-based protocol-specific manifestations of SLE:

• BILAG A or B score in the mucocutaneous body system.

• BILAG A or B score in the musculoskeletal body system due to arthritis.

• If only 1 B and no A score is present in the mucocutaneous body system or inthe musculoskeletal body system due to arthritis, then at least 1 B score mustbe present in one of the other body systems, for a total of >=2 BILAG B bodysystem scores.

5. Background therapy with at least 1 of the following medications is required for >=12weeks before the screening visit and must remain stable until randomization andthroughout study participation:

• 1 immunosuppressant (combination of immunosuppressants is not permitted),stable at least 8 weeks prior to screening.

• 1 antimalarial, stable at least 8 weeks prior to screening. In addition, oralcorticosteroids (CS) (prednisone or equivalent) and/or NSAIDs backgroundtherapy is permitted but not required:

• CS (prednisone or equivalent; <=30 mg/day; CS monotherapy is not permitted),stable at least 2 weeks prior to screening; AND/OR

• Non-steroidal anti-inflammatory drugs (NSAIDs; NSAIDs monotherapy is notpermitted), stable at least 2 weeks prior to screening.

Key Exclusion Criteria:

1. Participant with active, severe lupus nephritis (World Health Organization ClassIII, IV) that requires or may require treatment with cytotoxic agents or high-doseCS are excluded.

2. Participants with pre-existing, controlled renal disease with serum creatinine≥ 2 xupper limit of normal (ULN) and either residual proteinuria up to 3 grams/day (g/day) or a urine protein: creatinine ratio (UPCR) of up to 3 milligrams/milligrams (mg/mg) or 339 milligrams of albumin per millimole of creatinine (mg/mmol) areallowed. Control of renal disease must be documented with at least 2 measurements ofproteinuria or UPCR over the past 6 months.

3. Participants with a history of catastrophic antiphospholipid syndrome are excluded.This includes Participants with a serious thrombotic event (e.g. pulmonary embolism,stroke, deep vein thrombosis) or unexplained pregnancy loss within 1 year before thescreening visit or history of 3 or more unexplained consecutive pregnancy losses.Participants with antiphospholipid antibody syndrome on stable anticoagulant therapyat an effective dose are allowed.

4. Participants with active or unstable lupus neuropsychiatric manifestations,including but not limited to any condition defined by BILAG A criteria are excluded,with the exception of participants with mononeuritis multiplex and polyneuropathy,who are allowed.

5. Drug-induced SLE.

6. Participant has a chronic hepatitis B virus (HBV) infection, as defined by positiveHBV surface antigen (HBsAg) at screening and detectable HBV core antibody (HBcAb).

7. Participant has chronic hepatitis C virus (HCV) infection, as defined by positiveHCV antibody (Ab) at screening and detectable HCV viremia. Participants withpositive HCV Ab must undergo reflex HCV ribonucleic acid (RNA) testing, andParticipants with HCV RNA positivity will be excluded. Participants with positiveHCV Ab and negative HCV RNA are eligible.

8. Participant has a history of or a current immunosuppressive condition or a historyof opportunistic infections (e.g. human immunodeficiency virus [HIV] infection,histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis,herpes simplex, herpes zoster).

9. Participant testing positive for severe acute respiratory syndrome coronavirusdisease 2 (SARS-CoV-2) infection, even if fully vaccinated against SARS-CoV-2, asdetected by rapid antigen testing and/or revert transcription polymerase chainreaction (RT-PCR), test at screening and/or baseline (Day 1). Participant presentingany signs or symptoms suggestive of SARS-CoV-2 infection, as detected at screeningor baseline following careful physical examination (e.g. cough, fever, headaches,fatigue, dyspnoea, myalgia, anosmia, dysgeusia, anorexia, sore throat), shouldundergo testing even if fully vaccinated against SARS-CoV-2, as per locallyapplicable standard diagnostic criteria to diagnose SARS-CoV-2 infection andexcluded if positive.

10. Participant meets 1 of the following tuberculosis (TB) criteria at screening:

• A history of active or currently active TB (regardless of treatment).

• A positive QuantiFERON®-TB Gold Plus In-tube test at screening unless theinvestigator assesses this is due to a documented history of adequately treatedlatent TB infection. Note: If the test result is indeterminate, it may be repeated once; if indeterminateor positive on retest, Participant is not eligible.

11. Participant with poorly controlled chronic cardiac, pulmonary, or renal disease.

12. Participant has at screening, presence of severe renal impairment (defined asestimated glomerular filtration rate [eGFR] <30 mL/minute/1.73 m2, using the ChronicKidney Disease Epidemiology equation).

13. Prior exposure to tyrosine kinase 2 (TYK2) inhibitors.

14. Female participant is pregnant or breast feeding or intending to become pregnant orbreastfeed during the study.

15. Participant has taken any prohibited therapies within the defined washout periodsbefore screening, and during screening.