Exploring New Treatment Advances for Acid sphingomyelinase Deficiency

Exploring New Treatment Advances for
Acid Sphingomyelinase Deficiency in Adults
Neal Weinreb, MD, FACP
Voluntary Associate Professor of Human Genetics
University of Miami
Miller School of Medicine

Disclosures
Advisory board/panel: Avrobio, Pfizer, Sanofi, Takeda
Speaker’s bureau: Sanofi
Consultant: Pfizer, Sanofi
i3 Health has mitigated all relevant financial relationships

Learning Objectives
ASMD = acid sphingomyelinase deficiency; ASM = acid sphingomyelinase.
Assess the clinical presentation and diagnostic workup of chronic
ASMD in adults
Evaluate the mechanism of action, efficacy, and safety of ASM
enzyme replacement therapy for chronic ASMD in adults as elucidated
by recent clinical trials
Monitor and manage the multisystemic manifestations of ASMD
Counsel patients on supportive services for patients with ASMD,
including social services, genetic counseling, family counseling, and
patient/caregiver support groups

Acid Sphingomyelinase Deficiency
ASMD, historically known as Niemann-Pick disease (NPD) Types A, A/B and B, is
a rare, autosomal recessive disorder caused by a deficiency of acid
sphingomyelinase resulting from mutations in the SMPD1 gene
Sphingomyelins and other secondary lipid substrates such as cholesterol accumulate in
cells of the mononuclear phagocytic system and in other cells such as hepatocytes
Organs affected: liver, spleen, hematopoietic marrow, lungs, nervous system, and
skeletal system
Estimated worldwide incidence is 0.4 to 0.6 in 100,000 newborns
Current numbers are likely underestimated
Panethnic
Specific types of ASMD are more prevalent in certain ethnic groups,
eg, ASMD Type A (NPD A) in persons of Ashkenazi Jewish descent
Males and females equally affected
SMPD1 = sphingomyelin phosphodiesterase 1.
McGovern, Dionisi-Vici et al, 2017; McGovern, Avetisyan et al, 2017; McGovern et al, 2008; Schuchman, 2007; McGovern et al, 2013; Villarubia et al, 2015.

Lysosomal Hydrolase Deficiencies and Sphingolipid Accumulation
GalCer = galactosylceramide; GalCeramidase = galactosyl ceramidase GCS = glucosylceramide synthase;
SM = sphingomyelin; ⍺-gal = alpha galactosidase; GSL = glycosphingolipid.
Xu et al, 2010.
Galactosylceramide Ceramide Sphingomyelin
Galcerebroside-3-SO3 Glucosylceramide
(GL-1)
Globotriasylceramide
(GL-3)
Lactosylceramide Gangliosides
Downstream GSLs
derived from GL-1
3 main classes of
sphingolipids
X
X
X X
X
X
GalCer synthase
GalCeramidase
SM synthase
Sphingomyelinase
Aryl sulfatase
GL-3 synthase
α-Gal
Sialyl transferases
Glycosyl transferases
β-hexosamindase
β-galactosidase
Fabry disease
Gangliosidoses, Tay-Sachs, and others
ASMD
Krabbe Disease
Metachromatic
leukodystrophy
Glucocerebrosidase
Gaucher disease GCS

Clinical Spectrum of ASMD
Photo courtesy of the Pender and Ayik families on NNPDF.org.
McGovern, Dionisi-Vici et al, 2017.
ASMD Type A
NPD Type A
ASMD Type A/B
Intermediate NPD
NPD A/B
ASMD Type B
NPD Type B
Onset Early infancy Infancy to childhood Infancy to adulthood
Phenotype
Rapidly progressive,
progressive, severe
visceral disease and
and
neurodegeneration;
;
cherry red spot
Slowly progressive, variable
variable visceral disease and
and neurodegeneration that
that includes developmental
developmental delay,
intellectual disability, ataxia,
ataxia, and peripheral
neuropathy
Slowly progressive,
variable visceral disease
with little or no neurologic
neurologic involvement
Life expectancy Death by age 3
Death from childhood to
mid-adulthood
Death from childhood to
to late adulthood
MOST SEVERE INTERMEDIATE SEVERITY LEAST SEVERE

ASMD is an autosomal
recessive disorder
ASMD is caused by
pathogenic variants in
both parental copies of
the SMPD1 gene
ASMD and Gaucher Disease: Inheritance
Wasserstein & Schuchman, 2021.
Carrier mother
(unaffected)
Carrier father
(unaffected)
Normal
gene
Gene with
pathogenic
variants
Unaffected
child
Affected
child
Carrier child
(unaffected)
Carrier child
(unaffected)

Gaucher Disease and ASMD Pathways
Lyso = lysolipid; Lyso-GL-1 = glucosylsphingosine; AC = acid ceramidase.
Xu et al, 2010; Ishibashi et al, 2003; Stirnemann et al, 2017; Villarubia et al, 2015.
GL-1
GCS
Glucocerebrosidase
Sphingomyelin
Sphingomyelin synthase
Ceramide
Acid sphingomyelinase
X X
AC
Lyso-Sphingomyelin
AC
Lyso-GL-1
Accumulation within the
lysosomes of
monocyte/macrophage system
Gaucher disease ASMD

