<h2>Objective</h2>
<ul>
 <li>To demonstrate benefits of differential diagnosis within primary diagnostic testing.</li>
 <li>To improve detection rate of potential ASMD, avoid diagnostic delays.</li>
</ul>

<h2>A multicenter, prospective study</h2>

DBS testing
<ul>
 <li>GBA enzyme activity</li>
 <li>ASM enzyme activity</li>
</ul>

Positive Cases
<ul>
 <li>Genetic confirmatory testing</li>
</ul>

<h3>Genetic confirmatory testing done for 5933 cases</h3>

SMPD1 gene sequencing for 1171 cases

GBA gene sequencing for 4762 cases

ASMD:GD varies by region

Overall,&nbsp;1 out of 4&nbsp;patients with suspected GD suffered from ASMD.

Overall, 51% of ASMD cases were newborns.

5933&nbsp;symptomatic cases showed decreased enzyme activities

227&nbsp;distinct SMPD1 sequence variants identified

10&nbsp;more frequent variants

<h3>Most of the cases with ASMD from the Middle East were newborns and with GD were adults.</h3>

<table align="center" border="1" cellpadding="1" cellspacing="1" style="width: 1120px;">
 <tbody>
 <tr>
 <td>
 &nbsp;Higher number of confirmed ASMD patients in Pakistan, Iraq, Turkey, and Iran</td>
 </tr>
 </tbody>
</table>

<h3>Egypt had the highest number of GD cases followed by Turkey, while Iraq had the highest number of ASMD cases.</h3>

Abbreviations

Reference

Differential diagnostics for ASMD in patients suspected to have GD

ACID-SPHINGOMYLENASE-DEFICIENCY-NIEMANN-PICK

RARE-DISEASE

<h2>RSV Is a Common Respiratory Virus With Symptoms Varying by Age-Group</h2>

References

<h2>RSV Causes Substantial Disease Burden for Newborns and Infants Globally</h2>

Based on 2019 global data.

RESPIRATORY-SYNCYTIAL-VIRUS

VACCINES

Burden of Disease

<h2>RSV is a Leading Cause of LRTIs Among Infants Worldwide1,2</h2>
Estimated Percentage of acute LRTI attributable to RSV infection

LRTI, lower respiratory tract infection. 
 Data&nbsp;are derived from different studies and over different years.
aOnly includes hospitalizations due to bronchiolitis; bRSV was a cause of 28% of all hospitalization cases in infants in France.&nbsp;

<h2>Prevalence in RSV hospitalized with bronchiolitis during seasonal epidemics</h2>

&nbsp;aCoronavirus type OC43, 229E, NL63, and HKU1. Age range of children not specified.

<h2>RSV Average Hospitalization days</h2>

<h3>6.5 days in hospital</h3>
total of 754 beds (502 inpatient beds, 56 emergency beds, 77 ICU beds, 32 psychiatry beds, and 87 special auxiliary beds).

AComorbidities assessed: congenital cardiopathies, 2.3%; congenital defects with cardiac affectation, 0.7%; prematurity, 0.3%; bronchopulmonary dysplasia, 1%.

<h2>RSV Causes Substantial Hospitalization Among All Infants and Young Children In Spain</h2>
Epidemiologic survey in Spain estimating the burden of RSV in all&nbsp;children &lt;5 years of age during a 15-year period (1997–2011)1

Due to bronchiolitis in children &lt;5 years of age

326,175
 hospital discharges

on average in children ≤2 years of age

5.9 days
 in hospital

highest incidence among all age ranges

4,136/100,000 incidence of hospitalization during 1st year of life

355 (80%)&lt;12 months of age 335 (75%) without comorbidities*

446
 deaths

Only 3.2% of children &lt;5 years of age presented with ≥1 comorbidity*

96.8 %&nbsp;of children were otherwise healthy

AComorbidities assessed: congenital cardiopathies, 2.3%; congenital defects with cardiac affectation, 0.7%; prematurity, 0.3%; bronchopulmonary dysplasia, 1%.

<h2>RSV Classification</h2>
RSV is a 15 kb negative sense single stranded RNA virus encoding 11 proteins1,2

Humans and chimpanzees are the&nbsp;only known natural hosts&nbsp;for human RSV, although a variety of small animal species may be experimentally infected with RSV (Calves, Ferrets, Rodents)2. Currently, there is&nbsp;no known RSV reservoir&nbsp;in the off-season5.

