NINDS Clinical Trials Methods Course Iowa City July 2019
Transcript of NINDS Clinical Trials Methods Course Iowa City July 2019
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Biomarkers in Clinical Trials
Michael Benatar, MBChB, MS, DPhil
NINDS Clinical Trials Methods Course
Iowa CityJuly 2019
Supported by NINDS R25NS088248 U01NS077352
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Disclosures
• Research Funding– NIH, CDC, DOD, MDA, ALSA, Target ALS
• Industry Trials– ALS: Orphazyme, Biogen–MG: Alexion, UCB Pharma
• Consulting–MG: UCB Pharma– ALS: Denali, MT Pharma, AveXis, Biogen, Prilenia
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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Challenges …(that may be addressed by biomarkers)
• Translation– Selection of drugs from pre‐clinical models
• Etiological and biological heterogeneity– Identifying (subset of) patients most likely to benefit from an experimental therapeutic
• Signal detection– Clinically meaningful change vs. biological effect
• Phenotypic heterogeneity– Distinguishing the therapeutic ‘signal’ from the ‘noise’ of natural variability
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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Biomarkers: Good, Bad & Ugly
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Biomarkers: Good, Bad & Ugly• Plethora of candidate biomarkers
Biological Fluid‐Based Neuroimaging Neurophysiology
Neurofilament heavy DTI MUNE
Neurofilament light MRS MUNIX
Urinary p75NTRECD VBM CMAP
CSF SOD1 fMRI EIM
CSF Poly(GP) TMS
Example:ALS
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Biomarkers: Good, Bad & Ugly• Plethora of candidate biomarkers
Biological Fluid‐Based Neuroimaging Neurophysiology
Neurofilament heavy DTI MUNE
Neurofilament light MRS MUNIX
Urinary p75NTRECD VBM CMAP
CSF SOD1 fMRI EIM
CSF Poly(GP) TMS
• Very few that are useful in clinical trials?
Example:ALS
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Biomarkers: Good, Bad & Ugly• Plethora of candidate biomarkers
Biological Fluid‐Based Neuroimaging Neurophysiology
Neurofilament heavy DTI MUNE
Neurofilament light MRS MUNIX
Urinary p75NTRECD VBM CMAP
CSF SOD1 fMRI EIM
CSF Poly(GP) TMS
• Very few that are useful in clinical trials?
Example:ALS
• Discovery vs. validation• Failure to appreciate nuance of developing biomarkers that are “fit for purpose”
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Biomarkers: Good, Bad & Ugly• Plethora of candidate biomarkers
• Discovery vs. validation• Failure to appreciate nuance of developing biomarkers that are “fit for purpose”
• Surrogacy
Biological Fluid‐Based Neuroimaging Neurophysiology
Neurofilament heavy DTI MUNE
Neurofilament light MRS MUNIX
Urinary p75NTRECD VBM CMAP
CSF SOD1 fMRI EIM
CSF Poly(GP) TMS
• Very few that are useful in clinical trials?
Example:ALS
WHY?
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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DiscoveryDiscovery
• Establish proof of concept
• Clinical samples of convenience
• Begin defining context of use
Biomarker Development Process:Discovery and Validation
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DiscoveryDiscovery Analytic ValidationAnalytic Validation
• Establish assay performance characteristics
• Evaluate impact of potential confounding factors
• Refine context of use
• Establish proof of concept
• Clinical samples of convenience
• Begin defining context of use
Biomarker Development Process:Discovery and Validation
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DiscoveryDiscovery Analytic ValidationAnalytic Validation
Clinical UtilityClinical Utility
• Large, carefully‐defined clinical cohort
• Well‐defined SOPs
• Establish intended clinical use
• Establish assay performance characteristics
• Evaluate impact of potential confounding factors
• Refine context of use
• Establish proof of concept
• Clinical samples of convenience
• Begin defining context of use
Biomarker Development Process:Discovery and Validation
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DiscoveryDiscovery Analytic ValidationAnalytic Validation
Clinical UtilityClinical Utility QualificationQualification
• Demonstrated clinical utility
• Written context of use
• FDA review for qualification
• Large, carefully‐defined clinical cohort
• Well‐defined SOPs
• Establish intended clinical use
• Establish assay performance characteristics
• Evaluate impact of potential confounding factors
• Refine context of use
• Establish proof of concept
• Clinical samples of convenience
• Begin defining context of use
Validation
Biomarker Development Process:Discovery and Validation
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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Diagnostic
Prognostic
Pharmaco‐dynamic
Predictive
Biomarker Context of Use
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Diagnostic
Prognostic
Pharmaco‐dynamic
Predictive
