Study of M5049 in DM and PM Participants (NEPTUNIA)

A Phase IIa, Randomized, Parallel, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Enpatoran in Dermatomyositis and Polymyositis Participants Receiving Standard of Care (NEPTUNIA)

The purpose of this study is to evaluate the efficacy and safety of orally administered M5049 in idiopathic inflammatory myopathies, specifically dermatomyositis (DM) and polymyositis (PM) participants for 24 weeks.

Study Overview

• Status: Terminated
• Conditions: Dermatomyositis; Polymyositis
• Intervention / Treatment: Drug: Placebo; Drug: M5049 dose

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia
    • Institute of Rheumatology - Rheumatology
• Greece
  • Athens, Greece
    • Hippokration Hospital - 2nd Department of Medicine and Laboratory
  • Athens, Greece
    • National and Kapodistrian University of Athens (Egnitio Hospital)
  • Larissa, Greece
    • University General Hospital of Larissa
• Italy
  • Catania, Italy
    • Azienda Ospedaliero Universitaria Policlinico G. Rodolico-San Marco Di Catania (Vittorio Emanuele) - Reumatologia
  • Catania, Italy
    • Azienda Ospedaliero-Universitaria Policlinico G. Rodolico-San Marco Di Catania
  • Florence, Italy
    • Azienda Usl Toscana Centro
  • Reggio Emilia, Italy
    • Arcispedale S. Maria Nuova
  • Rome, Italy
    • Fondazione Policlinico Universitario A. Gemelli-IRCCS, UCSC - Scienze Mediche e Chirurgiche
• Poland
  • Warsaw, Poland
    • Instytut Reumatologii im. Eleonory Reicher - Department of Connective Tissue Diseases
• Spain
  • A Coruña, Spain
    • CHUAC - Complexo Hospitalario Universitario A Coruña - Rheumatology
  • Barcelona, Spain
    • Hospital Vall d'Hebron
  • Madrid, Spain
    • Hospital Universitario Ramon y Cajal, Madrid - Rheumatology Department
• United Kingdom
  • Doncaster, United Kingdom
    • Doncaster Royal Infirmary (3466)
  • London, United Kingdom
    • Royal Free London NHS Foundation Trust
  • London, United Kingdom
    • University College London Hospitals NHS Foundation Trust- Neuromuscular Diseases
  • Salford, United Kingdom
    • Salford Royal Hospital, Barnes Clinical Research Facility
  • Wolverhampton, United Kingdom
    • Royal Wolverhampton Hospitals (6493)
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85028
      • Neuromuscular Research Center
    • Scottsdale, Arizona, United States, 85251
      • HonorHealth Research Institute - Bob Bove Neuroscience Institute-Neuroscience Research
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Scottsdale (6365)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Barbara Davis Center
  • Florida
    • Orlando, Florida, United States, 32819
      • HMD Research LLC
    • Pembroke Pines, Florida, United States, 33026
      • Bolanos Clinical Research
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University-Rheumatology
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University - Department of Medicine, Division of Rheumatology
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota-Dermatology
  • Missouri
    • Kansas City, Missouri, United States, 66103
      • University of Kansas Medical Center-Neuromuscular
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Texas
    • Austin, Texas, United States, 78759
      • Austin Neuromuscular Center
    • Houston, Texas, United States, 77030
      • Nerve and Muscle Center of Texas-Clinical research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of probable or definite DM or PM as per 2017 ACR/EULAR classification criteria, with positive autoantibody status. Anti-synthetase syndrome (ASyS) participants that meet classification criteria are allowed
• Active disease on standard of care (SoC), must meet 1 of the criteria within 6 months prior to Screening: Pathological evidence of active myositis in muscle biopsy; Evidence of active myositis by Electromyography (EMG); Magnetic resonance imaging (MRI) with evidence of active myositis; or any muscle enzyme greater than or equal to (>=) 4 × upper limit of normal (ULN) at time of Screening; Active PM/DM skin rash as per cutaneous dermatomyositis area and severity index-A (CDASI-A) >= 7 at time of Screening
• Minimum disease severity defined by: moderate to severe myopathy with manual muscle testing-8 (MMT-8) >= 80 and less than or equal to (<=) 142 AND at least 2 of the following core set measures (CSM) abnormalities: Patient Global Activity (PtGA) >= 2 centimeters (cm); Physician Global Activity (PGA) derived from myositis disease activity assessment tool (MDAAT) >= 2 cm; Extramuscular Activity Assessment derived from MDAAT >2 cm; At least 1 muscle enzyme > 1.5 times ULN; health assessment questionnaire-disability index (HAQ-DI) >= 0.25
• Stable doses of oral corticosteroids (CS) and/or maximum of 1 non-corticosteroid immunosuppressive/immunomodulatory medications (methotrexate, 6 mercaptopurine, sulfasalazine, mycophenolate mofetil or sodium, azathioprine, leflunomide, cyclosporine, oral tacrolimus) for DM or PM
• Participants have a body mass index (BMI) lower or Equal to 40.0 kilograms per square meter (kg/m^2)
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Primary diagnosis of inclusion body myositis (IBM), malignancy-associated myositis (defined as diagnosis of myositis within 3 years of cancer), immune mediated necrotizing myopathy (IMNM) with a biopsy characterized as necrotizing biopsy or IMNM with positive anti-signal recognition particle antibody (SRP) or anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) auto antibodies. Participants with anti-transcription intermediary factor 1 (TIF1) gamma antibody or newly diagnosed (within 1 year) anti MDAT5 antibody should have had adequate screening for cancer within 12 months of Day 1. Adequate screening of cancer is defined as up-to-date age and gender appropriate screening as per national guidelines
• Primary diagnosis of juvenile DM, or adult participants previously diagnosed with juvenile DM
• Any other active concurrent connective tissue disease associated with inflammatory myopathy in the Investigator's opinion. Eligibility of participants with diagnosis of concurrent connective tissue disease(s) will be reviewed and approved by an idiopathic inflammatory myopathies (IIM) expert committee
• Severe interstitial lung disease defined as supplemental oxygen required at rest, or forced vital capacity (FVC) of <60 percent (%) predicted. Participants within 1 year of PM/DM diagnosis and anti-MDA5 antibody, should have been evaluated for interstitial lung disease (ILD) with high resolution computed tomography (HRCT) Chest