RSV is one of the&nbsp;last major causes&nbsp;of serious paediatric infections for which&nbsp;no vaccine&nbsp;or other&nbsp;wide-scale intervention&nbsp;is available1

RSV History

<h2>RSV is classified into two subtypes – RSV-A and RSV-B; based on variation in the G protein1</h2>

<h3>Appearance of RSV-A and RSV-B genotypes and dominance over time (1961–2014)1</h3>

<ul>
 <li>RSV-A and -B diverged in 17664</li>
 <li>RSV-A and RSV-B co-circulate</li>
 <li>Dominance shift between RSV-A and RSV-B types every 1-2 years2</li>
 <li>There are no significant differences in severity between RSV-A and B2</li>
</ul>
RSV-A
<ul>
 <li>9-16 distinct genotypes(GA1-GA7, SAA1, NA1-4 and ON1)3,5</li>
</ul>
RSV-B
<ul>
 <li>22-32 distinct genotypes(BA1-14, GB1-GB5, SAB1-4, URU1-2, NZB1-2, BA-CCA, BA-CCB, BA-C, CBB and CB)4,5</li>
</ul>
No consensus on RSV genotype definition6

<ul>
 <li>RSV&nbsp;is an enveloped, medium-sized (120 to 300 nm)&nbsp;RNA&nbsp;virus2</li>
 <li>Nonsegmented, single-stranded, negative-sense genome2</li>
 <li>The&nbsp;viral envelope&nbsp;has a bilipid layer derived from the plasma membrane of the host cells2</li>
 <li>Its surface has transmembrane surface glycoprotein spikes 11 to 12 nm in length and 6 to 10 nm apart2</li>
 <li>The&nbsp;10 viral genes&nbsp;are depicted by the divided bars2</li>
 <li>Each viral gene transcribes a single messenger RNA (mRNA) encoding a single protein, with the exception of M2 mRNA, which transcribes two proteins, M2-1 and M2-22</li>
</ul>

<h2>Classical FD (&lt;3% enzyme activity)</h2>

Neuropathic pain, angiokeratomas, and/or cornea verticillata are absent in females.

Childhood and adolescence

<table border="0" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td>
 <h3>Nonclassical or late-onset FD (3%–30% enzyme activity)</h3></td>
 </tr>
 <tr>
 <td>Variable disease course and single organ involvement</td>
 </tr>
 <tr>
 <td>Cardiac variant is common in late-onset FD</td>
 </tr>
 <tr>
 <td>Identified in patients with stroke, renal failure, or cardiomyopathy</td>
 </tr>
 <tr>
 <td>No neuropathic pain, angiokeratomas, and/or cornea verticillata</td>
 </tr>
 </tbody>
</table>

black

FD diagnosis requires a multidisciplinary team approach involving:

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">Biochemist</td>
 </tr>
 </tbody>
</table>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">Pediatrician</td>
 </tr>
 </tbody>
</table>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">Neurologist</td>
 </tr>
 </tbody>
</table>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">Cardiologist</td>
 </tr>
 </tbody>
</table>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">Dermatologist</td>
 </tr>
 </tbody>
</table>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">Nephrologist</td>
 </tr>
 </tbody>
</table>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">Geneticist</td>
 </tr>
 </tbody>
</table>

Suggested diagnostic algorithm for patient with clinically suspected FD

<h3>1.&nbsp;Lyso-Gb3 indicates severity of FD</h3>
2.&nbsp;Endomyocardial and renal biopsies are used
3.&nbsp;Genetic testing

<h3>Testing for FD</h3>

<ul>
 <li>Causative mutation</li>
 <li>Affected family members</li>
 <li>Eligibility for treatment with migalastat</li>
</ul>

LSD referral centers to manage FD from diagnosis to long-term follow-up

<table border="0" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td>
 Rare but underdiagnosed</td>
 <td>
 To be known and recognized by internal medicine physicians</td>
 <td>
 Early treatment can change the natural course of the disease.</td>
 </tr>
 </tbody>
</table>

FD:

*Eye involvement includes cornea verticillata, tortuous retinal vessels, cataracts, and conjunctival lymphangiectasia. 
 Rare but To be known and recognized by underdiagnosed internal medicine physicians α-Gal A: Alpha-galactosidase; eGFR: Estimated glomerular filtration rate; GLA: α-Galactosidase A; FD: Fabry disease; GI: Gastrointestinal; LSD: Lysosomal storage disease; Lyso-Gb3: Globotriaosylsphingosine; TIA: Transient ischemic attack.

