Enzyme Replacement Therapy for Lysosomal Storage Diseases

PHS Lecture Series Roy Maynard, MD

March 18, 2010

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Objectives

1. Understand the pathophysiology of lysosomal storage diseases

2. Identify lysosomal storage diseases amenable to enzyme replacement therapy

3. Understand the limitations of enzyme replacement therapy

4. Recognize side effects of IV enzyme replacement therapy

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What is a Lysosome?

• Spherical organelles, discovered 1949 • Contain enzymes (acid hydrolases) • Role in digestion “suicide sacs” • Low pH • Cells’ garbage disposal system

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Lysosomal Functions

• Phagocytosis • Endocytosis • Exocytosis • Autophagy • Foreign microbe destruction

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Cellular Biology

Desnick RJ, Schuchman EH. Nat Rev Genet. 2002 Dec;3(12):954-66. Erratum in Nat Rev Genet. 2003 Feb;4(2):157.

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Lysosomal Storage Diseases

• Mucopolysaccharidoses • GM2 gangliosidoses • Lipid storage disorders • Glycoproteinoses • Mucolipidoses • Leukodystrophies

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Pompe’s Disease

• Genetics – Autosomal recessive – Pan-ethnic 1/40,000 – 1/146,000 – Infantile and late onset forms – Glycogen storage disease type II – Acid alpha-glucosidase deficiency – Over 200 different mutations account for

clinical heterogeneity

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Pompe’s Disease Autosomal Recessive

http://www.pompe.com/en/healthcare-professionals/genetics-epidemiology.aspx. Accessed on March 16, 2010.

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Pompe’s Disease

• Clinical features infantile form – Normal birth history – Age at presentation 2–4 months – Muscle weakness, hypotonia – Macroglossia – Hypertrophic cardiomyopathy – Respiratory failure – Early death

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Infantile Pompe’s Disease Survival

http://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition. Accessed on March 16, 2010.

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Pompe’s Disease

Head lag caused by muscle weakness

http://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition/. Accessed on March 15, 2010.

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Pompe’s Disease

http://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition/. Accessed on March 15, 2010.

Cardiomegaly in infant

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Pompe’s Disease

• Clinical features late onset form – Normal birth history – Heterogeneous (childhood, juvenile, adult) – Adult onset 2nd to 6th decade – Typically no severe cardiomyopathy – Progressive skeletal myopathy

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Pompe’s Disease • Diagnosis

– Low or absent acid alpha glucosidase (GAA) – Muscle, fibroblast biopsy (gold standard) – Histopath vacuoles PAS stain positive – EKG (conduction, arrythmias) – Elevated creatinine kinase – DNA mutation analysis – Elevated liver enzymes

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Pompe’s Disease • Pathophysiology

– Accumulation glycogen in liver, heart, skeletal muscle, smooth muscle in GI tract, ear

– Large glycogen deposits in muscle cells (cardiac, skeletal, smooth) impair muscle fiber contraction

– Ultimately there is gross muscle hypertrophy due to increased glycogen storage at the expense of muscle atrophy and destruction

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Glycogen Buildup in Pompe Disease

http://www.mda.org/publications/quest/q161RescuedLives.html. Accessed on March 15, 2010.

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Electron Micrograph of Pompe Affected Muscle Cell

http://www.pompe.com/en/healthcare-professionals/overview/pathology.aspx. Accessed on March 15, 2010.

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Pompe’s Disease

• Treatment – Supportive

• Respiratory • Nutritional • Musculoskeletal/rehab • Cardiac

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Pompe’s Disease • Enzyme replacement therapy

– Alpha-glucosidase (GAA) – 1960’s enzyme replacement attempted – 2006 recombinant GAA available – IV dosing every 2 weeks – Early treatment – better outcome – Cell-surface receptors (mannose) plays a role in

endocytosis

• Mannose-6-phosphate (M6P) tag on enzymes

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Myozyme Production

Production of acid a-glucosidase in Chinese hamster ovary (CHO-) cells and in the milk of transgenic rabbits.

http://www.pompecenter.nl/en/?History. Accessed on March 16, 2010.

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Pompe’s Disease with Mannose 6-phosphate Tags

http://www.mda.org/publications/quest/q76resup.html. Accessed on March 15, 2010.

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Cellular Biology

http://www.mda.org/publications/quest/q102pompe.html. Accessed on March 15, 2010.

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Pompe’s Disease • Outcome after ERT

– Decrease glycogen in tissues – Improved quality and quantity of life – Decreased ventilator days – Study n=18, enrolled <7 mths/age

• 3 needed vent within 12 mths, 4 more needed vent beyond 12 mths treatment and 2/4 died

• 2/9 that had increased motor gains lost ground

– Decrease in LV size (no correlation to clinical outcome)

Kishnani PS, Corzo D, Leslie ND, et al. Pediatr Res. 2009 Sep;66(3):329-35.