Gaucher Type I
ASMD Type A/B and
B
Splenomegaly
Hepatomegaly
Hematologic abnormalities
• Anemia
• Thrombocytopenia
Bone involvement
• Erlenmeyer flask deformity
• Osteonecrosis
• Osteopenia
• Bone marrow infiltration
• Pathologic fracture
• Bone pain
Pulmonary involvement
• Interstitial lung disease
Rare
Dyslipidemia
• Low HDL
• Low total
cholesterol
• Low LDL
• Normal triglycerides
triglycerides
• Low HDL
• High total
cholesterol
• Elevated LDL
• Elevated
triglycerides
Liver disease
• Liver fibrosis
• Cirrhosis
• Liver dysfunction (elevated ALT/AST)
Infrequent
Cardiac disease
• Coronary artery disease/heart valve disease
None to rare ASCVD
ASMD Clinical Presentation in Adults
HDL = high-density lipoprotein; LDL = low-density lipoprotein; ALT = alanine transaminase; AST = aspartate aminotransferase; ASCVD = atherosclerotic cardiovascular disease.
Pastores & Hughes, 2023; Kaplan et al, 2006; Faden et al, 2009; Baris et al, 2014; McGovern, Avetisyan et al, 2017; McGovern, Dionisi-Vici et al, 2017; Charrow et al, 2000; McGovern et al, 2004.
Growth retardation
Atherogenic lipid profile
Pathologic fracture
Pulmonary
involvement
Thrombocytopenia
Osteopenia
Osteonecrosis
Bone marrow
infiltration
Cherry red macula
Bone pain
Hepatomegaly
Anemia splenomegaly
Erlenmeyer flask
deformity
ASMD & Gaucher Disease ASMD Gaucher Disease

Morbidity and Mortality in Chronic ASMD
McGovern et al, 2013.
10-year natural history study in 103 patients with ASMD
ASMD Type A/B (n=8) and ASMD Type B (n=95)
Serious morbidities associated with ASMD in this study included clinically significant hepatic,
cardiac, and neurologic diseases
Median age at death in 18 patients: 15.5 years (range: 1-72 years)
Most common causes of death
Pneumonia/respiratory failure (5 patients)
Liver failure (3 patients)
Bone marrow transplant complications (3 patients)
Causes of death in the remaining 7 patients
Hemorrhage (post-op bleed, splenic vein tear, subdural hematoma), liver cancer, congestive
heart failure, multisystem failure, unknown

Establishing the Diagnosis
Wasserstein & Schuchman 2021; Pastores & Hughes, 2023; Mistry et al, 2011; McGovern, Dionisi-Vici et al, 2017; Bronstein et al, 2014;
McGovern, Avetisyan et al, 2017.
Enzyme Activity
ASMD: acid sphingomyelinase enzyme assay
• <10% residual activity
• Residual activity does not predict clinical
outcome
• Consider ordering in parallel, or if
glucocerebrosidase is normal
Gaucher disease: glucocerebrosidase enzyme
assay
• Adults: usually 10%-30% of normal
• Children (severe cases) <10% of normal
• Residual activity does not predict clinical
outcome
Genetic Testing (DNA Sequencing)
ASMD: SMPD1 gene sequencing
• 2 pathogenic variants in trans
• ΔR610 appears to be neuroprotective, common
in chronic visceral form in multiple ethnic
groups
Gaucher disease: GBA gene sequencing
• 2 pathogenic variants in trans
• 6 variants account for 97% of all pathogenic
variants in patients of Ashkenazi heritage:
N370S, R496H, V394L, 84insG, A→1G+IVS2,
and L444P
• N370S is neuroprotective

SMPD1 Gene, cDNA, and Translated ASM Protein
cDNA = copy deoxyribonucleic acid.
Breiden & Sandhoff, 2021.
The gene SMPD1 of the ASM has been mapped to the chromosomal region
11p15.4
Mature human ASM domains:
Signal peptide
Amino acids 1–46
Sap-domain
Amino acids 89–165
Proline-rich domain
Catalytic metallophosphatase
domain
C-terminal domain
N-glycosylation sites and
disulfide bridges

SMPD1 Gene Sequencing
McGovern, Dionisi-Vici et al, 2017; Zampieri et al, 2016.
Gene sequencing analysis
revealed known mutations of
the SMPD1 gene for the
chronic visceral ASMD
phenotype1:
Homozygous
c.1829_1831delGCC
(p.ΔR610)
p.ΔR610 is the most
frequently reported
mutation worldwide,
and is associated with an
attenuated chronic visceral
ASMD phenotype
p.Q294K and
p.W393G
Chronic Neurovisceral
ASMD
Infantile Neurovisceral
ASMD
Homo- or
heteroallelic
p.ΔR610, p.P323A,
and p.P330R
(neuroprotective)
Chronic Visceral
ASMD
Known genotype/phenotype correlations, eg:
Unknown genotype/phenotype correlations:
Clinical assessment to determine phenotype
SMPD1 gene sequencing
Homoallelic for p.R498L,
p.L304P and
p.P333sfs*52
(Ashkenazi founder
mutations)