DIAGNOSING FABRY DISEASE IN CLINICAL PRACTICE

FABRY

<h2>RSV Is Seasonal, With Peak Incidence Varying by Region1,2</h2>

<ul>
 <li>Temperate countries in the&nbsp;Northern Hemisphere&nbsp;generally experience the start of the RSV season between September and January.</li>
 <li>Those in the&nbsp;Southern Hemisphere&nbsp;generally experience the start of the RSV season between March and June, closely aligned with colder temperatures.</li>
 <li>The seasonality of RSV in&nbsp;(sub)tropical climates&nbsp;appears less consistent—with studies indicating peak of RSV season closely aligns with the rainy season and/or higher temperatures.</li>
</ul>

<h2>RSV is a highly transmissible viral disease</h2>

<ul>
 <li>RSV&nbsp;is transmitted by respiratory droplets and considered “highly contagious”9-11</li>
 <li>R0&nbsp;of&nbsp;&nbsp;4.5 
 mean R0&nbsp;ranging from 1.7 to 8.212</li>
</ul>

<h2>RSV shedding in Infants, toddlers and immunecompromised</h2>

Duration of Virus Shedding in Infants and Toddlers

Duration of Virus Shedding in Immunecompromised patients

<h2>Most Infants Are Exposed to RSV Infection in the Community and Through Other Children1-3</h2>

Crowding and day-care exposure significantly increased the risk of severe RSV disease4-6

In the United States,&nbsp;more than 50 per cent of under-ones&nbsp;are in some form of childcare;&nbsp;~75% from the age of 4 months7
Network showing the sources of infection to the infant, as identified by social relationships in Kenya.1 The size of the circles is proportional to the number of cases.

All Infant Protection

RSV is a leading cause of hospitalization in all infants

All infants need protection from RSV

<h2>Most Hospitalizations for RSV occur in Healthy Full Term Infants1-3</h2>

<a href="https://publications.aap.org/pediatrics/article-abstract/132/2/e341/31332/Respiratory-Syncytial-Virus-Associated?redirectedFrom=fulltext?autologincheck=redirected">Respiratory Syncytial Virus–Associated Hospitalizations Among Children Less Than 24 Months of Age | Pediatrics | American Academy of Pediatrics (aap.org)</a>
aEstimate includes previously healthy premature subjects &lt;37 weeks’ gestation, and less than 2 years old.

<h2>RSV Infant ICU Admissions and Mechanical Ventilation in the US1</h2>
Surveillance through the Influenza Hospitalization Surveillance Network from October 2014-April 2015

Infant RSV ICU Admissions&nbsp;(n=336) 
 &nbsp;
<ul>
 <li>26%&nbsp;(221/851) of hospitalized&nbsp;healthy term infants&nbsp;were admitted to&nbsp;ICU1</li>
</ul>

Infant RSV Requiring Mechanical Ventilation&nbsp;(n=82)
<ul>
 <li>22% (49/221)&nbsp;of ICU admitted&nbsp;healthy term infants&nbsp;required&nbsp;mechanical ventilation1</li>
</ul>

CMC: chronic medical condition (includes chronic lung disease, cardiovascular disease, upper airway abnormality, asthma, neurologic/neuromuscular conditions, blood disease, renal disorder, immunocompromised, chronic metabolic disease, liver disease, and other);&nbsp;ICU: Intensive Care Unit; Preterm: born at &lt;37 weeks gestational age; Term: born at 37+ weeks gestational age. Data from the US, % of Infant RSV ICU admissions may vary in other countries.
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107566/">Estimated Burden of Community-Onset Respiratory Syncytial Virus–Associated Hospitalizations Among Children Aged &lt;2 Years in the United States, 2014–15 - PMC (nih.gov)</a>

<h3>"There is an urgent and universal need to develop products to reduce child mortality and morbidity through prevention of RSV disease"+</h3>
Ruth A. Karron, 
 MD Center for Immunization Research Department of International Health Johns Hopkins Bloomberg School of Public Health Baltimore, MD, USA Science. May 14, 2021:Vol. 372, Issue 6543, pp 686-687.

