Overview of the “International Guidelines for the Management and Treatment of Morquio A...

Overview of the “International Guidelines for the Management and Treatment of Morquio A Syndrome”

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Guidelines establish the standard of care for Morquio A1

Bronchodilator

International guidelines for the evaluation, treatment, and symptom-based management of Morquio A have recently been published1

• Guidelines were developed over 2 expert meetings of an international panel of specialists with extensive experience in managing Morquio A1

• Specialties represented included1

• Pediatrics

• Genetics

• Orthopedics

• Pulmonology

• Cardiology

• Anesthesiology

• The Guidelines were developed to provide a comprehensive standard of care to aid clinicians as they manage and treat this complex multisystemic disease1

Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.

• Also referred to as MPS IVA, mucopolysaccharidosis IVA4

• Serious, progressive, life-threatening disease5

• Autosomal recessive lysosomal storage disorder (LSD) 4

• Caused by deficient activity of N-acetylgalactosamine-6 sulfatase (GALNS), an enzyme that catalyzes the breakdown of 2 glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S) 5,6

• Accumulation of these GAGs in lysosomes leads to cell engorgement and disruption of normal cell function2,3,7

• Wide genotypic and phenotypic heterogeneity associated with Morquio A results in variable clinical presentation5

• Multisystemic manifestations contribute to loss of endurance5

• Varied spectrum of manifestations, organ involvement, and rate ofdisease progression necessitate an individualized managementplan for each patient1,8

References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Northover H, Cowie RA, Wraith JE. Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis. 1996;19(3):357-365. 3. Tomatsu S, Montaño AM, Oikawa H, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment: a special review. Curr Pharm Biotechnol. 2011;12(6):931-945. doi:1389-2010/11. 4. Tomatsu S, Montaño AM, Nishioka T, et al. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum Mutat. 2005;26(6):500-512. 5. Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021. 6. Bank RA, Groener JEM, van Gemund JJ, et al. Deficiency in N-acetylgalactosamine-6-sulfate sulfatase results in collagen perturbations in cartilage of Morquio syndrome A patients. Mol Genet Metab. 2009;97(3):196-201. doi:10.1016/j.ymgme.2009.03.008. 7. Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007;30(2):165-174. doi:10.1007/s10545-007-0529-7. 8. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1.

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The underlying cause of Morquio A is an enzyme deficiency that leads to multisystemic consequences1-3

Bronchodilator

Cell with GAG accumulation in lysosomes (Bank 2009)

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AUDIOLOGICALConductive and neurosensory hearing loss3,4

NEUROLOGICALOdontoid dysplasia, cervical myelopathy, cervical spine instability, tetraplegia2,3

MUSCULOSKELETALBone deformity, short stature, abnormal gait, joint laxity, contracturesand subluxation, dysostosis multiplex2,3

OPHTHALMOLOGICALDiffuse corneal clouding, cataracts, reduction in visual acuity3,6,7

DENTALDentinogenesis imperfecta, hypodontia, pointed cusps, spade-shaped incisors, thin enamel, abnormal buccal surfaces3,8

CARDIOVASCULARMitral and aortic valve stenosis and regurgitation, tricuspid regurgitation, hypertrophy3,9-11

RESPIRATORYObstructive sleep apnea, respiratory infections, respiratory failure2,3,9

ABDOMINALMild hepatosplenomegaly, hernias, loose stools, diarrhea, constipation, abdominal pain3-5

Morquio A leads to progressive organ damage and complex multisystemic manifestations1,2