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Pompe’s Disease Outcomes • French study

– N=21, 3–43 months age (median 13 mths) – Treated median 120 weeks – 71% alive study end – 44% of vent free patients at time of enrollment

remained vent free – Death reduced 79% – Vent risk reduced 58% – 86% functional independence skills (5 walking) – 52% infusion-associated reactions – 95% IgG antibodies

Nicolino M, Byrne B, Wraith JE, et al. Genet Med. 2009 Mar;11(3):210-9.

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Complications of Enzyme Replacement Therapy (Pompe’s)

• Life-threatening anaphylaxis/cardiac arrest – 1% • Allergic reaction – 14 % • Infusion reaction – 51% • 89% anti-IgG against GAA (higher incidence of

reactions in these patients and less efficacy of GAA)

• Serum sickness in IgG positive patients • Reactions can occur any time up to 2 hours after

infusion

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Complications of Enzyme Replacement Therapy (Pompe’s)

• 100% of patients had adverse events – Fever – Decrease oxygen sats – Tachycardia – Cyanosis – Hypotension – Rash, urticaria, flushing, pallor – Bronchospasm

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Gaucher’s Disease • Sometimes called glucocererebrosidase deficiency • Most prevalent metabolic storage disorder • Lipid storage disorder • Accumulation of glucosylceramide • Spleen, bone, and liver • Enzyme replacement since 1994 • Genetics autosomal recessive • 1/50,000 births, European Jewish population

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Gaucher’s Disease

• Clinical signs and symptoms – Easy bruising and bleeding – Fatigue – Anemia – Weak bones and fractures – Bone and joint pain – Hepatospleenomegaly

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Gaucher’s Disease

• Diagnosis – DNA mutation analysis chromosome 1 – Enzyme levels in blood or fibroblasts – Deficient glucocerebrosidase

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Gaucher’s Disease

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Gaucher’s Disease

http://wikidoc.org/images/thumb/e/e9/Gaucher_disease_004.jpg/400px-Gaucher_disease_004.jpg. Accessed on March 16, 2010.

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Gaucher’s Disease

• Enzyme replacement therapy – Cerezyme – Administered IV usually q 2 weeks – Allergic reactions – Reduction in symptoms – 13.8% adverse events – 1% < anaphylaxis

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Fabry’s Disease • Alpha galactosidase A deficiency • Accumulates glycolipid – globotriaosylceramide

(GL-3) • Blood vessels (vascular endothelium) • Genetics

– X-linked recessive – Males>females – 1/40,000–60,000 males – Survival mean age 41

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Fabry’s Disease and Hunter Syndrome X-linked Recessive

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Fabry’s Disease

• Clinical signs and symptoms – Renal failure 3rd decade – Cardiac – cardiomyopathy, hypertension – Skin – angiokeratomas, anhidrosis – Eyes – corneal issues – Neurostroke, fatigue, neuropathy – Pain in extremities

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Fabry’s Disease

• Diagnosis – Blood enzyme levels alpha-galactosidase – Chomosomal analysis of GLA gene for DNA

mutation

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Fabry’s Disease

• Treatment – Enzyme replacement therapy – Fabrazyme® (Genzyme Corp.) – Replagal® (Shire)

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Fabry’s Disease Outcome

• Decreased GL3 in tissues • May ameliorate disease expression

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Hurler’s Syndrome

• Mucopolysaccharidoses I (MPS I) – Autosomal recessive (chromosome 4)

1/100,000 births – Alpha-L-Iduronidase (Aldurazyme®)

• Aldurazyme® is manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corp.

– Accumulate dermatan and heparin sulphate

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Hurler’s Syndrome • Clinical features

– Progressive deterioration – Large liver and spleen – Dwarfism – Hearing loss – Macroglossia – Mental retardation – Cloudy corneas – Limited joint movement – Respiratory abnormalities

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Hurler’s Syndrome

http://deti.msk.ru/plaxin_egor.jpg. Accessed on March 15, 2010.

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Hurler’s Syndrome

• Variations amenable to enzyme replacement therapy include Hurler-Scheie and Scheie Syndrome

• Aldurazyme®

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Hurler’s Syndrome

• Outcome – Increased walk distance – Increased FVC – Decreased liver and spleen size

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Hurler’s Syndrome • Adverse events

– 97% positive for IgG antibody – Anaphylaxis – 35% infusion-related reactions

• Fever • Chills • Hypotension • Tachycardia • Decreased oxygen sats

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Hunter Syndrome • Mucopolysaccharidosis II

– Deficiency iduronate-2-sulfatase (Elaprase® - Shire) – Dermatan and heparin sulfate – X-linked recessive (rare disease, >200 mutations) – Airway obstruction – Skeletal deformities – Cardiomyopathy – Neurological decline – Death 2nd decade

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Hunter Syndrome

http://davechidley.ca/wp-content/uploads/2009/02/szymon-cajmer900w.jpg. Accessed on March 15, 2010.