Algorithm for the Laboratory Diagnosis of ASMD
DBS = dried blood spots; VUS = variants of uncertain significance.
Geberhiwot et al, 2023.
Clinical Suspicion
ASM Activity
Leukocytes (DBS)
NP Biomarkers
Plasma (DBS)
SMPD1 Sequencing
Borderline Normal
Deficient
Abnormal profile Normal
Biallelic pathogenic variants
1 pathogenic variant and/or
VUS or no variants
Genetic Counseling
Not ASMD
=> Assess biomarkers
if not done and/or genetic tests
ASMD Confirmed
Assay ASM if not done before
=> If not done, assess ASM activity
And biomarkers
If ASM deficient, discuss more refined genetic tests
ASMD Confirmed
=> add genetic tests

Case Study
Case courtesy of Dr. Eugen Mengel and modified by Dr. Neal Weinreb.
The patient stated that his overall health had
always been good
He did not mention any physical impairments,
although he rarely participated in sports or
outdoor activities
He completed a university education at 23 years
of age and has been able to perform his job
duties without limitations
A 31-year-old male
presented to his
primary care
physician with a
swollen and tender
abdomen and
excessive bruising
on his right leg

Case Study (cont.)
RR = respiratory rate; SpO2 = oxygen saturation; BP = blood pressure; BMI = body-mass index.
Johns Hopkins Medicine, 2023; ACS, 2020.
Clinical Examination at Presentation: Age 31 Years
A 31-year-old male
presented to his
primary care
physician with a
swollen and tender
abdomen and
excessive bruising
on his right leg
● Temperature: 99.1F (37.3C), orally (average normal 98.0 F-98.6 F [36.6C-37C])
● RR: 22 breaths per minute (normal RR adults at rest: 16-20 breaths per min)
● SpO2 (RA, rest) 95% (normal young adult 95%-98%)
● BP: 110/68 mm Hg (normal BP in adults: 120/80 mm Hg)
● Pulse: 80 beats per min (normal pulse in adults: 50-80 beats per minute)
Vital signs:
Physical examination:
● Height: 170.4 cm (67.1 in)
● Weight: 64.4 kg (142 lbs)
● BMI: 22.2 (normal: 18.5-24.9)
● Cranial nerve examination: normal
findings

Clinical Examination:
Testing and Imaging:
Case Study (cont.)
EOM = extraocular movement; LUQ = left upper quadrant; EKG = electrocardiography; FVC = forced vital capacity; FEV1 = forced expiratory volume in 1 second;
DLCO = diffusing capacity for carbon monoxide.
Chow et al, 2016.
Clinical Examination at Presentation: Age 31 Years
Respiratory:
FVC: 133% (normal: >80%)
FEV1: 118% (normal: >80%)
DLCO: 107% predicted, no diffusion dysfunction
Abdominal Ultrasonography:
Marked hepatosplenomegaly
Spleen craniocaudal length: 18.7 cm
• Normal spleen size in adults: ~11 cm
• 70% larger than normal
Eyes:
No EOM
abnormalities
Cardiovascular:
EKG: normal findings
Echocardiography: normal findings
Abdomen:
Enlarged liver
Tender LUQ
A 31-year-old male
presented to his
primary care
physician with a
swollen and tender
abdomen and
excessive bruising on
his right leg

Case Study (cont.)
aRoutine blood work for work physical. Abnormal values prompted annual follow-up.
TG = triglycerides.
Pagana et al, 2014; Lopez-Jimenez, 2015; Thein et al, 2017.
Laboratory Test (Normal Value)
Value:
Age 30 yearsa
Value:
Age 31 years
ALT (4-36 U/L) 24 21
AST (≤35 U/L) 37 29
Hemoglobin (14-18 g/dL) 12.9 12.5
Leukocytes (5,000-10,000 mm3) 4,100 3,800
Platelets (150,000-400,000 mm3) 102,000 73,000
TG (40-160 mg/dL) 172 194
Cholesterol (<200 mg/dL) 223 236
HDL-C (>45 mg/dL) 36 32
LDL-C (<130 mg/dL) 194 202
LDL/HDL ratio (<3.5:1) 5.4 6.3
Chitotriosidase (20.0 to 267.1 mU/mL) ND 1,995
Relevant Laboratory Results

Despite normal lung function
test results, unenhanced
transverse CT revealed mild
interlobular septal thickening
in the mid-lung zone
Radiologic findings and lung function tests may not
always correlate in patients with chronic visceral ASMD
Case Study (cont.)
CT = computed tomography.
Mendelson et al, 2006.
CT of Thorax

• Interstitial lung disease
• Thrombocytopenia
• Atherogenic dyslipidemia
• Hepatosplenomegaly
• (Characteristic but not
pathognomonic findings for ASMD B)
Case Study (cont.)
Wasserstein & Schuchman, 2021.
Summary of Patient’s Signs and Symptoms
Adult