<h3>"Because most children hospitalized with RSV have no underlying medical condition or history of prematurity, interventions against RSV used to broadly target all young infants are likely to result in the greatest impact. "</h3>
Brian Rha, MD MSPH 
 Division of Viral Diseases Centers for Disease Control and Prevention Atlanta, GA, USA Pediatrics. July 2020: Vol. 146, Issue 1, p. e20193611.

<h2>Study Design</h2>
<h3>Preclinical trials</h3>

Phase 1a1 
 NCT02114268&nbsp;&nbsp; &nbsp;

“1st&nbsp;Time in Healthy Adults”

Healthy adults aged 18 to 49 years (n=136)

Evaluation of pharmacokinetics and safety profile of Nirsevimab before initiating a clinical study in infants

Phase 1b/2a2 
 NCT02290340

“1stTime in Healthy Preterm Infants”

Healthy preterm infants 32-35 wGA (n=89)

Evaluation of pharmacokinetics and safety profile of Nirsevimab in healthy preterm infants

<h3>Pivotal clinical trials</h3>

2016

Phase 2b3 
 NCT02878330

“Infants not eligible to receive Palivizumab as per AAP / other guidelines”

Healthy preterm infants in healthy infants 29-34 weeks 6 days wGA (n=1453)

Evaluation of nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants

2019

Phase 34,5 
 NCT03979313

Healthy late preterm and term infants ≥ 35 wGA (n=3012)

Evaluation of efficacy and safety of nirsevimab in healthy late-preterm and term infants entering their first RSV season

Due to COVID-19, no RSV cases were observed. Therefore, a joint decision with health authorities was taken to analyze the primary endpoint (primary cohort). MELODY trial restarted to further characterize nirsevimab safety in this population (secondary cohort)

Phase 2/36-8 
 NCT03959488

‘MEDLEY’

Preterm cohort 
 (n=615)

Evaluation of safety of nirsevimab in preterm infants with OR without CHD or CLD of prematurity

2019
Season 2†&nbsp;(n=262)

CHD/CLD cohort 
 (n=310)

2020

Phase 29,31 
 NCT04484935

‘MUSIC’

Immunocompromised children who are ≤ 24 months of age at the time of dose administration. (n=100)

Evaluation of safety and tolerability, for nirsevimab in immunocompromised children

2022

Phase 3b10 
 NCT05437510

‘HARMONIE’

Healthy infants ≥29 wGA not eligible for palivizumab (n=8058)

Determination of efficacy and safety of nirsevimab for the prevention of hospitalizations due to RSV-LRTI in all palivizumab ineligible infants under 12 months

