Robin Lachmann, MD, PhD, and Melissa Wasserstein, MD, prepared useful Practice Aids pertaining to acid sphingomyelinase deficiency for this CME activity titled “Assessing the Potential Role of Emerging Therapies in the Early Diagnosis and Optimal Management of Chronic Visceral Acid Sphingomyelinase Deficiency.” For the full presentation, complete CME information, and to apply for credit, please visit us at https://bit.ly/35KVwoE. CME credit will be available until June 3, 2021.

1. Clinical Manifestations
of Chronic Visceral ASMD1
PRACTICE AID
ASMD: acid sphingomyelinase deficiency; BMC: bone mineral content; BMD: bone mineral density; ILD: interstitial lung disease; NPD-B: Niemann-Pick disease type B.
1. McGovern MM et al. Orphanet J Rare Dis. 2017;12:41.
Skeletal Disease
Cardiac Disease
Neurological Manifestations
Pulmonary Disease
Disease of Spleen
Hematologic Abnormalities
Liver Disease
• Atherogenic lipid profile is typical (low HDL: 74%; high total
cholesterol: 41%; high triglycerides: 62%; high LDL: 46%;
very low–density lipoprotein cholesterol: 62%)
• Cardiac and cardiovascular disturbances manifest at an
early age (eg, elevated coronary artery calcium score)
• ~10% of patients have coronary artery or heart valve disease
• Cardiac disease accounts for >7% of deaths among adults
(with chronic visceral or chronic neurovisceral ASMD
[NPD-B and B variant])
• Liver fibrosis (88%), including minimal, mild, or moderate
fibrosis, and cirrhosis (13% of all fibrosis)
• Liver dysfunction (elevated ALT and AST) is common
(50%-75% of patients); however, in some cases LFT may
be normal despite detected localized or initial signs of
fibrosis or cirrhosis
• Together with pulmonary disease, liver failure is the most
common cause of death
• Majority of patients have back, limb, or joint pain
• Skeletal fractures are common
• Osteopenia and osteoporosis common in adults
• Decreased BMC and BMD in pediatric patients
• Adolescents often experience growth delay; adult height
at low normal range
• Bleeding is the third most common cause of death
• Easy bruising and excessive bleeding is common
• Among cytopenias, thrombocytopenia is most common (>50%
of patients); anemia and leukemia each affect approximately
20%-30% of patients
• Anemia rarely necessitates red blood cell transfusions
• Splenomegaly is a typical disease
manifestation (>90% of patients)
• Early diagnostic sign; symptoms include
pain, feeling of pressure, and early satiety
• Can be massive (up to 30 multiples of
normal); increased risk of potentially fatal
bleeding (rupture)
• Splenectomy not associated with better
outcomes, but indicated in case of spleen
rupture or extensive necrosis
• ILD (based on radiologic findings) present in >80% of patients
• Frequent respiratory infections, including pneumonia
• Leading cause of death, because of progressive loss of pulmonary function
• Present in ~30% of patients with NPD-B (“intermediate
phenotype”)
– Range from mild hypotonia/hyporeflexia to severe
progressive abnormalities (eg, loss of motor function,
cognitive impairment)
– Often present in patients with macular cherry red spots
– Associated with reduced life expectancy
Access the activity, “Assessing the Potential Role of Emerging Therapies in the Early Diagnosis and
Optimal Management of Chronic Visceral Acid Sphingomyelinase Deficiency,” at PeerView.com/NPH40

2. Diagnostic Algorithms for ASMD
Based on Consensus Recommendations1
PRACTICE AID
Diagnostic Algorithm for ASMD Presenting in Infancy and Childhood
• Infection
• Malignancy/lymphoma
• Other LSDs
• Liver disease
• CHF
• Hemolytic anemia
Rule out other causes
Splenomegaly ± hepatomegaly
• Cherry red maculae
• Developmental delay
• Hypotonia
• Low HDL-C
≥1 features suggestive of ASMD
No
Equivocal
Yes
Low
ASM enzyme activity Repeat enzyme assay
Known genotype/phenotype correlations
Homoallelic for p.R498L,
p.L304P, and p.P333Sfs*52
(Ashkenazi founder mutations)
Infantile neurovisceral
ASMD (NPD type A)
p.Q294K and p.W393G
Chronic neurovisceral
ASMD (NPD type A/B)
Homo- or heteroallelic p.ΔR610,
p.P325A, and p.P332R
(neuroprotective); p.W393G
Chronic visceral
ASMD (NPD type B)
SPMD1 gene sequencing
Unknown Genotype/Phenotype Correlations
Clinical assessment to determine phenotype
Access the activity, “Assessing the Potential Role of Emerging Therapies in the Early Diagnosis and
Optimal Management of Chronic Visceral Acid Sphingomyelinase Deficiency,” at PeerView.com/NPH40

