A Phase 2 Proof of Concept Study to Evaluate the Efficacy and Safety of Daxdilimab in Participants With Dermatomyositis (DM) or Anti-synthetase Inflammatory Myositis (ASIM)

Amgen12 enrolled

Overview

The primary efficacy objective: To evaluate the effect of daxdilimab compared with placebo in reducing disease activity at Week 24. The secondary efficacy objectives include: 1. To evaluate the effect of daxdilimab compared with placebo in reducing disease activity at Week 24. 2. To evaluate the effect of daxdilimab compared with placebo on skin symptoms at Week 24. 3. To evaluate the effect of daxdilimab on decreasing the use of corticosteroid at Week 24. Other secondary objectives include: 1. To characterize the pharmacokinetics (PK) and immunogenicity of daxdilimab in participants. 2. To evaluate the safety and tolerability of daxdilimab in participants.

The study will enroll participants with 2 idiopathic inflammatory myositis populations: * Population 1 or dermatomyositis (DM): participants with DM with definite or probable myositis according to the American College of Rheumatology/European League Against Rheumatism 2017 (ACR/EULAR 2017) criteria and a DM rash. * Population 2 or anti-synthetase inflammatory myositis (ASIM): participants with ASIM with definite or probable myositis according to ACR/EULAR 2017 criteria and a positive ASIM associated antibody. Participants will be randomized by population in a 1:1 ratio and receive investigational product (IP) daxdilimab or placebo by subcutaneous injection. The estimated total study duration will be up to 36 weeks (up to 60 weeks for those participants who entered the open-label extension prior to amendment 2.) Acquired from Horizon in 2024.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Adult men or women 18 and ≤ 75 years of age at the time of signing the informed consent (ICF). 2. A diagnosis of definite or probable myositis according to American College of Rheumatology/European League Against Rheumatism 2017 (ACR/EULAR 2017) criteria: 1. Population 1: DM * Diagnosis of DM with DM rash current or historical, or 2. Population 2: ASIM * Anti-histidyl tRNA synthetase-(Anti-Jo-1) antibodies must be positive during screening by central laboratory testing, or * One of following antibodies must be positive by historical testing: directed against anti-alanyl- (anti-PL-12), anti-threonyl-(anti PL-7), anti-asparaginyl-(anti-KS), anti-glycyl-(anti-EJ), anti-isoleucyl-(anti-OJ), anti-phenylalanyl-transfer RNA synthetase-(anti-ZO), anti-tyrosil-YRS(HA). 3. Currently active myositis with all the following (a, b, and c) during screening: 1. Manual Muscle Testing (MMT 8) score \< 142 2. At least 2 other abnormal core set measures (CSM) from the following list: * Patient global disease activity (PtGDA) ≥ 2 cm in a 10 cm visual analog scale (VAS) * Physician's Global Disease Activity (PhGDA) ≥ 2 cm in a 10 cm VAS * Extramuscular activity ≥ 2cm in a 10 cm VAS * At least one muscle enzyme 1.5 times upper limit of normal (ULN) * Health assessment questionnaire-disability index (HAQ-DI) ≥ 0.5 3. Global muscle damage score ≤ 5 on a 10 cm VAS on the myositis damage index (MDI). 4. Participants should be on stable standard of care therapy if tolerated; if they are not able to tolerate it or have failed standard of care, medications should have a washed out period. 5. Participants should be willing to taper corticosteroid dose per protocol when stable or improving. Exclusion Criteria: 1. Any condition that, in the opinion of the investigator or sponsor, would interfere with the evaluation of investigational product (IP) or interpretation of participant safety or study results. 2. Weight \> 160 kg (352 pounds) at screening. 3. Breastfeeding or pregnant women or women who intend to become pregnant anytime from signing the ICF through 6 months after receiving the last dose of IP. 4. History of clinically meaningful cardiac disease including unstable angina, myocardial infarction, congestive heart failure within 6 months prior to randomization; arrhythmia requiring active therapy, except for clinically insignificant extra systoles, or minor conduction abnormalities; or presence of clinically meaningful abnormality on electrocardiogram (ECG) if, in the opinion of the Investigator, it would increase the risk of study participation. 5. History of cancer within the past 5 years except cutaneous basal cell or squamous cell carcinoma treated with curative therapy. 6. Any underlying condition that in the opinion of the Investigator significantly predisposes the participant to infection (eg. hepatitis C). 7. Known history of a primary immunodeficiency or an underlying condition, such as known human immunodeficiency virus (HIV) infection, or a positive result for HIV infection per central laboratory. 8. All participants will undergo testing for hepatitis B virus serology as defined in the protocol. 9. Active tuberculosis (TB), or a positive interferon gamma (IFN-γ) release assay (IGRA) test at screening, unless documented history of appropriate treatment for active or latent TB according to local guidelines. 10. Any severe herpes virus family infection (including Epstein-Barr virus, cytomegalovirus \[CMV\]) at any time prior to randomization. 11. Opportunistic infection requiring hospitalization or parenteral antimicrobial treatment within 2 years prior to randomization. 12. Significant organ system involvement or myositis damage (global muscle damage score \> 5 on a 10 cm VAS scale on the MDI) that poses risks in the study or impedes assessments. 13. Diagnosis of immune-mediated necrotizing myopathy (IMNM) \[(positive 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGR), anti-signal recognition particle (anti- SRP), or antibody negative)\], inclusion body myositis (IBM) (including positive anti-cytosolic 5'-nucleotidase 1A (anti cN1A), or drug-induced myositis. 14. Current musculoskeletal, joint, or inflammatory disease, including significant joint contractures or calcinosis that in the opinion of the investigator, could interfere with the muscle strength assessments and confound the disease activity assessments. 15. Wheelchair bound participants. 16. Current inflammatory skin disease other than DM or ASIM that, in the opinion of the investigator, could interfere with the inflammatory skin assessments or confound the disease activity assessments. 17. Severe interstitial lung disease where respiratory symptoms limit participant function or progressive pulmonary fibrosis. 18. Myositis in overlap with another connective tissue disease that precludes the accurate assessment of a treatment response (for example, difficulty in assessing muscle strength in a scleroderma patient with associated myositis).

