Disease Specific Areas in Biomarker Names Context of Use Why Is The Biomarker Useful in area/Organ Critical Need for Drug Development? toxicity Biomarker Development Alzheimer's Disease N/A i) Selecting patients at risk for Monitoring patients receiving (AD) AD AD treatments to shorten ii) Monitoring patients clinical trial treatment period. receiving AD treatments Alzheimer's Disease Imaging biomarkers (PET More accurate diagnosis, Brain imaging such as PET and (AD) and other and MRI) stratification of patients and MRI can assess changes in brain Dementia surrogate endpoint. activity and structure comparing specific areas relevant to dementia.

Alzheimer's Disease Cerebrospinal fluid (CSF) Prognostic or Efficacy N/A (AD) levels of neurogranin peptide; Molecular Neuroimaging of Tau Neurodegenerative protein. Diseases Development of drug- Measurement of i) As a pharmacodynamic i) To make clinical assessment target biomarker and Huntington biomarkers in biomarker in early clinical of a drug by demonstrating the therapies for CSF trials to demonstrate target presence of agent in target Huntington disease engagement and proof of organ and the real likelihood of principle (immediate goal). a clinical effect. ii) Additionally it could be ii) Biomarkers are helpful to used to guide dose-escalation. ascertain biological activity.

Alzheimer's Disease Neuro-imaging and blood i) Screening patients for N/A (AD), Parkinson's tests for neural insulin prodromal Alzheimer's Disease (PD) resistance and p-tau. disease. ii) Using biomarkers as a benchmark for efficacy during clinical trials. Duchenne muscular Global function i) For the upper extremity 3D Development of a scalable and dystrophy (DMD), biomarkers reachable workspace outcome sustainable remote Becker muscular measure, a global function measurement platform for dystrophy (BMD), marker in patients with upper upper extremity function will Facioscapulohumeral extremity mobility limitation. facilitate translational science muscular dystrophy ii) For use in efficacy testing of and promises to be a novel tool (FSHD), and therapeutics targeting to for conducting clinical trials by Amyotrophic Lateral improve upper extremity reducing cost and participant Sclerosis (ALS) function. burden while improving efficiency through automation. Duchenne Muscular Dystrophin as a Dose selection, proof of There is an urgent unmet need Dystrophy (DMD) biomarker, qualifying concept, utilization in study to develop new treatments for skeletal MRI as a (e.g. patient enrichment, DMD as there are currently no biomarker and qualifying patient stratification), PK/PD, FDA approved therapies for the assessment of upper disease progression (e.g. DMD and no way to reverse the extremity function based prognostic endpoint), underlying condition. on the concept of 3- treatment response (e.g. dimensional reachable predictive endpoint, workspace. composite endpoint, etc.) and Neuromuscular as surrogate endpoint. Disease Myotonic dystrophy i) Biomarkers for cardiac Biomarkers for patient This RNA biomarker could be (DM) and central nervous selection and surrogate analyzed in any target tissue system. endpoints. and it has a direct link to the ii) Predictive genetic disease process, so it is likely to biomarkers. CELF1 protein be useful for determining target (upregulated in DM1 engagement of drugs that affect tissues, particularly in the root causes of the disease, as heart). well as predicting drug effect.

i) Frataxin protein, mRNA i) Proof of principle in Selection of cohorts of patients or miRNA biomarkers. preclinical models and in that are likely to progress in a ii) Structural and early stage trials. similar manner in the short functional imaging of ii) Demonstration of target term so that that cohort can be Friedreich’s Ataxia muscle, heart and central engagement. studied in a clinical trial. (FA) nervous system. iii) Demonstration of effective iii) Secondary dose. symptomatic iv) Potentially accelerated measurements (e.g. vision, approval. gait, speech in FA). iv) Markers which predict cardiac risk, in the central nervous system that can be used to signal response to treatment or target engagement and for patient selection.