Case Study (cont.)
Beutler & Saven, 1990.
The following diseases/conditions were ruled out:
Pulmonary diseases
Pulmonary edema, cystic fibrosis
Diabetes mellitus
Normal fasting blood sugar and hemoglobin A1c (HbA1c) test results
Leukemia/lymphoma
Bone marrow biopsy revealed presence of classic foamy macrophages.
(Bone marrow biopsy could have been avoided had ASMD been previously
considered)
Gaucher disease
Normal glucocerebrosidase enzyme activity
Differential Diagnosis

Case Study (cont.)
McGovern, Dionisi-Vici et al, 2017; Wasserstein & Schuchman, 2021.
ASM enzyme testing
showed reduced ASM
enzyme activity in
leukocytes:
0.7553 nmol/mg/17 h
(normal range: 8.8-30.62
nmol/mg/17 h)
Residual enzyme activity:
4.51% of normal levels
ASM Active Enzyme Testing
• When a patient presents with signs and
symptoms and clinical test results indicative of
ASMD, ASM enzyme testing is the next step in
the diagnostic process
• Simultaneous testing of glucocerebrosidase
activity to rule out Gaucher disease is
recommended
• Testing can be performed using dried blood
spots, leukocytes, peripheral blood
lymphocytes, and cultured skin fibroblasts
• Residual ASM enzyme activity of <10% of
normal levels suggests ASMD

Case Study (cont.)
A diagnosis of chronic visceral ASMD was
made based on clinical presentation and
laboratory results:
Family history of ASMD (retrospective!)
Reduction of ASM enzyme activity in leukocytes
dyslipidemia
Elevation of chitotriosidase levels
Hepatosplenomegaly
Intralobular interstitial thickening in the
mid-lung
Lung involvement is common in chronic visceral
ASMD1
Gene sequencing revealed known mutations of
the SMPD1 gene: ΔR610
McGovern et al, 2013; Mendelson et al, 2006.
Diagnosis: Chronic Visceral ASMD
Although patients with chronic
visceral ASMD can live into
adulthood, many die before
reaching their 20s. Throughout
their lifetime, they may also
experience ongoing health
concerns involving lung
disease and thrombocytopenia
(characterized by bruising and
bleeding)

Case Study (cont.)
At 32 years of age, the patient continues to have no neurologic signs, as would
be expected, and no growth impairment or skeletal involvement
He continues to be in good general health, experiencing 2 intermittent, mild lung
infections over the past year
He subjectively reports no physical impairment and continues to work without
limitations
He has refrained (due to splenomegaly) from participating in activities that put
him at risk of bruising and bleeding, such as contact sports
The patient continues to be under surveillance for:
Changes in his activity levels, bleeding, shortness of breath, abdominal pain, neurologic
function, laboratory parameters, pulmonary function,
and worsening of interstitial lung disease
Patient Outcome: Chronic Visceral ASMD

ASMD Impact and Burden: Patient and Caregiver Perspective
Pokrzywinski et al, 2021.
Most common disease manifestations:
Respiratory (n=26, 89.7%)
Abdominal (n=25, 86.2%)
Musculoskeletal symptoms (n=23, 79.3%)
Excessive bleeding or bruising (n=20, 69%)
Fatigue (n=20, 69%)
Gastrointestinal symptoms (n=18, 62.1%)
Headache (n=15, 51.7%)
Dermatologic (skin tightness, rashes, and warts)
Little is known about how ASMD symptoms affect the lives of patients and their
caregivers
17 adult patients (mean age 38.7 years) and 3 caregivers
12 pediatric/adolescent patients with ASMD (mean age 10.5 years) and 12 caregivers
Negative impact on patients:
Physical function (n=23, 79.3%)
Self-esteem (n=18, 62.1%)
Emotions (n=16, 55.2%)
Social function and relationships
(n=16, 55.2%)
Personal care (n=9, 31%)

ASMD Impact and Burden: Patient and Caregiver Perspective (cont.)
Pokrzywinski et al, 2021.
“I have lost sleep because I was in pain and especially because
not just the liver, but just general abdominal pain... it’s just—it’s
uncomfortable. As much as I don’t like the pain, it’s just
uncomfortable. That’s why I can’t sleep”
“Bones…especially when I was a kid, I had really, really bad
bone pain, and I still get it it… .I know it’s bone, I know it’s not
muscular”
“He feels that he looks like a bit of a wimp because he can’t do
contact sports, can’t carry his bag, you know, there are a lot of
things he can’t do, so he’s very self-conscious of that”
“She was bullied when she started high school. I don’t know if
it’s a girl thing or generally because she’s quite short”
Little is known about how ASMD symptoms affect the lives of patients and their
caregivers
17 adult patients (mean age 38.7 years) and 3 caregivers
12 pediatric/adolescent patients with ASMD (mean age 10.5 years) and 12 caregivers
Negative impact on caregivers
Emotional well-being (n=12, 80%)
Social function (n=4, 26.7%)
Relationships (n=6, 40%)
Financial security (n=7, 46.7%)
Physical toll of providing care; need
for lifestyle changes
Responsibility for making medical
decisions

