INCLUSION CRITERIA
Study participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18-\<80 years of age at the time of signing the informed consent.
Type of participant and disease characteristics
2. Physician diagnosis of asthma (according to GINA 2025) for ≥6 months, with documented historical airflow variability by one of the following:
* Positive reversibility test: ≥12% and 200 ml in FEV1 after SABA administration at any point prior to randomisation
* Airflow variability in clinic FEV1 \>12% and 200 mL between historical clinical visits
* Positive bronchial challenge test: fall in FEV1 of ≥20% with standard doses of methacholine (\<16 mg/mL or \<400mcg); or ≥10% with standardised hyperventilation, or exercise challenge test; or ≥15% with hypertonic saline or mannitol challenge
* Peak flow variability of \>20% between two assessments
3. Evidence of elevated type-2 biomarkers defined as both of:
1. peripheral BEC ≥ 0.3×109/L at screening visit
2. FeNO ≥ 35 ppb at screening visit
4. At least 1 asthma attack in the last 2 years, defined as acute asthma requiring SCS for ≥ 3 days or an emergency/hospital visit requiring SCS.
5. Treatment and evident adherence to a stable at-least medium-dose ICS (fluticasone propionate equivalent \>250 mcg/day) for at least 3 months (including run-in period) \[additional controllers e.g. LABA, LAMA or LTA are allowed\]. The ICS dosage will be defined as the dosage received on a regularly basis, excluding extra reliever doses taken in the context of anti-inflammatory reliever (AIR) therapy from the calculation. AIR is allowed in the context of the study. Thus, the high-dose ICS trial population (fluticasone propionate equivalent \>500 mcg/day)\* will represent patients who are not meeting the exacerbation criteria for biological reimbursement.
\*As per section 6.2, we will cap recruitment to 60% of target population on medium-dose ICS, 40% on high-dose ICS, with randomisation also stratified by these categories.
6. Presence of one (or more) of the following additional risk factors for asthma attacks32 at screening or baseline: (i) uncontrolled asthma symptoms indicated by ACQ5 score of ≥ 1.5; (ii) impaired lung function indicated by post-bronchodilator FEV1 of ≤ 80% predicted; (iii) high-dose maintenance ICS therapy (iv) severe asthma attack in past 1-\<12 months.
Sex, contraceptive/barrier method and pregnancy testing requirements
7. Female participants
a. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
i. Is a woman of nonchildbearing potential (WONCBP) as defined in the Study Manual.
OR ii. Is a WOCBP and agrees to use a contraceptive method that is highly effective, with a failure rate of \<1%, during the intervention period (to be effective before starting the intervention) and for at least 12 weeks after the last dose of study intervention.
b. A WOCBP must have a negative highly sensitive serum pregnancy test at V1 (screening visit) and urine or serum pregnancy test (as required by local regulations) on Day 1 before the first dose of study intervention, c. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
d. Additional requirements for pregnancy testing during and after study intervention are imposed.
e. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female participant with an early undetected pregnancy.
Informed consent
8. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
4.2 EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1. Use of SCS \< 1 months prior to screening or on maintenance SCS.
2. Current tobacco smoker or recently stopped smoker (\<6 months)
3. Ex-smoker with greater than 10 pack-years AND post bronchodilator FEV1/FVC ratio below the lower limit of normal according to GLI race-neutral standards. 69
4. Documented nonadherence to ICS, defined as dispensing of less than 75% of the prescribed ICS dose over the past 12 months (or annualised if less than 12 months), based on pharmacy refill records checked at screening.
5. Presence of significant and uncorrectable inhaler technique deficiencies, as assessed by the research team during inhaler technique evaluation at screening.
6. Contra-indication to study drug
7. Immunological disease, condition or medication that may affect the inflammatory response according to Investigator.
8. History of other significant lung disease e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, clinically significant bronchiectasis, chronic obstructive lung disease, or Churg-Strauss.
9. Severe concomitant illness (including known or suspected immunodeficiency) that, in the Investigator's judgement will adversely affect the participant's participation in the study.
10. Active malignancy or history of malignancy within 5 years (except for basal cell carcinoma of the skin).
11. Exposure to monoclonal antibody therapy for asthma or another investigational medicinal product within 5 half-lives of the drug.
12. Eligibility to Dupilumab based on licensed and reimbursed indications in the participant's jurisdiction (e.g. nasal polyposis, atopic dermatitis, eosinophilic esophagitis, prurigo nodularis, etc.)
13. Treatment with live (attenuated) vaccine in the past 4 weeks.
14. Prohibited medication
→
INCLUSION CRITERIA
Study participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18-\<80 years of age at the time of signing the informed consent.
Type of participant and disease characteristics
2. Physician diagnosis of asthma (according to GINA 2025) for ≥6 months, with documented historical airflow variability by one of the following:
* Positive reversibility test: ≥12% and 200 ml in FEV1 after SABA administration at any point prior to randomisation
* Airflow variability in clinic FEV1 \>12% and 200 mL between historical clinical visits
* Positive bronchial challenge test: fall in FEV1 of ≥20% with standard doses of methacholine (\<16 mg/mL or \<400mcg); or ≥10% with standardised hyperventilation, or exercise challenge test; or ≥15% with hypertonic saline or mannitol challenge
* Peak flow variability of \>20% between two assessments
3. Evidence of elevated type-2 biomarkers defined as both of:
1. peripheral BEC ≥ 0.3×109/L at screening visit
2. FeNO ≥ 35 ppb at screening visit
4. At least 1 asthma attack in the last 2 years, defined as acute asthma requiring SCS for ≥ 3 days or an emergency/hospital visit requiring SCS.
5. Treatment and evident adherence to a stable at-least medium-dose ICS (fluticasone propionate equivalent \>250 mcg/day) for at least 3 months (including run-in period) \[additional controllers e.g. LABA, LAMA or LTA are allowed\]. The ICS dosage will be defined as the dosage received on a regularly basis, excluding extra reliever doses taken in the context of anti-inflammatory reliever (AIR) therapy from the calculation. AIR is allowed in the context of the study. Thus, the high-dose ICS trial population (fluticasone propionate equivalent \>500 mcg/day)\* will represent patients who are not meeting the exacerbation criteria for biological reimbursement.
\*As per section 6.2, we will cap recruitment to 60% of target population on medium-dose ICS, 40% on high-dose ICS, with randomisation also stratified by these categories.
6. Presence of one (or more) of the following additional risk factors for asthma attacks32 at screening or baseline: (i) uncontrolled asthma symptoms indicated by ACQ5 score of ≥ 1.5; (ii) impaired lung function indicated by post-bronchodilator FEV1 of ≤ 80% predicted; (iii) high-dose maintenance ICS therapy (iv) severe asthma attack in past 1-\<12 months.
Sex, contraceptive/barrier method and pregnancy testing requirements
7. Female participants
a. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
i. Is a woman of nonchildbearing potential (WONCBP) as defined in the Study Manual.
OR ii. Is a WOCBP and agrees to use a contraceptive method that is highly effective, with a failure rate of \<1%, during the intervention period (to be effective before starting the intervention) and for at least 12 weeks after the last dose of study intervention.
b. A WOCBP must have a negative highly sensitive serum pregnancy test at V1 (screening visit) and urine or serum pregnancy test (as required by local regulations) on Day 1 before the first dose of study intervention, c. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
d. Additional requirements for pregnancy testing during and after study intervention are imposed.
e. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female participant with an early undetected pregnancy.
Informed consent
8. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
4.2 EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1. Use of SCS \< 1 months prior to screening or on maintenance SCS.
2. Current tobacco smoker or recently stopped smoker (\<6 months)
3. Ex-smoker with greater than 10 pack-years AND post bronchodilator FEV1/FVC ratio below the lower limit of normal according to GLI race-neutral standards. 69
4. Documented nonadherence to ICS, defined as dispensing of less than 75% of the prescribed ICS dose over the past 12 months (or annualised if less than 12 months), based on pharmacy refill records checked at screening.
5. Presence of significant and uncorrectable inhaler technique deficiencies, as assessed by the research team during inhaler technique evaluation at screening.
6. Contra-indication to study drug
7. Immunological disease, condition or medication that may affect the inflammatory response according to Investigator.
8. History of other significant lung disease e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, clinically significant bronchiectasis, chronic obstructive lung disease, or Churg-Strauss.
9. Severe concomitant illness (including known or suspected immunodeficiency) that, in the Investigator's judgement will adversely affect the participant's participation in the study.
10. Active malignancy or history of malignancy within 5 years (except for basal cell carcinoma of the skin or fully resected Cervical Intraepithelial Neoplasia/dysplasia).
11. Exposure to monoclonal antibody therapy for asthma or another investigational medicinal product within 5 half-lives of the drug.
12. Eligibility to Dupilumab based on licensed and reimbursed indications in the participant's jurisdiction (e.g. nasal polyposis, atopic dermatitis, eosinophilic esophagitis, prurigo nodularis, etc.)
13. Treatment with live (attenuated) vaccine in the past 4 weeks.
14. Prohibited medication 15 Current helminth infection
Inclusion Criteria:
* N- NDMM based on IMWG criteria with clonal bone marrow plasma cells ≥10% or biopsy proven bony or extramedullary disease/plasmacytoma (EMD) with any one or more CRAB-features or myeloma defining events (Rajkumar, 2024) (See Appendix E)
* \- Age 18 - 75 years. (Patients aged 71-75 years who are deemed transplant-eligible by investigator may be enrolled after discussion with and approval from the Sponsor - Investigator)
* \- Eligible for HDM-ASCT, at time of registration per investigator's assessment, and willing to defer HDM-ASCT if in Cohort 1 or be randomized to HDM-ASCT vs. linvoseltamab if in Cohort 2 (Cohort assignment may not be known until after induction therapy)
* \- Bone marrow analysis with cytogenetic risk status established by fluorescence in situ hybridization (FISH) and NGS with TP53 by PlasmaSEQ at screening and positive identification of B-cell Clonality (ID) conducted by Adaptive Biotechnologies clonoSEQ® assay
* Qualified archival BMA may be submitted to Adaptive Biotechnologies clonoSEQ® assay.
* Results from a previously performed clonoSEQ® assay as standard of care may be acceptable if they meet the requirement of B-cell clonality ID.
* Previously performed BMA for FISH is acceptable if it can establish cytogenetic risk per Section 5.4.2 along with NGS for TP53 by PlasmaSEQ.
* Results must be within 1 year of screening and be representative of current NDMM. Results older than one year must be approved by the Sponsor-Investigator.