Tau, Neurofilament i) Using Some custom Both neurological and proteins, alpha-synuclein, biomarker panels (Imaging , neuropsychiatric disorders calbindin, Neuron-Specific Efficacy, Predictive, suffer from a lack of disease- Enolase, S100b, PSD95, Diagnostic) as a link to relevant markers that could be drebrin. imaging results and to longer used to assess early signals of term clinical assessments of efficacy in a clinical setting. Alzheimer's disease, disease activity/progression. Other than imaging modalities Mood Disorders, ii) By serving as early signals like MRS, DTI, PET and MRI, Epilepsy, Huntington's of efficacy for more rapidly there is a definite need to better disease, Alcohol evaluating the impact of monitor drug-mediated effects Dependence, potential disease-modifying on neurodegeneration, Schizophrenia and therapies. neuroinflammation and Neurological and Parkinson's disease cognition including markers for Neuropsychiatric synaptic plasticity and Diseases neurogenesis. Neuro-immunology For patient stratification in markers clinical trials. Tau imaging markers AD diagnosis and staging; progression monitoring, PD measurement. Genetic & epigenetic Diagnosis, stratification and Disease risk biomarker signatures (AD outcome measures. and Mood disorders) Screening biomarkers for Patient enrichment for clinical AD, Mood disorders (blood trials. tests, neurofunctional and behavioral measurements) Novel strategies to N/A approach outcome measures (different than patient reported outcomes) Biomarkers of functional Objective measures for motor outcome measures dysfunction. Imaging measures (PET, For stratification purposes in tMRJ) and physiological CNS disorders in general. (EEG) Translocator Protein Patient Selection Neuroinflammatory biomarkers (TSPO) PET ligand such as the TSPO PET Ligand should thus be considered in the context of experimental medicine to potentially enrich clinical study designs and improve the testing of clinical hypotheses. Utilizing composite Identification of target The field acknowledges that biomarker population based on disease given the heterogeneity and biology and/or drug target for complexity of CNS disorders, a predicting drug efficacy single biomarker (e.g.. Gene, /response. SNP, micro RNA, protein or metabolite) will be unlikely to identify a subpopulation and/ or explain predictive efficacy of a drug. Phosphodiesterase(PDE)- Diagnostic, Dose selection. The PDE10A PET ligand will 10A PET ligand serve multiple purposes. Firstly it will confirm that a given drug enters the CNS, reaches and binds to the PDE10A enzyme. Furthermore, the PET ligand will enable the establishment of plasma exposure of a drug to target occupancy. This will be critical in determining the therapeutic dose range.

Alzheimer’s Disease N/A N/A biomarker to identify subjects "at risk”, which would help in Treatment Response. patient stratification. Multiple Sclerosis N/A N/A

i) Cardio-vascular i) Patient stratification i) Proof of concept (POC) using N/A system, liver, kidney biomarkers pharmacodynamic for safety(toxicity) ii) Drug efficacy and safety biomarkers biomarkers. biomarkers ii) Patient stratification in ii) Efficacy biomarkers enrollment using drug efficacy based on genomics are (also subset of largely studied in pharmacodynamic and safety oncology. biomarkers) Oncology iii) Monitoring clinical safety using safety biomarkers. Cancer - all types, N/A N/A They will improve the efficiency importantly NSCLC of clinical decision making and (Non-small-cell lung potentially reduce overall carcinoma). health system cost, while improving outcomes if patients are directed to more effective treatments. Pancreatic cancer CCK-B receptor SNP; Screening for pancreatic This biomarker is the only SNP rs1800843. The resulting cancer risk in patients with found at a very high frequency splice isoform is termed as family history or chronic (35-40%) in pancreatic cancer. CCK-C receptor. pancreatitis. In addition, further development of this biomarker may lead to the ability to