NextGen 2024: Unmet Needs & Clinical Trial Challenges Session Part 2

    NextGen 2024: Unmet Needs & Clinical Trial Challenges Session Part 2

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    6 months ago 333

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    Key Insights

    Clinical Trials in Still´s disease (sJIA/AOSD)
Fabrizio de Benedetti
Rheumatology, Children Hospital Bambino Gesu’, Rome - Italy
    1/11
    Clinical trials in Still‘s disease
Present scenario
•IL-1 or IL-6 inhibitors are very efficacious in 70-80% of patients
• Early treatment with biologics is more and more standard of care with 
IL-1 and IL-6 inhibitors being widely available
Patient/Parent perspectives (physicians also)
•Acceptability of “experimental” drugs vs established approach
•Acceptability of randomization (experimental drug vs placebo or 
experimental drug vs active control)
    2/11
    Clinical trials in Still‘s disease
Present scenario
•IL-1 or IL-6 inhibitors are very efficacious in 70-80% of patients
• Early treatment with biologics is more and more standard of care with 
IL-1 and IL-6 inhibitors being widely available
Patient/Parent perspectives (physicians also)
•Acceptability of “experimental” drugs vs established approach
•Acceptability of randomization (experimental drug vs placebo or 
experimental drug vs active control)
Refractory or D2T Still‘ disease
    3/11
    Refractory (D2T) Still‘s disease
•Persistent chronic arthritis (with or without active syst features)
•Relapsing/smouldering MAS with or without LD
•Acute MAS flare (with or without LD)
• Difficult if not impossible to lump them in the same trial
• Overall they are very rare 
• Only one trial is doable
    4/11
    Refractory (D2T) Still‘s disease
1. persistent chronic arthritis (with or without active systemic features)
Classification criteria: OK with ILAR, Yamaguchi, provisional PRINTO
Response criteria: 
• OK with JIA-ACR response + absence of fever, systJADAS (merging adults and children 
criteria)
• Tapering/withdrawal of background treatment (e.g. GC)
Eligible for ongoing trials in pcJIA (e.g. Jak inhibitors), only if systemic symptoms are absent
• Need new MoA (limited safety data) 
• 12 and older 🡪 PK modeling for dosing in <12yo
• Sample size
• Randomization (placebo? Active control?)
• Open label
• External (historical) controls
    5/11
    Refractory (D2T) Still‘s disease
1. persistent chronic arthritis (with or without active systemic features)
Classification criteria: OK with ILAR, Yamaguchi, provisional PRINTO
Response criteria: 
• OK with JIA-ACR response + absence of fever, systJADAS (merging adults and children 
criteria 
• Tapering/withdrawal of background treatment (e.g. GC)
• Eligible for ongoing trials in JIA (e.g. Jak inhibitors), only if systemic symptoms are absent
• Need new MoA (limited safety data) 
• 12 and older 🡪 PK modeling for dosing in <12yo
• Sample size
• Randomization (placebo? Active control?)
• Open label
• External (historical) controls
    6/11
    Refractory (D2T) Still‘s disease
2. Relapsing/smouldering MAS with or without LD
Syst features - little, if any arthritis 
Lung disease (LD)
Relapsing and/or smouldering MAS
Classification criteria 
• NOT OK with ILAR, might be OK with Yamaguchi or provisional PRINTO
• Response criteria
• NOT OK with JIA-ACR response + absence of fever
• MAYBE syst-JADAS (merging adults and children criteria)
• Tapering/withdrawal of background treatment (e.g. GC, biologics)
• Largely overlapping subset
• Mostly IL-18 high
• Many reccurrent eosinophilia
• Many DRB1*15 carriers
    7/11
    Refractory (D2T) Still‘s disease
2. Relapsing/smouldering MAS with or without LD
Syst features - little, if any arthritis 
Lung disease (LD)
Relapsing and/or smouldering MAS
Classification criteria 
• NOT OK with ILAR, OK with Yamaguchi or provisional PRINTO
• Response criteria
• NOT OK with JIA-ACR response + absence of fever
• MAYBE syst-JADAS (merging adults and children criteria?)
• Need to capture MAS features (MAS remission?)
• Need to capture LD course (O2 requirement, O2 overnight saturation)
• Tapering/withdrawal of background treatment (e.g. GC, biologics)
• Largely overlapping subset
• Mostly IL-18 high
• Many recurrent eosinophilia
• Many DRB1*15 carriers
    8/11
    Refractory (D2T) Still‘s disease
2. Relapsing/smouldering MAS with or without LD
Syst features - little, if any arthritis 
Lung disease (LD)
Relapsing and/or smouldering MAS
• Design
• Placebo controlled unethical
• No active comparable available (no SoC)
• Sample size
• Historical controls
• Largely overlapping subset
• Mostly IL-18 high
• Many reccurrent eosinophilia
• Many DRB1*15 carriers
    9/11
    Refractory (D2T) Still‘s disease
3. Acute MAS flare (with or without LD)
Classification criteria 
• OK with 2016 MAS criteria
• NOT OK with ILAR because severe MAS present often at disease onset
• OK with Yamaguchi or provisional PRINTO
Response criteria
• MAS remission as defined in the emapalumab trial -> no formal validation
• Tapering/withdrawal of background treatment (e.g. GC, biologics)
Design
• Placebo controlled unethical
• No active comparable available (SoC?)
• Background treatment for Still´s disease
• Sample size
• Historical controls
    10/11
    Refractory (D2T) Still‘s disease
3. Acute MAS flare (with or without LD)
Classification criteria 
• OK with 2016 MAS criteria
• NOT OK with ILAR because severe MAS present often at disease onset
• OK with Yamaguchi or provisional PRINTO
Response criteria
• MAS remission as defined in the emapalumab trial -> no formal validation
• Tapering/withdrawal of background treatment (e.g. GC, biologics)
Design
• Placebo controlled unethical
• No active comparable available (SoC?)
• Background treatment for Still´s disease
• Sample size
• Historical controls
    11/11