References: 1. Northover H, Cowie RA, Wraith JE. Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis. 1996;19(3):357-365. 2. Tomatsu S, Montaño AM, Oikawa H, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment: a special review. Curr Pharm Biotechnol. 2011;12(6):931-945. doi:1389-2010/11. 3. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 4. Hendriksz CJ, Al-Jawad M, Berger KI, et al. Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis. 2013;36(2):309-322. doi:10.1007/s10545-012-9459-0. 5. Shunji Tomatsu; International Morquio Organization. Mucopolysaccharidosis type IVA: Morquio A syndrome. http://www.arianascure.com/edcd.pdf. Published 2005. Accessed November 12, 2014. 6. Danes BS. Corneal clouding in the genetic mucopolysaccharidoses: a cell culture study. Clin Genet. 1973;4(1):1-7. 7. Leslie T, Siddiqui MAR, Aitken DA, Kirkness CM, Lee WR, Fern AI. Morquio syndrome: electron microscopic findings. Br J Ophthalmol. 2005;89:917-929. 8. Kinirons MJ, Nelson J. Dental findings in mucopolysaccharidosis type IV A (Morquio’s disease type A). Oral Surg Oral Med Oral Pathol. 1990;70(2):176-179. 9. Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021. 10. Ireland MA, Rowlands DB. Mucopolysaccharidosis type IV as a cause of mitral stenosis in an adult. Br Heart J. 1981;46(1):113-115. 11. John RM, Hunter D, Swanton RH. Echocardiographic abnormalities in type IV mucopolysaccharidosis. Arch Dis Child. 1990;65(7):746-749.

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Management of the multisystemic consequences of Morquio A requires a multidisciplinary approach1

To address both the underlying cause and multisystemic complications, the Guidelines call for a coordinated approach consisting of a team of specialists anchored by a geneticist or metabolic physician1

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Ophthalmologist

Cardiologist

Neurosurgeon

Orthopedic specialist

Pulmonologist

Dentist

Audiologist

Geneticist/metabolic specialist

Gastroenterologist


Recommended management starts with diagnosis and continues with care throughout the patient’s lifetime1

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At diagnosis, a team of specialists should be assembled by the patient’s geneticist or metabolic specialist to perform comprehensive assessments and to begin long-term management1

• Diagnosis should be confirmed with an enzyme assay2,3

• The Guidelines recommend the immediate initiation of enzyme replacement therapy (ERT) to mitigate disease progression and improve overall patient outcomes1

DIAGNOSIS

The Guidelines outline essential ongoing assessments that allow for early intervention to address clinical manifestations and help the patient avoid permanent damage1

• A coordinated healthcare team led by a geneticist or metabolic specialist is essential to ensure comprehensive care1

ONGOING ASSESSMENTS AND INTERVENTIONS

Continued coordination is important as new specialists join the patient’s healthcare team1

TRANSITION TO ADULT CARE

References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Clarke LA, Winchester B, Giugliani R, Tylki-Szymańska A, Amartino H. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab. 2012;106(4):396-402. doi:10.1016/j.ymgme.2012.05.003. 3. Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int. 2012;2012:471325. doi:10.1155/2012/471325.

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MUSCULOSKELETALPhysical examination, standardized upper/lower extremity function test, radiographs

RESPIRATORY Forced vital capacity (FVC), maximum voluntary ventilation (MVV), respiratory rate, oxygen saturation, overnight sleep study

NEUROLOGICAL Neurological exam, plain radiograph, magnetic resonance imaging (MRI) scan

CARDIOVASCULAR Electrocardiogram, echocardiogram, heart rate

OPHTHALMOLOGICAL Slit-lamp biomicroscopy of cornea, intraocular pressure, refractive error, examination of posterior segment

AUDIOLOGICAL Multimodal hearing assessment

ABDOMINALAssessments of gastrointestinal problems

DENTAL Evaluation of oral health

ASSESSMENTS RECOMMENDED AT DIAGNOSIS 1,a

a For a comprehensive list of assessments, consult the Guidelines.

Prompt diagnosis and comprehensive multisystemic evaluation is a critical first step toward establishing an individualized management plan1

• Multidisciplinary collaboration and referrals are recommended for optimal treatment, starting with comprehensive baseline assessments performed by the appropriate specialists1

ENDURANCE 6-minute walk test (6MWT)

QUALITY OF LIFE (QoL)Reproducible, age-appropriate QoL questionnaires (eg, EQ-5D-5L)

QoL


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ERT should be initiated upon diagnosis to replace deficient GALNS1

Please see Important Safety Information, including boxed warning, on slide 38.