select targeted therapies that regulate the pathways constitutively activated by CCK-C. Pancreatic cancer HER2-amplified cancers, i) As a predictive biomarker to The use of biomarkers can aid in BrCa2; Mutant pancreatic determine if a targeted- understanding the prediction, cancer; A change in the treatment is efficacious cause, diagnosis, progression, levels of the CA-19-9 enough for accelerated regression, or outcome of serum protein biomarker; approval in pancreatic cancer treatment of disease. Enumeration of circulating patients whose tumor tumor cells; Levels of contains that biomarker. circulating tumor DNA. ii) A blood-based biomarker representing a surrogate endpoint for survival in pancreatic cancer clinical trials for accelerated approval of a therapeutic. N/A i) Archived and fresh i) Tumor staging immune- Acceptance of a biomarker can tumor biopsy assessment score classification surrogate be expedited with the for classical tumor endpoint to predict treatment generation of high quality morphology outcome. clinical data. Surrogate ii) Blood or plasma ii) Immuno-oncology endpoint measurements for the monitoring. contextual assessment assessment of therapeutic iii) Non-invasive surrogate immune scoring: Tumor efficacy can potentially offer biomarkers infiltrating T-cell (CD3+CD8+ greater flexibility for drug iv) Tumor infiltrating T- cytotoxic T cells and CD45RO+ approval mechanisms and cell (CD3+CD8+ cytotoxic T memory T cells) patient access to promising cells and CD45RO+ quantification. therapies. memory T cells) quantification N/A Circulating tumor cells i) Patient-selection Recent progress in analyzing (CTCs) and cell-free DNA biomarkers that help guide circulating tumor cells (CTCs) (cfDNA) the use of immuno-oncology and cell-free DNA (cfDNA) drugs. indicate these blood-based ii) Use of MRD data as methods may significantly help surrogate biomarkers in some to inform decision making in cancers to accelerate drug oncology, particularly in the development. solid tumor setting where access to tumor-derived material has traditionally been very difficult. They will also help speed the application of these promising drugs across all cancers and facilitate the testing of rational combinations of immuno-oncology drugs together and with other active therapies. N/A Imaging biomarkers for Utilization of FDG-PET as an FDG-PET treatment related chemotherapy response in endpoint and drug response differences across trial cancer (FDG-PET/CT) development tool. is likely to predict the magnitude of the treatment effects seen in primary clinical outcome measures. Solid Tumors. i) Minimal Residual i) A surrogate marker such as RECIST criteria have been useful Disease (MRD) as Minimal Residual Disease but are outdated. Therefore, surrogate endpoint could shorten the timelines there is an immediate need for ii) Predictive biomarker for clinical trials. sensitive markers for rapid ii) The ability to follow the effect of therapies on tumors disease course and modify that are not related to 2D therapies to improve outcome variable measures. based on predictors of early response to treatment, early detection of relapse/disease progression and identifying mechanisms of resistance. NSCLC (Non-small-cell N/A N/A N/A lung carcinoma) N/A Cell-Free DNA N/A N/A

N/A Pharmacokinetic/ N/A N/A Pharmacodynamic biomarkers N/A N/A N/A i) Biomarkers could be used to determine better dosing without having to go to MTD. ii) Biomarkers could be used to better understand the kinetics/ effectiveness of a drug. Systemic Lupus SLE markers of disease i) To improve the efficacy and Need for biomarkers that Erythematosus (SLE) activity and prediction of decrease the adverse effects of forecast Lupus Nephritis flare flare: C4d, C1q, CD27, IFN- immunosuppression. well before thresholds of a, other complement and ii) Predict clinical proteinuria, decreased renal IFN associated proteins , manifestation, disease function and urine sediment. SNP and autoantibody progression rates and Such a predictive biomarker (ANA, dsDNA, NMDA) pathogenic mechanisms of could be followed serially and panels Lupus and Lupus nephritis based on levels; treatment could Lupus Nephritis Biomarkers predictive of and adjust therapy be initiated before development renal flare, development of appropriately. of significant inflammatory in chronic kidney disease or jnury in the kidney. Autoimmune and reflect kidney histology at Inflammatory the time of flare: MCP-1, Diseases NGAL, Transferrin, FOXP3, CXCL10, MEPCR Rheumatoid Arthritis Biomarkers for vascular i) Stratification od RA patients The lack of an RA specific CV (RA) inflammation and CV risk with elevated risk of CV co- risk toll hampers evidence in RA patients. FDG- morbities in standard of care. based guidelines and creates PET/CT as a novel imaging ii) Addition of an anti- uncertainty for patients and biomarker to detect inflammatory biologic. providers in managing RA and baseline and DMARD- its comorbidities. associated changes in vascular inflammation of RA patients Rheumatoid Arthritis Highly sensitive MRI RAMRIS s a surrogate to be Because of the higher sensitivity (RA) imaging of joints using the used in place of bone erosion and more detailed and RA-MRI scoring system and joint space narrowing in quantitative nature of MRI (RAMRIS) registration clinical imaging compared to clinical interventional trials in examination and basic X-ray rheumatoid arthritis patients. films, RA clinical trials of shorter duration can be conducted using lower numbers of patients to assess the efficacy of experimental compounds. Crohn’s disease, Anti-TNF, antibodies to Diagnostic, Predictive, A subset of patients does not Ulcerative colitis (UC) anti-TNF and circulating Imaging, Efficacy respond to anti-TNF-a therapies anti-TNF from the onset of treatment or develop resistance to treatment over time. Biomarkers that can predict which patients will be resistant to anti-TNF treatment would assist in the development of novel therapies for this subpopulation. Ankylosing Cox 1, RANKL; BMP-2, OPG, Prediction of AS patients with Little to no biomarkers for AS Spondylitis (AS) PINP, Sclerostin, DKK1 chronic low back pain at risk for disease diagnosis, for radiographic progression activity/severity or therapeutic to AS or increased progression response. with AS. Acute Immunotoxicity N/A N/A The major benefit would come if a biomarker specific for inflammation could be found, better than C-Reactive Protein (CRP) and if it could indicate tissue of origin. Imaging Biomarkers Fluorodeoxyglucose (FDG), [F-18]FDG-PET/CT detection [F-18]FDG-PET/CT can be used labeled with a positron of inflammation-associated to detect lung parenchymal emitting fluorine-18 [F- metabolic activity involvement at any chest X-ray 18]FDG ( [F-18]FDG- stage, including therapy- PET/CT) resistant disease, and also provides information on extra- pulmonary disease.

Liver pathology: Non- Movel MRI imaging device i) To measure the efficacy of With the increasing prevalence Alcoholic that measures fibrosis/ new treatments for liver of liver disease worldwide, Steatohepatitis inflammation in disease. there is an urgent clinical need (NASH), Non- milliseconds and measures ii) For drug development in for reliable methods to diagnose Alcoholic Fatty Liver iron levels (in mg/g) and clincial trials. and stage liver pathology. Liver Disease (NAFLD), fat fraction (in %) iii) As a tool to aid clinicians in biopsy, the current gold Primary Biliary the assessment of patients standard, has severe limitations, Cirrhosis (PBC), with suspected liver disease to i.e. invasiveness, complications Primary Sclerosing diagnose and to detect (including death in 1:1000), Cholangitis (PSC), changes over time. discomfort, and substantial Viral Hepatitis B sampling-dependent and (VHB) and C (VHC), observer-dependent variability. Hepatocellular Carcinoma (HCC), Alcoholic Liver Hepatic Diseases Disease (ALD) and Autoimmune hepatitis

