4/5/2012

Enzyme Replacement Therapy

for Lysosomal Storage Diseases

Laurie Bailey, MS, CGC

Lysosomal Disease Center
Cincinnati Children’s Hospital

Presentation Objectives
• Describe several lysosomal storage
diseases for which enzyme therapy is
currentlyy available.
• Discuss the benefits and limitations of
enzyme therapy for each condition.
• Discuss the role of the infusion nurse as
it relates to total patient management.

What are Lysosomal

Storage Diseases?
• Family of > 40 disorders1
• Enzyme deficiency or decreased enzyme
activity causes lysosomes to become
engorged1
• Each disease is a consequence of the type of
substrate stored and where it accumulates1
• Progressive accumulation of substrate may
result in irreversible damage2

1. Meikle P et al. JAMA. 1999;281:249-254.

2. Wraith JE, et al. J Pedr. 2004;144:581-588.

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A Storage Cell
Normal Macrophage Gaucher Cell

Example: Gaucher

Normal Macrophage
Function

Courtesy of Gregory A. Grabowski, MD copyright

Abnormal Macrophages
in Gaucher Disease

Courtesy of Gregory A. Grabowski, MD copyright

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Macrophages on Enzyme
Therapy

Courtesy of Gregory A. Grabowski, MD copyright

Incidence of LSDs1
• Individually rare but collectively more common
– Individual incidence: 1:40,000 to 1:1,000,000 births
– Collective incidence: 1:7,700 to 1:10,000 births
– 500-800 people born each year with a LSD (US data)

• Most are panethnic

• Some more prevalent in certain ethnic groups:

– Ashkenazi Jewish descent—Gaucher, Niemann-Pick
– African Americans—Infantile-onset Pompe disease

1. Meikle P et al. JAMA. 1999;281:249-254.

Lysosomal Storage Disorders

Sandoff 2%
Gaucher
Gm1 Gangliosidosis 2%
14%
Mucolipidosis II/III 2%
Niemann Pick A/B 3%
Maroteaux-Lamy 3% MPS I H/S
9%
Niemann Pick C
4%
Sanfilippo B
4% Metachromatic
Tay-Sachs Leukodystrophy
4% 8%

Cystinosis
4% Sanfilippo A
Morquio 7%
5%
Pompe Fabry
5% Krabbe Hunter 7%
(For Australia1980-1996; Meikle et al., 1999a) 5% 6%
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CNS Involvement
Significant or severe CNS involvement No or minimal CNS involvement
(~ 54%) (~ 46%)
Mucolipidosis type II / III
2% Sandhoff
GM 1
Niemann-Pick A 2% Gaucher type I
Gangliosidosis
2% Other Scheie (MPS I)
2% 13%
2% 1%
Niemann-Pick C
4% Hurler/Scheie (MPS I)
Sanfilippo B 4%
4%
Fabry
Tay-Sachs 7%
4%
Hunter Mild
Krabbe 1%
6% Pompe
5%

Hunter Severe
5% Morquio
5%
Cystinosis
Sanfilippo A
Sanfilippo D 4%
7% Metachromatic
1%
Leukodystophy a-Mannosidosis Maroteaux-Lamy
8% Hurler (MPS I)
Gaucher type 2 & 3 Niemann-Pick B 3%
4% 1% 1%
2%

Adapted from Meikle P et al. JAMA. 1999;281:249-254.

Data on file Genzyme

Inheritance
• Most are autosomal recessive1

Father Mother
Carrier Carrier

1 2 3 4
Affected Unaffected Unaffected
Individual Carriers Noncarrier
(25%) (50%) (25%)

1. Hirschhorn R et al. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3389-3420.

Inheritance
• X-linked: Fabry and MPS II

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Disease Progression

10 months 12 months

39 months
Patient with severe MPS I
22 months 34 months

Photos courtesy of the MPS Society.

Gaucher Disease
Pathology Inheritance
Glucocerebrosidase deficiency leads Autosomal recessive
to macrophage engorgement

Onset Incidence
Usually in first or second decade Panethnic ~ 1:60,0001
May present in infancy to adulthood Ashkenazi Jewish descent ~
1:4502

Progression
Early age of onset can indicate a greater likelihood of aggressive
disease
Variable progression
Can be life threatening

1. Grabowski GA. Genet Test. 1997;1:5-12.

2. Zimran A et al. Am J Hum Genet. 1991;49:855-859.

Type 1 Gaucher
Bone crisis Pathologic
fracture

Collapsed
Growth vertebrae
retardation

Anemia
Osteonecrosis/
Thrombocytopenia Osteopenia

Hepatosplenomegaly
Erlenmeyer flask
deformity

Cox TM, Schofield JP. Bailliere’s Clin Haematol.

1997;10:657-689.