<h3>Key results from the clinical development program of nirsevimabs</h3>
Safety

Nirsevimab (N=3580): Favorable Safety Profile Across All Infants in pivotal studies
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td colspan="2" rowspan="1" style="background-color: rgb(35, 0, 76);">&nbsp;</td>
 <td style="background-color: rgb(35, 0, 76);">Variables</td>
 <td style="background-color: rgb(35, 0, 76);">Serious adverse events</td>
 <td style="background-color: rgb(35, 0, 76);">Adverse events of Grade 3 or higher</td>
 <td style="background-color: rgb(35, 0, 76);">Adverse events of special interest (AESI)</td>
 <td style="background-color: rgb(35, 0, 76);">Deaths</td>
 </tr>
 <tr>
 <td colspan="2" rowspan="2" style="background-color: rgb(35, 0, 76);">Ph2b3 
 29-&lt;35 wGA</td>
 <td style="background-color: rgb(35, 0, 76);">Placebo 
 (N=479)</td>
 <td>16.9%</td>
 <td style="background-color: rgb(244, 242, 246);">12.5%</td>
 <td>0.6%</td>
 <td style="background-color: rgb(244, 242, 246);">3</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Nirsevimab 
 (N=968)</td>
 <td>11.2%</td>
 <td style="background-color: rgb(244, 242, 246);">8.0%</td>
 <td>0.5%</td>
 <td style="background-color: rgb(244, 242, 246);">2</td>
 </tr>
 <tr>
 <td colspan="2" rowspan="2" style="background-color: rgb(35, 0, 76);">MELODY4 
 ≥35 wGA</td>
 <td style="background-color: rgb(35, 0, 76);">Placebo 
 (N=996)</td>
 <td>7.4%</td>
 <td style="background-color: rgb(244, 242, 246);">3.8%</td>
 <td>0.0%</td>
 <td style="background-color: rgb(244, 242, 246);">0</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Nirsevimab 
 (N=1998)</td>
 <td>6.3%</td>
 <td style="background-color: rgb(244, 242, 246);">3.1%</td>
 <td>0.2%</td>
 <td style="background-color: rgb(244, 242, 246);">4</td>
 </tr>
 <tr>
 <td colspan="1" rowspan="4" style="background-color: rgb(35, 0, 76);">MEDLEY First season6</td>
 <td colspan="1" rowspan="2" style="background-color: rgb(35, 0, 76);">Preterm</td>
 <td style="background-color: rgb(35, 0, 76);">Palivizumab 
 (N=206)</td>
 <td>5.3%</td>
 <td style="background-color: rgb(244, 242, 246);">3.4</td>
 <td>0.0%</td>
 <td style="background-color: rgb(244, 242, 246);">0</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Nirsevimab 
 (N=406)</td>
 <td>6.9%</td>
 <td style="background-color: rgb(244, 242, 246);">3.4%</td>
 <td>0.2%</td>
 <td style="background-color: rgb(244, 242, 246);">2</td>
 </tr>
 <tr>
 <td colspan="1" rowspan="2" style="background-color: rgb(35, 0, 76);">CHD/CLD</td>
 <td style="background-color: rgb(35, 0, 76);">Palivizumab 
 (N=98)</td>
 <td>20.4%</td>
 <td style="background-color: rgb(244, 242, 246);">13.3%</td>
 <td>0.0%</td>
 <td style="background-color: rgb(244, 242, 246);">1</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Nirsevimab 
 (N=208)</td>
 <td>19.2%</td>
 <td style="background-color: rgb(244, 242, 246);">14.4%</td>
 <td>0.5%</td>
 <td style="background-color: rgb(244, 242, 246);">3</td>
 </tr>
 </tbody>
</table>
<ul>
 <li>None of the serious adverse events or deaths were considered as related to nirsevimab</li>
 <li>Overall, incidence of nirsevimab antidrug antibody was low across studies with no safety concerns 
 <ul>
 <li>MELODY: Four AESI cases of hypersensitivity limited to cutaneous signs and symptoms</li>
 <li>MEDLEY: 2 AESIs (nirsevimab arm): Maculopapular rash (preterm cohort) 92 days post nirsevimab dose and heparin-induced thrombocytopenia (CHD/CLD cohort) unrelated to treatment</li>
 </ul></li>
</ul>

Clinical experience of nirsevimab continues with HARMONIE, MUSIC, and MELODY
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td colspan="1" rowspan="2" style="background-color: rgb(35, 0, 76);">&nbsp;</td>
 <td colspan="2" rowspan="2" style="background-color: rgb(35, 0, 76);">HARMONIE10,11</td>
 <td colspan="1" rowspan="2" style="background-color: rgb(35, 0, 76);">MUSIC9</td>
 <td colspan="3" rowspan="1" style="background-color: rgb(35, 0, 76);">MEDLEY Second&nbsp;season12</td>
 </tr>
 <tr>
 <td colspan="3" rowspan="1" style="background-color: rgb(35, 0, 76);">CHD/CLD</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Variables</td>
 <td style="background-color: rgb(35, 0, 76);">No intervention 
 (N=4020)</td>
 <td style="background-color: rgb(35, 0, 76);">Nirsevimab 
 (N=4016)</td>
 <td style="background-color: rgb(35, 0, 76);">Nirsevimab 
 (N=100)</td>
 <td style="background-color: rgb(35, 0, 76);">P/P 
 (N=42)</td>
 <td style="background-color: rgb(35, 0, 76);">P/N 
 (N=40)</td>
 <td style="background-color: rgb(35, 0, 76);">N/N 
 (N=180)</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Serious adverse events</td>
 <td>1.7%</td>
 <td>2.2%</td>
 <td>30%</td>
 <td>0%</td>
 <td>10%</td>
 <td>9.4%</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Adverse events of Grade 3 or higher</td>
 <td style="background-color: rgb(244, 242, 246);">1.1%</td>
 <td style="background-color: rgb(244, 242, 246);">1.2%</td>
 <td style="background-color: rgb(244, 242, 246);">31.7</td>
 <td style="background-color: rgb(244, 242, 246);">31.7</td>
 <td style="background-color: rgb(244, 242, 246);">10%</td>
 <td style="background-color: rgb(244, 242, 246);">7.8%</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Adverse events of special interest (AESI)</td>
 <td>&lt;0.1</td>
 <td>&lt;0.1</td>
 <td>6.7%</td>
 <td>6.7%</td>
 <td>0.0%</td>
 <td>0%</td>
 </tr>
 <tr>
 <td style="background-color: rgb(35, 0, 76);">Deaths</td>
 <td style="background-color: rgb(244, 242, 246);">0</td>
 <td style="background-color: rgb(244, 242, 246);">0</td>
 <td style="background-color: rgb(244, 242, 246);">1</td>
 <td style="background-color: rgb(244, 242, 246);">1</td>
 <td style="background-color: rgb(244, 242, 246);">0</td>
 <td style="background-color: rgb(244, 242, 246);">0</td>
 </tr>
 </tbody>
</table>
<ul>
 <li>Overall incidence of adverse events (AEs)13,14
 <ul>
 <li>Serious AEs and treatment-related AEs were balanced&nbsp;between Nirsevimab and placebo groups</li>
 <li>No anaphylaxis&nbsp;or other serious allergic reactions</li>
 <li>No thrombocytopenia&nbsp;attributed to study drug</li>
 <li>No immune complex disease</li>
 </ul></li>
 <li>Nonserious cutaneous&nbsp;hypersensibility&nbsp;reactions occurred in&nbsp;0.2% of nirsevimab recipients</li>
 <li>Levels of&nbsp;ADA were low</li>
 <li>Incidence of&nbsp;deaths were low and similar between groups
 <ul>
 <li>None were considered treatment-related</li>
 </ul></li>
</ul>