Fibrosis (Liver): NASH, ALT, AST, AP for PSC; N/A N/A PSC, PBC TIMP-1, Osteopontin, Collagen-1, Collagen fragments, MMPs, CK-18, CCL-2, FaL, NAFIC score, fibrosure, ELF test N/A Plasma/serum miR-122, N/A N/A glutamate dehydrogenase (GLDH), arginase (ARG-1), sorbitol dehydrogenase (SDH) and glutathione S- transferase (GST-α) Non Alcoholic Fatty Liver cT1 and cT2 Biomarkers to determine Non It is a magnetic resonance Liver Disease (NAFLD) Alcoholic Fatty Liver (NAFL) imaging procedure; therefore

Activity Score (NAS) without non-invasive. performing histology. Anti-fibrotic activity Hepatic Venous Pressure Hepatic Venous Pressure Hepatic Venous Pressure Gradient (HVPG). Gradient (HVPG) as a Gradient (HVPG) should be surrogate to measure anti- qualified by FDA for use as a fibrotic activity. surrogate replacing liver transplant and death for measuring anti-fibrotic activity in patients with compensated cirrhosis in registration interventional clinical trials. Safety biomarkers for miRNA-122 i) Demonstration of organ A new biomarker that could Acute Hepatotoxicity toxicity. discriminate between drug- (Non-clinical and ii) Safety in dose escalation. induced liver injury at risk of Clinical) iii) drug-induced liver injury, progressing and drug-related two context of use have been adaptive processes. proposed by the IMI SAFE-T consortium. Safety biomarkers for miRNA-123, Fibrosis Demonstration of organ Biomarkers predicting chronic Chronic marker and CK-18 toxicity without hepatotoxicity would translate Hepatotoxicity (Non- histopathology. to tremendous cost savings and

clinical and Clinical) lower risk for drug development but may benefit fewer programs than acute markers. Urinary CTX-II and Urinary i) Identification of the right N/A alpha-CTX-I), Serum C1M, patient phenotype. C3M and CRPM ii) Early detection of efficacy. iii) Early decision making, prediction of responders. Musculoskeletal Osteoarthritis (OA) Using MRI for direct Assessment of osteoarthritic MRI can allow for a sensitive Diseases visualization of joint knee joint structures by MRI. and reliable joint marker, structures including the superior to that of radiography, cartilage, subchondral of global joint structural bone, menisci, synovial changes along the cross-section fluid and other tissues. and longitudinally. Biomarkers that can Burden of Disease, Enrichment of trials for enrich OA trials for investigational, prognostic, progressors can increase trial progressors and efficacy of intervention, power and decrease trial costs biomarkers that could diagnostic and safety due to requirement for lower serve as more sensitive biomarkers. subject number and shorter efficacy of intervention trial duration required to show markers than the current a treatment effect. joint space loss of plain radiographs. Assessment of DMOAD RCTs in knee, hip, and Magnetic resonance imaging osteoarthritis joint hand osteoarthritis (MRI) to assess osteoarthritis structural changes by MRI joint structural changes and with the change in response to treatment of cartilage volume used as a disease-modifying primary outcome. osteoarthritis drugs (DMOADs) in randomized controlled trials (RCTs). Quantitative MRI cartilage To establish the predictive Assist in planning and design of morphometry, cartilage validity and responsiveness of clinical trials focused on defects and bone marrow disease progression facilitating scientific discovery lesions; semi-quantitative biomarkers and assess the and establishing efficacy of analysis of bone shape and responsiveness of several future disease-modifying attrition and subchondral imaging and biochemical regimens for knee OA. bone area; Bone trabecular markers pertinent to knee OA. integrity by facial signature analysis. Serum and urine measures of bone and cartilage: Serum HA, PIIAMP, CTX-1, C2C, CI,2C, NTX-1, COMP, Urine CTX-1 & II, C2C, Coi21N02 Osteoporosis i) Bone quality biomarkers To be used for osteoporesis These biomarkers may provide ii) Imaging biomarkers patient management and as a precise estimates of the (with sufficient resolution substitute for failure relationship between to capture microstructure) endpoints in