At a cellular level, GAGs accumulate in the lysosomes and occupy an increasingly greater area of the cytoplasm, which disrupts normal cell function.3,4

VIMIZIM is an exogenous recombinant human enzyme that replaces deficient GALNS in the lysosome.1

Within the lysosome, VIMIZIM increases catabolism of GAGs (KS and C6S)—restoring cell function. 1,2

• The goal of ERT in Morquio A is to reduce GAG accumulation in order to restore cellular function1,2

• VIMIZIM® (elosulfase alfa) is the only ERT indicated for patients with Morquio A1

References: 1. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014. 2. Wood TC, Harvey K, Beck M, et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis. 2013;36(2):293-307. doi:10.1007/s10545-013-9587-1. 3. Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int. 2012;2012:471325. doi:10.1155/2012/471325. 4. Hendriksz CJ, Al-Jawad M, Berger KI, et al. Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis. 2013;36(2):309-322. doi:10.1007/s10545-012-9459-0.

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• Compared with placebo, VIMIZIM® (elosulfase alfa) 2 mg/kg/week demonstrated a statistically significant improvement of 22.5 meters (14.9%) in 6MWT distance in only 24 weeks (P=0.0174)1,2

• Patients who continued receiving VIMIZIM through the extension trial stabilized walking ability after 72 weeks in extension study1,2

Initiating ERT with VIMIZIM at diagnosis is considered an essential first step toward creating an effective management plan for patients with Morquio A.3

VIMIZIM® (elosulfase alfa) significantly improves endurance as measured by the 6MWT1,2Guidelines confirm the 6MWT as a validated measure of endurance3

References: 1. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014. 2. Hendriksz CJ, Giugliani R, Harmatz P, et al. Multi-domain impact of elosulfase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2013;36(2):309-322. doi:10.1016/j.ymgme.2014.08.012. 3. Hendriksz CJ, Al-Jawad M, Berger KI, et al. Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis. 2013;36(2):309-322. doi:10.1007/s10545-012-9459-0.


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16 years old

VIMIZIM® (elosulfase alfa) demonstrated a favorable trend in most additional trial end points1

Summary of VIMIZIM® (elosulfase alfa) clinical trial Week 24 efficacy end points1

Reference: 1. Hendriksz CJ, Giugliani R, Harmatz P, et al. Multi-domain impact of elosulfase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2013;36(2):309-322. doi:10.1016/j.ymgme.2014.08.012.


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16 years old

VIMIZIM® (elosulfase alfa) has also shown a positive trend related to activities of daily living (ADL)1

ADL measured using MPS health assessment questionnaire (HAQ)1

• Of the 52 HAQ questions, responses to 34 questions favored weekly treatment, 12 favored placebo, and 6 showed no difference1

Reference: 1. Hendriksz CJ, Giugliani R, Harmatz P, et al. Multi-domain impact of elosulfase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2013;36(2):309-322. doi:10.1016/j.ymgme.2014.08.012.


Justin Rebello

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• 176 patients ages 5 to 57 were enrolled in the 24-week, phase 3 pivotal study1

• The most common adverse reactions that occurred were pyrexia, vomiting, headache, nausea, abdominal pain, chills, and fatigue1

• Acute reactions requiring intervention were managed by

• Temporarily interrupting or discontinuing the infusion1

• Administering additional antihistamines, antipyretics, or corticosteroids1

Reference: 1. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014.