* Measurable disease defined by at least one of the following:
* Serum protein electrophoresis (SPEP): Serum M protein ≥0.5 mg/dL
* Urine protein electrophoresis (UPEP): Urine M protein ≥200 mg/24 hours
* Serum free light chain (FLC) assay: involved FLC ≥10 mg/dL (≥100 mg/L) and abnormal serum FLC ratio (\<0.26 or \>1.65)
* Screening laboratory evaluations meeting the following parameters:
* Absolute neutrophil count (ANC) ≥1,000 cells/dL (1.0 × 10\^9/L). Growth factor support is not permitted within 10 days \[14 days for pegfilgrastim\], prior to registration
* Platelet count ≥ 75,000 cells/dL (75 x 109/L) without transfusions required during the 14 days prior to registration)
* Total Bilirubin ≤ 2 X upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
* Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 3.0 x ULN
* Calculated creatinine clearance ≥30 mL/min (See Appendix B)
* Hemoglobin ≥ 8.0 g/dl (red blood cell \[RBC\] transfusions are permitted)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix A)
* Ability and willingness to complete HRQoL and PRO-CTCAE® assessments
* Must be able to take antithrombotic prophylaxis
* Sexually active IOCBP agree to use protocol-specified contraceptive methods, at least 28 days prior to starting study drug, while taking study drug, including interruptions in study drugs, and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib, or males (including those who have had a vasectomy), sexually active with IOCBP, agree to use protocol specified contraceptive methods while taking study drug, including interruptions in study drug and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib according the PPP (See Appendix G)
* All patients (male and female with or without childbearing potential) agree to counseling according to the PPP and to abstain from donating blood products for at least 28 days after the last dose of iberdomide and semen or sperm while taking study drug and for at least 28 days after the last dose of iberdomide according to the PPP (See Appendix G) and for 3 months after the last dose of isatuximab, 6 months after the last dose of linvoseltamab and bortezomib
* Both men and women of all races and ethnic groups are eligible for this trial.
Exclusion Criteria:
* Prior therapy for MM. Patients may have received:
* Corticosteroids for management of MM not exceeding the equivalent of 160 mg of dexamethasone in a 2-week period and without change in dosing requirements within 7 days prior to registration
* Focal palliative radiation for the management of bone pain ≥ 7 days prior to registration
* Treatment for smoldering multiple myeloma (SMM) if the prior treatment was not an anti-CD38 or anti-BCMA-based therapy:
* Patients with a prior history of serious allergic reactions associated with thalidomide, lenalidomide, or pomalidomide should not receive iberdomide as they could be at higher risk of hypersensitivity
* Resolution of symptoms of prior treatment to ≤ grade 1or baseline
* Known intolerance to steroid therapy
* Central nervous system (CNS) involvement of MM
* History of progressive multifocal leukoencephalopathy (PML), known or suspected PML, or history of a neurocognitive condition, CNS movement disorder, history of seizure within 12 months prior to enrollment
* Peripheral neuropathy grade ≥3, or grade 2 with pain on clinical exam during screening period
* Prior history of malignancies, other than MM, will be excluded unless the participant has been free of the disease for ≥ 3 years, except for the following non-invasive malignancies: basal or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological findings of prostate cancer (T1a or T1b using the TNM clinical staging system), or prostate cancer that is curative
* Any medical or psychiatric illness that in the investigator's opinion would impose excessive risk or would adversely affect patient participation
* Concurrent uncontrolled cardiovascular conditions (uncontrolled hypertension \[HTN\], uncontrolled arrhythmias, congestive heart failure \[CHF\], unstable angina, grade 3 thromboembolic event or myocardial infarction in the past 6 months)
* Concurrent symptomatic amyloidosis or plasma cell leukemia
* POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
* Pregnant or breast feeding female or female who intends to become pregnant during the study
* Seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B (defined as positive hepatitis B surface antigen \[HepBSAg\] or Hepatitis B core antibody \[HepBcore Ab\]) or hepatitis C (Hep C Ab), or acute hepatitis A; if any history of exposure to hepatitis B or C, then PCR should be negative
* History of tuberculosis or systemic fungal disease
* Concurrent active infection requiring therapeutic treatment
* Lack of clonal identification by Adaptive Biotechnologies clonoSEQ® test
→
Inclusion Criteria:
* N- NDMM based on IMWG criteria with clonal bone marrow plasma cells ≥10% or biopsy proven bony or extramedullary disease/plasmacytoma (EMD) with any one or more CRAB-features or myeloma defining events (Rajkumar, 2024) (See Appendix E)
* \- Age 18 - 75 years. (Patients aged 71-75 years who are deemed transplant-eligible by investigator may be enrolled after discussion with and approval from the Sponsor - Investigator)
* \- Eligible for HDM-ASCT, at time of registration per investigator's assessment, and willing to defer HDM-ASCT if in Cohort 1 or be randomized to HDM-ASCT vs. linvoseltamab if in Cohort 2 (Cohort assignment may not be known until after induction therapy)
* \- Bone marrow analysis with cytogenetic risk status established by fluorescence in situ hybridization (FISH) and NGS with TP53 by PlasmaSEQ at screening and positive identification of B-cell Clonality (ID) conducted by Adaptive Biotechnologies clonoSEQ® assay
* Qualified archival BMA may be submitted to Adaptive Biotechnologies clonoSEQ® assay.
* Results from a previously performed clonoSEQ® assay as standard of care may be acceptable if they meet the requirement of B-cell clonality ID.
* Previously performed BMA for FISH is acceptable if it can establish cytogenetic risk per Section 5.4.2 along with NGS for TP53 by PlasmaSEQ.
* Results must be within 1 year of screening and be representative of current NDMM. Results older than one year must be approved by the Sponsor-Investigator.
* Measurable disease defined by at least one of the following:
* Serum protein electrophoresis (SPEP): Serum M protein ≥0.5 mg/dL
* Urine protein electrophoresis (UPEP): Urine M protein ≥200 mg/24 hours
* Serum free light chain (FLC) assay: involved FLC ≥10 mg/dL (≥100 mg/L) and abnormal serum FLC ratio (\<0.26 or \>1.65)
* Screening laboratory evaluations meeting the following parameters:
* Absolute neutrophil count (ANC) ≥1,000 cells/dL (1.0 × 10\^9/L). Growth factor support is not permitted within 10 days \[14 days for pegfilgrastim\], prior to registration
* Platelet count ≥ 75,000 cells/dL (75 x 109/L) without transfusions required during the 14 days prior to registration
* Total Bilirubin ≤ 2 X upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
* Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 3.0 x ULN
* Calculated creatinine clearance ≥30 mL/min (See Appendix B)
* Hemoglobin ≥ 8.0 g/dl (red blood cell \[RBC\] transfusions are permitted)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix A)
* Ability and willingness to complete HRQoL and PRO-CTCAE® assessments
* Must be able to take antithrombotic prophylaxis
* Sexually active IOCBP agree to use protocol-specified contraceptive methods, at least 28 days prior to starting study drug, while taking study drug, including interruptions in study drugs, and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib, or males (including those who have had a vasectomy), sexually active with IOCBP, agree to use protocol specified contraceptive methods while taking study drug, including interruptions in study drug and for at least 28 days after the last dose of iberdomide, 5 months after isatuximab, 6 months after linvoseltamab and bortezomib according the PPP (See Appendix G)
* All patients (male and female with or without childbearing potential) agree to counseling according to the PPP and to abstain from donating blood products for at least 28 days after the last dose of iberdomide and semen or sperm while taking study drug and for at least 28 days after the last dose of iberdomide according to the PPP (See Appendix G) and for 3 months after the last dose of isatuximab, 6 months after the last dose of linvoseltamab and bortezomib
* Both men and women of all races and ethnic groups are eligible for this trial.
Exclusion Criteria:
* Prior therapy for MM. Patients may have received:
* Corticosteroids for management of MM not exceeding the equivalent of 160 mg of dexamethasone in a 2-week period and without change in dosing requirements within 7 days prior to registration
* Focal palliative radiation for the management of bone pain ≥ 7 days prior to registration
* Treatment for smoldering multiple myeloma (SMM) if the prior treatment was not an anti-CD38 or anti-BCMA-based therapy:
* Patients with a prior history of serious allergic reactions associated with thalidomide, lenalidomide, or pomalidomide should not receive iberdomide as they could be at higher risk of hypersensitivity
* Resolution of symptoms of prior treatment to ≤ grade 1or baseline
* Known intolerance to steroid therapy
* Central nervous system (CNS) involvement of MM
* History of progressive multifocal leukoencephalopathy (PML), known or suspected PML, or history of a neurocognitive condition, CNS movement disorder, history of seizure within 12 months prior to enrollment
* Peripheral neuropathy grade ≥3, or grade 2 with pain on clinical exam during screening period
* Prior history of malignancies, other than MM, will be excluded unless the participant has been free of the disease for ≥ 3 years, except for the following non-invasive malignancies: basal or squamous cell skin carcinoma, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological findings of prostate cancer (T1a or T1b using the TNM clinical staging system), or prostate cancer that is curative
* Any medical or psychiatric illness that in the investigator's opinion would impose excessive risk or would adversely affect patient participation
* Concurrent uncontrolled cardiovascular conditions (uncontrolled hypertension \[HTN\], uncontrolled arrhythmias, congestive heart failure \[CHF\], unstable angina, grade 3 thromboembolic event or myocardial infarction in the past 6 months)
* Concurrent symptomatic amyloidosis or plasma cell leukemia
* POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
* Pregnant or breast feeding female or female who intends to become pregnant during the study
* Seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B (defined as positive hepatitis B surface antigen \[HepBSAg\] or Hepatitis B core antibody \[HepBcore Ab\]) or hepatitis C (Hep C Ab), or acute hepatitis A; if any history of exposure to hepatitis B or C, then PCR should be negative
* History of tuberculosis or systemic fungal disease
* Concurrent active infection requiring therapeutic treatment
* Lack of clonal identification by Adaptive Biotechnologies clonoSEQ® test
Key Inclusion Criteria:
1\. Advanced non-small cell lung cancer (aNSCLC) (defined as stage IIIB/C or stage IV) treated with cemiplimab in combination with platinum-doublet chemotherapy in the 1L setting from Nov 2022 to Jun 2026 as described in the protocol
Key Exclusion Criteria:
1. Patients who have EGFR, ALK or ROS1 variants
2. Treatment with EGFR, ALK or ROS1 inhibitors at any time prior to the index date
3. Patients actively enrolled in a clinical trial in which they receive treatment with cemiplimab in combination with platinum-doublet chemotherapy
Note: Other protocol-defined Inclusion/ Exclusion Criteria apply
→
Key Inclusion Criteria:
1\. Advanced non-small cell lung cancer (aNSCLC) (defined as stage IIIB/C or stage IV) treated with cemiplimab in combination with platinum-doublet chemotherapy in the 1L setting from Nov 2022 to Jun 2026 as described in the protocol
Key Exclusion Criteria:
1. Participants who have EGFR, ALK or ROS1 variants
2. Treatment with EGFR, ALK or ROS1 inhibitors at any time prior to the index date
3. Participants actively enrolled in a clinical trial in which they receive treatment with cemiplimab in combination with platinum-doublet chemotherapy
Note: Other protocol-defined Inclusion/ Exclusion Criteria apply
Key Inclusion Criteria:
1. Medical history of type 2 diabetes and receiving medical therapy or lifestyle interventions for glucose management
2. Hemoglobin A1C (HbA1c) of 6.5 to 10% at screening
3. eGFR 30 to 90 mL/min/1.73 m\^2 using 2021 Chronic Kidney Disease-Epidemiology Collaboration-Estimated Glomerular Filtration Rate using Creatinine and Cystatin C (CKD-EPI eGFRcr-cys) equation at screening
4. Albuminuria: Urine Albumin to Creatinine Ratio (UACR) of 500 to 5000 mg/g at screening
Key Exclusion Criteria:
1. Known medical history or clinical evidence indicative of non-diabetic renal disease
2. Renal disease that required treatment with systemic immunosuppressive therapy, or a history of dialysis or renal transplant
3. Medically unstable as assessed by the investigator
4. Hospitalization (ie, \>24 hours) within 30 days of the screening visit
NOTE: Other Protocol-Defined Inclusion/Exclusion Criteria Apply
→
Key Inclusion Criteria:
1. Medical history of type 2 diabetes and receiving medical therapy or lifestyle interventions for glucose management
2. Hemoglobin A1C (HbA1c) of 6.5 to 10% at screening
3. eGFR 30 to 90 mL/min/1.73 m\^2 using 2021 Chronic Kidney Disease-Epidemiology Collaboration-Estimated Glomerular Filtration Rate using Creatinine and Cystatin C (CKD-EPI eGFRcr-cys) equation at screening
4. Albuminuria: Urine Albumin to Creatinine Ratio (UACR) of 500 to 5000 mg/g at screening
Key Exclusion Criteria:
1. Known medical history or clinical evidence indicative of non-diabetic renal disease
2. Renal disease that required treatment with systemic immunosuppressive therapy (prior or current), or a history of end-stage kidney disease requiring treatment with chronic dialysis or kidney transplantation
3. Medically unstable as assessed by the investigator or hospitalization (ie, \>24 hours) within 30 days of the screening visit
NOTE: Other Protocol-Defined Inclusion/Exclusion Criteria Apply
Inclusion Criteria:
* Patients with physician-diagnosed CRSwNP, with or without comorbid asthma that meet indication criteria for FDA-approved use of Dupilumab.
