Clinical Data to Support Qualification:Cross-Sectional Surveys and

Natural History Studies

P. K. Tandon, Ph.D.Clinical Science OfficerGenzyme, a Sanofi Company

Clinical data to support biomarker/endpoint qualification: most difficult to obtain• Often no prior clinical studies of any kind• No prior therapeutics or treatments• Little systematic work on clinical condition

and any biomarkers• Often clinical use of biomarkers is not well

established• Time and cost to develop data may be

prohibitive

Rare Diseases Require Different Approaches to Support QualificationWhat clinical data can be collected with no prior clinical studies

Cross-Sectional Studies• Single day assessment of clinical/biomarker• Wide range of severity/outcome• Utilize clinical history data, onset, severity etc.• Can be done with less time and be useful

Natural History Studies• Longer term evaluation• Provides longitudinal with-in patient data• More valuable if obtainable• Often too long or costly to implement

Niemann-Pick B Disease is Caused by Acid Sphingomyelinase Deficiency (ASMD)

•

A patient with Neimann - Pick B Disease

Niemann-Pick B is a autosomal recessive lysosomal storage disorder that is chronically debilitating and, for some, life-threatening

Premature death can occur due to cirrhosis, hemorrhage, respiratory failure, or coronary artery disease

Age of presentation is variable (from infancy to adulthood) and symptoms are heterogeneous

Current therapy is palliative

Estimated incidence rate is 1:250,000, worldwide prevalence in developed countries is approximately 3,000 to 5,000 patients

Niemann-Pick Type B and Gaucher Disease Type 1 Have Similar Clinical Presentations

Niemann-Pick Disease Type B Gaucher Disease Type 1

• Hepatomegaly

• Splenomegaly

• Thrombocytopenia

• Bleeding/bruising

• Anemia

• Fatigue

• Growth retardation

• CNS and non-CNS forms

• GD>NP− Bone disease and pain

• NP>GD− Lung disease and cirrhosis

We Are Conducting a Niemann-Pick B Natural History Study to Better Characterize the Disease

• A prospective, observational, natural history study

• 59 patients enrolled from 5 countries: US, Italy, France, Germany, and Brazil

• 3 study visits: baseline, 1-yr, and long-term follow-up (7-12 yrs)

Baseline visits

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

1-year visits

Long-term follow-up visits

The Study Timeline Spans 12 Years

Baseline & Pulmonary Findings from the Natural History Study Have Been Published

Baseline findings, McGovern et al., 2008

Pulmonary findings, Mendelson et al., 2006

Niemann-Pick B Natural History Study: Design

• Series of 2-3 day evaluations at each site

• 3 visits occurring at Baseline, Year 1, and Years 5-11– Demographics – incl. enzyme assay and genotype

– Medical history – age at onset and diagnosis, medical problems, and treatment

– Physical examination – incl. growth, ophthalmologic, and neurologic

– Laboratory tests – chem, UA, hematol, lipids, biomarkers (chitotriosidase, SMN)

– Evaluations – liver/spleen MRI, chest X-ray/HRCT, and echo/ECG

– Functional status – 6MWT, cycle ergometry, pulmonary function tests

– Quality of life – CHQ (pediatric) and SF-36 (adult)

– Niemann-Pick HAQ – incl. validated fatigue, dyspnea, and pain questionnaires. (Developed while study in progress and is being implemented at final visit)

McGovern MM et al. “A prospective cross-sectional survey study of the natural history of Niemann-Pick disease type B”. Pediatrics 2008;122:e341-e349

• Patients (N=59)− Ages 7-65 yrs, median 17.6 yrs, 53% male, 92% Caucasian

− 25% of mutation R608del

• Presentation− 78% splenomegaly, 73% hepatomegaly

• Signs/Symptoms− 49% bleeding, 42% pulmonary infections, 42% dypsnea, 39% joint/limb

pain

− Growth retardation, especially during puberty

− Abnormal lipid profile (↑ cholesterol (91%), LDL (46%), TG (62%); low HDL (74%)

− ↓ platelets (53%), hemoglobin (26%), white blood cells (21%)

− ↑ ALT (51%), bilirubin (33%), chitotriosidase (95%), PBMC SMN (63%)

Natural History Study: Respiratory Function and Exercise Capacity

McGovern MM et al. A prospective cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics 2008;122:e341-e349.

Spleen Volume Correlated with Several Aspects of Disease Severity

Type B Niemann-Pick Natural History Study: Summary• Study provided important new information about the spectrum of

disease manifestations

• Diversity of the patient populations from various countries was identified (e.g., pulmonary involvement in Saudi Arabia patients whereas a high neurological prevalence in European patients)

• 6 patient deaths (10%)during follow-up, most in adolescence to mid-adulthood

• Spleen volume was correlated with disease severity – a surrogate clinical marker for the Phase 2 study

• Chitotriosidase (biomarker; a marker of activated macrophases) may play a role in monitoring patient treatment responses

Niemann-Pick B DiseaseBoth cross-sectional survey and natural history information were useful• Cross-sectional data

– Immediate establishment of proportional relationships between biomarkers and severity

– No information on longitudinal stability, or change over time

• Natural history data– Collected 12 years of follow-up– Supported cross sectional data

Clinical Data to Support QualificationDevelopment of data from no-drug studies can help• Natural history and survey studies can provide needed

support for biomarkers/endpoints– Relationship to onset/severity/progression– Establish rate of change/slope of decline

• Cross-Sectional studies are easier to conduct– Less time & lower cost; can provide good info

• Natural history with sufficient observations– More information in individual variation– More precise estimate of decline