randomized treatment-related changes in clinical trials. imaging and fracture outcomes. Cystic Fibrosis i) Sweat chloride and i) Qualification of CF The CF research community chloride conductance to biomarkers as surrogate faces a serious challenge in determine CFTR activity endpoints. designing and executing trials of ii) Serum, plasma and ii) Identification of drugs for CF patients with sputum, which might biomarkers for use in especially rare mutations even determine degree of targeting approved disease- though these agents are likely to inflammation modifying drugs to patients be efficacious. iii) Nasal and intestinal with rare mutations in whom epithelial cell these drugs are not yet indicated. Fibrosis High resolution CT To provide quantitative N/A (HRCT)-based biomarkers assessment of therapeutic interventions based on structural changes in lung geometry as well as on functional changes in regional Pulmonary airway volumes and airway Diseases resistance. Chronic Obstructive Biomarkers of recovered Genomic and proteomic No biomarker exists for Pulmonary Disease lung function or decline biosignature(s) that predict pathogenesis of COPD that (COPD) and prediction of risk for accelerated lung function associated with a clinically COPD or flare decline in COPD patients and important outcome or are (exacerbation) provide a surrogate marker of known to be modified by an FEV1. effective intervention to change the target outcome. Chronic Obstructive N/A A prognostic biomarker that N/A Pulmonary Disease predicts disease progression (COPD) and exacerbation frequency that is responding to treatment options would decrease tremendously development timelines, and development costs. Nephrotoxicity Urinary osteopontin N/A N/A (OPN), Clusterin (CLU), Renal Diseases Cystatin C (CysC), Kidney injury molecule-1 (KIM-1), N-Acetyl-beta-D- glucosaminidase (NAG), Neutrophil gelatinase- associated lipocalin (NGAL), Total protein and Albumin Autosomal Dominant N/A Total Kidney Volume as an N/A Polycystic Kidney efficacy biomarker for ADPKD Disease (ADPKD) Acute Nephrotoxicity NGAL, Kim-1 Acute Kidney Injury (AKI) To demonstrate the Lowest (Non-clinical and biomarkers at early stage and observed adverse effect level Clinical) reversible stages of injury. (LOAEL) and organ toxicity. New Chronic GFR, Kim-1 Novel biomarkers to detect candidate biomarkers with Nephrotoxicity (Non- GFR (other than creatinine renal safety signals in animal clinical and Clinical) clearance). toxicology studies that cannot be monitored using conventional biomarkers will be immensely important. Therapies in acute Natriuretic peptides (e.g. Phase II studies should i) Applications for heart failure. and chronic heart NT‐proBNP, b‐type include biomarkers as ii) Applications for Acute failure with reduced natriuretic peptide [BNP]), primary endpoints to aid in Coronary Syndrome. or preserved ejection ST2, and Cystatin C assessing the efficacy and dose iii) As an outcome measure in fraction. selection of potential heart clinical trials of therapeutic failure therapies. efficacy. iv) Drug-induced cardiotoxicity. Heart Failure i) Imaging biomarkers Cardiac MRI ima ges as Using cardiac MRI, ii) A blood/urine based biomarkers to provide multi- measurement of edema volume panel of biomarkers parametric quantitative (using T2 mapping), fibrosis Cardiovascular representing cardiac regional and global metrics of (utilizing late gadolinium Diseases functionality, cardiac cardiac tissue abnormalities. enhancing volume for focal damage, fibrosis in various lesions and extracellular organ systems, renal volume form T1 mapping pre function and fluid and post–contrast), tissue phase overload. mapping and wall motion would be possible. Safety Biomarkers for i) Cardiac Troponin-I i) Demonstration of organ Acute clinical cardiotoxicity Acute Cardiotoxicity (cTnI) toxicity without biomarkers are immensely (Non-clinical and ii) Fatty-acid-binding histopathology important to developing new Clinical) proteins (FABP) ii) Demonstration of organ drugs