* Patients aged 18 years and older.
* Patient willing to provide consent to be a participant in the study.
* Patients with insurance that allows Dupilumab coverage or Dupilumab coverage obtained through "Dupixent MyWay Program"
Exclusion Criteria:
* Age under 18
* Suspected or diagnosed allergic fungal rhinosinusitis.
* Suspected or diagnosed cystic fibrosis.
* Dupilumab coverage denied through insurance or "Dupixent MyWay Program"
* Patients who required a steroid taper in the preceding 30 days. However, patients on chronic steroids less or equal to 20 mg of prednisone daily, are eligible.
* Patients who were on a different biologic medication in the preceding 3 months.
* Patients with a diagnosis of EGPA/Churg-Strauss Syndrome
* Pregnant patients
* Patients with inverted papilloma growth
→
Inclusion Criteria:
* Patients with physician-diagnosed CRSwNP, with or without comorbid asthma that meet indication criteria for FDA-approved use of Dupilumab.
* Patients aged 18 years and older.
* Patient willing to provide consent to be a participant in the study.
* Patients with insurance that allows Dupilumab coverage or Dupilumab coverage obtained through "Dupixent MyWay Program"
Exclusion Criteria:
* Age under 18
* Suspected or diagnosed allergic fungal rhinosinusitis.
* Suspected or diagnosed cystic fibrosis.
* Dupilumab coverage denied through insurance or "Dupixent MyWay Program"
* Patients who required a steroid taper in the preceding 30 days. However, patients on chronic steroids less or equal to 20 mg of prednisone daily, are eligible.
* Patients who were on a different biologic medication in the preceding 3 months.
* Patients with a diagnosis of Eosinophilic granulomatosis with polyangiitis (EGPA)/Churg-Strauss Syndrome
* Pregnant patients
* Patients with inverted papilloma growth
Key Inclusion Criteria:
1. Diagnosis of FHA after exclusion of anatomic or organic causes of amenorrhea
2. Has had no menstrual bleeding episode within 3 months (or longer) prior to day 1, as described in the protocol
3. Has a Body Mass Index (BMI) ≥18.5 and \<25 kg/m\^2 at screening, or BMI ≥25 to \<30 kg/m\^2 at screening AND percentage of body fat \<20% from rigorous exercise as determined by the investigator through Standard of Care (SoC) methods (eg, skinfold thickness, DXA, bioimpedance) within 6 months of screening, as described in the protocol
Key Exclusion Criteria:
1. Has presence of primary amenorrhea (failure to reach menarche, first menstrual cycle)
2. Has blood estradiol ≥50 pg/mL or blood progesterone ≥1 ng/mL at screening
3. Has uterine (eg, absence of uterus, prior endometrial ablation, endometriosis, outflow tract disorders) or ovarian (eg, absence of an ovary, presence of polycystic ovaries) conditions that impact assessment of menses or of the HPO axis
4. Has conditions other than FHA that may cause amenorrhea or menstrual cycle disturbances (eg, polycystic ovarian syndrome, hyperprolactinemia, primary ovarian insufficiency, untreated primary hypothyroidism, primary hyperthyroidism)
5. Polycystic ovarian morphology with an ovarian volume \>10 cc on TransVaginal UltraSound (TVUS) \[or TransAbdominal Pelvic Ultrasound (TAPU) if applicable\] at baseline
6. Presence of follicle ≥17 mm, evidence of ruptured follicle, and/or evidence of corpus luteum on TVUS (or TAPU if applicable) at baseline
NOTE: Other protocol-defined Inclusion/Exclusion criteria apply
→
Key Inclusion Criteria:
1. Diagnosis of FHA after exclusion of anatomic or organic causes of amenorrhea
2. Has had no menstrual bleeding episode within 3 months prior to day 1, as described in the protocol
3. Has a Body Mass Index (BMI) ≥18.5 and \<25 kg/m\^2 at screening, or BMI ≥25 to \<30 kg/m\^2 at screening AND percentage of body fat \<23% from rigorous exercise as determined by the investigator through Standard of Care (SoC) methods (eg, skinfold thickness, DXA, bioimpedance) within 6 months of screening
Key Exclusion Criteria:
1. Has presence of primary amenorrhea (failure to reach menarche, first menstrual cycle)
2. Has blood estradiol ≥50 pg/mL or blood progesterone ≥1 ng/mL at screening, as described in the protocol
3. Has uterine (eg, absence of uterus, prior endometrial ablation, endometriosis, outflow tract disorders) or ovarian conditions (eg, absence of an ovary, presence of large polycystic ovaries i.e. greater than 10 cc) that impact assessment of menses or of the HPO axis
4. Has conditions other than FHA that may cause amenorrhea or menstrual cycle disturbances (eg, polycystic ovarian syndrome, hyperprolactinemia, primary ovarian insufficiency, untreated primary hypothyroidism, primary hyperthyroidism), as described in the protocol
5. Polycystic ovarian morphology with an ovarian volume \>10 cc on TransVaginal UltraSound (TVUS) \[or TransAbdominal Pelvic Ultrasound (TAPU) if applicable\] at baseline
6. Presence of follicle ≥17 mm, evidence of ruptured follicle, and/or evidence of corpus luteum on TVUS (or TAPU if applicable) at baseline
NOTE: Other protocol-defined Inclusion/Exclusion criteria apply
INCLUSION CRITERIA
Study participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18-\<80 years of age at the time of signing the informed consent.
Type of participant and disease characteristics
2. Physician diagnosis of asthma (according to GINA 2025) for ≥6 months, with documented historical airflow variability by one of the following:
* Positive reversibility test: ≥12% and 200 ml in FEV1 after SABA administration at any point prior to randomisation
* Airflow variability in clinic FEV1 \>12% and 200 mL between historical clinical visits
* Positive bronchial challenge test: fall in FEV1 of ≥20% with standard doses of methacholine (\<16 mg/mL or \<400mcg); or ≥10% with standardised hyperventilation, or exercise challenge test; or ≥15% with hypertonic saline or mannitol challenge
* Peak flow variability of \>20% between two assessments
3. Evidence of elevated type-2 biomarkers defined as both of:
1. peripheral BEC ≥ 0.3×109/L at screening visit
2. FeNO ≥ 35 ppb at screening visit
4. At least 1 asthma attack in the last 2 years, defined as acute asthma requiring SCS for ≥ 3 days or an emergency/hospital visit requiring SCS.
5. Treatment and evident adherence to a stable at-least medium-dose ICS (fluticasone propionate equivalent \>250 mcg/day) for at least 3 months (including run-in period) \[additional controllers e.g. LABA, LAMA or LTA are allowed\]. The ICS dosage will be defined as the dosage received on a regularly basis, excluding extra reliever doses taken in the context of anti-inflammatory reliever (AIR) therapy from the calculation. AIR is allowed in the context of the study. Thus, the high-dose ICS trial population (fluticasone propionate equivalent \>500 mcg/day)\* will represent patients who are not meeting the exacerbation criteria for biological reimbursement.
\*As per section 6.2, we will cap recruitment to 60% of target population on medium-dose ICS, 40% on high-dose ICS, with randomisation also stratified by these categories.
6. Presence of one (or more) of the following additional risk factors for asthma attacks32 at screening or baseline: (i) uncontrolled asthma symptoms indicated by ACQ5 score of ≥ 1.5; (ii) impaired lung function indicated by post-bronchodilator FEV1 of ≤ 80% predicted; (iii) high-dose maintenance ICS therapy (iv) severe asthma attack in past 1-\<12 months.
Sex, contraceptive/barrier method and pregnancy testing requirements
7. Female participants
a. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
i. Is a woman of nonchildbearing potential (WONCBP) as defined in the Study Manual.
OR ii. Is a WOCBP and agrees to use a contraceptive method that is highly effective, with a failure rate of \<1%, during the intervention period (to be effective before starting the intervention) and for at least 12 weeks after the last dose of study intervention.
b. A WOCBP must have a negative highly sensitive serum pregnancy test at V1 (screening visit) and urine or serum pregnancy test (as required by local regulations) on Day 1 before the first dose of study intervention, c. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
d. Additional requirements for pregnancy testing during and after study intervention are imposed.
e. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female participant with an early undetected pregnancy.
Informed consent
8. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
4.2 EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1. Use of SCS \< 1 months prior to screening or on maintenance SCS.
2. Current tobacco smoker or recently stopped smoker (\<6 months)
3. Ex-smoker with greater than 10 pack-years AND post bronchodilator FEV1/FVC ratio below the lower limit of normal according to GLI race-neutral standards. 69
4. Documented nonadherence to ICS, defined as dispensing of less than 75% of the prescribed ICS dose over the past 12 months (or annualised if less than 12 months), based on pharmacy refill records checked at screening.
5. Presence of significant and uncorrectable inhaler technique deficiencies, as assessed by the research team during inhaler technique evaluation at screening.
6. Contra-indication to study drug
7. Immunological disease, condition or medication that may affect the inflammatory response according to Investigator.
8. History of other significant lung disease e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, clinically significant bronchiectasis, chronic obstructive lung disease, or Churg-Strauss.
9. Severe concomitant illness (including known or suspected immunodeficiency) that, in the Investigator's judgement will adversely affect the participant's participation in the study.
10. Active malignancy or history of malignancy within 5 years (except for basal cell carcinoma of the skin or fully resected Cervical Intraepithelial Neoplasia/dysplasia).
11. Exposure to monoclonal antibody therapy for asthma or another investigational medicinal product within 5 half-lives of the drug.
12. Eligibility to Dupilumab based on licensed and reimbursed indications in the participant's jurisdiction (e.g. nasal polyposis, atopic dermatitis, eosinophilic esophagitis, prurigo nodularis, etc.)
13. Treatment with live (attenuated) vaccine in the past 4 weeks.
14. Prohibited medication 15 Current helminth infection
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INCLUSION CRITERIA
Study participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18-\<80 years of age at the time of signing the informed consent.
