Translational Science in Drug Development: Surrogate Endpoints, Biomarkers, and More Use Case Videos

Presentation Title: Development of Response Biomarkers in Rare Disease Datasets: Application to Organic Acidemias

Session 2: Identification and Development of Novel Surrogate Endpoints for Use in Clinical Development Programs

Speakers: Oleg Shchelochkov, MD and Charles Venditti, MD, PhD

Summary:

Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare genetic metabolic disorders which lead to multisystemic organ failure.  Researchers at NIH used mouse models and transplant data from natural history studies to investigate the applicability of conventional diagnostic biomarkers. Natural history studies shed light on limitations of conventional biomarkers of methylmalonic acid, propionylcarnitine, and 2-methyl citrate. However, 1-13C propionate oxidation demonstrated promise as candidate response biomarker in in vivo conditions. Additionally, researchers found that machine learning approaches can be helpful in determining candidate biomarkers.

Key Takeaways:

• Combination of natural history data with animal studies revealed candidate biomarker shortcomings
• A strong understanding of the underlying biology of these rare conditions helped identify new candidate biomarkers that have showed encouraging and significant clinical results
• An analytical framework was created for assessing candidate biomarkers and combined with machine learning to prioritize the most promising candidates to study further

Presentation Title: Quantitative Susceptibility Mapping on Magnetic Resonance Imaging (QSM MRI) as a Biomarker of Rebleeding in Cavernous Angiomas with Symptomatic Hemorrhage (CASH)

Session 2: Identification and Development of Novel Surrogate Endpoints for Use in Clinical Development Programs

Speaker: Issam A. Awad, MD, MSc

Summary:

Cavernous angiomas (CA) or cerebral cavernous malformations (CCM) are clusters of dilated capillaries which are prone to hemorrhage that can either be symptomatic or asymptomatic. Cavernous angioma with symptomatic hemorrhage (CASH) is a rare disease and associated with higher likelihood of rebleed and significant co-morbidities. Researchers studied quantitative susceptibility mapping on magnetic resonance imaging (QSM MRI) as a biomarker for rebleeding over one year by measuring iron content of lesions. Researchers compared imaging results to ex vivo lesions and found that iron content matched that of imaging results in humans and in mouse models. Researchers also used QSM to measure the effect of atorvastatin on CASH in a proof-of-concept trial. Qualification of this imaging biomarker is in process.

Key Takeaways:

• Because not all hemorrhages are symptomatic, the identification of a stable biomarker to identify asymptomatic hemorrhage was needed
• Non-heme iron mineralization was identified as a potential imaging biomarker
• Validation in human and mouse models showed excellent sensitivity to symptomatic and asymptomatic rebleeding in lesions
• Currently being assessed in a single site, proof of concept trial and pending favorable results it may be applied to other trials

Presentation Title: Proteomic Prediction of Cardiovascular (CV) Risk, Sensitive to Change in Outcomes

Session 2: Identification and Development of Novel Surrogate Endpoints for Use in Clinical Development Programs

Speaker: Stephen A. Williams, MD, PhD

Summary: 

Using proteins identified through the SomaScan aptamer-based platform, researchers used a machine-learning approach to derive a 27-protein prognostic model in people with confirmed cardiovascular disease. The 27-protein model was validated to predict outcomes including death, hospitalization, heart failure, etc. and allowed for demographic, ethnic, racial, geographic, and morbidity variations. The protein model performed better than biomarkers in comparison to epidemiological data. 

Key Takeaways: 

• Use of less than perfectly homogenous training data allowed for learning and corrections of this variation during the machine learning process 
• Access to plasma samples and known clinical outcomes was crucial to generating the multivariate protein model 
• The protein model was shown to be more sensitive than clinical risk factors and common biomarkers 

Presentation Title: Neurofilament Light Chain in Neurodegenerative Diseases – Status Update

Session 2: Identification and Development of Novel Surrogate Endpoints for Use in Clinical Development Programs

Speaker: Terina Martinez, PhD 

Summary: 

Neurofilament Light Chain (NfL) has been used to study many neurodegenerative diseases including Multiple Sclerosis (MS), Alzheimer’s Disease, Parkinson’s Disease, and frontal temporal dementia. NfL has been an especially successful biomarker in clinical trials for progressive MS, demonstrating analytical and clinical validity. The Critical Path Institute is currently working to evaluate NfL as a surrogate biomarker across different neurodegenerative diseases. 