<h3>Key results from the clinical development program</h3>

Phase 
 1a1

Nirsevimab administration resulted in a&nbsp;4X increase&nbsp;in neutralizing antibodies persisting until day 181 
 (ranging from 50% in 100 mg IM cohort to 83% in 3000 mg IV cohort)

Phase 
 1b/2a2

The extended half-life&nbsp;and the demonstrated&nbsp;RSV-neutralizing activity supported the potential for protection against RSV 
 disease for the duration of a typical 5-month season with a single 50 mg IM dose of nirsevimab

Consistent efficacy against RSV-LRTI and associated hospitalizations
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td>&nbsp;</td>
 <td style="text-align: center; background-color: rgb(35, 0, 76);">RSV 
 MA-LRTI</td>
 <td style="text-align: center; background-color: rgb(122, 0, 230);">RSV LRTI 
 Hospitalization</td>
 <td style="text-align: center; background-color: rgb(241, 109, 78);">RSV Very severe 
 MA-LRTI</td>
 <td style="text-align: center; background-color: rgb(88, 212, 135);">All Cause LRTI 
 Hospitalization</td>
 <td style="text-align: center; background-color: rgb(248, 195, 65);">All Cause 
 MA-LRTI</td>
 </tr>
 <tr>
 <td>Phase 2b3,15</td>
 <td style="text-align: center;">70.1% 
 (95% CI, 52.3-81.2)</td>
 <td style="text-align: center;">78.4% 
 (95% CI, 51.9-90.3)</td>
 <td style="text-align: center;">87.5% 
 (95% CI, 62.9, 95.8)</td>
 <td style="text-align: center;">42.5% 
 (95% CI, 16.3-60.5)</td>
 <td style="text-align: center;">23.5% 
 (95% CI, 7.1-37.0)</td>
 </tr>
 <tr>
 <td>MELODY STUDY All</td>
 <td style="text-align: center;">76.4% 
 (95% CI, 62.3–85.2)</td>
 <td style="text-align: center;">76.8% 
 (95% CI, 49.4–89.4)</td>
 <td style="text-align: center;">78.6% 
 (95% CI, 48.8–91.0)</td>
 <td style="text-align: center;">38.9% 
 (95% CI, 6.3-60.2)</td>
 <td style="text-align: center;">38.2% 
 (95% CI, 23.7-50.0)</td>
 </tr>
 <tr>
 <td>
 Phase 2b 
 + MELODY STUDY All 
 (Pooled)5</td>
 <td style="text-align: center;">79.0% 
 (95% CI, 68.5-86.1)</td>
 <td style="text-align: center;">80.6% 
 (95% CI, 62.3-90.1)</td>
 <td style="text-align: center;">86.2% 
 (95% CI, 68.1-94.0)</td>
 <td>&nbsp;</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>HARMONIE STUDY10</td>
 <td>&nbsp;</td>
 <td style="text-align: center;">83.2% 
 (95% CI, 67.7-92.0)</td>
 <td style="text-align: center;">75.7% 
 (95% CI, 32.8-92.9)&nbsp;&nbsp; &nbsp;</td>
 <td style="text-align: center;">58.0% 
 (95% CI, 39.7-71.2)</td>
 <td>&nbsp;</td>
 </tr>
 </tbody>
</table>

All infants need protection from RSV16-21.