VIMIZIM® (elosulfase alfa) safety and tolerability

aSafety and effectiveness in pediatric patients <5 years of age has not been established and is currently being evaluated.17

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MUSCULOSKELETALStandardized upper extremity function test, radiographs •At diagnosis/baseline, annually

ASSESSMENTS1,a

RESPIRATORY FVC, MVV, respiratory rate, oxygen saturation, overnight sleep study

NEUROLOGICAL Neurological examplain radiographMRI scanCT scan

CARDIOVASCULAR Electrocardiogram echocardiogram heart rate

OPHTHALMOLOGICAL Refractive error and intraocular pressure

AUDIOLOGICAL Multimodal hearing assessment

ABDOMINALAssessments of gastrointestinal problems

DENTAL Evaluation of oral health

a Note: For additional detail, please consult the Guidelines.

•At diagnosis/baseline, annually

•At diagnosis/baseline, every visit (minimum, every 6 months)•At diagnosis, every 1 to 3 years•At diagnosis, annually•As clinically indicated

•At diagnosis, every 1 to 3 years, as clinically indicated•At diagnosis, every 2 to 3 years, as clinically indicated•At diagnosis, annually

•At diagnosis, as clinically indicated

•At diagnosis, annually

•As clinically indicated


FREQUENCY1,a

Guidelines emphasize need for ongoing multisystemic assessments1

ENDURANCE 6MWT •At diagnosis, annually, before and regularly after initiation of ERT

•At diagnosis, annuallyQUALITY OF LIFE (QoL)Reproducible, age-appropriate QoL questionnaires (eg, EQ-5D-5L)

QoL


•Upon diagnosis, refer to MPS-experienced orthopedic surgeon

INTERVENTIONS1,a

•Pursue supportive therapies – Influenza and pneumococcus vaccinations– Bronchodilators– Prompt treatment of upper respiratory infections

•Spinal decompression•Spinal fusion

•Avoid beta-blockers to treat tachycardia

•Refractive correction/low vision aids•Corneal transplantation

•Ventilation tubes•Postaural hearing aids

•Surgical repair of recurrent hernias

•Preventative measures against formation of caries•Fissure sealing of dentition

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MUSCULOSKELETAL

RESPIRATORY

NEUROLOGICAL

CARDIOVASCULAR

OPHTHALMOLOGICAL

AUDIOLOGICAL

ABDOMINAL

DENTAL

MANIFESTATION ASSESSED1,a

a Note: For additional detail, please consult the Guidelines.

Assessments can reveal the need for specialized interventions to optimize patient outcomes1

ENDURANCE •ERT provides a systemic treatment approach

•Efforts should be made to keep patients independently mobile as long as possible as QoL drops dramatically when patients become wheelchair dependent

QUALITY OF LIFE (QoL)QoL


Specialty area: Orthopedics

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• Common manifestations include short stature, abnormalities in the spine, upper extremities, thorax, hips, and/or lower extremities, and joint and gait abnormalities1

- Unlike most other MPS disorders, patients with Morquio A have joint hypermobility throughout the body which can lead to spinal cord complications1 (see neurological involvement, slide 19)

Skeletal and joint abnormalities are the most apparent and prevalent disease manifestations of Morquio A1

(Left: Image courtesy of Christina Lampe, MD and Ralph Lachman, MD)

(Right: Atinga 2008)

Focus on: musculoskeletal involvement

More than 70% of patients with Morquio A have had at least 1 surgical procedure.2

Note: For additional detail, please consult the Guidelines.

Dysostosis multiplex changesin the pelvis and hips

Knee valgus

References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021.