• Any uncontrolled disease (for example [e.g.], severe respiratory, cardiovascular, gastrointestinal, neurological, psychiatric, hematological, metabolic [including thyroiditis with increased/decreased thyroid stimulating hormone (TSH)], renal [Estimated glomerular filtration rate < 40 milliliter per minute/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation by the central laboratory], hepatic, endocrine/reproductive organ disease) other than DM/PM, that in the Investigator's or Sponsor/designee's opinion constitutes an inappropriate risk or contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: DBPC Period: Placebo	Drug: Placebo; Participants will receive placebo matched to M5049 orally, twice daily up to 24 weeks.
Experimental: Double-blind Placebo Controlled (DBPC) Period: M5049 dose	Drug: M5049 dose; Participants will receive film-coated tablets of M5049 dose orally, twice daily up to 24 weeks.; Other Names: Enpatoran
Experimental: Open Label Extension (OLE) Period: M5049 dose	Drug: M5049 dose; Participants will receive film-coated tablets of M5049 dose orally, twice daily up to 24 weeks.; Other Names: Enpatoran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Double Blind Placebo Control Period (DBPC): American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Total Improvement Score (TIS) at Week 24	The ACR/EULAR TIS was derived from evaluation of results from 6 Core Set Measures(CSMs) of myositis disease activity in participants with Dermatomyositis and Polymyositis.TIS was determined by summing scores for each CSM,based on improvement in absolute percent change which is calculated by subtracting the baseline value from the final value,dividing difference by the range, and then multiplying the result by100 and relative weight of each core set measure. The TIS scale ranges from 0 to 100 with thresholds for minimal [more than or equal to(>= 20)],moderate(>= 40) and major(>= 60)improvement in combined 6 CSM.The CSMs include,physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index(0-3) along with checks for most abnormal muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10).	At Week 24 (end of DBPC period)
DBPC Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs)	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether considered related to the medicinal product or protocol-specified procedure. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and were closely followed.	Up to Week 26 (Safety follow up)
DBPC Period: Number of Participants With Clinically Meaningful Changes From Baseline in Laboratory Parameters	Laboratory parameters included hematology, biochemistry, urinalysis and reflex testing for HBV DNA. Number of participants with clinically meaningful changes from baseline in laboratory parameters were reported. Clinical meaningfulness was assessed by the investigator.	Up to Week 26 (Safety follow up)
DBPC Period: Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs	Vital signs included body temperature, systolic and diastolic blood pressure, respiration rate, pulse rate, weight, height and body mass index. Number of participants with clinically meaningful changes from baseline in vital signs were reported. Clinical meaningfulness was assessed by the investigator.	Up to Week 26 (Safety follow up)
DBPC Period: Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiograms (ECG) Parameters	12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. Number of participants with clinically meaningful changes from baseline in ECG parameters were reported. Clinical meaningfulness was assessed by the investigator.	Up to Week 26 (Safety follow up)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DBPC Period: Number of Participants With American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Total Improvement Score (TIS) Greater Than or Equal to (>=) 20, >= 40 and >= 60	The ACR/EULAR TIS was derived from evaluation of results from 6 Core Set Measures(CSMs) of myositis disease activity in participants with Dermatomyositis and Polymyositis.TIS was determined by summing scores for each CSM,based on improvement in absolute percent change which is calculated by subtracting the baseline value from the final value,dividing difference by the range, and then multiplying the result by100 and relative weight of each core set measure. The TIS scale ranges from 0 to 100 with thresholds for minimal [more than or equal to(>= 20)],moderate(>=40) and major(>=60)improvement in combined 6 CSM.The CSMs include,physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index(0-3) along with checks for most abnormal muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10).	At Week 16 and Week 24
DBPC Period: Participant's Total Improvement Score (TIS)	The ACR/EULAR TIS was derived from evaluation of results from 6 Core Set Measures(CSMs) of myositis disease activity in participants with Dermatomyositis and Polymyositis.TIS was determined by summing scores for each CSM,based on improvement in absolute percent change which is calculated by subtracting the baseline value from the final value,dividing difference by the range, and then multiplying the result by100 and relative weight of each core set measure. The TIS scale ranges from 0 to 100 with thresholds for minimal [more than or equal to(>= 20)],moderate(>=40) and major(>=60)improvement in combined 6 CSM.The CSMs include,physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index(0-3) along with checks for most abnormal muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10).	Week 4, 8, 12, 16, 20 and 24
DBPC Period: Change From Baseline in Physician Global Activity (PGA) Scores From Myositis Disease Activity Assessment Tool (MDAAT)	The Physician's Global Assessment of Disease Activity was an assessment of overall global disease activity by the physician that was taken from Myositis Disease Activity Assessment Tool (MDAAT). Physician rated participant's disease activity on a 0-10 centimeter (cm) visual analog scale (VAS). Extra-muscular activity ranged between 0 and 10, where, 0 cm = absent and 10 cm = maximum disease activity.	Baseline, Week 4, 8, 12, 16, 20 and 24
DBPC Period: Change From Baseline in Patient Global Activity (PtGA) Visual Analog Scale (VAS) Score	PtGA was the assessment of the severity of disease by the participant/participant's guardian, using a VAS from 0 mm (no evidence of disease activity) to 100 mm (extremely active or severe disease activity). Higher score indicated worse status.	Baseline, Week 4, 8, 12, 16, 20 and 24