Key Takeaways: 

• NfL is a disease agnostic marker of axonal damage that can be measured in blood or cerebrospinal fluid that shows promise as a prognostic biomarker in several neurodegenerative diseases 
• Understanding the biology of NfL release in healthy aging people as well as people with various neurodegenerative disorders would be beneficial to the advancement of this biomarker 
• Use of a standardized assay for measuring NfL has advanced the use of NfL as a biomarker in MS 

Presentation Title: Use of Imported Clinical Assessment Tools in Rare Disease: A Case Study

Session 3: Clinical Validation and Regulatory Acceptance of Biomarkers as Surrogate Endpoints

Speaker: Steve Ryder, MD

Summary:

This case example highlights the adaptation of a mobility test for geriatric populations (Performance-Oriented Mobility Assessment) for use in juvenile-onset hypophosphatasia. The adaptation of this clinical test allowed for assessment of historical control data using the modified test to provide a quantitative measurement of improvement of children treated with asfotase alfa. While this test is not a surrogate endpoint, the collaborative and cross-cutting approaches allowed for use of historical data in a new context to support drug approval years later, and are relevant to the validation of biomarkers and surrogate endpoints. 

Key Takeaways: 

• Collaboration with expert consultants was critical for successfully adapting the mobility test 
• Working with a center of excellence allowed for use of historical data in a new context to support drug approval years later 
• While challenging, obtaining informed consent for historical data is not impossible 
• Ongoing dialogue with FDA helped guide development of the modified test 

Presentation Title: Development and Validation of Cerebrospinal Fluid and Blood Biomarkers for Neurodegenerative Diseases

Session 3: Clinical Validation and Regulatory Acceptance of Biomarkers as Surrogate Endpoints

Speaker: Henrik Zetterberg, MD, PhD 

Summary: 

This use case reviews the development and validation of cerebrospinal fluid (CSF) and blood-based biomarkers for Alzheimer's Disease. The presentation reviews amyloid and tau pathologies and the associated biomarkers of Aβ42/Aβ40 and phosphorylated Tau as measured in both cerebrospinal fluid and blood, and discusses their use in diagnosing and measuring the progression of Alzheimer’s disease. The challenges and successes of parsing these results at an aggregate level and individual level are discussed. 

Key Takeaways: 

• Understanding how candidate biomarkers behave in a variety of conditions, including the indicated disease state and related conditions, is critical 
• Reproducible results across different forms of the assay is essential to the validation process for a candidate biomarker 
• Understanding the distribution of biomarker data between affected and unaffected populations in different locations (CSF vs blood) determines whether a candidate biomarker is able to be used for diagnosis at the individual level versus general group enrichment, or may not be usable for any purpose

Presentation Title: GFR Decline as a Surrogate Endpoint for Progression of Chronic Kidney Disease

Session 3: Clinical Validation and Regulatory Acceptance of Biomarkers as Surrogate Endpoints

Speaker: Lesley A. Inker, MD, MS

Summary: 

This case study highlights the considerations for developing the slope of decline in Glomerular Filtration Rate (GFR slope) as a surrogate endpoint for use in chronic kidney disease following a workshop that involved collaboration of the National Kidney Foundation, the FDA, and the European Medicines Agency. The presentation addresses the benefits and challenges for using this surrogate endpoint and how the challenges were addressed in the statistical model of GFR slope. Notably, treatment producing a small change in GFR slope can predict a statistically significant change in clinical endpoint. The model was validated with retrospective analysis and can also be used to assess suitability for use in future trials.   

Key Takeaways: 

• Ongoing collaboration between regulators and the National Kidney Foundation helped drive examination of candidate surrogate endpoints in chronic kidney disease 
• Identification of a stable funding source facilitated the exploration of GFR slope as a surrogate endpoint 
• Collaboration with a senior biostatistician allowed the challenges with GFR slope as an endpoint to be addressed in a highly sophisticated manner. While the model parameters are complex, they address the complexities of changes in GFR slope in chronic kidney disease. 

Presentation Title: Use of Surrogate Endpoints in Oncology

Session 3: Clinical Validation and Regulatory Acceptance of Biomarkers as Surrogate Endpoints

Speaker: Nicole Gormley, MD

Summary: 

This case study reviews the use of meta-analysis methods to assess the suitability of pathological complete response and minimum residual disease as biomarkers in various forms of cancer. Analysis of each candidate biomarker highlights the importance of including several trials with both positive and negative treatment effects and mixed trial populations to be able to draw accurate conclusions about the candidate biomarker.  