Specialty area: Orthopedics

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Guideline-recommended assessments

Guideline-recommended interventions

• Immediately refer patients to a geneticist to begin ERT with VIMIZIM® (elosulfase alfa)1

• Refer to an orthopedic surgeon with experience treating MPS diseases1

Standardized upper extremity function test, radiographs •At diagnosis, annually

Focus on: musculoskeletal involvement

ASSESSMENTS1 FREQUENCY1




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Focus on: respiratory involvement

• Respiratory impairment can be due to obstructive or restrictive disease1

• Narrowed and tortuous airways can be caused by a combination of GAG deposits in airway walls, abnormalities in the skull and spine, tracheal distortion, tracheobronchomalacia, and thickened secretions1

• Respiratory complications can contribute to reduced endurance in patients with Morquio A1

• Patients with Morquio A have a significant increase in surgical risks as a result of respiratory manifestations of the condition1

• Sleep-disordered breathing can be an early sign of respiratory impairment1

Respiratory impairment is the leading cause of morbidity and mortality in patients with Morquio A1


GAG deposits

Narrow trachea

Narrow, tortuous trachea

Specialty area: Pulmonology

(Left: Berger 2013)

(Right: Image FPO)

GAG deposits within the upper airway causing narrowingof the pharynx and larynx


Specialty area: Pulmonology

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16 years old

Focus on: respiratory involvement

Respiratory complications pose an increased surgical risk. 1 See Surgical intervention section, slide 33.



FVC, MVV, respiratory rate, oxygen saturation, overnight sleep study




• Patients may benefit from supportive therapies such as regular influenza and pneumococcus vaccinations, bronchodilators, and aggressive, timely treatment of upper respiratory infections1


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16 years old

• Identify spinal cord compression early and correlate findings with imaging studies of the spine to avoid long-term consequences1

• Signs of severe spinal cord compression1

• sensory anomalies

• upper and lower extremity weakness

• lower back pain

• urinary dysfunction

• unsteady gait

• radiating leg pain

• paralysis

Cervical spine instability, spinal cord compression and resulting surgical risks drive the critical need to identify and treat instability in the spine1

Specialty area: Neurology

Focus on: neurological involvement

(Solanki 2013)

T2 hyperintensity and focal atrophy

Note: For additional detail, please consult the Guidelines.Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.

Specialty area: Neurology

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16 years old

Pre-surgical assessments are required to minimize the risks associated with spinal cord compression.1 See surgical intervention, slide 33.


Focus on: neurological involvement


Neurological exam

Plain radiograph

MRI scan

CT scan

•At diagnosis/baseline, every visit (minimum, every 6 months)

•At diagnosis, every 1 to 3 years





• When warranted, interventions can include spinal decompression, fusion, or a combination of both1


Specialty area: Cardiology

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16 years old

• Cardiac valve abnormalities can include valve thickening, regurgitation, and/or stenosis1

• Patients with Morquio A may also experience myocardial hypertrophy and/or cardiomegaly1,2

• Impaired cardiac function contributes to reduced endurance in patients with Morquio A1,2

High heart rate in patients with Morquio A compensates for small cardiac stroke volume1


Autopsy specimen of patient with Morquio A shows thickening of mitral valve cusps, tricuspid valve cusps, and chordae

(Ireland 1981)

Focus on: cardiovascular involvement

References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021.

Specialty area: Cardiology

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16 years old


Focus on: cardiovascular involvement


Electrocardiogram

Echocardiogram

Heart rate

•At diagnosis, every 1 to 3 years, as clinically indicated

•At diagnosis, every 2 to 3 years, as clinically indicated




• Treatment of tachycardia with beta-blockers should be avoided1

• Valve replacement may be considered for patients with severe aortic or mitral valve disease1


Specialty area: Ophthalmology

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16 years old

• Diffuse corneal clouding and refractive error problems (eg, astigmatism, myopia, and hyperopia) are typical for patients with Morquio A1

Ongoing assessments of ophthalmological conditions related to Morquio A help identify the need for corrective interventions1

Focus on: ophthalmological involvement


(Image courtesy of C Gail Summers)

Corneal clouding


Specialty area: Ophthalmology

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16 years old


Focus on: ophthalmological involvement


Slit-lamp biomicroscopy of cornea

Intraocular pressure

Refractive error

Examination of posterior segment

Scotopic and photopic electroretinogram








• Corneal clouding can be managed surgically by corneal transplant; note that concomitant retinopathy, glaucoma, or optic nerve atrophy can reduce efficacy of corneal transplant1

