A Study of Outcomes in Chinese Patients Treated With Anifrolumab Who Have Active Mod-severe Systemic Lupus Erythematosus

LOTUS is a multicentre, open-label, single-arm, ph3b study to evaluate the efficacy and safety outcomes in Chinese patients treated with anifrolumab who have active moderate-severe SLE. Clinical outcomes, safety, and participant-reported outcomes (PRO) data will be collected during the study.

The study will be performed in Chinese patients aged between 18 and 70 years. Participants with a confirmed diagnosis of moderate to severe SLE and are currently receiving SOC comprising of GC and/or antimalarial, and/or immunosuppressants, either alone or any combination of them, for a required duration of treatment at a stable dose, as described in the inclusion criteria. Participants must have eligible scores for disease activity index ([SLEDAI-2K ≥6 OR clinical SLEDAI ≥4] And PGA >1).

Eligible patients will receive a fixed IV dose in addition to SOC for a total of 13 doses (from Week 0 to Week 48), with the primary endpoint being evaluated at the Week 52 visit.

Inclusion criteria

• Informed Consent

• Capable of giving signed informed consent. Age
• Participant must be 18 to 70 years of age inclusive, at the time of signing the ICF.

Disease Characteristics

• Participants who have a diagnosis of SLE according to the 2019 EULAR/American College of Rheumatology (ACR) criteria (Appendix D), confirmed by a rheumatologist
• ANA-positive as determined by a documented historical test result confirmed at Screening, for Antinuclear antibody (ANA) immunofluorescent assay test (titre ≥ 1:80), or at least one of the following:

• Anti-dsDNA (b) Anti-Smith (anti-Sm) Note: Retesting of autoantibodies is allowed once during Screening.
• To be eligible a participant must have SLEDAI-2K ≥6 or clinical SLEDAI-2K ≥ 4 points:

• In order to qualify for SLEDAI-2K score for arthritis at Screening, participant must have at least 3 joints with tenderness AND swelling (same joints) due to SLE.
• In order to qualify for SLEDAI-2K score for rash at Screening, participant must have rash with significant erythema (not only faint pink erythema)
• Clinical SLEDAI-2K points at Screening cannot only be due to one of the following (but a combination is permitted): fever, diffuse alopecia or mucosal ulcers. NB. Presence of fever or mucosal ulcers must be documented by the investigator at the visit. Patchy alopecia which includes a change in normal scalp colour, is permitted as a sole contributor to Clinical SLEDAI-2K score.
• PGA score ≥ 1.0 on a 0 to 3 visual analogue scale (VAS) at Screening.
• Must be receiving at least one of the following standard therapy regimens at Screening:

a) Oral prednisone (or equivalent) monotherapy: i. Must be stable (including prednisone or equivalent = 0 mg/day) for > 2 weeks before 1st anifrolumab infusion.

ii. Maximum daily dose: ≤ 40 mg/day. b) Antimalarials and/or immunosuppressant(s) with or without GC: i. Permitted medications include: antimalarials, azathioprine, mycophenolate mofetil/mycophenolic acid, methotrexate, mizoribine, tacrolimus, and cyclosporine (Note: The combination of azathioprine and methotrexate is not allowed due to known safety issues. The combinations of tacrolimus/cyclosporine with other immunosuppressants above should be avoided. Combination with antimalarials is allowed.).

ii. Start date: ≥ 12 weeks prior to signing the ICF. iii. Must be stable ≥ 8 weeks prior to signing the ICF. iv. The daily dose should follow the medical practice and not exceed the maximum allowed daily dose: v. Azathioprine: ≤ 200 mg/day. vi. Mycophenolate mofetil ≤ 2 g/day or mycophenolic acid ≤ 1.44 g/day. vii. Oral, subcutaneous (SC), or intramuscular methotrexate ≤ 25 mg/week. viii. Mizoribine ≤ 150 mg/day. ix. Tacrolimus ≤ 0.2 mg/kg/day or cyclosporine ≤ 5 mg/kg/day, monitoring of serum concentration may be performed at the discretion of Investigator where practice guidelines mandate or in case of safety concerns.

c) Oral prednisone (or equivalent) plus immunosuppressant(s): i. Start dates for GC and immunosuppressants must be met. ii. Stability requirements for each medication must be met. iii. No minimum daily dose for GC when in combination with immunosuppressants. iv. Maximum daily dosages for each medication in (a) and (b) must not be exceeded.

