Summit on Drug Discovery

Tuberous Sclerosis Alliance

July 7, 2011

Biomarkers in TSC and LAM

Definition of a biomarker

• A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to a therapeutic intervention.”

Types of biomarkers• Diagnostic/Screening• Risk

– Prognostic-risk of disease development or progression (e.g.-HER-2 overexpression in breast CA)

– Predictive-likelihood of response to therapy (e.g.-HER-2 overexpression in breast CA)

• Pharmacodynamic-markers of drug effect– Proximal-e.g.-phosphorylation of target kinase– Distal-e.g.-FDG-PET

• Biological progression-markers of tumor progression– Tumor markers-PSA doubling time after treatment, CTC– Anatomical imaging markers-e.g-CT scanning

• Surrogate clinical endpoints– Response, disease free survival

The ideal biomarker

• Repeatable• Reproducible• Minimally invasive• Little or no risk• Inform audit trail• Reflect biology of tumor

Clinical ‘manifestations’ in need of diagnostic, predictive, prognostic biomarkers in TSC and LAM

• CNS– Seizures– SEGAs– Hydrocephalus– Cognition– Autism

• Renal– Renal failure– AML growth– AML bleeding– Renal cancer

• Lung (LAM)– Respiratory

insufficiency– Pneumothorax– Exercise tolerance

– Heart– Rhabdomyomas

Discussion of selected diagnostic, predictive, and prognostic biomarkers in TSC and LAM

• CNS– Seizures

• serial EEGs to detect & preemptively treat epileptiform activity before the first seizure

Renal– AML bleeding

• AML volume, aneurysm size and fat content on MRI imaging can be used to predict bleeding

• LAM- Diagnosis

. Circulating tumor cells

. VEGF-D-SLAM &TSCLAM

. MMP-9- Respiratory insufficiency

. Prolactin levels

. Bronchodilator response

. Menopausal status

. LAM histology score

. DLCO– Pneumothorax

• Cyst size• Collagen, MMP-1

• Heart– Rhabdomyoma

• Intrauterine ultrasound is a useful biomarker for TSC

Serum VEGF-D levels distinguish women with Sporadic LAM from those with other cystic lung diseases.

n=155 female subjects with definitive diagnosis by biopsy or geneticsSerum VEGF-D evaluated by ELISA (R&D Systems)

Elevated serum VEGF-D levels are associated with the presence of LAM in women with TSC.

Women with TSC only had a normal chest HRCT within 18 months of testing.

Young et al, Chest 2010

In the MILES trial, VEGF-D declined on sirolimus

In the MILES cohort, baseline serum VEGF-D correlated with

• Baseline markers of airflow obstruction, hyperinflation, diffusing capacity and quality of life

• Lung function (FVC) response to sirolimus

Biomarker tool kit for TSC and LAM trials

• Need biomarkers that:– Optimize patient selection– Demonstrate treatment effect earlier (target

modulation, cell/tissue effects)– Perform well as surrogate endpoints that correlate

with response and survival

The Pharmacologic Audit Trail

• Effect of the drug on the target, pathway, cell, tissue

• Effect of body on the drug– PK and metabolism

• Therapeutic and toxicological effects of the drug

Sarker D. Biomarker Med 2007Sarker D. Adv Cancer Res 2007Workman P. Mol Canc Ther 2003

Pharmacologic audit trail

Sarker D. Biomarker Med 2007Sarker D. Adv Cancer Res 2007Workman P. Mol Canc Ther 2003

John Lennon’s playlist on Omni DC Stationary for 1st US Concert at Washington Coliseum, Feb 11, 1964

• Beethoven• From Me to You• I Saw Her Standin’ There• This Boy• All My Lovin’• I Wanna Be Your Man• Please Please Me• Till There Was You• She Loves You• Twist and Shout• Long Tall Sally

Group B playlist for TSC and LAM biomarker development

• Incorporate proven and exploratory biomarker analyses early and often into all phases of trials

• Consider molecular context when designing selection criteria, audit trail and surrogate endpoints for trials

• Mine data and conduct high throughput biomarker screens of serum/tissue from completed RCTs

• Establish functional and efficient central repository for TSC data and tissue