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Type 1 Gaucher

Asymptomatic Mildly affected Severely affected

80-year-old man young adult girl

Type 1 Gaucher
• Supportive care
• Enzyme replacement therapy (ERT)
–Alglucerase (Ceredase®-no longer produced)
–Imiglucerase
Imiglucerase (Cerezyme®)
–Velaglucerase (Vpriv®)
• Substrate inhibition therapy
–Miglustat (Zavesca®)
• Oral; to be used when patient cannot tolerate ERT

Type 1 Gaucher
• ERT:
– Produced by recombinant DNA technology
– Addresses underlying enzyme deficiency
– Indicated for long
long-term
term ERT for pediatric and adult patients
with a confirmed diagnosis of type 1 Gaucher disease
– Reduces or reverses hepatosplenomegaly1
– Improves anemia and thrombocytopenia1
– Reduces or eliminates bone pain or bone crisis1
1. Weinreb NJ, Charrow J, Anderson HC et al. Am J Med. 2002;113:112-119.

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Progression and ET in GD Type 1

Photos used with permission from patient and

family.

Photos used with permission of patient and family.

Fabry Disease
Pathology Inheritance
-galactosidase A (-GAL) deficiency1 X-linked recessive
Accumulation of globotriaosylceramide
(GL-3)1

O
Onset
t I id
Incidence
May present in childhood or adolescence ~1:40,000 males1
~1:117,000 individuals2
Progression
Often life threatening
Death often due to renal, cardiac, or cerebrovascular complications
Average life expectancy of males ~ 50 years3
1. Desnick RJ et al. In: Scriver C,Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 2001;3733-3774.
2. Meikle P et al. JAMA. 1999;281:249-254.
3. MacDermot KD et al. J Med Genet. 2001;38:750-760.

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Fabry Disease
Early ischemic
stroke

Left ventricular
hypertrophy
Recurrent fever

Progressive renal
Corneal whorls insufficiency

Psychosocial
manifestations Angiokeratomas

Heat & cold

intolerance
Hypohidrosis
Acroparesthesia

Fabry Disease

Angiokeratomas1 Cardiomyopathy1

“Whorllike” or “spokelike”
corneal opacities1

1. Courtesy of R. J. Desnick, PhD, MD

Fabry Disease
• Supportive care
- Pain management
- Valve replacement
- Dialysis or renal transplantation
• Enzyme replacement therapy
–Agalsidase beta (Fabrazyme®)
–Agalsidase alfa (Replagal® - outside US)

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Improvements With ERT

• By biopsy, clear GL-3 from
– Skin
– Kidney
– Heart
• Stabilization of serum creatinine
• Less fatigue / increased energy
• Pain / Pain crises?

Pompe Disease
• Disease Classification
– Classified in three disease families (including lysosomal storage
disorder, glycogen storage disease, and neuromuscular/metabolic
muscle disease)
– Also considered a “cardiac disorder” due to prominent
cardiomyopathy/cardiomegaly in infants
– Spectrum of disease with a range of signs and symptoms
• Pathology
– Progressive, and often fatal
– Irreversible pathology caused by deficiency of lysosomal acid
alpha-glucosidase (GAA)
• Inheritance
– Autosomal recessive genetic mutations
Hirschhorn R, et al. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3389-3420.
Raben N, et al. Curr Mol Med. 2002;2:145-166.

Pompe Disease
Pompe Disease Continuum
Rapidly Progressive and Relentlessly Progressive
Often Fatal by One Year of Age and Often Fatal
Musculoskeletal
• Profound and rapidly progressive • Progressive proximal muscle
muscle weakness ((hypotonia,
yp , floppy
ppy weakness ((trunk and lower limbs))
baby, head lag) • Gait abnormalities
• Delayed motor milestones • Muscle pain
• Difficulty climbing stairs
• Frequent falls
• Scapular winging
Respiratory
• Frequent respiratory infections • Respiratory failure/insufficiency
• Progression to respiratory insufficiency • Orthopnea
• Premature death due to cardiorespiratory • Exertional dyspnea
failure • Respiratory infections
• Sleep disordered breathing • Daytime somnolence
• Morning headache
• Nocturnal hypoventilation

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Pompe Disease
Pompe Disease Continuum
Rapidly Progressive and Relentlessly Progressive
Often Fatal by One Year of Age and Often Fatal
Cardiac
• Marked cardiomegaly/cardiomyopathy • Less common
• Progression
g to cardiac failure

Gastrointestinal
• Difficulty feeding/failure to thrive • Feeding and swallowing difficulties
• Organomegaly (hepatomegaly/macroglossia) • Poor weight gain/maintenance
• Difficulty chewing or jaw muscle
fatigue

1. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver C, Beaudet A, Sly W, et al. The Metabolic
and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2001: 3389-3420.
2. Winkel LP, Hagemans ML, van Doorn PA, et al. The natural course of non-classic Pompe's disease; a review of 225 published cases. J Neurol 2005; 252:875-84.
3. van den Hout HM, Hop W, van Diggelen OP, et al. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature.
Pediatrics 2003; 112:332-40.
4. Kishnani PS, Hwu W-L, Mandel H, et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr
2006;148:671-6.