Outcomes

Primary Outcomes

Mean Total Improvement Score (TIS) at Week 24

Total improvement score was derived from standardized clinical response criteria which was calculated by sum of improvement scores of 6 core set measures (CSMs) included physician global disease activity (PhGDA), patient global disease activity (PtGDA), manual muscle testing 8 (MMT8) bilateral, health assessment questionnaire-disability index (HAQ-DI), extramuscular global assessment (EGA), and laboratory muscle enzymes (LME). Total improvement score was ranged from 0 to 100, where higher scores indicated greater improvement. The TIS improvement categories are defined as minimal (TIS greater than or equal to \[≥\]20), moderate (TIS ≥40) and major improvement (TIS ≥60). Mean TIS at week 24 was reported in this outcome measure.

Time frame: At Week 24

Secondary Outcomes

Percentage of Participants With Improvement of TIS ≥ 40 and Without Deterioration at 2 Consecutive Visits at 24 Weeks

The percentage of participants who achieved moderate improvement (TIS ≥ 40), and do not experience confirmed disease deterioration at two consecutive visits through Week 24 were reported. Confirmed deterioration is defined as any of the following occurred at two consecutive visits compared with baseline: (i) Worsening of PhGDA by ≥ 2 cm and worsening of MMT8 by ≥ 20%, or (ii) Worsening of EGA by ≥ 2 cm, or (iii) Worsening of ≥ 3 of 5 core set measures (excluding laboratory enzymes) by ≥ 30%.

Time frame: Up to Week 24

Percentage of Participants With Improvement of TIS ≥ 20 and Without Deterioration at 2 Consecutive Visits at 24 Weeks

The percentage of participants who achieved minimal improvement (TIS ≥ 20), and do not experience confirmed disease deterioration at two consecutive visits through Week 24 were reported. Confirmed deterioration is defined as any of the following occurred at two consecutive visits compared with baseline: (i) Worsening of PhGDA by ≥ 2 cm and worsening of MMT8 by ≥ 20%, or (ii) Worsening of EGA by ≥ 2 cm, or (iii) Worsening of ≥ 3 of 5 core set measures (excluding laboratory enzymes) by ≥ 30%.