DBPC Period: Change From Baseline in Extra Muscular Global Assessment From Myositis Disease Activity Assessment Tool (MDAAT) Score	MDAAT was a combined tool capturing physician's assessment of disease activity of various organ systems- constitutional, cutaneous, pulmonary, gastrointestinal, joints and cardiovascular, muscular using: Myositis Intention to Treat Activity Index (MITAX), a scale from 0("Not present in the last 4 weeks") to 4("New - in the last 4 weeks [compared to the previous 4 weeks]") and Myositis Disease Activity Assessment Visual Analogue Scales (MYOACT), a 10 cm VAS assessing disease activity in the last 4 weeks of various organ systems from 0 cm("No evidence of disease activity") to 10 cm("Extremely active or severe disease activity"), disease activity being defined as potentially reversible pathology or physiology resulting from the myositis. Left end of line = no evidence of disease activity, midpoint of line = moderate disease activity, and right end of line = extreme or maximum disease activity. An assessment of extramuscular activity assessment was taken from MDAAT using a 10cm VAS scale.	Baseline, Week 4, 8, 12, 16, 20 and 24
DBPC Period: Change From Baseline in Manual Muscle Testing-8 (MMT-8) Score	MMT-8 was an International Myositis Assessment and Clinical Studies (IMACS) Core Set Measure used in the calculation of the IMACS Definition of Improvement (DOI) and ACR/EULAR TIS. It is a set of 8 designated muscles tested unilaterally (generally on right side) -which include 1 axial, 5 proximal (2 upper extremity, 3 lower extremity), and 2 distal muscles (1 upper, 1 lower extremity). Total score for unilateral testing ranges from 0 to 80, and bilateral testing ranges from 0 to 150 with normal strength represented by a higher score at or near the top of the scale. The total score for bilateral testing (item "MMT8 score (0 - 150)" from the MANUAL MUSCLE TESTING-8 (mmt8) form) is used in the derivation of the Total Improvement Score.	Baseline, Week 4, 8, 12, 16, 20 and 24
DBPC Period: Change From Baseline in Health Assessment Questionnaire -Disability Index (HAQ-DI) Score	HAQ-DI was an IMACS Core Set Measure used in the calculation of the IMACS DOI and ACR/EULAR TIS. It is a generic rather than a disease-specific instrument comprised of 8 sections (dressing, arising, eating, walking, hygiene, reach, grip, and activities), with 2 to 3 questions per section. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section the score given to that section is the worst score within the section. The 8 scores of the 8 sections are summed and divided by 8. Overall score ranges from 0-3.	Baseline, Week 4, 8, 12, 16, 20 and 24
DBPC Period: Relative Change From Baseline in Most Abnormal Muscle-associated Enzyme	For each participant, the most abnormal muscle-associated enzyme was defined as the baseline muscle-associated enzyme with the highest ratio of the observed value to the upper limit of the normal range (ULN) among creatinine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and aldolase. The relative abnormality could be expressed as a percentage of ULN, calculated as (enzyme value divided by ULN) multiplied by 100.	Baseline, Week 4, 8, 12, 16, 20 and 24
DBPC Period: Number of Participants Who Achieved International Myositis Assessment and Clinical Studies (IMACS) Response	A participant was defined as an International Myositis Assessment and Clinical Studies (IMACS) Responder if 3 of any 6 IMACS Core Set Measures (CSMs) have been improved by more than equal to (>= 20) percent (%), with no more than 2 IMACS CSMs worse by >= 25%. The CSMs include, physician global activity visual analogue scale(VAS) score(0-10), patient global activity VAS score(0-10), manual muscle testing-8 score(0-150), health assessment questionnaire-disability index (0-3) along with checks for muscle-associated enzymes and extra muscular activity assessment derived using myositis disease activity assessment tool(0-10).	At Week 16 and 24
DBPC Period: Change From Baseline in Cutaneous Dermatomyositis Area and Severity Index-A (CDASI-A) and Cutaneous Dermatomyositis Area and Severity Index-D (CDASI-D) Subscale Score	CDASI is a clinician-scored single page instrument that separately measures activity and damage in the skin of DM participants. CDASI has 3 activity measures (CDASI-A: erythema, scale, and erosion/ulceration) and 2 damage measures (CDASI-D: poikiloderma and calcinosis) which are assessed over 15 body areas. In addition, Gottron's papules on the hands, periungual changes and alopecia are evaluated separately both for activity and damage. Activity and Damage Subscale scores range from 0 to 100 and 0 to 32, respectively, where higher scores indicate greater disease severity.	Baseline, Week 4, 8, 12, 16, 20 and 24
DBPC Period: Change From Baseline in Investigator's Global Assessment (IGA) Skin Activity Score	The IGA skin activity is a five-point score that defines the level of disease severity based on overall lesion characteristics where 0 is "clear" and "4" is severe.	Baseline, Week 4, 8, 12, 16, 20 and 24
Open-label Extension (OLE) Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs)	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether considered related to the medicinal product or protocol-specified procedure. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and were closely followed.	From start of OLE period (Week 1) up to safety follow up (Week 26)
OLE Period: Number of Participants With Clinically Meaningful Changes From Baseline in Laboratory Parameters	Laboratory parameters included hematology, biochemistry, urinalysis and reflex testing for HBV DNA. Number of participants with clinically meaningful changes from baseline in laboratory parameters were reported. Clinical meaningfulness was assessed by the investigator.	From start of OLE period (Week 1) up to safety follow up (Week 26)
OLE Period: Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs	Vital signs included body temperature, systolic and diastolic blood pressure, respiration rate, pulse rate, weight, height and body mass index. Number of participants with clinically meaningful changes from baseline in vital signs were reported. Clinical meaningfulness was assessed by the investigator.	From start of OLE period (Week 1) up to safety follow up (Week 26)
OLE Period: Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiograms (ECG) Parameters	12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. Number of participants with clinically meaningful changes from baseline in ECG parameters were reported. Clinical meaningfulness was assessed by the investigator.	From start of OLE period (Week 1) up to safety follow up (Week 26)