    NextGen 2024: Unmet Needs & Clinical Trial Challenges Session Part 2

    • 1. Clinical Trials in Still´s disease (sJIA/AOSD) Fabrizio de Benedetti Rheumatology, Children Hospital Bambino Gesu’, Rome - Italy
    • 2. Clinical trials in Still‘s disease Present scenario •IL-1 or IL-6 inhibitors are very efficacious in 70-80% of patients • Early treatment with biologics is more and more standard of care with IL-1 and IL-6 inhibitors being widely available Patient/Parent perspectives (physicians also) •Acceptability of “experimental” drugs vs established approach •Acceptability of randomization (experimental drug vs placebo or experimental drug vs active control)
    • 3. Clinical trials in Still‘s disease Present scenario •IL-1 or IL-6 inhibitors are very efficacious in 70-80% of patients • Early treatment with biologics is more and more standard of care with IL-1 and IL-6 inhibitors being widely available Patient/Parent perspectives (physicians also) •Acceptability of “experimental” drugs vs established approach •Acceptability of randomization (experimental drug vs placebo or experimental drug vs active control) Refractory or D2T Still‘ disease
    • 4. Refractory (D2T) Still‘s disease •Persistent chronic arthritis (with or without active syst features) •Relapsing/smouldering MAS with or without LD •Acute MAS flare (with or without LD) • Difficult if not impossible to lump them in the same trial • Overall they are very rare • Only one trial is doable
    • 5. Refractory (D2T) Still‘s disease 1. persistent chronic arthritis (with or without active systemic features) Classification criteria: OK with ILAR, Yamaguchi, provisional PRINTO Response criteria: • OK with JIA-ACR response + absence of fever, systJADAS (merging adults and children criteria) • Tapering/withdrawal of background treatment (e.g. GC) Eligible for ongoing trials in pcJIA (e.g. Jak inhibitors), only if systemic symptoms are absent • Need new MoA (limited safety data) • 12 and older 🡪 PK modeling for dosing in <12yo • Sample size • Randomization (placebo? Active control?) • Open label • External (historical) controls
    • 6. Refractory (D2T) Still‘s disease 1. persistent chronic arthritis (with or without active systemic features) Classification criteria: OK with ILAR, Yamaguchi, provisional PRINTO Response criteria: • OK with JIA-ACR response + absence of fever, systJADAS (merging adults and children criteria • Tapering/withdrawal of background treatment (e.g. GC) • Eligible for ongoing trials in JIA (e.g. Jak inhibitors), only if systemic symptoms are absent • Need new MoA (limited safety data) • 12 and older 🡪 PK modeling for dosing in <12yo • Sample size • Randomization (placebo? Active control?) • Open label • External (historical) controls
    • 7. Refractory (D2T) Still‘s disease 2. Relapsing/smouldering MAS with or without LD Syst features - little, if any arthritis Lung disease (LD) Relapsing and/or smouldering MAS Classification criteria • NOT OK with ILAR, might be OK with Yamaguchi or provisional PRINTO • Response criteria • NOT OK with JIA-ACR response + absence of fever • MAYBE syst-JADAS (merging adults and children criteria) • Tapering/withdrawal of background treatment (e.g. GC, biologics) • Largely overlapping subset • Mostly IL-18 high • Many reccurrent eosinophilia • Many DRB1*15 carriers
    • 8. Refractory (D2T) Still‘s disease 2. Relapsing/smouldering MAS with or without LD Syst features - little, if any arthritis Lung disease (LD) Relapsing and/or smouldering MAS Classification criteria • NOT OK with ILAR, OK with Yamaguchi or provisional PRINTO • Response criteria • NOT OK with JIA-ACR response + absence of fever • MAYBE syst-JADAS (merging adults and children criteria?) • Need to capture MAS features (MAS remission?) • Need to capture LD course (O2 requirement, O2 overnight saturation) • Tapering/withdrawal of background treatment (e.g. GC, biologics) • Largely overlapping subset • Mostly IL-18 high • Many recurrent eosinophilia • Many DRB1*15 carriers
    • 9. Refractory (D2T) Still‘s disease 2. Relapsing/smouldering MAS with or without LD Syst features - little, if any arthritis Lung disease (LD) Relapsing and/or smouldering MAS • Design • Placebo controlled unethical • No active comparable available (no SoC) • Sample size • Historical controls • Largely overlapping subset • Mostly IL-18 high • Many reccurrent eosinophilia • Many DRB1*15 carriers
    • 10. Refractory (D2T) Still‘s disease 3. Acute MAS flare (with or without LD) Classification criteria • OK with 2016 MAS criteria • NOT OK with ILAR because severe MAS present often at disease onset • OK with Yamaguchi or provisional PRINTO Response criteria • MAS remission as defined in the emapalumab trial -> no formal validation • Tapering/withdrawal of background treatment (e.g. GC, biologics) Design • Placebo controlled unethical • No active comparable available (SoC?) • Background treatment for Still´s disease • Sample size • Historical controls
    • 11. Refractory (D2T) Still‘s disease 3. Acute MAS flare (with or without LD) Classification criteria • OK with 2016 MAS criteria • NOT OK with ILAR because severe MAS present often at disease onset • OK with Yamaguchi or provisional PRINTO Response criteria • MAS remission as defined in the emapalumab trial -> no formal validation • Tapering/withdrawal of background treatment (e.g. GC, biologics) Design • Placebo controlled unethical • No active comparable available (SoC?) • Background treatment for Still´s disease • Sample size • Historical controls


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