• Chest x-ray (obtained during Screening or within 12 weeks prior to signing of the ICF) or a computed tomography (CT) scan of the chest (within 12 weeks of signing the informed consent) which meets all the following:

• No evidence of current active infection (e.g., pneumonia, tuberculosis [TB]) or previous TB; and
• No evidence of malignancy; and
• No clinically significant abnormalities (unless due to SLE).
• TB Testing for Inclusion in the study: the participant must undergo an IGRA (e.g., QuantiFERON-Tuberculosis Gold [QFT G test]) test for TB obtained from the study central laboratory at Screening with any of the following results:

Negative test result Positive test result: referral to a TB specialist for evaluation and for which active TB has been ruled out (as described in the protocol definition), and initiation of treatment for latent TB prior to the first administration of study intervention in accordance with local SoC.

Indeterminate test result confirmed by repeat test using the same assay o The participant must be referred to a TB specialist for evaluation (with assessment and treatment recommendation comprehensively documented in source) and initiation of appropriate latent TB treatment, if warranted, prior to the first administration of study intervention. If no latent TB treatment is warranted, the participant may enter the study without latent TB treatment but must be retested at least every 12 months. If the retest result is indeterminate or negative, the participant may continue in the study with routine testing.

o If, upon retest, the result is indeterminate, the participant may continue in the study without treatment. The participant will continue routine TB testing as outlined in the SoA (Section 1.3).

Weight

• Body weight ≥ 40 kg. Sex
• Female participants:

a) Negative serum β-hCG test at Screening (females of childbearing potential only).

b) Women of childbearing potential must have a negative urine pregnancy test at Week0(Day 1), prior to administration of study intervention.

c) Women of non-childbearing potential must be postmenopausal or have been surgically sterilized (for example: bilateral oophorectomy, bilateral salpingectomy, or complete hysterectomy), which should be documented in the participant's medical records. The following age-specific requirements may apply for a postmenopausal state: i. Women who were taking HRT (Hormone Replacement Therapy):

<!-- -->

• Women < 50 years old will be considered postmenopausal if they have been amenorrhoeic for ≥ 12 months following cessation of HRT and the FSH level in a sample collected during Screening is in the laboratory's normal range for postmenopausal women. Until FSH is documented to be within menopausal range, the patient should be considered as a WOCBP.
• Women ≥ 50 years old will be considered postmenopausal if they have been amenorrhoeic for ≥12 months following cessation of all HRT.

ii. Women who were not taking HRT:

• Women < 60 years old will be considered postmenopausal by a history of ≥ 12 months of amenorrhea and if the FSH level in a sample collected during Screening is in the laboratory's normal range for postmenopausal women.
• Women ≥ 60 years old will be considered postmenopausal if they have been amenorrhoeic for ≥ 12 months prior to the Week 0(Day 1)without an alternative medical cause.

iii. If the above criteria are not met, the patient should be regarded as a WOCBP.

• Contraceptive methods should be used in all sexually active men and women. Highly effective methods include oral contraceptives, contraceptive implants, intrauterine device, condoms and vasectomy. Female participants must not get pregnant, donate eggs or breastfeed a child during the study and up to 16 weeks after the last dose of the study medication.

• Male participants must not donate sperm during the study and for 16 weeks after the last dose of the IMP.