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• US Medical Information website, Medical Resources
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2023
• Primary Completion (Actual): June 25, 2025
• Study Completion (Actual): June 25, 2025

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: December 6, 2022
• First Posted (Actual): December 14, 2022

Study Record Updates

• Last Update Posted (Actual): September 9, 2026
• Last Update Submitted That Met QC Criteria: August 17, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Myositis; Toll-like Receptor 7; Toll-like Receptor 8; M5049; Anti-synthetase syndrome; Idiopathic immune myopathies
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Connective Tissue Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Dermatomyositis; Polymyositis; Myositis
• Other Study ID Numbers: MS200569_0041; 2022-501351-82-00 (Other Identifier: EUCT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD supporting publicly available results will be evaluated for sharing.

IPD Sharing Time Frame

IPD from completed trials will be publicly available within 6 months after all of the following events:

• Approval of a product/new indication by major authorities (FDA, EMA, PMDA if requested) with no pending submissions
• Public results via primary manuscript or trial registry disclosure
• Legal authority to share data
• Privacy protections are in place If approval is not sought or development is globally discontinued, data will be publicly available within 18 months after global trial completion. Further information on how to request data can be found on our website bit.ly/IPD21

• IPD Sharing Access Criteria: Qualified researchers may propose access to IPD from sponsored trials via https://vivli.org/members/ourmembers/.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No