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Complications of Elaprase® Therapy for Hunter Syndrome

• Anaphylaxis (biphasic anaphylaxis 24 hrs after infusion)

• Respiratory distress, hypoxia, seizure, hypotension

• Fever – 63% • Headache – 59% • Joint pain – 31% • 51% have IgG against Elaprase®

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Hunter Syndrome

• Outcome – Increased walking capacity – Trend towards increased FVC – Decreased organ size

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Maroteaux-Lamy Syndrome

• Mucopolysaccharidosis VI (MPS VI) – Arylsulphatase B deficiency (Naglazyme® –

BioMarin Pharmaceutical Inc.) – Accumulate dermatan sulphate – Genetics

• Autosomal recessive • Rare disorder

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Maroteaux-Lamy Syndrome • Clinical signs and symptoms

– Coarse facial features – Skeletal damage – Hepatospleenomegaly – Corneal clouding – Cardiac valvular disease – Short stature – Normal intelligence – Respiratory

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Maroteaux-Lamy Syndrome

http://www.maroteaux-lamy.com/English/images/HCP/Patients.jpg. Accessed on March 15, 2010.

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Maroteaux-Lamy Syndrome Normal Storage Disorder

http://www.naglazyme.com/en/Images/Patients/StorageDisorderCells.JPG. Accessed on March 15, 2010.

Left: In a healthy cell with sufficient ASB activity, lysosomes constitute a negligible portion of cellular volume (about 1%).15

Right: In an MPS cell, lysosomes, replete with excess GAG, increase in both size and number, crowding the nucleus and other critical organelles, engorging the cell.

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Maroteaux-Lamy Syndrome

• Treatment – Palliative – Bone marrow transplant – Enzyme replacement therapy

• Naglazyme®

• Approved in 2005 • IV administration once/week

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Maroteaux-Lamy Syndrome • Initial reactions occurred as late as week 55 • The most frequent serious adverse events

related to Naglazyme® occurring during infusions included urticaria of the face and neck, bronchospasm, respiratory distress, and apnea.

• Almost all patients develop IgG antibodies

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Maroteaux-Lamy Syndrome

• Outcome – Improved walking and stair climbing ability – Decreased joint pain – No change in facial features or skeletal

deformities

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Treatment of Adverse Events

• Stop infusion or slow down infusion • Steroids • Antihistamines • Epinephrine • B-agonist nebulizer • Antipyretics

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Lysosomal Storage Diseases Conclusions

• Orphan disease for many, not funded • Enzyme replacement therapy very expensive • Long-term outcomes largely unknown • Limited results with CNS disease • Not curative • Difficult to target specific tissue (e.g. skeletal

muscle in Pompe’s Disease) • Tissues involved may not sufficiently remodel,

need to diagnose early for best results

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Future Considerations

• CNS penetration • Improved tissue-specific penetration • Stem cell transplant • Endogenous enzyme modulation • Gene therapy • In the future, more genetic diseases

amendable to enzyme replacement therapy will be discovered.

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Essentials of Successful Home Treatment Program

• Careful patient selection • Experienced home infusion team • Detailed management plan for potential

anaphylaxis and infusion-associated reactions

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Journal References • Burton BK, Wiesman C, Paras A, Kim K, Katz R. Mol Genet

Metab. 2009 Jul;97(3):234-6. Epub 2009 Apr 21. • Desnick RJ, Schuchman EH. Nat Rev Genet. 2002

Dec;3(12):954-66. Erratum in Nat Rev Genet. 2003 Feb;4(2):157. • Kishnani PS, Corzo D, Leslie ND, et al. Pediatr Res. 2009

Sep;66(3):329-35. • Nicolino M, Byrne B, Wraith JE, et al. Genet Med. 2009

Mar;11(3):210-9. • Roscoe O Brady. Annual Review of Medicine. 2006;57: 283-96.

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Suggested Reading

• Kishnani PS, Steiner RD, Bali D, Berger K, et al: Pompe disease diagnosis and management guideline. Genet Med. 2006 May;8(5):267-88. No abstract available. Erratum in: Genet Med. 2006 Jun;8(6):382.

• Muenzer J, Wraith JE, Clarke LA: Mucopolysaccharidosis I: management and treatment guidelines. International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I. Pediatrics. 2009 Jan;123(1):19-29.