Summary
LSD = lysosomal storage disorders.
Mistry et al, 2011; McGovern, Avetisyan et al, 2017.
Gaucher disease and ASMD are inherited diseases caused by lysosomal enzyme deficiencies.
Progressive accumulation of glucosylceramide and sphingomyelin respectively within the
monocyte/macrophage system may cause debilitating hematologic, visceral, and skeletal
manifestations. In ASMD, functionally significant excesses of sphingomyelin can be found in many
cell types
Signs and symptoms may be non-specific, resulting in delayed diagnosis or misdiagnosis.
Because patients often present with thrombocytopenia and splenomegaly, they are frequently
referred to hematologists for evaluation and diagnosis
Both diseases can be diagnosed with a blood test that measures enzyme activity. Testing is widely
available from various commercial laboratories
Diagnostic delay can lead to irreversible complications that impact quality of life and longevity.
Hematologists should always consider a diagnosis of Gaucher disease when consulting on
patients with otherwise unexplained blood cytopenias and hepatosplenomegaly, and test for
ASMD if testing for Gaucher is negative. Parallel testing for both LSDs may sometimes be
reasonable

Treatment of ASMD B and A/B
Xu et al, 2010; Ishibashi et al, 2003; Villarrubia et al, 2015.
Sphingomyelin
Sphingomyelin synthase
Ceramide
Acid sphingomyelinase
X
ASMD
Lyso-Sphingomyelin
Accumulation within the
lysosomes of
monocyte/macrophage system
AC
Olipudase Alfa

Acid Sphingomyelinase Is a Promiscuous Phospholipase C
PC = phosphatidylcholine.
ASM is mostly thought to hydrolyze sphingomyelin
to ceramide
>20 different phospholipids are cleaved by ASM in
vitro, including phospholipids like growth factor
ceramide-1-phosphate and lysosomal lysolipid
bis(monoacylglycero)phosphate
ASM is important to several major cellular
functions involved in regulating an increasing
number of metabolic disorders
The extent to which infused and endocytosed
ASM participates in these additional ASM
functions requires further study and is a possible
concern when evaluating overall treatment efficacy
and safety

Topology of ASM Processing
NPC = Niemann-Pick disease protein C Type 2.
Pro-ASM matures to the active forms in the
endolysosomal compartment
If L-ASM cannot interact with the intraendolysosomal
luminal vesicles, the enzyme is degraded by
cathepsins (inactivated ASM)
This process leads to higher levels of sphingomyelin
Disturbed membrane homeostasis
Inactivation of other sphingolipid hydrolases and NPC2
Blocked cholesterol egress and accumulation
Lysosome membrane permeabilization (LMP), which
triggers autophagy and cell death by apoptosis and
apoptosis-like pathways
Pro-ASM is generated from pre-pro-ASM within the Golgi, mannose-6-phosphorylated, and
transferred by mannose-6-phosphate receptor–mediated vesicles to the endolysosomal
compartments (L-ASM) or, alternatively, secreted (S-ASM)

Autophagy-Lysosomal Pathway Dysfunction
LOF = loss of function; MPS = mucopolysaccharidoses.
Monaco & Fraldi, 2020.
Protein Aggregation Generates a Vicious Cycle in LSDs
LOF mutations in
lysosomal hydrolases or
in proteins involved in
lysosomal function
Lysosomal degradation
flaw and primary storage
Autophagy impairment
Amyloid protein
aggregation
α-synuclein, tau, Aβ
Neurodegeneration
Impairment of lysosomal enzyme trafficking
(as in Gaucher disease)
• Alteration of lysosomal distribution impairment
of the autophagosome clearance (as in MPSs)
• Other mechanisms

Cellular Pathogenesis of GD and ASMD B
GD = Gaucher disease.
Roh et al, 2022; Canonico et al, 2016.
The pathophysiological processes in GD that are interactive,
variably stimulated or suppressed, and potentially either adaptive or
deleterious, leading to several downstream complications
associated with oxidative stress and inflammation
Defective ASMase and lysosomal storage could lead to a reduced
ability of lysosomes to fuse with autophagosomes. This in turn
could result in a partial block of autophagy maturation and defective
degradation, accompanied by accumulation of autophagic
vacuoles, peroxidized lipid droplets and aberrant mitochondria
(autophagic stress)

Olipudase Alfa Placebo-Controlled Clinical Trial: Adults
SRS = splenomegaly-related score.
Wasserstein et al, 2022.
Eligible
(n=36)
R
A
N
D
O
M
I
Z
E
D
1:1
Olipudase alfa
(n=18)
Placebo
(n=18)
Completed
52 weeks
(n=18)
Completed
52 weeks
(n=17)
Assessed for eligibility n=62
• Withdrawn consent n=2
• Failed screening n=24
Patients may have multiple reasons for failing
20 failures to meet inclusion criteria
• Spleen volume (n=6)
• DLCO (n=5)
• SRS (n=6)
• Informed consent (n=2)
• Documented ASM deficiency/clinical ASMD
diagnosis
5 exclusion criteria met
• Medical conditions (n=2)
• Platelet count (n=1)
• ALT or AST (n=1)
• Unable to adhere to study requirements
(n=1)
1 patient discontinued due to noncompliance

Olipudase Alfa: Adult Trial
Pulmonary Response
HRCT-ILD = high resolution CT–interstitial lung disease;
LSmean = least square mean; SE = standard error.