in the clinical safety iii) QT interval toxicity arena. iii) No observable adverse effect level (NOAEL) Safety Biomarkers for i) N-terminal fragment of iv) Biomarker relating to i) Biomarkers distinguishing Chronic Cardiotoxicity proatrial natriuretic major adverse cardiac events reversible from irreversible (Non-clinical and peptide (NT-proANP) and (MACE) endpoints “injury” with strong Clinical) brain natriuretic peptide pathophysiologic evidence and (BNP) clinical event correlates. ii) hs-Troponin I ii) Biomarkers that qualitatively iii) Ejection fraction and quantitatively, can predict and accurately identify and confirm when a change in an acute clinical cardio toxicity biomarker will result in chronic clinical cardiotoxicity. Amyloid Light-chain N-terminal pro b-type Endpoint for accelerated i) Great predictor of survival in (AL) amyloidosis natriuretic peptide(NT- approval pathway in AL AL amyloidosis. proBNP), proteinuria amyloidosis. ii) Great predictor of delaying or stopping patients from progressing to dialysis. Protein NT-proBNP As a surrogate endpoint for The biomarker has an Misfolding accelerated approval in AL extremely strong correlation Diseases amyloidosis with cardiac with survival in many studies. involvement. As a surrogate endpoint, it could reduce time to develop new treatments through clinical development. Protein amyloid Non-native Transthyretin i) Identification of patients The change in NNTTR levels is diseases, specifically, (NNTTR) who can benefit from the TTR quantitative and can be transthyretin amyloid disease modifying measured within a few months amyloidosis with drugs. after drug treatment. Qualifying polyneuropathy ii) Efficacy biomarker which it as a surrogate biomarker has and/or provides mechanistic link the potential to significantly cardiomyopathy bridging the currently used shorten the required time of a phenotypes. pharmacodynamics clinical trial, drastically biomarker. reducing the cost of drug iii) In dose-setting studies to development, expediting drug optimize efficacious dose. availability to patients. iv) A surrogate biomarker reasonably likely to predict clinical outcome. ATTR (Transthyretin) i) NT-proBNP In the context of a pivotal Biomarkers should be used for amyloidosis and AL ii) Urinary albumin study for approval, the use of a diagnosis and staging, as well as amyloidosis; including iii) Modified Neuropathy validated biomarker as a for assessing the response to disease-related Impairment Score +7 and surrogate endpoint for therapy. There remains a dysfunction of the Norfolk Quality of Life- accelerated approval (for significant need to utilize heart, kidneys and Diabetic Neuropathy in cardiac and renal expedient surrogate endpoints liver. patients with ATTR-FAP involvement). based on biomarkers in order to provide therapeutics to patients, within a reasonable timeframe, in rare fatal diseases. Diabetes (Type 1) i) islet autoantibodies i) To distinguish between type The lifetime risk of developing ii) Diagnostic biomarkers 1 and type 2 diabetes. symptomatic type 1 diabetes iii) Prognostic biomarkers ii) To stratify patients based approaches 100% once two or iv) Predictive biomarkers on risk for devel oping more islet autoantibodies are v) Pharmacodynamic symptomatic type 1 diabetes detected in genetically at-risk biomarkers and/or rate of progression of children. The detection of two Metabolic the disease. or more islet autoantibodies Diseases iii) For identifying subgroups increases the rate of of patients likely to respond to progression to symptomatic a therapy. type 1 diabetes. The number of iv) For more efficient clinical detectable islet autoantibodies trials and identification of correlates with risk. efficacious therapies. Diabetes Beta cell function Benefit for tracking drug effect N/A measures on disease progression. Diabetic Nephropathy Monocyte Chemoattractant MCP-1 measurement in the KIM-1 is a sensitive and specific (DN) Protein-1 (MCP-1), Urine urine could be a promising biomarker for proximal tubular