Time frame: Up to Week 24

Change in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) Activity Score From Baseline (Day 1) to Week 24

The CDASI activity score used to assess the severity of cutaneous DM and detect the improvement in disease activity. The CDASI activity score evaluates erythema, scale, and erosion/ulceration across 15 different body areas including the presence and severity of Gottron's papules on the hands, periungual changes and alopecia. The CDASI activity score ranges from 0 to 100 and higher scores indicate greater disease severity. A negative change from baseline indicates a reduction in disease severity.

Time frame: From Baseline (Day 1) to Week 24

Percentage of Participants With Clinically Meaningful Oral Corticosteroid (OCS) Reduction at Week 24

The percentage of participants who received OCS dose ≥ 10 milligram per day (mg/day) of prednisone or equivalent at baseline and who achieved a clinically meaningful reduction in oral corticosteroid dose either: a 25% reduction or an OCS dose of 7.5 mg/day of prednisone or equivalent at Week 24 were reported.

Time frame: Up to Week 24

Serum Concentration of Daxdilimab During Stage I

Mean concentrations of DAX were reported. Values below the lower limit of quantitation (LLOQ) were set to zero before calculation of the descriptive statistics. If the calculated mean concentration from observed values was less than the LLOQ of the assay, the mean value was set to " below the limit of quantification (BLQ)".

Time frame: Stage I: Day 1 (predose and 2 hours postdose), predose on Weeks 4, 8, 12, 16, and any time on Week 24

Serum Concentration of Daxdilimab During Stage II

Mean concentrations of DAX were reported. Values below the lower limit of quantitation (LLOQ) were set to zero before calculation of the descriptive statistics.

Time frame: Stage II: Predose on Week 36 and Week 48

Number of Participants Who Developed Anti-drug Antibodies (ADA)

Number of participants who developed ADAs were reported. The ADA status was summarized by the categories included; ADA prevalence: ADA positive observed at least once during the trial (baseline included); Only baseline positive: ADA positive observed at baseline but not observed at any post-baseline; Only post-baseline positive (treatment-induced): ADA positive not observed at baseline but observed at least once post-baseline; Both baseline and post-baseline positive: ADA positive observed at both baseline and at least once post-baseline; Incidence (treatment emergent ADA): ADA positive post-baseline only or boosted their pre-existing ADA titer (≥ 4-fold increase) during the trial period.

Time frame: Up to Week 56

Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious AEs (TESAEs), and Treatment-emergent AEs of Special Interest (TEAESIs) During Stage I

An AE is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of trial intervention, whether or not considered related to the trial intervention. If an AE occurs on or after the first dose of trial intervention, the AE was considered as a TEAE. An SAE is defined as any untoward medical occurrence that, at any dose results in death or is life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. An AESI is an AE of scientific or medical concern specific to the trial intervention that requires ongoing monitoring and prompt communication by the investigator. AESIs in this trial were hypersensitivity reaction, including anaphylaxis, herpes zoster infection, severe viral infection/reactivation (CTCAE Grade 3 or higher), opportunistic infection, and malignancy (except non-melanoma skin cancer).

Time frame: From first dose of trial intervention in stage I, to first dose of trial intervention in stage II or study end for non-stage II participants; median (min, max) duration was 24 (3, 34) weeks

Number of Participants Who Experienced TEAEs, TESAEs, and TEAESIs During Stage II

Time frame: From first dose of trial intervention in stage II to study end; median (min, max) duration was 24 (18, 33) weeks

A Phase 2 Proof of Concept Study to Evaluate the Efficacy and Safety of Daxdilimab in Participants With Dermatomyositis (DM) or Anti-synthetase Inflammatory Myositis (ASIM)

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes