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)

Study Overview
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Brief Summary
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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: To evaluate the effect of daxdilimab compared with placebo in reducing disease activity at Week 24. To evaluate the effect of daxdilimab compared with placebo on skin symptoms at Week 24. To evaluate the effect of daxdilimab on decreasing the use of corticosteroid at Week 24. Other secondary objectives include: To characterize the pharmacokinetics (PK) and immunogenicity of daxdilimab in participants. To evaluate the safety and tolerability of daxdilimab in participants.

Detailed Description
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The study will enroll 96 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 60 weeks.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled, Efficacy and Safety Study of Daxdilimab Subcutaneous Injection in Adult Participants With Inadequately Controlled Dermatomyositis or Anti-synthetase Inflammatory Myositis.

Conditions
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Idiopathic Inflammatory Myositis

Intervention / Treatment
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* Drug: Daxdilimab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adult men or women 18 and ≤ 75 years of age at the time of signing the informed consent (ICF). A diagnosis of definite or probable myositis according to American College of Rheumatology/European League Against Rheumatism 2017 (ACR/EULAR 2017) criteria: Population 1: DM Diagnosis of DM with DM rash current or historical, or 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). Currently active myositis with all the following (a, b, and c) during screening: Manual Muscle Testing (MMT 8) score < 142 At least 2 other abnormal core set measures (CSM) from the following list: Patient global disease activity (PtGDA) ≥ 2cm 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 Global muscle damage score ≤ 5 on a 10 cm VAS on the myositis damage index (MDI). 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. Participants should be willing to taper corticosteroid dose per protocol when stable or improving. Exclusion Criteria: 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. Weight > 160 kg (352 pounds) at screening. 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. 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. History of cancer within the past 5 years, except as follows: In situ carcinoma of the cervix treated with apparent success with curative therapy > 12 months prior to screening, or Cutaneous basal cell or squamous cell carcinoma treated with curative therapy. Any underlying condition that in the opinion of the Investigator significantly predisposes the participant to infection. 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. Confirmed positive test for hepatitis B virus serology as defined in the protocol. 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. Any severe herpes virus family infection (including Epstein-Barr virus, cytomegalovirus [CMV]) at any time prior to randomization. Opportunistic infection requiring hospitalization or parenteral antimicrobial treatment within 2 years prior to randomization. Significant organ system involvement or myositis damage (global muscle damage score > 5 on a 10cm VAS scale on the MDI) that poses risks in the study or impedes assessments. 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. 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. Wheelchair bound participants. 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. Severe interstitial lung disease where respiratory symptoms limit participant function or progressive pulmonary fibrosis. 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daxdilimab<br>Daxdilimab will be administered by subcutaneous (SC) injection over a total of 44 weeks. | Drug: Daxdilimab<br>* Participants will be administered daxdilimab by subcutaneous (SC) injection<br>* Other names: HZN-7734;|
| Placebo Comparator: Placebo<br>Matching placebo will be administered by SC injection over a total of 24 weeks, then will be administered active drug by SC injection up to Week 44 | Drug: Daxdilimab<br>* Participants will be administered daxdilimab by subcutaneous (SC) injection<br>* Other names: HZN-7734;Drug: Placebo<br>* Participants will be administered identically matching placebo by SC injection over a total of 24 weeks, then participants will be given active treatment for the remainder of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of daxdilimab compared to placebo as measured by Total Improvement Score (TIS) | TIS is a composite endpoint based on improvement in the 6 Disease Activity Core Set Measure (CSM) scores and range from 0 to 100 (2016 European League Against Rheumatism [EULAR]/American College of Rheumatology [ACR] Myositis Response Criteria) where a higher score is indicative of more improvement | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with improvement of TIS ≥ 40 and without deterioration at 2 consecutive visits at 24 weeks | TIS is a composite endpoint based on improvement in the 6 Disease Activity Core Set Measure (CSM) scores and range from 0 to 100 (2016 European League Against Rheumatism [EULAR]/American College of Rheumatology [ACR] Myositis Response Criteria) where a higher score is indicative of more improvement | At 24 Weeks | 
| Proportion of participants with improvement of TIS ≥ 20 and without deterioration at 2 consecutive visits at 24 weeks | TIS is a composite endpoint based on improvement in the 6 Disease Activity Core Set Measure (CSM) scores and range from 0 to 100 (2016 European League Against Rheumatism [EULAR]/American College of Rheumatology [ACR] Myositis Response Criteria) where a higher score is indicative of more improvement | At 24 Weeks | 
| Change in the cutaneous dermatomyositis disease area and severity index (CDASI) activity score from Baseline (Day 1) to Week 24 | The CDASI is used to assess the severity of cutaneous DM and detect improvement in disease activity. The scale rates disease involvement in 15 different body areas using 3 activity (erythema, scale, erosion/ulceration) and 2 damage (poikiloderma, calcinosis) measures. The activity score ranges from 0 to 100 and the damage score from 0 to 32. Higher scores indicate greater disease severity | Baseline (Day1) to Week 24 | 
| Proportion of participants on an oral corticosteroid (OCS) dose ≥ 10 mg of prednisone or equivalent at baseline who achieve a clinically meaningful reduction in the OCS dose at Week 24 | A clinically meaningful reduction is measured as either a 25% decrease or an OCS dose of 7.5 mg/day of prednisone or equivalent | Baseline to Week 24 | 
| Serum concentration of daxdilimab over time |  | Baseline to Week 56 | 
| Proportion of the participants with anti-drug antibodies (ADA) positive post-baseline only or boosted their pre-existing ADA during the study period. |  | Baseline to Week 56 | 
| Incidence of ADA directed against daxdilimab over time |  | Baseline to Week 56 | 
| Titer of ADA to daxdilimab over time |  | Baseline to Week 56 | 
| Incidence of treatment emergent adverse events (TEAEs) |  | Baseline to Week 56 | 
| Incidence of treatment emergent serious adverse events (TESAEs) |  | Baseline to Week 56 | 
| Incidence of treatment emergent adverse events of special interest (TEAESIs) | TEAESIs including hypersensitivity reactions, anaphylaxis, herpes zoster infection, severe [(common terminology criteria for adverse events (CTCAE)] Grade 3 or higher) viral infection/reactivation, opportunistic infection, and malignancy (except non melanoma skin cancer) | Baseline to Week 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-synthetase syndrome, Myositis, Polymyositis