Type of participant and disease characteristics
2. Physician diagnosis of asthma (according to GINA 2025) for ≥6 months, with documented historical airflow variability by one of the following:
* Positive reversibility test: ≥12% and 200 ml in FEV1 after SABA administration at any point prior to randomisation
* Airflow variability in clinic FEV1 \>12% and 200 mL between historical clinical visits
* Positive bronchial challenge test: fall in FEV1 of ≥20% with standard doses of methacholine (\<16 mg/mL or \<400mcg); or ≥10% with standardised hyperventilation, or exercise challenge test; or ≥15% with hypertonic saline or mannitol challenge
* Peak flow variability of \>20% between two assessments
3. Evidence of elevated type-2 biomarkers defined as both of:
1. peripheral BEC ≥ 0.3×109/L at screening visit
2. FeNO ≥ 35 ppb at screening visit
4. At least 1 asthma attack in the last 2 years, defined as acute asthma requiring SCS for ≥ 3 days or an emergency/hospital visit requiring SCS.
5. Treatment and evident adherence to a stable at-least medium-dose ICS (fluticasone propionate equivalent \>250 mcg/day) for at least 3 months (including run-in period) \[additional controllers e.g. LABA, LAMA or LTA are allowed\]. The ICS dosage will be defined as the dosage received on a regularly basis, excluding extra reliever doses taken in the context of anti-inflammatory reliever (AIR) therapy from the calculation. AIR is allowed in the context of the study. Thus, the high-dose ICS trial population (fluticasone propionate equivalent \>500 mcg/day)\* will represent patients who are not meeting the exacerbation criteria for biological reimbursement.
\*As per section 6.2, we will cap recruitment to 60% of target population on medium-dose ICS, 40% on high-dose ICS, with randomisation also stratified by these categories.
6. Presence of one (or more) of the following additional risk factors for asthma attacks32 at screening or baseline: (i) uncontrolled asthma symptoms indicated by ACQ5 score of ≥ 1.5; (ii) impaired lung function indicated by post-bronchodilator FEV1 of ≤ 80% predicted; (iii) high-dose maintenance ICS therapy (iv) severe asthma attack in past 1-\<12 months.
Sex, contraceptive/barrier method and pregnancy testing requirements
7. Female participants
a. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
i. Is a woman of nonchildbearing potential (WONCBP) as defined in the Study Manual.
OR ii. Is a WOCBP and agrees to use a contraceptive method that is highly effective, with a failure rate of \<1%, during the intervention period (to be effective before starting the intervention) and for at least 12 weeks after the last dose of study intervention.
b. A WOCBP must have a negative highly sensitive serum pregnancy test at V1 (screening visit) and urine or serum pregnancy test (as required by local regulations) on Day 1 before the first dose of study intervention, c. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
d. Additional requirements for pregnancy testing during and after study intervention are imposed.
e. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female participant with an early undetected pregnancy.
Informed consent
8. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
4.2 EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1. Use of SCS \< 1 months prior to screening or on maintenance SCS.
2. Current tobacco smoker or recently stopped smoker (\<6 months)
3. Ex-smoker with greater than 10 pack-years AND post bronchodilator FEV1/FVC ratio below the lower limit of normal according to GLI race-neutral standards. 69
4. Documented nonadherence to ICS, defined as dispensing of less than 75% of the prescribed ICS dose over the past 12 months (or annualised if less than 12 months), based on pharmacy refill records checked at screening.
5. Presence of significant and uncorrectable inhaler technique deficiencies, as assessed by the research team during inhaler technique evaluation at screening.
6. Contra-indication to study drug
7. Immunological disease, condition or medication that may affect the inflammatory response according to Investigator.
8. History of other significant lung disease e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, clinically significant bronchiectasis, chronic obstructive lung disease, or Churg-Strauss.
9. Severe concomitant illness (including known or suspected immunodeficiency) that, in the Investigator's judgement will adversely affect the participant's participation in the study.
10. Active malignancy or history of malignancy within 5 years (except for basal cell carcinoma of the skin or fully resected Cervical Intraepithelial Neoplasia/dysplasia).
11. Exposure to monoclonal antibody therapy for asthma or another investigational medicinal product within 5 half-lives of the drug.
12. Eligibility to Dupilumab based on licensed and reimbursed indications in the participant's jurisdiction (e.g. nasal polyposis, atopic dermatitis, eosinophilic esophagitis, prurigo nodularis, etc.)
13. Treatment with live (attenuated) vaccine in the past 4 weeks.
14. Prohibited medication
15. Current helminth infection
Inclusion Criteria:
* Participant must be 18 to 85 years of age inclusive.
* Clinical history consistent with NCFB (cough, chronic sputum production and/or recurrent respiratory infections).
* Participants with a FEV1 % predicted ≥30%.
* Participants with at least 2 moderate or 1 severe Pulmonary exacerbations (PEs) in the past 12 months.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
* Have bronchiectasis due to CF, hypogammaglobulinemia, common variable immunodeficiency, known active nontuberculous mycobacteria (NTM) lung infection, or pulmonary fibrosis.
* Known or suspected immunodeficiency disorder.
* Pulmonary exacerbation which has not resolved clinically during screening period.
* Have significant haemoptysis.
* Have any clinically significant abnormal laboratory values at Screening or diseases or disorders.
* History of lung transplantation.
* History of malignancy within 5 years before Screening, or during the screening period
* Currently being treated with antimicrobial therapy for tuberculosis (TB).
* Currently on active treatment for allergic bronchopulmonary aspergillosis (ABPA).
* Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease
* Known allergy to itepekimab or to excipients
* Live-attenuated vaccine(s) within 4 weeks prior to Screening or plans to receive such vaccines during the study
* Unstable ischemic heart disease
* Cardiomyopathy or other relevant cardiovascular disorder
* Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening
* History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening.
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
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Inclusion Criteria:
* Participant must be 18 to 85 years of age inclusive
* Clinical history consistent with NCFB (cough, chronic sputum production and/or recurrent respiratory infections)
* Participants with a FEV1 % predicted ≥30%
* Participants with at least 2 moderate or 1 severe Pulmonary exacerbations (PEs) in the past 12 months
Exclusion Criteria:
Participants were excluded from the study if any of the following criteria apply:
* Had bronchiectasis due to CF, hypogammaglobulinemia, common variable immunodeficiency, known active nontuberculous mycobacteria (NTM) lung infection, or pulmonary fibrosis
* Known or suspected immunodeficiency disorder
* Pulmonary exacerbation which had not resolved clinically during screening period
* Had significant haemoptysis
* Had any clinically significant abnormal laboratory values at Screening or diseases or disorders
* History of lung transplantation
* History of malignancy within 5 years before Screening, or during the screening period
* Was being treated with antimicrobial therapy for tuberculosis (TB)
* Was on active treatment for allergic bronchopulmonary aspergillosis (ABPA)
* Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease
* Known allergy to itepekimab or to excipients
* Live-attenuated vaccine(s) within 4 weeks prior to Screening or planned to receive such vaccines during the study
* Unstable ischemic heart disease
* Cardiomyopathy or other relevant cardiovascular disorder
* Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening
* History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Key Inclusion Criteria:
1. For USA participants, age criteria are 4 to \< 18 years old, at the time of the administration of the first dose of study intervention. Non-USA participants age criteria are 2 to \< 18 years old
2. Must have a confirmation of FOP diagnosis, as described in the protocol
3. At the time of enrollment, participants must weight:
1. Cohort 1 \> 30 kg
2. Cohort 2 \> 30 kg
3. Cohort 3 ≤ 30 kg
Key Exclusion Criteria:
1. Cumulative Analog Joint Involvement Scale (CAJIS) score \> 19 at the time of screening
2. Participant has significant concomitant illness or history of significant illness, as described in the protocol
3. Previous history or diagnosis of cancer
4. Ongoing significant viral or bacterial illness, within 2 weeks of the first study drug administration
5. History of severe respiratory compromise requiring oxygen, respiratory support
6. Known history of cerebral vascular malformation
7. Participants with a history of severe, non-traumatic bleeding requiring transfusion or hospitalization for hemodynamic compromise
8. Participants with a known pre-existing medical history of a bleeding diathesis, as described in the protocol
NOTE: Other Protocol-defined Inclusion/Exclusion Criteria Apply
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Key Inclusion Criteria:
1. For USA participants, age criteria are 4 to \< 18 years old, at the time of the administration of the first dose of study intervention. Non-USA participants age criteria are 2 to \< 18 years old
2. Must have a confirmation of FOP diagnosis, as described in the protocol
3. At the time of enrollment, participants must weight:
1. Cohort 1: more than 30 kg (or 66.1 pounds)
2. Cohort 2: more than 30 kg (or 66.1 pounds)
3. Cohort 3: less than or equal to 30 kg (or 66.1 pounds)
Key Exclusion Criteria:
1. Cumulative Analog Joint Involvement Scale (CAJIS) score \> 19 at the time of screening
2. Participant has significant concomitant illness or history of significant illness, as described in the protocol
3. Previous history or diagnosis of cancer
4. Ongoing significant viral or bacterial illness, within 2 weeks of the first study drug administration
5. History of severe respiratory compromise requiring oxygen, respiratory support
6. Known history of cerebral vascular malformation
7. Participants with a history of severe, non-traumatic bleeding requiring transfusion or hospitalization for hemodynamic compromise
8. Participants with a known pre-existing medical history of a bleeding diathesis, as described in the protocol
9. Participants who have used palovarotene in the last 30 days or within 5 half-lives of the therapy, whichever is longer from the day of randomization
NOTE: Other Protocol-defined Inclusion/Exclusion Criteria Apply
Inclusion criteria :
* Participant must be 40 to 85 years of age inclusive.
* Physician diagnosis of COPD for at least 1 year (based on Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] definition).
* Smoking history of ≥10 pack-years:
* For former smokers: participants who report that they are not currently smoking and smoking cessation must have occurred ≥6 months prior to Screening (Visit 1A) with an intention to quit permanently.
* For current smokers: participants who report that they are currently smoking tobacco (participant smoked at least 1 cigarette per day on average during the past 7 days) at Screening (Visit 1A) and who are not currently participating in or planning to initiate a smoking cessation intervention at Screening (Visit 1A) or during Screening period.
* Participants with moderate-to-severe COPD
* Participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months in the year prior to Screening in a participant in whom other causes of chronic cough \[eg, inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis\] has been excluded).
* Documented history of high exacerbation risk defined as having had ≥2 moderate or ≥1 severe exacerbations within the year prior to Screening (Visit 1A), with at least 1 exacerbation treated with systemic corticosteroids. At least one exacerbation must have occurred while participants were on their current controller therapy:
* Moderate exacerbations will be recorded by the Investigator and are defined as acute worsening of respiratory symptoms that requires either systemic corticosteroids (IM, IV, or oral) and/or antibiotics.
* Severe exacerbations will be recorded by the Investigator and are defined as AECOPD that require hospitalization or observation for \>24 hours in emergency department/urgent care facility.
* Participants with standard of care controller therapy, for ≥3 months prior to Screening (Visit 1A) and at a stable dose of controller therapy for at least 1 month prior to the Screening, including either: inhaled corticosteroid (ICS) + long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA) + LABA or LAMA + LABA + ICS.
* Body mass index (BMI) ≥18.0 kg/m\^2, or BMI ≥16.0 kg/m\^2 for participants enrolled in East-Asian countries.
* Female participant is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* not a women of child-bearing potential (WOCBP) OR
* a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 20 weeks after the last dose of study intervention. -
Exclusion criteria:
* Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma unless asthma resolved before 18 years of age and has not recurred.
* For former smokers: Active smoking or vaping of any products (eg, nicotine, tetrahydrocannabinol \[THC\]) within 6 months prior to Screening (Visit 1A).
* For current smokers: vaping of any products (eg, nicotine, THC) within 6 months prior to Screening (Visit 1A).
* Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening (Visit 1A) that may affect the participant's participation in the study.
* Clinically significant and current pulmonary disease other than COPD, eg, sarcoidosis, interstitial lung disease, bronchiectasis (clinical diagnosis), diagnosis of α-1 anti-trypsin deficiency, or another diagnosed pulmonary disease.
* Diagnosis of cor pulmonale, evidence of right cardiac failure, or moderate-to-severe pulmonary hypertension.
* Hypercapnia requiring bilevel positive airway pressure (BiPAP).
* Moderate or severe exacerbation of COPD (AECOPD) within 4 weeks prior to Screening (Visit 1A).
* Prior history of / planned: lung pneumonectomy for any reason, or lung volume reduction procedures (including bronchoscopic volume reduction) for COPD. Note: Surgical biopsy, or segmentectomy, or wedge resection, or lobectomy for other diseases would not be excluded.
* Unstable ischemic heart disease, including acute myocardial infarction within the past 1 year prior to Screening, or unstable angina in the 6 months prior to Screening (Visit 1A).
* Cardiac arrhythmias including paroxysmal (eg, intermittent) atrial fibrillation.
* Uncontrolled hypertension (ie, systolic blood pressure \[BP\] \>180 mm Hg or diastolic BP \>110 mm Hg with or without use of anti-hypertensive therapy).
* Participants with active tuberculosis (TB), latent TB, a history of incompletely treated TB, suspected extrapulmonary TB infection (TBI), or who are at high risk of contracting TB (such as close contact with individuals with active or latent TB) or received Bacillus Calmette-Guérin (BCG)-vaccination within 12 weeks prior to Screening (Visit 1A).
* History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening (Visit 1A).
* Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection or in contact with known exposure to COVID-19 at Screening (Visit 1A); known history of COVID-19 infection within 4 weeks prior to Screening (Visit 1A); history of requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to COVID-19 within 3 months prior to Screening (Visit 1A); participants who have had a COVID-19 infection prior Screening (Visit 1A) who have not yet sufficiently recovered to participate in the procedures of a clinical trial.
* Evidence of acute or chronic infection requiring systemic treatment with antibacterial, antiviral, antifungal, antiparasitic, or antiprotozoal medications within 4 weeks before Screening (Visit 1A), significant viral infections within 4 weeks before Screening (Visit 1A) that may not have been treated with antiviral treatment (eg, influenza receiving only symptomatic treatment).
* Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis.
* History of malignancy within 5 years before Screening (Visit 1A), except completely treated in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin.
* Previous use of itepekimab.
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
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Inclusion criteria :
* Participant must be 40 to 85 years of age inclusive.
* Physician diagnosis of COPD for at least 1 year (based on Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] definition).
* Smoking history of ≥10 pack-years:
* For former smokers: participants who reported that they were not currently smoking and smoking cessation must had occurred ≥6 months prior to Screening (Visit 1A) with an intention to quit permanently.
* For current smokers: participants who reported that they were currently smoking tobacco (participant smoked at least 1 cigarette per day on average during the past 7 days) at Screening (Visit 1A) and who were not currently participating in or planning to initiate a smoking cessation intervention at Screening (Visit 1A) or during Screening period.
* Participants with moderate-to-severe COPD
* Participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months in the year prior to Screening in a participant in whom other causes of chronic cough \[eg, inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis\] had been excluded).
* Documented history of high exacerbation risk defined as having had ≥2 moderate or ≥1 severe exacerbations within the year prior to Screening (Visit 1A), with at least 1 exacerbation treated with systemic corticosteroids. At least one exacerbation must had occurred while participants were on their current controller therapy:
* Moderate exacerbations would be recorded by the Investigator and were defined as acute worsening of respiratory symptoms that requires either systemic corticosteroids (IM, IV, or oral) and/or antibiotics.
* Severe exacerbations would be recorded by the Investigator and were defined as AECOPD that required hospitalization or observation for \>24 hours in emergency department/urgent care facility.
* Participants with standard of care controller therapy, for ≥3 months prior to Screening (Visit 1A) and at a stable dose of controller therapy for at least 1 month prior to the Screening, including either: inhaled corticosteroid (ICS) + long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA) + LABA or LAMA + LABA + ICS.
* Body mass index (BMI) ≥18.0 kg/m\^2, or BMI ≥16.0 kg/m\^2 for participants enrolled in East-Asian countries.
* Female participant was not pregnant, not breastfeeding, and at least one of the following conditions applies:
* not a women of child-bearing potential (WOCBP) OR
* a WOCBP who agreed to follow the contraceptive guidance during the intervention period and for at least 20 weeks after the last dose of study intervention. -
Exclusion criteria:
* Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma unless asthma resolved before 18 years of age and has not recurred.
* For former smokers: Active smoking or vaping of any products (eg, nicotine, tetrahydrocannabinol \[THC\]) within 6 months prior to Screening (Visit 1A).
* For current smokers: vaping of any products (eg, nicotine, THC) within 6 months prior to Screening (Visit 1A).
* Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening (Visit 1A) that might affect the participant's participation in the study.
* Clinically significant and current pulmonary disease other than COPD, eg, sarcoidosis, interstitial lung disease, bronchiectasis (clinical diagnosis), diagnosis of α-1 anti-trypsin deficiency, or another diagnosed pulmonary disease.
* Diagnosis of cor pulmonale, evidence of right cardiac failure, or moderate-to-severe pulmonary hypertension.
* Hypercapnia requiring bilevel positive airway pressure (BiPAP).
* Moderate or severe exacerbation of COPD (AECOPD) within 4 weeks prior to Screening (Visit 1A).
* Prior history of / planned: lung pneumonectomy for any reason, or lung volume reduction procedures (including bronchoscopic volume reduction) for COPD. Note: Surgical biopsy, or segmentectomy, or wedge resection, or lobectomy for other diseases would not be excluded.
* Unstable ischemic heart disease, including acute myocardial infarction within the past 1 year prior to Screening, or unstable angina in the 6 months prior to Screening (Visit 1A).
* Cardiac arrhythmias including paroxysmal (eg, intermittent) atrial fibrillation.
* Uncontrolled hypertension (ie, systolic blood pressure \[BP\] \>180 mm Hg or diastolic BP \>110 mm Hg with or without use of anti-hypertensive therapy).
* Participants with active tuberculosis (TB), latent TB, a history of incompletely treated TB, suspected extrapulmonary TB infection (TBI), or who were at high risk of contracting TB (such as close contact with individuals with active or latent TB) or received Bacillus Calmette-Guérin (BCG)-vaccination within 12 weeks prior to Screening (Visit 1A).
* History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening (Visit 1A).
* Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection or in contact with known exposure to COVID-19 at Screening (Visit 1A); known history of COVID-19 infection within 4 weeks prior to Screening (Visit 1A); history of requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to COVID-19 within 3 months prior to Screening (Visit 1A); participants who have had a COVID-19 infection prior Screening (Visit 1A) who had not yet sufficiently recovered to participate in the procedures of a clinical trial.
* Evidence of acute or chronic infection requiring systemic treatment with antibacterial, antiviral, antifungal, antiparasitic, or antiprotozoal medications within 4 weeks before Screening (Visit 1A), significant viral infections within 4 weeks before Screening (Visit 1A) that might not have been treated with antiviral treatment (eg, influenza receiving only symptomatic treatment).
* Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis.
* History of malignancy within 5 years before Screening (Visit 1A), except completely treated in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin.
* Previous use of itepekimab.
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Inclusion Criteria:
* Participants must be ≥6 months to \<18 years of age, at the time of signing the informed consent.
* A clinical diagnosis of prurigo nodularis (PN) at least 3 months prior to screening, an Investigator's global assessment for prurigo nodularis stage (IGA PN-S) score of ≥2 with presence of ≥6 pruriginous lesions at Baseline. The lesions should be present on ≥2 different body surface areas at Baseline.
* On the worst itch numerical rating scale (WI-NRS) (for participants aged ≥6 years to \<18 years old at the screening visit) or worst-scratch/itch NRS (for participants aged ≥6 months to \<6 years at the screening visit) ranging from 0 to 10, participants must have an average worst itch score of ≥7 in the 7 days prior to Day 1.
NOTE: Baseline pruritus NRS average score for maximum itch intensity will be determined based on the average of daily NRS scores for maximum intensity (the daily score ranges from 0 to 10) during the 7 days immediately preceding the Day 1/Baseline visit. A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score.
* Participants/Caregivers must be willing and able to complete a daily symptom e-Diary for the duration of the study.
* Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
* Presence of active moderate to severe lesions of atopic dermatitis (AD), and/or other skin conditions that may interfere with the PN diagnosis including but not limited to the following: scabies, psoriasis, lymphomatoid papulosis, habitual picking, dermatitis herpetiformis, sporotrichosis, and bullous disease.
* Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the screening visit or during the screening period.
NOTE: Participants may be rescreened after infection resolves.
* Known or suspected immunodeficiency, including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting an immune compromised status, as judged by the Investigator.
* Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant's participation in the study.
* Planned or anticipated major surgical procedure during the participant's participation in this clinical trial.
* Participants who has taken biologic therapy/systemic immunosuppressant/ immunomodulator within 4 weeks before the screening visit or 5 half-lives, whichever is longer.
* Current participation to any clinical trial of an investigational drug or device or participation within 3 months before the screening visit or 5 half-lives of the investigational compound, whichever is longer.
* Participation in prior dupilumab clinical study or have been treated with commercially available dupilumab.
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Inclusion Criteria:
* Participants must be ≥6 months to \<18 years of age, at the time of signing the informed consent.
* A clinical diagnosis of prurigo nodularis (PN) at least 3 months prior to screening, an Investigator's global assessment for prurigo nodularis stage (IGA PN-S) score of ≥2 with presence of ≥6 pruriginous lesions at Baseline. The lesions should be present on ≥2 different body surface areas at Baseline.
* On the worst itch numerical rating scale (WI-NRS) (for participants aged ≥6 years to \<18 years old at the screening visit) or worst-scratch/itch NRS (for participants aged ≥6 months to \<6 years at the screening visit) ranging from 0 to 10, participants must have an average worst itch score of ≥7 in the 7 days prior to Day 1.
NOTE: Baseline pruritus NRS average score for maximum itch intensity will be determined based on the average of daily NRS scores for maximum intensity (the daily score ranges from 0 to 10) during the 7 days immediately preceding the Day 1/Baseline visit. A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score.
* Participants/Caregivers must be willing and able to complete a daily symptom e-Diary for the duration of the study.
* Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
* Presence of active moderate to severe lesions of atopic dermatitis (AD), and/or other skin conditions that may interfere with the PN diagnosis including but not limited to the following: scabies, psoriasis, lymphomatoid papulosis, habitual picking, dermatitis herpetiformis, sporotrichosis, and bullous disease.
* Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the screening visit or during the screening period.
NOTE: Participants may be rescreened after infection resolves.
* Known or suspected immunodeficiency, including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting an immune compromised status, as judged by the Investigator.
* Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant's participation in the study.
* Planned or anticipated major surgical procedure during the participant's participation in this clinical trial.
* Participants who has taken biologic therapy/systemic immunosuppressant/ immunomodulator within 4 weeks before the screening visit or 5 half-lives, whichever is longer.
* Current participation to any clinical trial of an investigational drug or device or participation within 3 months before the screening visit or 5 half-lives of the investigational compound, whichever is longer.
* Participation in prior dupilumab clinical study or have been treated with commercially available dupilumab.