Nirsevimab is designed to provide protection for all infants for the length of typical RSV season with a single dose3,22.

Nirsevimab has demonstrated an efficacy of 79% against RSV-MA-LRTI (MELODY/Ph2b pooled), and 83% against hospitalizations (HARMONIE), for 150 days5,10.

Nirsevimab is the first-in-class and only prevention strategy approved by FDA and EMA and is designed to protect all infants from RSV-LRTI in their first RSV season23-25.

&nbsp;Regulatory approvals

<h3 style="text-align: center;">NITAGs Recommend Nirsevimab for All Infants</h3>

Advisory Committee on Immunization Practices28
<ul>
 <li>First RSV Season:&nbsp;All infants below 8 months of age</li>
 <li>Second RSV Season:&nbsp;Infants and children (8-19 months) at increased risk of severe RSV</li>
</ul>

Haute Autorité de santé29
<ul>
 <li>First RSV Season:&nbsp;All infants with reimbursements</li>
</ul>

inisterio de Sanidad30
<ul>
 <li>First RSV Season:&nbsp;All infants below 6 months of age</li>
 <li>Second RSV Season:&nbsp;High risk under 24 months</li>
</ul>

Useful Links

Nirsevimab : Clinical Experience

<h3 style="text-align: center;">Methods</h3>

Compare passive immunization with LA mAb for all infants to the current standard of care using a static decision-analytic model in a cohort of KSA infants experiencing their first RSV season 
 &nbsp;
Subpopulations: 
 &nbsp;
<ul>
 <li>term and late preterm infants (≥35 wGA)</li>
 <li>Healthy preterm infants (29w GA - 34w6d GA, not eligible for palivizumab)</li>
 <li>palivizumab-eligible infants* 
 According to the SIBRO guidelines</li>
</ul>

STUDY DESIGN

Entire KSA infant birth cohort(&lt;12 months of age) during their 1st RSV season 
 (October – March)

PARTICIPANTS &amp; SEASON

Standard of Care:&nbsp;healthy infants born at least 29w GA, administered monthly to eligible infants during the season LA mAb (Nirsevimab) Single dose administered to all infants at the beginning of the RSV season or at birth

IMMUNIZATION STRATEGIES

Static decision-analytic model 
 RSV burden and nirsevimab impact were considered and stratified by: 
 &nbsp;
<ul>
 <li>Population-based approach (comorbidities, monoclonal antibody)</li>
 <li>Age-based approach</li>
</ul>

ANALYSIS

<h3 style="text-align: center;">Assumptions</h3>
Hospitalizations rates per age groups &amp; subpopulations in local birth cohort in KSA
2021 Saudi birth = 509,139

<h4>Highest risk of hospitalizations</h4>
Per subpopulation
<ul>
 <li>Palivizumab eligible: early preterm ≤28 weeks of GA, with CHD or CLDP</li>
 <li>Preterm infants &gt;28 weeks of GA</li>
</ul>
Per chronological age
<ul>
 <li>with risk decreasing with increasing age in months</li>
</ul>

CHD,&nbsp;congenital heart disease;&nbsp;CLDP,&nbsp;chronic lung disease of prematurity;&nbsp;GA,&nbsp;gestational age; mo, month. 
 Ahmed A, Parveen S, Al-Hassinah SM, Al-Amery SF. An overview of respiratory syncytial virus infections in Saudi Arabia. The Journal of Infection in Developing Countries. 2018;12(11):929-36

<h3 style="text-align: center;">Results</h3>
Disease burden under the current standard of care

<h3 style="text-align: center;">428,264 RSV cases 
 84%&nbsp;from KSA birth cohort</h3>
Distribution of RSV MALRTIs by health event over the first RSV season of KSA infants 
 &nbsp;

<h3 style="text-align: center;">SAR ~607 million</h3>
Direct economic burden of RSV in infants
Distribution of RSV MALRTIs by related direct medical costs over the first RSV season of KSA infants

Percentages may not add to 100% due to rounding. All costs are in 2021 United States dollars. ED,&nbsp;emergency department;&nbsp;ICU,&nbsp;intensive care unit;&nbsp;MV,&nbsp;mechanical ventilation;&nbsp;LRTI,&nbsp;lower respiratory tract illness;&nbsp;MA,&nbsp;medically attended;&nbsp;RSV,&nbsp;respiratory syncytial virus;&nbsp;SoC,&nbsp;standard of care;&nbsp;US,&nbsp;United States.