albumin-to-creatinine biomarker to establish the injury which could be helpful to ratio (UACR), KIM-1 effect of a compound on predict the outcome of clinical kidney inflammation. The trials with respect to regression later is also associated with a or progression of the disease. higher risk for end stage renal disease (ESRD) and chronic kidney disease (CKD3) stage. Vaccines against N/A Testing the efficacy of PCV N/A Pneumococcal disease vaccines against invasive pneumococcal disease (IPD) Acute Bacterial Skin N/A Development of Patient N/A and Skin Structure Reported Outcomes Infections (ABSSSI), Instruments to assess how a Community-Acquired patient feels, functions and Infectious Disease Bacterial Pneumonia survives for ABSSSI, CABP, (CABP), Hospital- HABP and VABP. Acquired Bacterial Pneumonia (HABP) and Ventilator Associated Bacterial Pneumonia (VABP). Safety biomarkers for Acute pancreatic toxicity is i) Demonstration of absence of N/A Acute Pancreatic not commonly toxicity. Toxicity (Non-clinical encountered in drug ii) Demonstration of organ and Clinical) development and to date, toxicity without no specific biomarker has histopathology. The benefit of been identified that could new qualified biomarkers of Pancreatic be considered for pancreatic toxicity should Diseases qualification. demonstrate correlations with the gold standard and are therefore appropriate to monitor for the effect with the ultimate goal of using them to demonstrate the lack of effect in humans. Safety biomarkers for N/A N/A N/A Chronic Pancreatic Toxicity (Non-clinical and Clinical) N/A i) Glial fibrillary acidic i) Use of TBI protein There is a critical need for protein (GFAP) and its biomarker as a patient simple, bio fluid-based breakdown products), stratification tool to select for biomarkers capable of ii) Ubiquitin C-terminal TBI patients who are most measuring injury severity and hydrolase- L1 likely to respond to a specific injury mechanism and selecting iii) Tau (p-tau), S100b therapeutic treatment in a patients for trials of targeted iv) aII- Spectrin clinical trial setting. therapeutic drug development. Breakdown Products ii) Use of TBI protein (SBDP 150, SBDP 145, biomarker as a response- Traumatic Brain SBDP120, SNTF) indicator biomarker. Injury (TBI) v) Myelin Basic Protein iii) Use of a TBI protein (MBP). biomarker to track efficacy of vi) Neoron Specific Enolase TBI therapies. (NSE) viii) Neurofilament protein-light chain (NF-L), neurofilament protein heavy chain (NF-H) (including phospho- neurofikament H) Pathoanatomic lesions on Use of pathoanatomic lesions Brain MRI is a non-invasive brain magnetic resonance on brain MRI as a diagnostic technology widely available and imaging (MRI). tool to evaluate patients with has great sensitivity. Therefore, mTBI and to measures clinical as a new biomarker, it can be outcome in patients with quickly operationalized into mTBI. practice for drug development trials. Rare diseases N/A N/A N/A Immuno-oncology, N/A N/A Increased drug safety Pain medications, application- certain genotypes Neuroscience/Psychia may need to avoid specific tric medications, medicines/alter doses. Also Nutrigenomics there may be increased efficacy /Nutritional medicine. for certain drugs in specific populations based on biomarkers, certain drugs could be marketed to precise populations. Drug use and BRAF (v-Raf murine N/A N/A biomarker interaction sarcoma viral oncogene effect on current drug homolog B) Miscellaneous efficacy and effectiveness. Oncology, Non- N/A N/A i) Early detection of patient alcoholic safety risks Steatohepatitis ii) Identification of patients at (NASH) and high risk of disease progression progression to iii) Replacement of invasive cirrhosis and assessments with non-invasive hepatocellular methods carcinoma, Chronic Kidney Disease (CKD), Toxicity (pulmonary, cognitive, auditive, renal, hepatic, gastro- intestinal, cardiac toxicity). Fall Detection N/A Fall reduction as a FDA- N/A qualified surrogate for the traditional six minute walk.

N/A : not available