Biomarker Context of Use
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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Biomarker Candidate Possible Context of Use
Serum and CSF NfL Prognostic and pharmacodynamic
Serum and CSF pNfH Prognostic and pharmacodynamic
Urinary p75ECD Prognostic, disease progression and pharmacodynamic
CSF and PBMC poly(GP) Pharmacodynamic
Lead Biological Fluid Biomarkers
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p75ECD NfL pNfH
Matrices Urine Blood, CSF Blood, CSF
Platform Sandwich ELISA Simoa (Uman Abs) Simoa
Analytic sensitivity 70pg/ml 0.0174 pg/ml 0.663 pg/ml
Dynamic range 70pg/ml – 2.5ng/ml 0‐2,000 pg/ml 0‐8,400 pg/ml
Confounds• Renal failure• Diabetes• Neuropathy
• Other causes of axonal injury
• Other causes of axonal injury
• ? Immune response
Normal range ≤ 2.6ng/mg creatinine (±0.96)
Blood: ≤ 6.6 pg/mlCSF: ≤ 2,467 pg/ml
Blood: ≤ 29 pg/mlCSF: ≤ 24,406 pg/ml
Assay reliabilityIntra‐assay COVInter‐assay COV
~7%~13%
~7%~5%
~5%~10%
OtherStable at RT, 4°C andfreeze‐thaw cyclesNo diurnal ∆
Stable at RT, 4°C, ‐80°C, and freeze‐thaw cycles
Stable at RT, 4°C, ‐80°C, and freeze‐thaw cycles
Assay Performance / Analytics
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Baseline Characteristics ALS/FTD(N=225)
PMA(N=11)
PLS(N=10)
Age (years) Mean ± SD 60 ± 11.8 56.8 ± 11.6 58.8 ± 11.1Male N (%) 130 (58%) 8 (73%) 9 (45%)
Genotype C9orf72 27 (12%) 0 0
Years Since Onset Median (IQR) 1.8 (1.0‐3.2) 2.4 (1.7‐9.0) 7.9 (3.8‐11.6)
Years Since Dx Median (IQR) 0.7 (0.3‐1.6) 1.0 (0.6‐4.3) 2.5 (1.5‐5.5)ALSFRS‐R Mean ± SD 34.6 ± 7.5 33.5 ± 8.5 35.2 ± 8.1∆FRS Mean ± SD 0.62 ± 0.65 0.34 ± 0.36 0.17 ± 0.12ALSFRS‐R Slope Mean ± SD ‐0.65 ±0.65 ‐0.57 ±0.34 ‐0.09 ±0.46# of collections Median (range) 3 (2‐5) 3 (2‐5) 3 (2‐5)F/U duration (yrs) Median (range) 0.8 (0.3‐1.9) 0.6 (0.5‐1.5) 1.0 (0.8‐2.0)
Longitudinal subset: ALS (n=106), PMA (n‐3), PLS (n=4)
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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‐0.8 ‐0.6 ‐0.4 ‐0.2 0 0.2 0.4 0.6
Baseline age
Male vs. Female
C9orf72 = 1 vs. 0
Weak Bulbar = 1 vs. 0
Weak Limb = 1 vs. 0
Weak DeltaFRS
Baseline log(NfL)
Baseline log(pNfH)
p = 0.67
p = 0.49
p = 0.40
p = 0.95
p = 0.92
p = 0.004*
p = 0.001*
p = 0.11
Change in ALSFRS‐R slope
ALSFRS
‐R
Time
Low biomarker
High biomarker
Prognostic Utility of Serum Neurofilament
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C9orf72
Baseline NfL
∆FRS
Baseline pNfH
Survival
Time
Low biomarker
High biomarker
Prognostic Utility of Serum Neurofilament
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C9orf72
Baseline NfL
∆FRS
Baseline pNfH
Survival
Time
Low biomarker
High biomarker
Prognostic Utility of Serum Neurofilament
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0 0.5 1 1.5 2 2.5 3 3.5 4
Baseline age
Male vs. Female
C9orf72 = 1 vs. 0
Weak Bulbar = 1 vs. 0
Weak Limb = 1 vs. 0
Weak DeltaFRS
Baseline FRS
Baseline log(NfL)
Baseline log(pNfH)
Hazard Ratios
p = 0.049*
p = 0.213
p = 0.098
p = 0.913
p = 0.019*
p = 0.022*
p = 0.0005*
p = 0.881
p = 0.795
Survival
Time
Low biomarker
High biomarker
Prognostic Utility of Serum Neurofilament
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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0‐0.1
0.10.2
0‐0.1
0.10.2
Potential Pharmacodynamic Utility of Neurofilaments
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Potential Pharmacodynamic Utility of Neurofilaments
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Outline• Challenges that biomarkers may address• Biomarkers
– Introduction– Discovery and validation– Context of use
• Leading ALS biofluid biomarker candidates– Prognostic utility– Potential pharmacodynamic utility– Relevance to disease prevention
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The Pre‐fALS Study• Pre‐Symptomatic Familial ALS; initiated in 2007• Longitudinal natural history and biomarker study of people at genetic risk for ALS
• Includes carriers of any ALS‐causing gene mutation, the only population known to be at risk for ALS– SOD1, C9orf72, TARDBP, FUS, VCP, etc.– Option to learn result of genetic testing or not
• Goals– Identify biomarker of pre‐symptomatic disease and/or predictors of symptomatic disease
– Prepare for a disease prevention trial
Benatar and Wuu. Neurology 2012, 79:1732‐1739
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Serum NfL: LongitudinalControls At‐risk
ALSConverter
Benatar, Wuu, et al. Ann Neurol (2018)
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Converter: Longitudinal Serum NfL
max value in controls
Benatar, Wuu, et al. Ann Neurol (2018)
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Conclusions
• Biomarkers have great potential to aid therapeutic development
• Critically important to:– Follow discovery with validation (analytic & clinical)– Develop with a view to a specific ‘context of use’
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Discussion & Questions