Pompe Disease

Data on file, Genzyme.

Hypotonia/head lag/ Courtesy of R. R. Howell, MD

Floppy baby Enlarged tongue/ Cardiomegaly

lax facial features

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Pompe Princess Party

Photo used with permission from all patients’ families.

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Little Angels

Photo used with permission from patients’ families

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Adult Onset Pompe

Disease

Photo used with permission from patient and her’ family.

Mucopolysaccharidosis I
(MPS I)

Courtesy of Emil Kakkis, MD.

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MPS I
Pathology Inheritance
-L-iduronidase enzyme deficiency Autosomal Recessive
Accumulation of glycosaminoglycans
(GAG)

Onset Incidence
Severe form: first 6 months after birth ≈1:100,0001
Attenuated form: 3 to 8 years of age

Progression
Often life threatening
Severe cases life span < 10 y
Attenuated cases life span ≈ normal
.
1. Meikle P et al. JAMA. 1999;281:249-254

MPS I/II

Carpal tunnel syndrome2

Skeletal deformities Hepatosplenomegaly2

(Gibbus)1 (MPS I only)
Short stature2

Umbilical/ inguinal
hernia3

Corneal clouding3(MPS 1 only)

1. Courtesy of Emil Kakkis, MD.
2. Courtesy of MPS Society.
3. Nyhan and Ozand, 1998. Photo reproduced by permission of Hodder/Arnold Publishers.

MPS I
Attenuated Severe
“Scheie” “Hurler-Scheie” “Hurler”
MPS I S MPS I HS MPS I H

Courtesy of Emil Kakkis, MD.

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Physical Appearance

• Facial dysmorphism
• Short nose
• Flat face
• P
Prominent
i fforehead
h d
• Large head
– scaphocephaly

MPS I
• Supportive care
– E.g., physical therapy, CPAP, hearing aids, surgery
– Does not address enzyme deficiency
• Hematopoietic stem cell transplantation (HSCT)
– Bone marrow
marrow, umbilical cord
cord, or peripheral blood
– Best outcomes are in severe MPS I (<2 y)1-4
– High morbidity and mortality
• Enzyme replacement therapy (ERT)
– Not shown to impact central nervous system
1. Vellodi A et al. Arch Dis Child. 1997;76:92.
2. Whitley C et al. Am J Med Genet. 1993;46:209-218.
3. Neufeld EF, Muenzer J. In: Scriver C,Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease.
New York: McGraw Hill; 2001:3421-3452.
4. Peters C et al. Blood. 1998;91:2601-2608.

Bone Marrow Transplant

for MPS I
• Standard of care for Hurler syndrome
• If performed <2 yrs
– Improvements:
H
Hepatosplenomegaly,
l l cardiomyopathy,
di h
coronary occlusion, airway obstruction, and
neurological degeneration, facial coarseness
--No effects:
Bone dysplasia, heart valvular deterioration, or
corneal clouding

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MPS I/II
• ERT: Aldurazyme® (laronidase) for MPS I and Elaprase® for MPS II
– FDA approved April 2003 and July 2006 respectively
– Produced by recombinant DNA technology
– Addresses the enzyme deficiency
– Aldurazyme Indicated for Hurler and Hurler-Scheie forms of MPS
I and for moderate to severe Scheie form. Elaprase for Hunter.
– Risks/benefits of treating mild Scheie form have not
been established
– Shown to improve pulmonary function and walking capacity
– Not evaluated for effects on CNS

Commercially Available
Pharmacologic Therapies
LSD Therapy Company

MPS I ERT BioMarin-Genzyme LLC

Genzyme
Type 1 Gaucher ERT
Shire

Type
yp 1 Gaucher Substrate inhibition Actelion

Genzyme
Fabry ERT
Shire*

Pompe ERT Genzyme (2 products)

MPS II ERT Shire

MPS VI ERT BioMarin

Lysosomal Therapies in
Development
• ERT
• Substrate inhibition
– GD, Wolman/CESD,
MPS IIIA, MLD, MPS – Tay-Sachs, NPC, GD,
IVA, NPB GM2

