Fabry Disease A profile of Fabry disease Gregory A

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Fabry Disease

• A profile of Fabry disease
• Gregory A. Grabowski, M.D.
• Professor
• Departments of Pediatrics, and Molecular Genetics
  and Biochemistry
• of the University of Cincinnati
• Director, Division of Human Genetics
• Children's Hospital Research Foundation
• Cincinnati, Ohio

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Fabry Disease

• Progressive
• Multiple organ systems
• Morbidity
• Cardiac complications
• Stroke
• Renal failure
• Decreased lifespan

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Fabry Disease

• X-linked inborn error of metabolism
• Deficient ?-Galactosidase A (?-GAL A) enzyme
  activity
• Progressive globotriaosylceramide (GL-3)
  accumulation
• multiple cell types and tissues -- end organ
  impairment

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Metabolic Pathway
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Vascular Endothelium
SevereendothelialGL-3 accumulation
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Fabry Disease
Clinical
Fabry Disease or Hypercholesterolemia?
Pathological
10 20 30 40 50 60
Age (years)
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Fabry Disease A profile of Fabry disease
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Early Diagnosis is Key

• Early diagnosis can lead to better disease
  management
• Diagnosis of one patient can uncover many others
  in the family
• family pedigree is essential
• genetic counseling is important

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Fabry Disease is an Inherited Disorder

• X-linked (like hemophilia)
• no male-to-male transmission (fathers cannot
  pass the mutation on to their sons)
• Symptomatic females
• carriers can experience symptoms to varying
  degrees (from severe to no symptoms)
• Panethnic (effects every ethnicity)
• Incidence estimated to be 140,000 males

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Inheritance Pattern
Carrier females have a 50 chance during each
pregnancy of transmitting the gene to their
children.
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Inheritance Pattern
Affected males transmit the disease to all of
their daughters and none of their sons.
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Fabry Disease Progression
Cardiac Disease
CNS Disease
Renal Disease
Acroparesthesia
0
40
Age
Clinical Presentation
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Fabry Disease Other Signs/Symptoms

• Fatigue
• ? Growth, delayed puberty
• Impaired fertility
• Changes in joints and bones
• Chronic bronchitis
• Impaired social functioning
• Depression
• ? Quality of life

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Pain in Fabry Disease

• Multiple variants of Acroparesthesia (pain in
  hands and feet)
• constant
• affects hands and feet
• described as burning, tingling, pain and
  discomfort
• unresponsive to narcotic analgesics
• triggered by fever, exercise, fatigue, stress,
  weather changes
• Patient defined types of pain

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Skin Manifestations

• Hypohidrosis or anhidrosis (decreased or no
  sweating)
• Heat and cold intolerance
• Angiokeratomas

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Fabry Disease --Angiokeratoma
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Corneal Opacity

• Note spoke-like pattern on cornea, visible
  through slit lamp ophthalmoscopy (does not affect
  vision)

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Conjunctival Involvement

• Note the sausage-like and markedly dilated
  vessels in the eye.

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Gastro-Intestinal (GI) Manifestations --
Unappreciated Frequency

• Episodic diarrhea
• Post-prandial (eating) bloating and pain
• Early satiety (feeling full)
• Nausea and vomiting
• Weight loss

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Kidney Manifestations

• Progressive renal insufficiency
• proteinuria, isosthenuria, azotemia
• elevated serum creatinine levels
• End-stage renal disease
• Most frequent cause of death among untreated males

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Heart Manifestations

• Left ventricular hypertrophy
• Coronary artery disease
• Valvular disease
• Arrhythmias
• Congestive heart failure

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Diagnosis of Fabry Disease

• Presumptive diagnosis
• observation of symptoms and laboratory findings
• family history/medical pedigree
• Definitive diagnosis
• enzyme assay in plasma, leukocytes, tears, or
  biopsied tissue
• gene mutation analysis or linkage analysis

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Enzyme Assay

• ?-GAL activity
• measure in plasma, serum, leukocytes
• Markedly deficient in affected males (very low to
  no enzyme activity)
• Carrier females can have low to normal levels
• Therefore it can be used to screen the males in a
  family but not the females

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Mutation Analysis

• Mutation analysis (DNA)
• determine specific genetic mutation within family
• useful for precise carrier ID and prenatal
  diagnosis (therefore is diagnostic testing for
  women)
• requires small blood sample

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Potential Misdiagnoses -- Many

• Potential misdiagnoses can be anything causing
• Kidney disease
• Heart disease
• Strokes
• The cause of pain may be difficult to diagnose
  and may be misbelieved

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Symptom Management

• Addresses affected organ systems separately
• Does not address the underlying cause of Fabry
  disease

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Symptom Management

• Fabry disease pain
• avoid stimuli that precipitate pain
• responds poorly to conventional analgesics
• prophylactic neuroleptic treatment
• narcotics
• concerns about side effects

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Symptom Management

• Angiokeratomas
• argon laser treatment
• Gastrointestinal Manifestations
• diet
• pancreatic enzyme supplements
• Stroke Prevention
• ?prophylactic antiplatelet/anticoagulant treatment

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Symptom Management

• Renal Manifestations
• diet
• dialysis
• transplantation

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Fabrazyme in USA

• Fabrazyme approved -- April 24, 2003
• Fabrazyme reduces globotriosylceramide (GL-3) in
  kidney cells
• Prevent the development of life-threatening organ
  damage
• A positive health effect on patients
• Ongoing studies to verify clinical benefit to
  patients

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Phase 4 Program
Develop Fabry Disease Natural History Database
Compare to Phase 4 Study (Historical Control)
Compare to Phase 3 Population
0
60
10
20
30
40
50
Decline in GFR
Age (years)
Pathological accumulation of GL-3
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Issues with ERT in Fabry Disease

• Reactions to infusion
• Long-term outcomes
• Time to event (unknowns)
• When is there improvement of organs
• When is there stabilization
• When is there clinical improvement
• When do I feel better

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Percent Fever and/or Rigors and Seroconversion at
each InfusionAs Treated Population -
Placebo/Fabrazyme, n 27 (at last visit)
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Clinical-Pathologic Correlation Potential
Benefits
Clinical
Phase 3 population
Treat early and prevent pathological
accumulations and avoid renal damage
Phase 4 population
Treat later and slow rate of progression of renal
disease
10 20 30 40 50 60
Age (years)
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Fabry RegistryLong-term clinical data collection

• Fabry Registry
• Fulfill US FDA post-marketing commitment
• Includes Kidney, Brain, Heart, GI and other
  clinical findings
• Program supported by Genzyme
• Modeled after the Gaucher disease registry

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Fabry Registry

• Established to better understand the variability
  and progression of Fabry disease
• Established to monitor and evaluate long-term
  treatment effects of Fabrazyme
• Patients should be encouraged to participate and
  advised that their participation is voluntary and
  may involve long-term follow-up

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Fabry Registry

• Global resource for enhanced understanding of
  Fabry disease and tracking patient outcomes
• Features confidential database (no patient
  names)
• Backed by experience and expertise of Gaucher
  Registry

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