3. Diagnostic Algorithms for ASMD
Based on Consensus Recommendations1
PRACTICE AID
ASM: acid sphingomyelinase; ASMD: acid sphingomyelinase deficiency; ILD: interstitial lung disease; LSDs: lysosomal storage disorders; MS/MS: tandem mass spectrometry; NPD: Niemann-Pick disease; SMPD1: sphingomyelin phosphodiesterase 1.
1. McGovern MM et al. Genet Med. 2017;19:967-974.
Diagnostic Algorithm for ASMD Presenting After Childhood
• Infection
• Malignancy/lymphoma
• Other LSDs
• Liver disease
• CHF
• Hemolytic anemia
Rule out other causes
Splenomegaly ± hepatomegaly
SPMD1 gene sequencing
Chronic visceral ASMD
• Low HDL-C
• ILD
• Pathologic fractures
≥1 features suggestive of ASMD
No
Equivocal
Yes
Low
ASM enzyme activity Repeat enzyme assay
Access the activity, “Assessing the Potential Role of Emerging Therapies in the Early Diagnosis and
Optimal Management of Chronic Visceral Acid Sphingomyelinase Deficiency,” at PeerView.com/NPH40

4. Olipudase Alfa for the Treatment
of ASMD in Pediatric and Adult Patients1-3
PRACTICE AID
Primary endpoints: lung disease measured by DLCO and
spleen volume measured by MRI (all sites) and SRS
(United States only)
Patient population: 36 adults (aged ≥18 years) with ASMD
in 16 countries
Treatment: randomized to receive OA 3 mg/kg IV
infusion every 2 weeks for 52 weeks or placebo
Secondary endpoints: safety of OA over 52 weeks and SRS
(all sites outside of the United States)
ASCEND
A phase 2/3 study evaluating the efficacy, safety, PD, and PK of OA in adult patients with ASMD
• ASMD: a rare lysosomal storage disorder with no approved treatments
• Olipudase alfa (OA): first and only enzyme replacement therapy in late-stage development for the treatment of ASMD
– OA designations: orphan drug, fast track, and breakthrough therapy PRIME Sakigake
• Lung function improvement: 22% with OA vs 3%
with placebo (P = .0004)
• Spleen volume: 39.5% reduction with OA vs
0.5% increase with placebo (P < .0001)
• SRS (United States only): 8.0-point reduction
with OA vs 9.3-point reduction with placebo
(P = .70)
• AEs and severe AEs occurred less often in
patients treated with OA compared with placebo
• Most common AEs occurring more often with
OA vs placebo: headache, nasopharyngitis,
URTI, cough, and arthralgia
Results
Access the activity, “Assessing the Potential Role of Emerging Therapies in the Early Diagnosis and
Optimal Management of Chronic Visceral Acid Sphingomyelinase Deficiency,” at PeerView.com/NPH40

5. Olipudase Alfa for the Treatment
of ASMD in Pediatric and Adult Patients1-3
PRACTICE AID
ASMD: acid sphingomyelinase deficiency; DLCO
: diffusing capacity of the lungs for carbon monoxide; PD: pharmacodynamics; PK: pharmacokinetics; SAEs: serious adverse events; SRS: splenomegaly-related score; URTI: upper respiratory tract infection.
1. https://nnpdf.org/research/clinical-trials/sanofi-genzyme-2/. 2. https://www.clinicaltrials.gov/ct2/show/NCT02004691?term=NCT02004691. 3. https://www.clinicaltrials.gov/ct2/show/NCT02292654?term=nct02292654.
ASCEND-Peds
A phase 1/2 study evaluating the safety, tolerability, PK, and efficacy of OA in pediatric patients with ASMD
OA global regulatory submissions expected to begin in the second half of 2021
Primary endpoints: safety and tolerability of OA over
64 weeks
Patient population: 20 children (aged ≤17 years) with ASMD
in 6 countries
Treatment: OA up to 3 mg/kg IV infusion every 2 weeks
for 64 weeks
Secondary endpoints: lung disease measured by DLCO
and spleen volume measured MRI
• All patients experienced at least one AE (mostly mild
and moderate)
• Five treatment-related SAEs were observed in three
patients: two asymptomatic ALT increases in one
patient, urticaria and rash in one patient, and an
anaphylactic reaction in one patient
• No patients permanently discontinued treatment
because of an AE
• Most common AEs: pyrexia, cough, vomiting,
nasopharyngitis, diarrhea, headache, URTI, contusion,
abdominal pain, nasal congestion, rash, urticaria,
scratch, and epistaxis
• Lung disease: improved by mean of 33% in nine
patients who performed the test at baseline
• Spleen volume: decreased by 49% (range: 23%-61%)
Results
Access the activity, “Assessing the Potential Role of Emerging Therapies in the Early Diagnosis and
Optimal Management of Chronic Visceral Acid Sphingomyelinase Deficiency,” at PeerView.com/NPH40