• Impaired vision may be improved by refractive correction or low-vision aids1


Specialty area: Audiology

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16 years old

• Patients with Morquio A typically develop neurosensory or mixed conductive and neurosensory hearing loss1

• Common causes of hearing loss can include recurrent respiratory tract infections or otitis media, deformity of the ossicles, and/or abnormalities of the inner ear1

Hearing loss is underestimated in patients with Morquio A despite the onset of auditory impairment in the first decade of life1


Focus on: audiological involvement


Specialty area: Audiology

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16 years old


T-tubes should be used the first time fluid is retained in the middle ear due to the anesthetic risks and risk of reoccurrence.1

Focus on: audiological involvement

Guideline-recommended assessment


• Ventilation tubes treat conductive hearing loss from middle ear fluid1

• Postaural hearing aids may be most appropriate if a progressive neurosensory element to hearing loss is present1

Multimodal hearing assessment •At diagnosis, annually

ASSESSMENT1 FREQUENCY1


Specialty area: Gastroenterology

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16 years old

• Routine clinical evaluations may reveal umbilical, inguinal, or bilateral diaphragmatic hernias, hepatomegaly, splenomegaly, and other gastrointestinal disorders (eg, chronic constipation, diarrhea)1

Although the prevalence of abdominal conditions is lower in patients with Morquio A than in other MPS disorders, regular assessment is recommended1


Focus on: abdominal involvement


• Hernias can be surgically repaired by herniorrhaphy and frequently recur1


Specialty area: Dentistry

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16 years old


• Small, widely spaced teeth, often with thin, structurally weak enamel and small pointed cusps, spade-shaped incisors, pitted buccal surfaces, and other abnormalities of dentition are characteristic of Morquio A1

• Regular dental visits are recommended1

Physiological abnormalities in dentition results in caries formation susceptibility1

Focus on: dental involvement


• Caries prevention can include fluoride supplementation and/or fissure sealing as appropriate1

(Hendriksz 2014)

Pediatric (top) and adult (bottom) teeth with typical features: widely spaced teeth, pointed cusps, and spade-shaped incisors


Specialty area: Genetics

29

16 years old

• Impaired cardiac, respiratory, musculoskeletal, and/or neurological function can contribute to reduced endurance and a resulting impact on functional status/mobility and quality of life1,2

• VIMIZIM® (elosulfase alfa) has been approved for Morquio A syndrome and improves endurance as measured by 6MWT3

Multisystemic factors may reduce the endurance of patients with Morquio A and warrant a systemic treatment approach1,2

Focus on: endurance involvement

References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021. 3. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014.



Specialty area: Genetics

30

16 years old

The initiation of ERT with VIMIZIM® (elosulfase alfa) at diagnosis is critical to help maximize patient outcomes and improve overall care.1

Focus on: endurance involvement

Guideline-recommended assessment

6MWT •At diagnosis, annually, before and regularly after initiation of ERT

ASSESSMENT1 FREQUENCY1


• The guidelines highlight the importance of initiating ERT as soon as possible upon diagnosis to address the progressive decline in endurance caused by Morquio A1




Specialty area: Primary care

31

16 years old


Focus on: disease burdenQoL

• Pain is a major but underreported symptom of Morquio A that is often related to musculoskeletal problems and may occur throughout the body1

• Loss of independent mobility considerably contributes to diminution of QoL1

Pain, loss of mobility, frequent surgical interventions, and other factors significantly impact the QoL of patients with Morquio A1


Pain assessment

QoL questionnaire

Functional test/ADL questionnaire

•At diagnosis, every 6 months, pre-ERT

•At diagnosis, annually, pre-ERT

•At diagnosis, annually, pre-ERT



• Simple interventions may considerably improve the functional capacity and QoL of patients with Morquio A1

• Efforts should be made to keep patients independently mobile as long as possible1


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Patients with Morquio A face high surgical risk1-3

Cervical instability

Compromisedrespiratory function

Cardiac problems

High anesthesia

risk

Inability to ventilate/

intubate

Need for reintubation

Airway obstruction

Surgical complications result in an 11% mortality rate in the Morquio A population.4

References: 1. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1. 2. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management . J Inherit Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2. 3. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 4. Lavery C, Hendriksz C. Mortality in patients with Morquio syndrome A. J Inherit Metab Dis Rep. 2015;15:59-66. doi:10.1007/8904_2014_298.