 Key Takeaways:

• Use of biomarkers as intermediate and surrogate endpoints is a high-risk effort in the regulatory setting 
• Assessment at the trial and individual level is critical in the assessment of candidate biomarkers 
• FDA is committed to working with the community on the development of biomarkers 

Presentation Title: Hutchinson-Gilford Progeria Syndrome Case Study

Session 4: Beyond Surrogate Endpoints: Other Ways Translational Science Can Support Drug Development

Speaker: Leslie B. Gordon, MD, PhD

Summary: 

Hutchinson-Guilford Progeria Syndrome is an ultrarare disease causing failure to thrive, premature aging, and cardiovascular symptoms including pediatric heart attacks and strokes. Bench research into the etiology of this disease revealed a mutation in the gene LMNA and the accumulation of a protein “progerin”, and helped inform a valuable transgenic mouse model and a potential drug target. Treatment with the farnesyltransferase inhibitor Lonafarnib improved cardiovascular outcomes in the mouse model, and showed similar success in cardiovascular outcomes and mortality in human clinical trials. 

Key Takeaways: 

• A transgenic mouse model helped establish evidence of effectiveness for progeria treatment in humans using Lonafarnib 
• Successful collaboration between bench research and clinical research was essential to enable the translation of the therapies 
• Animal models helped optimize care and produce statistically significant trial results despite a small patient population but can have limitations which are important to consider when applying findings to human populations

1. 1. Animal models may not always perfectly model disease progression in humans 

2. 2. In order to develop a biologically relevant animal model, researchers had to induce cardiovascular disease and plaque calcification seen in human patients 

Presentation Title: Optimizing Early Clinical Investigations by Increasing the Predictive Value of Non-Clinical Activities

Session 4: Beyond Surrogate Endpoints: Other Ways Translational Science Can Support Drug Development

Speaker: Estelle Marrer-Berger, PhD 

Summary:

Certain immunological therapy targets are exclusively human, making animal models impossible. New Approach Methodologies have informed a patient-centric approach, which uses human primary cells from patients and healthy donors to model the clinical response to therapies in vitro and ex vivo over a broad time course. In this case study, the models were successfully used to define a therapeutic index, minimize risk, and improve starting dose selection in a T-cell bispecific antibody therapy in Wilms Tumor 1 in Acute Myeloid Leukemia. 

Key Takeaways: 

• New in vitro techniques have enabled more detailed (cell-specific) toxicity testing of oncology treatments before beginning clinical trials 
• Patient-centric MABEL (minimum anticipated biological effect level) framework is of high predictive value for the estimation of the pharmacologically active dose range 

  ○ Instead of predicting safe dosage using the most sensitive tumor cell line, using cells from patients and healthy donors allows investigators to reach a safe, therapeutic dosage. Using T-cell activation from the tumor line cell allows for a safe and potentially lower therapeutic dose. 

Presentation Title: Clinical Translational Science: Leveraging Adult Efficacy Data for Pediatrics Using Bridging Biomarkers

Session 4: Beyond Surrogate Endpoints: Other Ways Translational Science Can Support Drug Development

Speaker: Christine Garnett, PharmD

Summary: 

For conditions that affect pediatric and adult populations, there may be effective medications or other interventions that are approved for adult populations but have not been studied in traditional clinical trials with pediatric populations due to ethical and logistical limitations. Bridging biomarkers present an opportunity to build on an existing approved medication to evaluate effectiveness in a pediatric population using a smaller, more efficient clinical trial than a traditional clinical endpoint would allow. This case study presented the successful use of pulmonary vascular resistance as a bridging biomarker to extrapolate efficacy of a drug, Bosentan, from adults to pediatric patients with pulmonary arterial hypertension, resulting in approval in pediatric populations. 

Key Takeaways: 

• Establishing a bridging biomarker must satisfy the 5 core criteria 

1. Disease must be similar in pediatric and adult populations

2. In adults, drug must be safe and effective, and have an effect on clinical outcome and proposed biomarker 

3. Biomarker must capture principal causal pathway 

4. Drug must not have negative effects not captured by biomarker 

5. In adults, clinical effects must be somewhat proportional to biomarker effects 

• Pediatric extrapolation using bridging biomarkers has been an important process for drug approvals, especially given ethical and logistic challenges in running clinical trials in children