Exclusion criteria

• Medical Conditions

• History of, or current diagnosis of, a clinically significant non-SLE related vasculitis syndrome Vasculitis due to SLE is allowed in the study.
• Non-SLE diseases that potentially require systemic glucocorticoids (e.g. IV or oral), as determined by medical judgment, e.g. asthma, chronic obstructive pulmonary disease (COPD).
• Active severe or unstable neuropsychiatric SLE including, but not limited to aseptic meningitis, cerebral vasculitis, myelopathy, demyelination syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy), acute confusional state, impaired level of consciousness, psychosis, acute stroke or stroke syndrome, cranial neuropathy, status epilepticus, cerebellar ataxia, lupus headache and mononeuritis multiplex, where, in the opinion of primary investigator or AstraZeneca, protocol-specified standard therapy is insufficient and utilisation of a more aggressive therapeutic approach, such as adding IV cyclophosphamide and/or high dose IV pulse corticosteroid therapy or other treatments not permitted in the protocol, is indicated.
• Active severe SLE-driven renal disease where, in the opinion of the primary investigator or AstraZeneca, protocol-specified standard therapy is insufficient and utilisation of a more aggressive therapeutic approach, such as adding IV cyclophosphamide and/or high dose IV pulse corticosteroid therapy or other treatments not permitted in the protocol, is indicated.
• Subjects with SLE overlap syndromes such as scleroderma and mixed connective tissue disease are excluded. Subjects with an overlap syndrome of SLE with rheumatoid arthritis are not excluded as long as they meet the criteria for the classification of SLE.
• Subjects with other autoimmune diseases (e.g., multiple sclerosis, psoriasis, IBD, etc.) are excluded. Subjects with type I autoimmune diabetes mellitus, thyroid autoimmune disease, Celiac disease, or secondary Sjögren's syndrome are not excluded.
• History of, or current diagnosis of, catastrophic anti-phospholipid syndrome (APS) within one year prior to signing the ICF. Subjects with a serious thrombotic event (e.g., pulmonary embolism stroke, deep vein thrombosis) or unexplained pregnancy loss within 1 year before the screening visit are excluded. Subjects with a history of catastrophic antiphospholipid syndrome or saddle embolism are excluded. Subjects with a history of 3 or more unexplained consecutive pregnancy losses would also be excluded. Participants with other degrees of APS adequately controlled by anticoagulants ((i.e., if on warfarin, an international normalized ratio [INR] target 2 to 3 or as appropriate for the clinical situation) or aspirin for at least 12 weeks can be recruited to the study.
• Current or history of Hypothalamic-Pituitary-Adrenal (HPA) axis related disease, Addison disease, adrenal haemorrhage etc.
• Current infections requiring hospitalisation.
• History of recurrent infection requiring hospitalisation and IV antibiotics (e.g., 3 or more of the same type of infection over the previous 52 weeks).
• Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the participant to infection, or a positive result for human immunodeficiency virus (HIV) infection confirmed by central laboratory at Screening:

a) An HIV test must be performed during Screening, and the result should be available prior to Week 0 (Day 1). The participant is ineligible to participate in the study when positive for HIV antibody or infection (i.e., positive nucleic acid test) performed by the central laboratory. Participants refusing HIV testing during the Screening Period will not be eligible for study participation.

• Severe herpes zoster or recurrent herpes zoster:

• Any severe case, as defined by study guidelines, of herpes zoster infection at any time prior to Week 0 (Day 1), including, but not limited to, non-cutaneous herpes (ever), herpes encephalitis (ever), recurrent herpes zoster (defined as 2 episodes within 2 years) or ophthalmic herpes involving the retina (ever).
• Any herpes zoster infection that has not completely resolved within 12 weeks prior to signing the ICF.
• Confirmed positive test for hepatitis B serology for:

• Hepatitis B surface antigen (HBsAg), OR
• Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA detected above the lower limit of quantitation (LLOQ) by reflex testing by the central laboratory at screening.