• Small Molecule • Small Molecule +

– GD, FD ERT
– PD
**For more information visit www.clinicaltrials.gov

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Infusions
• Administered every 1-2 weeks depending on drug
and patient response
• Usually administer pre-medications of Tylenol and
Benadryl (less likely in Gaucher disease or women
with Fabry disease)
• Ramp the infusion rates (except Gaucher disease)
• Reactions treated by decreasing infusion rate and
administering medications
• Antibodies (IgG vs IgE)
• Administer drug in a unit with access to emergency
medical interventions

Comparing ERT
Gaucher Fabry MPS I, II, IV Pompe

ERT drug Cerezyme® Fabrazyme® Aldurazyme® Myozyme® (infantile-

Vpriv® Elaprase® onset US only)
Naglazyme® Lumizyme® (late-
onset)
Premeds Not typical Yes women may
Yes, Yes Not initially,
initially but will
not need use once a reaction
occurs
Infusion length Cerezyme®: 1-3 2-6 hours 3-4 hours 3-4 hours
hours
Vpriv®: 1 hour
Ramp Rate No Yes Yes Yes

Antibodies Cerezyme®: 15% 50-90% 50-90% 50-90%

Vpriv®: ?
Dose 30-60 units/kg every 1 mg/kg every 2 wks Aldurazyme®: 0.58 20 mg/kg every 2
2 wks mg/kg weekly wks
Elaprase®: 0.5
mg/kg weekly
Naglazyme®: 1
mg/kg weekly

Infusion Associated
Reactions
Associated With Suggestive of
Administration Hypersensitivity Other
Discomfort Anaphylactoid reaction Nausea
Pruritus Pruritus Vomiting
B i
Burning Fl hi
Flushing Abd i l pain
Abdominal i
Swelling Urticaria Diarrhea
Sterile abscess at the site of Angioedema Rash
venipuncture Chest discomfort Fatigue
Dyspnea Headache
Coughing Fever
Cyanosis Dizziness
Hypotension Chills
Rigors Backache
Tachycardia

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Black Box Warning

Myozyme/Lumizyme/Aldurazyme/Elaprase/Naglazyme

Life-threatening anaphylactic reactions have been

observed in some patients during Myozyme infusions.
Therefore appropriate medical support should be
Therefore,
readily available when Myozyme is administered.
Risk of Cardiorespiratory Failure - Patients with
compromised cardiac or respiratory function may be at
risk of serious acute exacerbation of their cardiac or
respiratory compromise due to infusion reactions, and
require additional monitoring.

Cost
• $200,000-$300,000 per year for drug alone*

• Drug mark-up, office visits, infusion charges,

other medications
medications, other evaluations

• Concerned about insurance coverage

• Inconvenient and time consuming requiring a

day off of school or work to travel to clinics

Conclusions
• ERT is a treatment, NOT a cure
• Benefits of ERT are different for each disorder
• Does not work on CNS disease or existing bone disease
• The phenotype of each disease is changing – emergence of
new disease complications
• It remains to be determined if the benefits of ERT for some
disorders outweigh the cost of the drug and inconvenience to
the patient
• Diagnose early and start treatment early before irreversible
damage occurs

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Role of the
Nurse

49

Roles for Nurses

• Infusion reactions
• Advocates for patients with poor peripheral IV access
(need for ports/central lines)
• Teaching regarding home infusions
• Evaluation of patient coping strategies with regard to
diagnosis and treatment
• Referrals to community support agencies; early
intervention
• Coordination of complex care – care conferences
• Development of mobile medical record

Resources

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LSD Resources
Web sites
– www.LysosomalLearning.com (includes links to additional
disease-specific sites and resources)
– www.rarediseases.org
– www.nih.gov
– www.geneclinics.org
g g
– www.clinicaltrials.gov
Physicians with experience treating LSDs
– Consult with geneticists and metabolic specialists who have
experience in these diseases
– Contact ACMG and ASHG for information on treatment centers
in the United States
– Contact wwwNSGC.org to find a genetic counselor near you.

Further Informational
•
Resources
“Prevalence of lysosomal storage disorders” (Meikle et al. JAMA.
1999;281:249-254)
• “Insights into diagnosis and treatment of LSDs” (Wenger et al. Arch
Neurol. 2003;60:322-328)
• “Enzyme replacement therapy for MPS I” (Wraith et al. J Pediatr.
2004;144:581 588)
2004;144:581-588)
• “Pediatric non-neuronopathic Gaucher disease: presentation,
diagnosis and assessment” (Grabowski et al. Eur J Pediatr.
2004;163:58-66). “The mucopolysaccharidoses” (Neufeld &
Muenzer. In: The Metabolic and Molecular Bases of Inherited
Disease. 2001:3421-3451).
• “Glycogen storage disease type II: acid alpha-glucosidase (acid
maltase) deficiency” (Hirschhorn & Reuser. In: The Metabolic and
Molecular Bases of Inherited Disease. 2001:3389-3420).

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