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Inclusion criteria :
* Participant must be 40 to 85 years of age inclusive.
* Physician diagnosis of COPD for at least 1 year (based on Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] definition).
* Smoking history of ≥10 pack-years, but who are not currently smoking, and smoking cessation must have occurred ≥6 months prior to Screening (Visit 1A) with an intention to quit permanently.
* Participants with moderate-to-severe COPD
* Participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months in the year prior to screening in a participant in whom other causes of chronic cough \[eg, inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis\] has been excluded).
* Documented history of high exacerbation risk defined as having had ≥2 moderate or ≥1 severe exacerbations within the year prior to Screening (Visit 1A), with at least 1 exacerbation treated with systemic corticosteroids. At least one exacerbation must have occurred while participants were on their current controller therapy:
* Moderate exacerbations will be recorded by the Investigator and are defined as acute worsening of respiratory symptoms that requires either systemic corticosteroids (IM, IV, or oral) and/or antibiotics.
* Severe exacerbations will be recorded by the Investigator and are defined as AECOPD that require hospitalization or observation for \>24 hours in emergency department/urgent care facility.
* Participants with standard of care controller therapy, for ≥3 months prior to Screening (Visit 1A) and at a stable dose of controller therapy for at least 1 month prior to the screening, including either: inhaled corticosteroid (ICS) + long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA) + LABA or LAMA + LABA + ICS.
* Body mass index (BMI) ≥18.0 kg/m\^2, or BMI ≥16.0 kg/m\^2 for participants enrolled in East-Asian countries.
* Female participant is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* not a women of child-bearing potential (WOCBP) OR
* a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 20 weeks after the last dose of study intervention.
Exclusion criteria:
* Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma unless asthma resolved before 18 years of age and has not recurred.
* Active smoking or vaping of any products (eg, nicotine, tetrahydrocannabinol \[THC\]) within 6 months prior to Screening (Visit 1A).
* Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening (Visit 1A) that may affect the participant's participation in the study.
* Clinically significant and current pulmonary disease other than COPD, eg, sarcoidosis, interstitial lung disease, bronchiectasis (clinical diagnosis), diagnosis of α-1 anti-trypsin deficiency, or another diagnosed pulmonary disease.
* Diagnosis of cor pulmonale, evidence of right cardiac failure, or moderate-to-severe pulmonary hypertension.
* Hypercapnia requiring bilevel positive airway pressure (BiPAP).
* Moderate or severe exacerbation of COPD (AECOPD) within 4 weeks prior to Screening (Visit 1A).
* Prior history of / planned: lung pneumonectomy for any reason, or lung volume reduction procedures (including bronchoscopic volume reduction) for COPD. Note: Surgical biopsy, or segmentectomy, or wedge resection, or lobectomy for other diseases would not be excluded.
* Unstable ischemic heart disease, including acute myocardial infarction within the past 1 year prior to Screening, or unstable angina in the 6 months prior to Screening (Visit 1A).
* Cardiac arrhythmias including paroxysmal (eg, intermittent) atrial fibrillation.
* Uncontrolled hypertension (ie, systolic blood pressure \[BP\] \>180 mm Hg or diastolic BP \>110 mm Hg with or without use of anti-hypertensive therapy).
* Participants with active tuberculosis (TB), latent TB, a history of incompletely treated TB, suspected extrapulmonary TB infection (TBI), or who are at high risk of contracting TB (such as close contact with individuals with active or latent TB) or received Bacillus Calmette-Guérin (BCG)-vaccination within 12 weeks prior to Screening (Visit 1A).
* History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening (Visit 1A).
* Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection or in contact with known exposure to COVID-19 at Screening (Visit 1A); known history of COVID-19 infection within 4 weeks prior to Screening (Visit 1A); history of requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to COVID-19 within 3 months prior to sScreening (Visit 1A); participants who have had a COVID-19 infection prior Screening (Visit 1A) who have not yet sufficiently recovered to participate in the procedures of a clinical trial.
* Evidence of acute or chronic infection requiring systemic treatment with antibacterial, antiviral, antifungal, antiparasitic, or antiprotozoal medications within 4 weeks before Screening (Visit 1A), significant viral infections within 4 weeks before Screening (Visit 1A) that may not have been treated with antiviral treatment (eg, influenza receiving only symptomatic treatment).
* Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis.
* History of malignancy within 5 years before Screening (Visit 1A), except completely treated in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin.
* Previous use of itepekimab.
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
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Inclusion criteria :
* Participant must be 40 to 85 years of age inclusive
* Physician diagnosis of COPD for at least 1 year (based on Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] definition)
* Smoking history of ≥10 pack-years, but who were not currently smoking, and smoking cessation must have occurred ≥6 months prior to Screening (Visit 1A) with an intention to quit permanently
* Participants with moderate-to-severe COPD
* Participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months in the year prior to screening in a participant in whom other causes of chronic cough \[eg, inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis\] has been excluded)
* Documented history of high exacerbation risk defined as having had ≥2 moderate or ≥1 severe exacerbations within the year prior to Screening (Visit 1A), with at least 1 exacerbation treated with systemic corticosteroids. At least one exacerbation must have occurred while participants were on their current controller therapy:
* Moderate exacerbations were recorded by the Investigator and were defined as acute worsening of respiratory symptoms that requires either systemic corticosteroids (IM, IV, or oral) and/or antibiotics
* Severe exacerbations were recorded by the Investigator and were defined as AECOPD that require hospitalization or observation for \>24 hours in emergency department/urgent care facility
* Participants with standard of care controller therapy, for ≥3 months prior to Screening (Visit 1A) and at a stable dose of controller therapy for at least 1 month prior to the screening, including either: inhaled corticosteroid (ICS) + long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA) + LABA or LAMA + LABA + ICS
* Body mass index (BMI) ≥18.0 kg/m\^2, or BMI ≥16.0 kg/m\^2 for participants enrolled in East-Asian countries
* Female participant was not pregnant, not breastfeeding, and at least one of the following conditions applies:
* not a women of child-bearing potential (WOCBP) OR
* a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 20 weeks after the last dose of study intervention
Exclusion criteria:
* Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma unless asthma resolved before 18 years of age and has not recurred
* Active smoking or vaping of any products (eg, nicotine, tetrahydrocannabinol \[THC\]) within 6 months prior to Screening (Visit 1A)
* Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening (Visit 1A) that may affect the participant's participation in the study
* Clinically significant and current pulmonary disease other than COPD, eg, sarcoidosis, interstitial lung disease, bronchiectasis (clinical diagnosis), diagnosis of α-1 anti-trypsin deficiency, or another diagnosed pulmonary disease
* Diagnosis of cor pulmonale, evidence of right cardiac failure, or moderate-to-severe pulmonary hypertension
* Hypercapnia requiring bilevel positive airway pressure (BiPAP)
* Moderate or severe exacerbation of COPD (AECOPD) within 4 weeks prior to Screening (Visit 1A)
* Prior history of / planned: lung pneumonectomy for any reason, or lung volume reduction procedures (including bronchoscopic volume reduction) for COPD. Note: Surgical biopsy, or segmentectomy, or wedge resection, or lobectomy for other diseases would not be excluded.
* Unstable ischemic heart disease, including acute myocardial infarction within the past 1 year prior to Screening, or unstable angina in the 6 months prior to Screening (Visit 1A)
* Cardiac arrhythmias including paroxysmal (eg, intermittent) atrial fibrillation
* Uncontrolled hypertension (ie, systolic blood pressure \[BP\] \>180 mm Hg or diastolic BP \>110 mm Hg with or without use of anti-hypertensive therapy)
* Participants with active tuberculosis (TB), latent TB, a history of incompletely treated TB, suspected extrapulmonary TB infection (TBI), or who were at high risk of contracting TB (such as close contact with individuals with active or latent TB) or received Bacillus Calmette-Guérin (BCG)-vaccination within 12 weeks prior to Screening (Visit 1A)
* History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening (Visit 1A)
* Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection or in contact with known exposure to COVID-19 at Screening (Visit 1A); known history of COVID-19 infection within 4 weeks prior to Screening (Visit 1A); history of requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to COVID-19 within 3 months prior to sScreening (Visit 1A); participants who have had a COVID-19 infection prior Screening (Visit 1A) who have not yet sufficiently recovered to participate in the procedures of a clinical trial
* Evidence of acute or chronic infection requiring systemic treatment with antibacterial, antiviral, antifungal, antiparasitic, or antiprotozoal medications within 4 weeks before Screening (Visit 1A), significant viral infections within 4 weeks before Screening (Visit 1A) that may not have been treated with antiviral treatment (eg, influenza receiving only symptomatic treatment)
* Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis
* History of malignancy within 5 years before Screening (Visit 1A), except completely treated in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin
* Previous use of itepekimab
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Inclusion Criteria:
* Histologically confirmed locoregionally advanced and unresectable or recurrent/metastatic cutaneous squamous cell carcinoma (CSCC). Definitions that encompass unresectable disease include any of the following, after discussion at the multidisciplinary meeting:
* Anatomically unresectable disease to include carotid artery encasement; invasion into the skull base, cavernous sinus, sagittal sinus; pre-vertebral fascia/vertebral body/vertebral artery; disseminated distant metastatic disease
* Functionally unresectable disease resulting in the loss of sight, oral competency/speech/swallowing, or limb
* Biologically unresectable disease to include satellitosis, in-transit/dermal metastasis, or disease which has failed 2 or more prior surgeries (by an experienced CSCC surgeon) or failed curative intent radiation therapy
* Measurable disease per RECIST 1.1.
* Received a kidney transplant. Must have a functioning allograft, be at least 6 months from last allograft transplantation, and have had no evidence of biopsy-proven allograft rejection (Banff 1A or above, requiring treatment) at any time. In order to be considered a functioning allograft, the following criteria must be met:
* Estimated glomerular filtration rate (GFR) ≥ 30 mL/min (using the CKD-EPI equation either by Cr or Cystatin C based measurement) (Inker LA et al, 2021)
* Baseline proteinuria \< 0.5 g/day (by spot urine protein-creatinine ratio or 24-hr urine collection, if available)
* Not receiving antiproliferative immunosuppressive medications. If patients are on antiproliferative immunosuppressive medications, they must be discontinued for at least 7 days before initiation of C1D1 (i.e. at the screening visit and/or during the lead-in period)
* At least 18 years of age.
* ECOG performance status ≤ 2
* Adequate bone marrow and organ function as defined below:
* Leukocytes ≥ 2.2 K/cumm
* Absolute neutrophil count ≥ 1.0 K/cumm
* Platelets ≥ 90 K/cumm
* Total bilirubin within normal institutional limits (except in cases where Gilbert syndrome is known or suspected, where total bilirubin should be \< 3 mg/dL)
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
* The effects of cemiplimab on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for 4 months after last dose of cemiplimab.
* Able to switch immunosuppression regimen to sirolimus and prednisone if not already receiving sirolimus and prednisone as SOC.
* Able to understand and willing to sign an IRB approved written informed consent document and willing and able to comply with clinic visits and study-related procedures. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
* Received chemotherapy or radiotherapy within 2 weeks prior to C1D1. Note: prior cetuximab exposure is permitted, but it must have been discontinued at least 2 weeks prior to the start of cemiplimab.
* Received prior anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CLTA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways (including chimeric antigen receptor \[CAR\] T-cell therapies).
Note: prior topical or intralesional immunotherapies (e.g., imiquimod, talimogene laherparepvec) are permitted.
* Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
* Currently receiving any other investigational agents.
* Unable to swallow pills.
* Currently receiving any medications or substances that are strong inhibitors or inducers of CYP3A4.
* Receipt of a live vaccine within 28 days of C1D1.
* Receipt of COVID-19 vaccination within 7 days of C1D1 or for which the planned COVID-19 vaccinations would not be completed 7 days prior to C1D1.
* Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression and if they are at least 4 weeks out from treatment. They must also be asymptomatic and on stable doses of anti-epileptic drugs (AEDs) and oral corticosteroids at the time of enrollment
* A history of allergic reactions attributed to or known hypersensitivity to cemiplimab or any of its components or other agents used in the study.
* Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. Note: the following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment. Patients with a history of Hashimoto thyroiditis who are stable on replacement hormone therapy are not excluded.
* Any condition that requires ongoing/continuous corticosteroid therapy (\> 10 mg prednisone/day or anti-inflammatory equivalent) within 7 days prior to C1D1. Patients who require a brief course of steroids (up to 2 days in the week before C1D1) or physiologic replacement are not excluded.
* Uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring hospitalization or treatment with IV anti-infectives within 14 days prior to C1D1; NYHA heart failure classifications of Class II, III, or IV; myocardial infarction or acute coronary syndrome within 12 months prior to C1D1; unstable angina pectoris; cardiac arrhythmia; transient ischemic attack or stroke within 12 months prior to C1D1.
* Known non-infectious pneumonitis or any history of interstitial lung disease.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry.
* Uncontrolled infection with HIV, hepatitis B or C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent).
* Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count \> 350 either spontaneously or on a stable antiviral regiment are eligible. For these participants, monitoring will be performed as per local standards.
* Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of cemiplimab.
* Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: if serum HBV DNA is above the limit of detection at screening, initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below the limit of detection, periodic monitoring of HBsAg must be performed.
* Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are eligible.
→
Inclusion Criteria:
* Histologically confirmed locoregionally advanced and unresectable or recurrent/metastatic cutaneous squamous cell carcinoma (CSCC). Definitions that encompass unresectable disease include any of the following, after discussion at the multidisciplinary meeting:
* Anatomically unresectable disease to include carotid artery encasement; invasion into the skull base, cavernous sinus, sagittal sinus; pre-vertebral fascia/vertebral body/vertebral artery; disseminated distant metastatic disease
* Functionally unresectable disease resulting in the loss of sight, oral competency/speech/swallowing, or limb
* Biologically unresectable disease to include satellitosis, in-transit/dermal metastasis, or disease which has failed 2 or more prior surgeries (by an experienced CSCC surgeon) or failed curative intent radiation therapy
* Measurable disease per RECIST 1.1.
* Received a kidney transplant. Must have a functioning allograft, be at least 6 months from last allograft transplantation, and have had no evidence of biopsy-proven allograft rejection (Banff 1A or above, requiring treatment) at any time. In order to be considered a functioning allograft, the following criteria must be met:
* Estimated glomerular filtration rate (GFR) ≥ 30 mL/min (using the CKD-EPI equation either by Cr or Cystatin C based measurement) (Inker LA et al, 2021)
* Baseline proteinuria \< 0.5 g/day (by spot urine protein-creatinine ratio or 24-hr urine collection, if available)
* Not receiving antiproliferative immunosuppressive medications. If patients are on antiproliferative immunosuppressive medications, they must be discontinued for at least 7 days before initiation of C1D1 (i.e. at the screening visit and/or during the lead-in period)
* At least 18 years of age.
* ECOG performance status ≤ 2
* Adequate bone marrow and organ function as defined below:
* Leukocytes ≥ 2.2 K/cumm
* Absolute neutrophil count ≥ 1.0 K/cumm
* Platelets ≥ 90 K/cumm
* Total bilirubin within normal institutional limits (except in cases where Gilbert syndrome is known or suspected, where total bilirubin should be \< 3 mg/dL)
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
* The effects of cemiplimab on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for 4 months after last dose of cemiplimab.
* Able to switch immunosuppression regimen to sirolimus and prednisone if not already receiving sirolimus and prednisone as SOC.
* Able to understand and willing to sign an IRB approved written informed consent document and willing and able to comply with clinic visits and study-related procedures. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
* Received chemotherapy or radiotherapy within 2 weeks prior to C1D1. Note: prior cetuximab exposure is permitted, but it must have been discontinued at least 2 weeks prior to the start of cemiplimab.
* Received prior anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CLTA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways (including chimeric antigen receptor \[CAR\] T-cell therapies).
Note: prior topical or intralesional immunotherapies (e.g., imiquimod, talimogene laherparepvec) are permitted.
* Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
* Currently receiving any other investigational agents.
* Unable to swallow pills.
* Currently receiving any medications or substances that are strong inhibitors or inducers of CYP3A4.
* Receipt of a live vaccine within 28 days of C1D1.
* Receipt of COVID-19 vaccination within 7 days of C1D1 or for which the planned COVID-19 vaccinations would not be completed 7 days prior to C1D1.
* Patients with untreated brain metastases. Patients with treated brain metastases are allowed if standard of care (SOC) post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression and if they are at least 4 weeks out from treatment. They must also be asymptomatic and on stable doses of anti-epileptic drugs (AEDs) and oral corticosteroids at the time of enrollment
* A history of allergic reactions attributed to or known hypersensitivity to cemiplimab or any of its components or other agents used in the study.
* Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. Note: the following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment. Patients with a history of Hashimoto thyroiditis who are stable on replacement hormone therapy are not excluded.
* Any condition that requires ongoing/continuous corticosteroid therapy (\> 10 mg prednisone/day or anti-inflammatory equivalent) within 7 days prior to C1D1. Patients who require a brief course of steroids (up to 2 days in the week before C1D1) or physiologic replacement are not excluded.
* Uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring hospitalization or treatment with IV anti-infectives within 14 days prior to C1D1; NYHA heart failure classifications of Class II, III, or IV; myocardial infarction or acute coronary syndrome within 12 months prior to C1D1; unstable angina pectoris; cardiac arrhythmia; transient ischemic attack or stroke within 12 months prior to C1D1.
* Known non-infectious pneumonitis or any history of interstitial lung disease.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry.
* Uncontrolled infection with HIV, hepatitis B or C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent).
* Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count \> 350 either spontaneously or on a stable antiviral regiment are eligible. For these participants, monitoring will be performed as per local standards.
* Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of cemiplimab.
* Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: if serum HBV DNA is above the limit of detection at screening, initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below the limit of detection, periodic monitoring of HBsAg must be performed.
* Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are eligible.
Inclusion Criteria:
1. Minimum of 18 years-old
2. Active Thyroid Eye Disease
3. Clinical Activity Score (CAS) between 3 and 5, inclusive
4. Phakic and pseudophakic eyes are allowed in the study.
5. Willing and able to provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
6. Willing and able to comply with clinic visits and study-related procedures
7. Only one eye will be enrolled. The worse eye (demonstrating any of these features:
worse HVF results, worse restricted motility, worse visual acuity, worse edema, worse proptosis, worse eyelid retraction) will be enrolled. If both eyes are equivalent, we will enroll the non-dominant eye.
Exclusion Criteria:
1. History of orbital, strabismus, or eyelid surgery or orbital radiation
2. Optic neuropathy or other vision-threatening signs
3. Patients currently on systemic or topical steroids. If they received steroids in the past, they would require a 6 week washout period and the cumulative dose of steroids must be less than 1 gram of methylprednisolone (or equivalent). During the washout period we will contact patients by phone weekly to monitor their safety and address any concerns they may have related to no longer taking steroids .
4. Patients who have taken teprotumumab (Tepezza.)
5. Patients who have received intraocular anti-VEGF medications within 1 year of screening
6. Patients who have a history of receiving systemic anti-VEGF
7. Presence of other retinal vascular diseases (diabetic retinopathy, vein occlusion) that could affect the VEGF levels within the eye
8. History of stroke or prior myocardial infarction
9. Known hypersensitivity to aflibercept
10. Infectious conjunctivitis, keratitis, or endophthalmitis of either eye
11. Presence of a glaucoma shunting or filtration device that is subconjunctival
12. Previous participation in any studies of investigational drugs within 1 month preceding Day 0
13. Any clinically significant acute or chronic medical condition that would preclude participation in a clinical study
14. Pregnant or breast-feeding women
15. Sexually active men\* or women of childbearing potential\*\* who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device \[IUD\]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly)
16. History of hyaluronidase (HA) injection after the diagnosis of thyroid eye disease
17. Taking part in other research studies in the past 12 months that have involved radiation exposure
18. Participated in other research studies in the past 12 months that required radiologic imaging (particularly CT scans and not MRIs)
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Inclusion Criteria:
1. Minimum of 18 years-old
2. Active Thyroid Eye Disease
3. Clinical Activity Score (CAS) between 3 and 5, inclusive
4. Phakic and pseudophakic eyes are allowed in the study.
5. Willing and able to provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
6. Willing and able to comply with clinic visits and study-related procedures
7. Only one eye will be enrolled. The worse eye (demonstrating any of these features:
worse Humphrey Visual Field (HVF) results, worse restricted motility, worse visual acuity, worse edema, worse proptosis, worse eyelid retraction) will be enrolled. If both eyes are equivalent, we will enroll the non-dominant eye.
Exclusion Criteria:
1. History of orbital, strabismus, or eyelid surgery or orbital radiation
2. Optic neuropathy or other vision-threatening signs
3. Patients currently on systemic or topical steroids. If they received steroids in the past, they would require a 6 week washout period and the cumulative dose of steroids must be less than 1 gram of methylprednisolone (or equivalent). During the washout period we will contact patients by phone weekly to monitor their safety and address any concerns they may have related to no longer taking steroids .