Olipudase Alfa: Adult Trial (cont.)
MN = multiples of normal.
Spleen and PLT Responses

Olipudase Alfa: Adult Trial (cont.)
Wasserstein et al, 2022; Jones et al, 2020.
Liver and Plasma Lipid Responses

Olipudase Adult Trial (cont.)
AE = adverse events; URI = upper respiratory tract infection; Bx = biopsy; TIA = transient ischemic attack.
All patients (n=18/18) experienced ≥AE:
olipudase alfa (NAE=242) and placebo (NAE =267)
No event led to permanent treatment discontinuation or
study withdrawal
Most AEs were mild (olipudase: 190/242 [79%]; placebo:
206/270 [76%])
No serious AEs were considered potentially related to the
study drug
Treatment-related AEs (including infusion-related events):
olipudase 12/18; placebo 6/18
The frequency of clinically significant abnormalities in lab
findings, vital signs, ECGs, or echocardiograms was
similar between treatment groups
Safety and Adverse Events
Serious AEs
None treatment-related
Olipudase: 3 patients (5 events)
• Bleeding post-liver Bx, cellulitis, viral
gastritis, TIA, lower-limb fracture
Placebo: 4 patients (11 events)
• Bleeding post-liver Bx, epistaxis (3),
liver abscess, appendicitis, peritonitis,
anemia, syncope, hemorrhagic shock,
and pleural effusion
Most Common AEs
Headache
Nasopharyngitis
Arthralgia
URI
Cough

Olipudase Adult Trial (cont.)
LFT = liver function test; DLT = dose-limiting toxicity; IAR = infusion-associated reactions.
Dose-limiting toxicities (LFT abnormalities ranked 1-3 by
severity):
Olipudase DLT1: 1 patient
Placebo DLT2: 4 patients (6 events); DLT3: 1 patient
IARs considered manifestations of hypersensitivity:
1 patient in the olipudase group (2 events of erythema and
urticaria)
2 placebo patients (2 events of erythema and 1 each of pruritus,
erythematous rash, and infusion site urticaria)
No reported cases of acute phase reactions of cytokine release
syndrome
Anti-drug antibodies (ADAs)
Baseline: olipudase (n=2/18), placebo (n=4/18); none had a
treatment-boosted response
Treatment-induced ADAs: olipudase (n=4; 2 transient and 2
persistent low titer); placebo (n=1; transient)
No neutralizing Abs that inhibited olipudase cellular uptake
Safety and Adverse Events
Serious AEs
None treatment-related
Olipudase: 3 patients (5 events)
• Bleeding post-liver Bx, cellulitis, viral
gastritis, TIA, lower-limb fracture
Placebo: 4 patients (11 events)
• Bleeding post-liver Bx, epistaxis (3),
liver abscess, appendicitis, peritonitis,
anemia, syncope, hemorrhagic shock,
and pleural effusion
Most Common AEs
Headache
Nasopharyngitis
Arthralgia
URI
Cough

Olipudase Alfa Pediatric Trial
Diaz et al, 2021.
Biomarker Responses

These highlights do not include all the information needed to use olipudase
alfa safely and effectively. See full prescribing information for olipudase alfa.
________________________________________________________________________
WARNING: SEVERE HYPERSENSITIVITY REACTIONS
See full prescribing information for complete boxed warning.
Hypersensitivity Reactions Including Anaphylaxis
• Appropriate medical support measures, including cardiopulmonary
resuscitation equipment, should be readily available. If a severe
hypersensitivity reaction occurs, olipudase alfa should be discontinued
immediately and appropriate medical treatment should be initiated.
_____________________________________________________________________
——————————— RECENT MAJOR CHANGES ———————————
Dosage and Administration, Preparation Instructions 3/2023
——————————— INDICATIONS AND USAGE ———————
Olipudase alfa is a hydrolytic lysosomal sphingomyelin-specific enzyme
indicated for treatment of non–central nervous system manifestations of acid
sphingomyelinase deficiency (ASMD) in adult and pediatric patients.
—————————— DOSAGE AND ADMINISTRATION ————————
• Prior to initiating treatment, verify pregnancy status in females of
reproductive potential and obtain baseline transaminase levels.
• Consider pretreating with antihistamines, antipyretics, and/or
corticosteroids.
• Adults: Recommended starting dose is 0.1 mg/kg administered as an
intravenous infusion.
• Pediatrics: Recommended starting dose is 0.03 mg/kg administered as an
intravenous infusion.
• See Full Prescribing Information for the recommended dose escalation and
maintenance dosage, dosage modifications to reduce the risk of adverse
reactions, and preparation and administration instructions.
———————WARNINGS AND PRECAUTIONS —————————
• Infusion-Associated Reactions (IARs): If severe IARs occur, discontinue
olipudase alfa and initiate appropriate medical treatment.
• Elevated Transaminases: Assess ALT and AST within one month prior to
initiation of olipudase alfa, within 72 hours prior to any infusion during dose
escalation, or prior to the next scheduled olipudase alfa infusion upon
resuming treatment following a missed dose.
• Pregnancy: Olipudase alfa dosage initiation or escalation, at any time
during pregnancy, is not recommended as it may lead to elevated
sphingomyelin metabolite levels that may increase the risk of fetal
malformations. Advise females of reproductive potential to use effective
contraception during treatment and for 14 days after the last dose if olipudase
alfa is discontinued.
————————— ADVERSE REACTIONS ———————————
• Most common adverse reactions in adult patients (incidence ≥10%) are
headache, cough, diarrhea, hypotension, and ocular hyperemia.
• Most common adverse reactions in pediatric patients (incidence ≥20%) are
pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache,
urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis.
Highlights of Prescribing Information
Xenpozyme® prescribing information, 2023.