<h2>Red Flags</h2>
<ul>
 <li>
 84 % from KSA birth cohort infected annually by RSV</li>
 <li>
 Among those hospitalized, 18% were admitted to a PICU , and 2% required MV</li>
 <li>
 RSV hospitalized cases accounted for &lt;6% of overall RSV-LRTIs burden, the associated with 60% direct cost.</li>
 <li>
 607 million Annually direct cost of RSV burden in Saudi Arabia</li>
 <li>
 Indirect effects were not captured, so potential benefits on indirect costs and virus spread were not estimated</li>
</ul>

<h3 style="text-align: center;">Results</h3>
Impact of LA mAb for all KSA infants
Cases Vs budget saving

<h3>Reduce RSV cases by more than 50% and associated healthcare costs by more than 60%</h3>
*Includes hospitalization that resulted in ICU admission or MV.
ED,&nbsp;emergency department;&nbsp;ICU,&nbsp;intensive care unit;&nbsp;MV,&nbsp;mechanical ventilation;&nbsp;RSV,&nbsp;respiratory syncytial virus;&nbsp;US,&nbsp;United States.

RSV Burden in Infants

<h2>Study Objective</h2>
<h3>Guideline development process: AGREE II system and classification</h3>
<ul>
 <li>To develop clinical guidelines</li>
 <li>Standard of care for ASMD patients</li>
 <li>Using an SLR and the experiences of multidisciplinary experts (GDG)</li>
</ul>

<h2>Experts’ Recommendations for Classification and Diagnosis of ASMD</h2>

Acute neurovisceral, ASMD type A 
 Hepatosplenomegaly, proatherogenic lipid profile, thrombocytopenia, interstitial lung disease, skeletal involvement, liver disease, cherry red macula, hypotonia, and&nbsp;rapidly progressive neurodegeneration
Chronic neurovisceral, ASMD type A/B 
 All symptoms of ASMD type A along with&nbsp;delayed growth and puberty, slowly progressive neurodegeneration and cherry red macula (in few patients), and hypotonia
Chronic visceral, ASMD type B 
 All symptoms of type A/B&nbsp;with the absence of hypotonia and neurodegeneration and few patients with cherry red macula

<h2>Experts’ Recommendations for the Management of ASMD</h2>

<h3>Multidisciplinary assessment&nbsp;is recommended for all ASMD patients or as needed by:</h3>
<ul>
 <li>Primary care physician</li>
 <li>Metabolic diseases specialist</li>
 <li>Neurologist</li>
</ul>

<h3>Management of ASMD</h3>
ERT
<ul>
 <li>All patients with a confirmed diagnosis of ASMD and significant non-CNS</li>
 <li>Effectiveness of treatment should be monitored</li>
</ul>
Use of HSCT is experimental
<h3>Symptomatic treatment</h3>
<ul>
 <li>CLD should be monitored and treated for gastrointestinal bleeding</li>
 <li>Pulmonary disease may require long-term oxygen therapy</li>
</ul>

<h3>Recommended assessments for all ASMD patients</h3>
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td>Assesment</td>
 <td>Frequency</td>
 </tr>
 <tr>
 <td>Baseline history</td>
 <td>At diagnosis 
 <ul>
 <li>Assess recurrent chest infections at diagnosis, then at each visit</li>
 </ul></td>
 </tr>
 <tr>
 <td>Pulmonary assessment</td>
 <td>
 <ul>
 <li>Chest radiograph and/or high-resolution chest CT to assess the extent of interstitial lung disease at diagnosis regardless of age, then every 2–4 years</li>
 </ul></td>
 </tr>
 <tr>
 <td>Musculoskeletal assessment</td>
 <td>At diagnosis, then at each visit</td>
 </tr>
 <tr>
 <td>Ophthalmologic evaluation</td>
 <td>At diagnosis</td>
 </tr>
 </tbody>
</table>

Consensus Guidelines for the Clinical Management of ASMD

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