A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging, Parallel and Adaptive Study to Evaluate the Efficacy and Safety of Enpatoran in Systemic Lupus Erythematosus and in Cutaneous Lupus Erythematosus (Subacute Cutaneous Lupus Erythematosus and/or Discoid Lupus Erythematosus) Participants Receiving Standard of Care

PHRR220325-004464

Unspecified

A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging, Parallel and Adaptive Study to Evaluate the Efficacy and Safety of Enpatoran in Systemic Lupus Erythematosus and in Cutaneous Lupus Erythematosus (Subacute Cutaneous Lupus Erythematosus and/or Discoid Lupus Erythematosus) Participants Receiving Standard of Care

This is a global, Phase II, basket proof-of-concept and dose-finding, randomized, double-blind,placebo-controlled, dose-ranging, parallel and adaptive multicenter study in participants with active SLE or CLE (active SCLE and/or DLE) treated with standard of care to evaluate the efficacy and safety of enpatoran administered orally twice per day for 24 weeks. The purpose of this PoC and DF study is to evaluate the efficacy and safety of orally administered enpatoran over 24weeks in systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE; subacute cutaneous lupus erythematosus [SCLE] and/or discoid lupus erythematosus [DLE]) patients in a randomized, double-blind, placebo-controlled, parallel, adaptive and dose-ranging setting.
• Study Duration: 33 weeks
• Visit Frequency: every 2 or 4 weeks
• Enpatoran is not available through an expanded access program. Up to 440 participants (100 in Cohort A + up to 340 in Cohort B) will be randomized, treated and followed-up in this study.

Ongoing

Clinical Trial

Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus (Subacute Cutaneous Lupus Erythematosus and/or Discoid Lupus Erythematosus)

a. Dose-response relationship of enpatoran in reducing disease activity based on Cutaneous Lupus Erythematosus Disease Area and Severity Index-A (CLASI-A) will be found (i.e.,Percent change from baseline in CLASI-A at Week 16 will be determined)

b. Dose-response relationship of enpatoran in reducing disease activity based on BILAG-Based Composite Lupus Assessment (BICLA) response rate will be found (i.e., BICLA response at Week 24 will be determined)

a. Following are the outcomes related to safety and tolerability from Day 1 to the end of Safety Follow-up period:

• Occurrence of TEAEs, SAEs and AESI
• Occurrence of abnormalities (Grade ³3) in laboratory parameters
• Occurrence of Clinically Important increases in QT Interval Corrected Using Fridericia's Formula (QTcF)

b. Following are the outcomes related to efficacy in disease control of enpatoran compared to placebo in lupus participants with active lupus rash:

• Change from baseline in CLA-IGA at Week 16 and Week 24
• Change from baseline in Physician’s Global Assessment of Cutaneous Lupus Disease Activity at Week 16 and 24

c. Below is the outcome related to the effect of enpatoran compared with placebo on achieving both BICLA response and clinically meaningful CS reduction in SLE participants on prednisone ≥ 10 mg at Day 1: BICLA response and clinically meaningful CS reduction, defined as reduction of daily prednisone-equivalent dose from ≥ 10 mg at Day 1 to ≤ 5 mg by the Week 12 visit and sustained through Week 24.

Refer Protocol Page Numbers 36 to 43

Pending

20211207161606

2022-03-10

0000-00-00

23

Unspecified

Unspecified

0000-00-00

INCLUSION CRITERIA: Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are ≥ 18 to ≤ 75 years of age at the time of signing the informed consent. If participants are enrolled in Japan, if a participant is < 20 years of age, the written informed consent from the participant’s parent or guardian will be required in addition to the participant’s written consent for this country.
Vaccinations
2. Are up to date, according to local guidelines, with vaccination against Streptococcus pneumoniae and influenza virus (as seasonally required for influenza virus). Active SCLE and/or DLE (Cohort A)
3. Diagnosis of SCLE or DLE documented in medical history. Predominant findings of active lupus rash must be SCLE and/or DLE, but other skin manifestations of CLE will be allowed (e.g., lupus tumidus, Acute Cutaneous Lupus Erythematosus [ACLE], etc) on a case-by-case basis if their main diagnosis is active SCLE and/or DLE. Diagnosis must include one of the following options:
a. Historical skin biopsy (i.e., pathology report; punch or shave biopsy) within 10 years prior to Screening visit and confirmation of current diagnosis by skin
photography at Screening visit.
OR
b. Fresh punch skin biopsy at Screening visit.
OR
c. If target lesion is unsuitable for biopsy (e.g., malar rash, bridge of the nose, scalp), skin photography at Screening visit may be allowed on a case-by-case basis.
4. Disease duration of ≥ 6 months from time of diagnosis to Screening.
5. CLASI-A ≥ 8 at Screening Visit; this must be confirmed at Day 1 Visit.
EXCLUSION CRITERIA: Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Primary diagnosis of autoimmune or rheumatic disease other than SLE or CLE (discuss with Medical Monitor if overlap syndrome). Note: Secondary Sjögren’s syndrome or an autoimmune thyroiditis are not exclusionary.
2. Drug-induced lupus (SLE or CLE).
3. Any condition including dermatological diseases other than cutaneous manifestations of SLE or CLE (e.g., psoriasis), or any uncontrolled disease (e.g., asthma, interstitial lung disease, pulmonary arterial hypertension, morbid obesity), that in Investigator’s or Sponsor/designee’s opinion constitutes inappropriate risk or contraindication for
participation.
4. Active lupus nephritis on induction therapy, or induction therapy completed within 3 months of Screening visit (stable maintenance therapy with mycophenolate or azathioprine allowed).
5. Urine protein: creatinine ratio (UPCR) > 4 mg/mg (> 339 mg/mmol), and/or estimated
glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation by the central laboratory:
eGFR = 175 × (serum creatinine in mg/dL)–1.154 × (age in years)–0.203 × 0.742 (if female)
× 1.212 (if race is black). Refer Protocol Page Numbers 49 to 57

Interventional

M5049 (Enpatoran)

This is a global, Phase II, basket proof-of-concept and dose-finding, randomized, double-blind, placebo-controlled, dose-ranging, parallel and adaptive multicenter study in participants with active SLE or CLE (active SCLE and/or DLE) treated with standard of care to evaluate the efficacy and safety of enpatoran administered orally twice per day for 24 weeks.

The planned total duration of the study for each participant will be up to approximately 33 weeks: up to a 7-Week Screening Period (5-Week Screening Period with the possibility to expand by an additional 2 weeks if needed to repeat a laboratory test or due to an unanticipated event), a 24-Week Double-Blind Placebo-Controlled (DBPC) Treatment Period followed by a 2-Week Safety Follow-up Period. Upon completion of the eligibility form, and confirmation of eligibility of active SLE, (active SCLE and/or DLE) by the Medical Monitor as well as Primary Investigator assessment that participant continues to meet inclusion/exclusion criteria, the participant will be randomized. The study will be conducted on an outpatient basis.

The study consists of 2 cohorts to establish PoC and dose-finding for enpatoran in 2 patient populations: Cohort A and Cohort B. Cohort B has a dose-finding adaptive design comprised of Part 1 and Part 2. Cohort A and Cohort B Part 1 will start in parallel with a subsequent initiation of Cohort B Part 2.
• Cohort A will have participants with CLE (active SCLE and/or DLE) (CLASI-A ≥ 8) or SLE with predominantly active lupus rash.

• Cohort B will have SLE participants who have moderate to high systemic disease activity.

Refer Protocol Page Numbers 44 to 45
(BILAG A and/or 2B)