Summary: Enzyme Replacement Trials for ASMD
ERT = enzyme replacement therapy; IV = intravenous.
Xenpozyme® prescribing information, 2023; Wasserstein et al, 2022; Diaz et al, 2021.
The pooled safety analysis from 3 clinical trials included a total of 38
olipudase-treated patients (30 adult, 8 pediatric) between 1.5-59 years old
receiving IV doses up to 3 mg/kg every 2 weeks. The median exposure
duration was 2.5 years (range: 0.4 to 3.7 years) in adult patients and 2.7 years
(range: 2.5 to 3.2 years) in pediatric patients
In adult patients, improvement in pulmonary function, high-resolution CT
lung imaging, spleen and liver volumes, thrombocytopenia, plasma HDL and
LDL, ALT, lyso-SM, and chitotriosidase were observed during Year 1 of ERT
In children (no ASMD A), major decreases in lyso-SM and chitotriosidase and
normalization of liver transaminases occurred by Week 26. Improvements in
liver and spleen volumes, DLCO, plasma lipid profiles and height Z-scores,
noted at Week 26, continued at Week 52
A and A/B

Summary: Enzyme Replacement Trials for ASMD (cont.)
CNS = central nervous system.
Xenpozyme® prescribing information, 2023; Wasserstein et al, 2022; Diaz et al, 2021.
IARs occurred in approximately 75% of pediatric and 50% of adult olipudase-
treated patients in the clinical trials; a severe IAR occurred in 1 (12.5%) of the
pediatric patients. There is a “black box” warning re: hypersensitivity
reactions
Dose escalation protocols are required for adults and children to achieve
recommended maximal therapeutic doses (see drug label). Antihistamines,
antipyretics, and/or corticosteroids may be given prior to olipudase
administration to reduce the risk of IARs; however, IARs may still occur in
patients after receiving pretreatment
Because olipudase does not cross the blood-brain barrier, it is unlikely that
neuronopathic manifestations in children and adults will be either
ameliorated or prevented unless, has been suggested for type 3 GD,
suppression of systemic inflammatory mediators that may be active in the
CNS, may also reduce neuroinflammatory manifestations
A and A/B

S1P = sphingosine-1-phosphate; GD-1 = Gaucher disease Type 1.
Xenpozyme® prescribing information, 2023.
Olipudase is not recommended for use in pregnancy because of
potential for fetal malformations on exposure to ceramide or S1P
Other than hypersensitivity reactions and increased transaminases,
the other reported side effects appear to be minor
Information on whether late complications seen in patients with GD-1
such as certain malignancies or Parkinsonism are part of the natural
history of ASMD is minimal at this time
A and A/B
Summary: Enzyme Replacement Trials for ASMD (cont.)

Recommended Multidisciplinary Assessment
Discipline Features of ASMD for Which This Discipline May Be of Assistance
For All or
Needed
Primary care physician Assist with general medical care; coordinate specialists; provide support for family All
Metabolic diseases specialist
specialist
Diagnosis of ASMD and exclusion of other disorders in the differential diagnosis; ongoing patient
ongoing patient assessment for disease progression and response to therapy; coordinate the
coordinate the overall care working with primary care physical
All
Neurologist Assess the possible neurological manifestation of disease and manage All
Hepatologist Periodic assessments of liver derangements; manage impending/existing liver failure As needed
Hematologist Assess the risk of bleeding disorder and long-term complications As needed
Pulmonologist
Assess baseline respiratory functions and periodic assessment for deterioration; manage
pulmonary disease and its complications
As needed
Genetic counselor
Inform affected persons and their families regarding nature and implications of ASMD and to
and to facilitate medical and personal decision making; provide counseling for families as to
as to recurrence risk and options for prenatal diagnosis if desired
All
Lipidologist/cardiologist
Manage the mixed dyslipidemia, and perform cardiovascular risk assessment for indicated
indicated primary or secondary prevention interventions
As needed

Discipline Features of ASMD for Which This Discipline May Be of Assistance
For All or
Needed
Psychiatrist/clinical
psychologist
Assess for behavioral disturbances, depression, and manage accordingly As needed
Speech and language
therapist
Assess for dysphagia and aspiration risk; speech and feeding therapy for children with
with neuronopathic phenotypes
As needed
Occupational and physical
physical
therapists/rehabilitation
physician
Assess and develop aids and home adjustments as needed for patients with communication
communication and physical challenges
As needed
Nutritionists
Periodic assessments of nutritional status in patients who may be losing weight due to
to dysphagia or side effects of therapy; gastrostomy tube insertion as indicated
As needed
Social worker
Support of patients and families living with disabilities who require enhanced resources in
resources in the community
As needed
Developmental and
behavioral pediatrician
Assess for the presence or absence of developmental delays in children; recommend
appropriate therapies and educational interventions
As needed
Recommended Multidisciplinary Assessment (cont.)