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Surgical interventions require strong planning and coordination1,2

Bronchodilator

Creating a surgical plan should involve a multidisciplinary team of specialists who are also experienced in treating patients with Morquio A3

Key components of surgical planning include anesthetic care, continuous monitoring, and postoperative care1-4

• Specialties represented may include anesthesiology, pulmonology, neurosurgery, cardiology, ENT, and radiology3

• In addition to the management guidelines, specialists should consult orthopedic and surgical guidelines (listed on slide 37)

References: 1. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1. 2. Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9):901-907. doi:10.1111/j.1460-9592.2012.03904.x. 3. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 4. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. J Inherit Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2.

• As patients get older they need to begin managing their own healthcare1

• Patients need you to help guide their transitions to ensure adult services are knowledgeable in managing Morquio A and to ensure that they aren’t lost to follow-up1

• It is important to have a formal, site-specific transition strategy1

• This should include joint visits with the pediatrician and physician (eg, coordinating the adult patient care for a few years and adding patient information to a registry accessible to the adult team)1

• Encourage patients and their families to be involved in this process1

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Make transitioning to adult care part of the individual management plan


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Highlights from the management and treatment guidelines• Morquio A syndrome is associated with profound skeletal and joint abnormalities and significant

nonskeletal manifestations1

• The multisystemic complications caused by Morquio A require coordinated multidisciplinary care across a wide range of specialists with a geneticist at the center of care1

• Early diagnosis and baseline testing establish the basis for a comprehensive management plan1

• The initiation of ERT with VIMIZIM® (elosulfase alfa) at diagnosis is critical to help maximize outcomes and mitigate disease progression, improving overall care1-3

• Ongoing assessments throughout the lifetime of each patient with Morquio A allow for interventions to help those individuals avoid permanent damage1

• Surgical risks associated with Morquio A require thorough peri- and postoperative planning and care4-6

For additional resources related to the optimal care of patients with Morquio A,please refer to slide 37.

References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014. 3. Hendriksz CJ, Giugliani R, Harmatz P, et al. Multi-domain impact of elosulfase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2013;36(2):309-322. doi:10.1016/j.ymgme.2014.08.012. 4. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1. 5. Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9):901-907. doi:10.1111/j.1460-9592.2012.03904.x. 6. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. J Inherit Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2.


36

Morquio A Registry Study (MARS)

• Morquio A Registry Study (MARS) is a multicenter, multinational, observational Registry of subjects diagnosed with Morquio A

• MARS is designed to gain better understanding of the variability and progression of the disease in the population as a whole, and to monitor and evaluate long-term treatment effects of VIMIZIM® (elosulfase alfa)

• All subjects with a confirmed diagnosis of Morquio A disease may be eligible to participate in this Registry

• It is not required that subjects receive VIMIZIM to be eligible to participate

• The Registry started enrollment and is currently open in the EU and USA

• For information on participation please contact the BioMarin MARS Team at [email protected]


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Key Morquio A treatment and management publicationsFor a more in-depth look at how to specifically manage and treat patients with Morquio A, experts recommend the following resources:

• Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.

• Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. J Inherit Metab Dis. 2013;36(2):339-355. doi: 10.1007/s10545-013-9586-2.

• Berger KI, Fagondes SC, Giugliani R, et al. Respiratory and sleep disorders in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):201-210. doi:10.1007/s10545-012-9555-1.

• Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9):901-907. doi:10.1111/j.1460-9592.2012.03904.x.

• American Thoracic Society Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-117. doi:10.1164/rccm.166/1/111.

• Hendriksz CJ, Burton B, Fleming TR, et al. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study [published online ahead of print May 9, 2014]. J Inherit Metab Dis. doi:10.1007/s10545-014-9715-6.

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INDICATIONVIMIZIM® (elosulfase alfa) is indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome).

Life-threatening anaphylactic reactions have occurred in some patients during VIMIZIM® (elosulfase alfa) infusions. Anaphylaxis, presenting as cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms (eg, nausea, abdominal pain, retching, and vomiting) in conjunction with urticaria, have been reported to occur during VIMIZIM infusions, regardless of duration of the course of treatment. Closely observe patients during and after VIMIZIM administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with acute respiratory illness may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring.

Due to the potential for anaphylaxis, appropriate medical support should be readily available when VIMIZIM is administered and for an appropriate period of time following administration. In clinical trials, cases of anaphylaxis occurred as early as 30 minutes from the start of infusion and up to three hours after infusion, and as late into treatment as the 47th infusion.

IMPORTANT SAFETY INFORMATION

Important Safety Information

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In clinical trials, hypersensitivity reactions have been observed as early as 30 minutes from the start of infusion but as late as six days after infusion. Frequent symptoms of hypersensitivity reactions (occurring in more than 2 patients) included anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea, and flushing.

Because of the potential for hypersensitivity reactions, administer antihistamines with or without antipyretics prior to infusion. Management of hypersensitivity reactions should be based on the severity of the reaction and include slowing or temporary interruption of the infusion and/or administration of additional antihistamines, antipyretics, and/or corticosteroids for mild reactions. However, if severe hypersensitivity reactions occur, immediately stop the infusion of VIMIZIM and initiate appropriate treatment. Consider the risks and benefits of re-administering VIMIZIM following a severe reaction. Patients with acute febrile or respiratory illness at the time of VIMIZIM infusion may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient’s clinical status prior to administration of VIMIZIM and consider delaying the VIMIZIM infusion. Sleep apnea is common in MPS IVA patients. Evaluation of airway patency should be considered prior to initiation of treatment with VIMIZIM. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an acute reaction, or extreme drowsiness/sleep induced by antihistamine use.

Important Safety Information (cont’d)


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Spinal or cervical cord compression (SCC) is a known and serious complication of MPS IVA and may occur as part of the natural history of the disease. In clinical trials, SCC was observed both in patients receiving VIMIZIM and patients receiving placebo. Patients with MPS IVA should be monitored for signs and symptoms of SCC (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care. All patients treated with VIMIZIM 2 mg/kg once per week in the placebo-controlled trial developed anti-drug antibodies. The relationship between the presence of neutralizing antibodies and long-term therapeutic response or occurrence of anaphylaxis or other hypersensitivity reactions could not be determined. VIMIZIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if VIMIZIM is present in human milk. Exercise caution when administering VIMIZIM to a nursing mother. There is a Morquio A Registry that collects data on pregnant women and nursing mothers with MPS IVA who are treated with VIMIZIM. Contact [email protected] for information and enrollment.

Safety and effectiveness in pediatric patients below 5 years of age has not been established and is currently being evaluated.

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In clinical trials, the most common adverse reactions (≥10%) occurring during infusion included pyrexia, vomiting, headache, nausea, abdominal pain, chills, and fatigue. The acute reactions requiring intervention were managed by either temporarily interrupting or discontinuing infusion, and administering additional antihistamine, antipyretics, or corticosteroids. To report SUSPECTED ADVERSE REACTIONS contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, or FDA at 1-800-FDA-1088 or go to www.fda.gov/medwatch. Please see accompanying full Prescribing Information, including boxed warning, or visit www.VIMIZIM.com.


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Overview of the “International Guidelines for the Management and Treatment of Morquio A...

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