Note: Participants who are HBcAb positive at screening will be tested at least every 12 months for HBV DNA. To remain eligible for the study, the participant's HBV DNA levels must remain below the LLOQ as per the central laboratory.

• Active hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody and detectable HCV ribonucleic acid (RNA) as confirmed by central laboratory.
• Any clinical cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection that has not completely resolved within 12 weeks prior to signing the ICF.
• Active tuberculosis (TB):

• Medical history or signs or symptoms of active TB prior to or during Screening.
• A chest x-ray during the Screening Period or within 12 weeks prior to signing of the ICF with evidence of active or signs of prior TB infection
• Recent contact with a person with active TB OR if there has been such contact, referral to a physician specializing in TB to undergo additional evaluation prior to Week 0 (Day 1) (documented comprehensively in source), and, if warranted, receipt of appropriate treatment for latent TB at or before the first administration of study intervention
• Opportunistic infection requiring hospitalization or IV antimicrobial treatment within 3 years of Week 0 (Day 1).
• Clinically significant chronic infection (e.g., osteomyelitis, bronchiectasis, etc.) within 8 weeks prior to signing the ICF (chronic nail infections are allowed).
• Current or previous history of malignancies, apart from:

• Squamous or basal cell carcinoma of the skin treated with documented success of curative therapy ≥3 months prior to Week 0 (Day 1).
• Cervical cancer in situ treated with apparent success with curative therapy ≥1 year prior to Week 0 (Day 1).
• Females with abnormal cervical cancer screening results Females who have been or are sexually active with an intact cervix must have documentation of a cervical cancer screening (Pap smear or human papilloma virus [HPV] tests as per local guidelines) with a normal test result within 2 years prior to Week 0 (Day 1). Any abnormal cervical cancer screening result documented within 2 years prior to Week 0 (Day 1) must be repeated to confirm participant eligibility.

Note: Females aged < 25 years, who have never been sexually active or have well-documented HPV vaccination records may not, at the investigator's discretion, require a cervical cancer screening test.

• Any history of an anaphylactic reaction to human proteins or monoclonal antibodies.

Prior/Concomitant Therapy

• Prior receipt of anifrolumab.
• Current receipt of other biologics or small molecule targeted treatments.
• Currently participating in an interventional clinical trial with an IMP.
• Participants with receipt of/use of any live or attenuated vaccine within 8 weeks prior to signing the ICF will be excluded from the study. Use of any live or attenuated vaccine is not allowed during the study up until study completion or at least 12 weeks after the last study dose.
• Receipt of any prohibited medication listed in Appendix H.
• Blood transfusion or receipt of blood products except albumin within 4 weeks prior to signing the ICF.

Diagnostic Assessments

• At Screening (within 4 weeks before Week 0), any of the following (note: retesting of laboratory test results during Screening may be repeated once):

• Serum creatinine > 2.0 mg/dL (or > 181 μmol/L)
• Urine protein/creatinine ratio > 2.0 mg/mg (or > 226.30 mg/mmol)
• Aspartate aminotransferase (AST) > 2.0 × upper limit of normal (ULN)
• Alanine aminotransferase (ALT) > 2.0 × ULN
• TBL > ULN (unless due to Gilbert's syndrome)
• Neutrophil count < 1000/μL (or < 1.0 × 109/L)
• Hb < 8 g/dL (or < 80 g/L), or < 7 g/dL (or < 70 g/L) related to participant's SLE such as in active haemolytic anaemia
• Glycosylated haemoglobin (HbA1c) > 8% (or > 0.08) at Screening (in diabetic participants only) Others
• Lactating, breastfeeding, or pregnant females or females who intend to become pregnant or begin breastfeeding anytime from initiation of Screening until 16 weeks following last dose of study intervention.
• Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to signing the ICF.
• Major surgery within 8 weeks before signing the ICF or elective major surgery planned during the study period .
• Any condition that, in the opinion of the investigator or AstraZeneca, would interfere with treatment outcomes of the study intervention or put participant at safety risk.