Management: Clinical Evaluation and Monitoring
Recommended
Assessment
Rationale Frequency
For All or As
Needed
Baseline history
Establish natural history, systemic involvement, current level of disease
disease severity, and estimate rate of progression
At diagnosis All
Interval history
Establish rate of disease progression; monitor for compliance with and side
and side effects from therapy
Every 3-12 months/
each visit
As needed
Physical
examination
Document growth parameters, assess for neurological features and
organomegaly, assess for fatigue, abdominal pain, and/or bleeding
tendency
At diagnosis then
every 6-12 months/
each visit
As needed
Nutrition Evaluation of nutritional status and safety of oral intake
At diagnosis then each
each visit
As needed
Pulmonary
assessment
Assess recurrent chest infections
Assess for shortness of breath
At diagnosis then at
each visit
All
Pulmonary function testing including assessment of diffusing capacity in
capacity in persons old enough to cooperate
At diagnosis then
annually
As needed
Chest radiograph and/or high-resolution chest CT to assess extent of
interstitial lung disease
At diagnosis
regardless of age then
then every 2-4 years
All

Management: Clinical Evaluation and Monitoring (cont.)
Recommended
Assessment
Rationale Frequency
For All or As
Needed
Musculoskeletal
assessment
Assess for fractures and/or extremity pain
At diagnosis then
each visit
All
Neurologic
assessment
Comprehensive neurologic evaluation
At diagnosis then
annually
As needed
Ophthalmology
evaluation
Presence of cherry-red spots at baseline and document At diagnosis All
Cardiac assessment
assessment (adult
only)
EKG, echocardiogram, coronary angiogram as indicated
At diagnosis and
every 3-5 years
As needed
Blood investigations
investigations
Serum chemistries including LFTs, albumin, and clotting factors to evaluate
evaluate for progression of hepatic dysfunction
Complete blood count to evaluate for cytopenia and increased bleeding
bleeding
Measurement of lipid profile
At diagnosis then at
least annually
As needed
Imaging studies Radiologic measurements of liver and spleen size as needed
At diagnosis and as
needed
As needed

Management: Clinical Evaluation and Monitoring (cont.)
Recommended
assessment
Rationale Frequency
For All or
Needed
Swallowing
assessment
Swallowing assessment in all patients at risk; document presence of
of dysphagia and aspiration and response to therapy
At diagnoses and then every 6 months in
in children; in adults, frequency could be
be reduced to every 12 months if
asymptomatic with stable disease
As needed
Developmental
and cognitive
assessment
Developmental assessment, monitor developmental progress and
and educational needs (evaluation for early intervention/
special education)
At diagnosis then at each visit As needed
Document baseline degree of cognitive impairment including motor,
motor, adaptive, cognitive and speech/language and monitor
response to therapy
At diagnosis, every 6 months in children,
children, every 12 months in adults
As needed
Neuropsychiatric
c evaluation
Document psychiatric manifestations and response to therapy
At diagnosis then 6-12 months as
indicated
As needed
Family support
and resources
Assess need for family support and resources
Assess need for community or online resources such as Parent to
Parent; social work involvement for parental support
Home nursing referral
Assess for any change in social, domestic, or school or work-related
related activities
At diagnosis, then each visit As needed

International Niemann-Pick Disease Alliance (INPDA)
www. inpda.org
International Niemann-Pick Disease Registry (INPDR)
www. inpdr.org
The Niemann-Pick Disease Community

International Niemann-Pick Disease Registry Platform
A Common Framework and Community
Patients
Registry Team
Health Care
Advocates
INPDA
Health System
Administrators
Family
Caregivers
Physicians
Other Health
Care Providers
Regulatory
Authorities
Role-Based Registry Experience
Data In Data Out
Site-entered
data
Patient-
reported data
Standard
reports
Regulatory
reports Publications
Ad hoc reports

Key Takeaways
ASMD is a rare lysosomal disease which can present with severe life-
limiting neurological manifestations or in a delayed onset presentation
in which the manifestations are primarily an enlargement of the spleen
and liver, liver dysfunction with cirrhosis, chronic lung disease, and
atherosclerotic heart disease
ASMD is frequently misdiagnosed or diagnosed only after late
symptoms have developed
Effective treatment has now been approved which reverses many of
the systemic manifestations in patients with type B variant and
appears to reduce morbidity and hopefully prolong life expectancy

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