4. Patients who have taken teprotumumab (Tepezza.)
5. Patients who have received intraocular anti-VEGF medications within 1 year of screening
6. Patients who have a history of receiving systemic anti-VEGF
7. Presence of other retinal vascular diseases (diabetic retinopathy, vein occlusion) that could affect the VEGF levels within the eye
8. History of stroke or prior myocardial infarction
9. Known hypersensitivity to aflibercept
10. Infectious conjunctivitis, keratitis, or endophthalmitis of either eye
11. Presence of a glaucoma shunting or filtration device that is subconjunctival
12. Previous participation in any studies of investigational drugs within 1 month preceding Day 0
13. Any clinically significant acute or chronic medical condition that would preclude participation in a clinical study
14. Pregnant or breast-feeding women
15. Sexually active men\* or women of childbearing potential\*\* who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device \[IUD\]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly)
16. History of hyaluronidase (HA) injection after the diagnosis of thyroid eye disease
17. Taking part in other research studies in the past 12 months that have involved radiation exposure
18. Participated in other research studies in the past 12 months that required radiologic imaging (particularly CT scans and not MRIs)
Inclusion Criteria:
* Adults ≥50 years with polymyalgia rheumatica according to the EULAR/ACR classification criteria
* Meet criteria for newly diagnosed PMR (received ≤6 weeks of corticosteroids prior to randomization) or for early relapsing PMR (initiated corticosteroid treatment within last year, treated with prednisone ≥10 mg/day for ≥ 8 weeks, and experienced flare within prior 12 weeks while receiving ≥5 mg/d prednisone)
* Participants must be willing and able to take prednisone of 15 mg/day at randomization
* Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
Exclusion Criteria:
* Diagnosis of Giant Cell Arteritis (GCA)
* Concurrent rheumatoid arthritis, inflammatory arthritis, connective tissue diseases, fibromyalgia
* Inadequately treated hypothyroidism
* Exclusion related to tuberculosis (TB), invasive opportunistic infections, recurrent or persistent infections including hepatitis B, C or HIV, recurrent herpes zoster or active herpes zoster
* Patients with uncontrolled diabetes mellitus (HbA1c ≥9%)
* Immunosuppressive therapies including systemic corticosteroids
* Malignancy
* Organ transplant recipient
The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
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Inclusion Criteria:
* Adults ≥50 years with polymyalgia rheumatica according to the EULAR/ACR classification criteria
* Meet criteria for newly diagnosed PMR (newly diagnosed PMR must have met the EULAR/ACR classification criteria for a first-time diagnosis of PMR within 8 weeks prior to randomization) OR for early relapsing PMR (early relapsing PMR must have met the EULAR/ACR classification criteria prior to initiating treatment for PMR) AND
* Have initiated treatment with corticosteroid(s) (CS) for PMR no more than 1 year prior to randomization,
* Be on a prednisone dose of at least 7.5 mg/day (or equivalent) and not exceeding 20 mg/day at screening and during the screening period,
* Have a history of being treated for at least 8 weeks with prednisone (at a dose of ≥10 mg/day prednisone or equivalent),
* Had at least one episode of unequivocal PMR flare while attempting to taper prednisone at a dose that is ≥5 mg/day (or equivalent) within the past 12 weeks prior to screening: (unequivocal symptoms of PMR flare include shoulder and/or hip girdle pain associated with inflammatory stiffness)
* Participants must be willing and able to take prednisone of 15 mg/day at randomization
* Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
Exclusion Criteria:
* Diagnosis of Giant Cell Arteritis (GCA)
* Concurrent rheumatoid arthritis, inflammatory arthritis, connective tissue diseases, fibromyalgia
* Inadequately treated hypothyroidism
* Exclusion related to tuberculosis (TB), invasive opportunistic infections, recurrent or persistent infections including hepatitis B, C or HIV, recurrent herpes zoster or active herpes zoster
* Patients with uncontrolled diabetes mellitus (HbA1c ≥9%)
* Immunosuppressive therapies including systemic corticosteroids
* Malignancy
* Organ transplant recipient
The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Key Inclusion Criteria:
1. Adult patients with FOP who must have completed the double-blind treatment period of the parent study OPTIMA (R2477-FOP-2175 \[NCT05394116\]), as defined in the protocol
2. If the patient has progression of disease with Cumulative Analogue Joint Involvement Scale (CAJIS) \>19 at the time of EAP enrollment, the case will require discussion and evaluation between the treating physician and EAP Medical Director to determine final eligibility
Key Exclusion Criteria:
1\. Patients participating in OPTIMA who are considered by the treating physician as inappropriate for this program for any reason
NOTE: Other protocol defined inclusion / exclusion criteria apply
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Key Inclusion Criteria:
1. Adult male and female patients with FOP, including patients who have completed the double-blind treatment period of the OPTIMA study (R2477-FOP-2175 \[NCT05394116\]).
2. If the patient has progression of disease with Cumulative Analogue Joint Involvement Scale (CAJIS) \>19 at the time of EAP enrollment, the case will require discussion and evaluation between the treating physician and EAP Medical Director to determine final eligibility
Key Exclusion Criteria:
1\. Participants who participated in OPTIMA and are considered by the treating physician as inappropriate for this program for any reason
NOTE: Other protocol defined inclusion / exclusion criteria apply
Key Inclusion Criteria:
1. A diagnosis of MASH documented in the participant's medical history, or a clinical suspicion of MASH based on non-invasive biomarkers and clinical risk factors, including having a history of 1 or more elements of metabolic syndrome as described in the protocol
2. Screening percutaneous liver biopsy demonstrating a NAFLD Activity Score (NAS) ≥4 and fibrosis stage F2 or F3 as described in the protocol
3. Has a FibroScan Aspartate aminotransferase (FAST) score \>0.35 either at Screening Visit 1 or within approximately 3 months of Screening Visit 1 as described in the protocol
Key Exclusion Criteria:
1. Known chronic liver disease other than Metabolic dysfunction-Associated steatotic Liver Disease (MASLD), as determined by the investigator as described in the protocol
2. Prior or current suspected or known drug-induced liver injury within approximately 1 year prior to Screening Visit 1
3. History of liver transplantation, current placement on a liver transplant list, or MELD score \>12
4. Known history of alcohol or other substance abuse within the last year or at any time during screening based on investigator's discretion and/or a score on the AUDIT questionnaire ≥8
5. Prior current, or planned future use of a Glucagon-Like Peptide-1 (GLP-1) receptor agonist-based therapy or any medication approved for the treatment of MASH unless used at a generally stable dose and regimen since at least 3 months prior to Screening Visit 1 or the qualifying historical liver biopsy and throughout the screening period with no change to the dose or regimen anticipated during the treatment period as described in the protocol
NOTE: Other Protocol-defined Inclusion/Exclusion Criteria Apply
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Key Inclusion Criteria:
1. A diagnosis of MASH documented in the participant's medical history, or a clinical suspicion of MASH based on non-invasive biomarkers and clinical risk factors, including having a history of 1 or more elements of metabolic syndrome as described in the protocol
2. Screening percutaneous liver biopsy demonstrating a NAFLD Activity Score (NAS) ≥4 and fibrosis stage F2 or F3 as described in the protocol
3. Has a FibroScan Aspartate aminotransferase (FAST) score \>0.35 either at Screening Visit 1 or within approximately 3 months of Screening Visit 1 as described in the protocol
Key Exclusion Criteria:
1. Known chronic liver disease other than Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), as determined by the investigator as described in the protocol
2. Prior or current suspected or known drug-induced liver injury within approximately 1 year prior to Screening Visit 1
3. History of liver transplantation, current placement on a liver transplant list, or MELD score \>12
4. Known history of alcohol or other substance abuse within the last year or at any time during screening based on investigator's discretion and/or a score on the AUDIT questionnaire ≥8
5. Prior current, or planned future use of a Glucagon-Like Peptide-1 (GLP-1) receptor agonist-based therapy or any medication approved for the treatment of MASH unless used at a generally stable dose and regimen since at least 3 months prior to Screening Visit 1 or the qualifying historical liver biopsy and throughout the screening period with no change to the dose or regimen anticipated during the treatment period as described in the protocol
NOTE: Other Protocol-defined Inclusion/Exclusion Criteria Apply
Key Inclusion Criteria:
1. Male or female participants ≥18 years of age at screening (or ≥ legal age of adulthood based on local regulations, whichever is older)
2. Participant with documented diagnosis of Myasthenia Gravis (MG) based on medical history and supported by previous evaluations as described in the protocol
3. Documented prior history of positive serologic test or a positive result during screening of Anti-acetylcholine Receptor (AChR) antibodies or anti-Lipoprotein Receptor-related Protein 4 (LRP4) antibodies.
4. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IVa at screening
5. Myasthenia Gravis-Activities of Daily Living (MG-ADL) score ≥6 at screening. Ocular items should not contribute more than 50% of MG-ADL total score as described in the protocol
6. Currently receiving an acetylcholinesterase inhibitor or documented reason for not using acetylcholinesterase inhibitor therapy per investigator
7. Currently receiving an Immunosuppressive Therapy (IST) for MG, or documented reason why the participant is not taking an IST per investigator
8. If currently receiving an IST, not anticipated to have IST dosage changed before randomization or during Double-Blind Treatment Period (DBTP).
9. Willing and able to comply with clinic visits and study-related procedures, including completion of the primary series of the meningococcal vaccinations required per protocol
Key Exclusion Criteria:
1. Patients with antibody profile that is only positive for Muscle-Specific tyrosine Kinase (MuSK) (MuSK positivity is based on a documented prior history of positive serologic test for antibodies to MuSK or a positive result during screening
2. History of thymectomy within 12 months prior to screening or planned during the study
3. History of malignant thymoma (patients with stage 1 may be enrolled), or history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
4. Myasthenic crisis or MGFA Class V within 1 month of screening
5. Not meeting meningococcal vaccination requirements and, at a minimum, documentation of quadrivalent meningococcal vaccination within 5 years prior to randomization and serotype B vaccine (when available) within 3 years prior to randomization as described in the protocol
6. Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines) as described in the protocol
7. Participants who require antibiotics for meningococcal prophylaxis and have a contraindication, warning, or precaution precluding the use of penicillin class and penicillin-alternative antibiotics planned to be used for prophylaxis, or a history of intolerance leading to the discontinuation of these antibiotics
8. Positive hepatitis B surface antigen or hepatitis C virus Ribonucleic Acid (RNA) during screening. NOTE: Cases with unclear interpretation should be discussed with the medical monitor
9. History of Human Immunodeficiency Virus (HIV) infection or a positive test at screening per local requirements
NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply
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Key Inclusion Criteria:
1. Male or female participants ≥18 years of age at screening (or ≥ legal age of adulthood based on local regulations, whichever is older)
2. Participant with documented diagnosis of Myasthenia Gravis (MG) based on medical history and supported by previous evaluations as described in the protocol
3. Documented prior history of positive serologic test or a positive result during screening of Anti-acetylcholine Receptor (AChR) antibodies or anti-Lipoprotein Receptor-related Protein 4 (LRP4) antibodies
4. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IVa at screening
5. Myasthenia Gravis-Activities of Daily Living (MG-ADL) score ≥6 at screening. Ocular items should not contribute more than 50% of MG-ADL total score as described in the protocol
6. Currently receiving an acetylcholinesterase inhibitor or documented reason for not using acetylcholinesterase inhibitor therapy per investigator
7. Currently receiving an Immunosuppressive Therapy (IST) for MG, or documented reason why the participant is not taking an IST per investigator
8. If currently receiving an IST, not anticipated to have IST dosage changed before randomization or during Double-Blind Treatment Period (DBTP)
9. Willing and able to comply with clinic visits and study-related procedures, including completion of the primary series of the meningococcal vaccinations required per protocol
10. For the optional PK sub-study: Must have a Body Mass Index (BMI) ≥ 18.5 kg/m\^2 and ≤ 30 kg/m\^2 at screening
Key Exclusion Criteria:
1. Participants with antibody profile that is only positive for Muscle-Specific tyrosine Kinase (MuSK) (MuSK positivity is based on a documented prior history of positive serologic test for antibodies to MuSK or a positive result during screening
2. History of thymectomy within 12 months prior to screening or planned during the study
3. History of malignant thymoma (patients with stage 1 may be enrolled), or history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
4. Myasthenic crisis or MGFA Class V within 1 month of screening
5. Not meeting meningococcal vaccination requirements and, at a minimum, documentation of quadrivalent meningococcal vaccination within 5 years prior to randomization and serotype B vaccine (when available) within 3 years prior to randomization as described in the protocol
6. Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines) as described in the protocol
7. Participants who require antibiotics for meningococcal prophylaxis and have a contraindication, warning, or precaution precluding the use of penicillin class and penicillin-alternative antibiotics planned to be used for prophylaxis, or a history of intolerance leading to the discontinuation of these antibiotics
8. Positive hepatitis B surface antigen or hepatitis C virus Ribonucleic Acid (RNA) during screening. NOTE: Cases with unclear interpretation should be discussed with the medical monitor
9. History of Human Immunodeficiency Virus (HIV) infection or a positive test at screening per local requirements
NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply