<h2>The Continuous burden of Atopic Dermatitis can have far-reaching Impact</h2>
The burden of inadequately controlled atopic dermatitis may become chronic, or even cumulative, impacting patients throughout their lives1,2

~70 - 80%&nbsp;of atopic dermatitis patients develop additional type 2 inflammatory diseases, such as asthma or allergic rhinitis, which correlate with atopic dermatitis severity5,6
*The age of children included in the Eczema Society of Canada Atopic Dermatitis Quality of Life Report survey ranged from 0 to 18 years

~70 - 80%&nbsp;of atopic dermatitis patients develop additional type 2 inflammatory diseases, such as asthma or allergic rhinitis, which correlate with atopic dermatitis severity5,6
* The age of children included in the Eczema Society of Canada Atopic Dermatitis Quality of Life Report survey ranged from 0 to 18 years

~70 - 80%&nbsp;of atopic dermatitis patients develop additional type 2 inflammatory diseases, such as asthma or allergic rhinitis, which correlate with atopic dermatitis severity5,6
* The age of children included in the Eczema Society of Canada Atopic Dermatitis Quality of Life Report survey ranged from 0 to 18 years

References

<h2>Around 3 in 5 adult Moderate-to-Severe Atopic Dermatitis patients are Inadequately controlled despite treatment1*</h2>

A chronic, inadequately controlled disease driven by persistent underlying inflammation7,8

Patients may experience intensified disease activity for 30–50% of the year2

Current treatment paradigm (OCS/ immunosuppressants) primarily addresses disease manifestation using a reactive, episodic approach9

Length of treatment with systemic steroids and other immunosuppressants is limited by common side effects and chance of rebounds11

<h2>Continuous treatment of underlying Inflammation is warranted for Long-term disease control10</h2>

A more sustainable treatment paradigm proactively targets the persistent underlying inflammation with a safety profile that allows for continuous treatment10-12

Adequately controlled disease with long-term improvements in signs, symptoms, and quality of life.

<h2>Dysregulation of the Type 2 Immune Response pathway leads to Underlying Type 2 Inflammation in Atopic Dermatitis and other Type 2 Inflammatory diseases*</h2>

Primary immune cells1-3 
 &nbsp;

Key cytokines1-4 
 &nbsp;

Associated intracellular signaling pathway4,5 
 &nbsp;

Natural defensive roles against:1,3,6 
 &nbsp;

Associated diseases when dysregulated7-8 
 &nbsp;

Viral infection 
 Intracellular bacterialinfection 
 Cancer cells

Psoriasis 
 Psoriatic arthritis

Allergens 
 Parasites 
 &nbsp;

Atopic dermatitis 
 Asthma 
 CRSwNP

Extracellular bacteria 
 Fungi 
 &nbsp;

Psoriasis 
 Psoriatic arthritis

*Simplified depiction based on key published information; not meant to be exhaustive in nature.

<h2>In Atopic Dermatitis, Type 2 Inflammation is always present throughout the body,even in nonlesional or normal-looking skin1–3</h2>
<ul>
 <li>Dysregulation of the type 2 immune response and increased IL-4 and IL-13 signaling drives and perpetuates type 2 inflammation, which contributes to clinical disease features in atopic dermatitis and other type 2 inflammatory diseases3-5</li>
 <li>
 IL-4 and IL-13 are produced by various cell types such as Th2 and ILC2 cells in response to increased signaling through the IL-4Rα present on those cells6-8</li>
</ul>

<h2>Nonlesional skin is not normal skin</h2>
In atopic dermatitis, subclinical inflammation is also present in nonlesional skin1–3

About Type 2 Inflammation – Atopic Dermatitis

ATOPIC-DERMATITIS

DERMATOLOGY

<h2>Summary of Effectiveness &amp; Reduction of RSV-Hospitalization Estimates</h2>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">LEGEND</td>
 </tr>
 </tbody>
</table>
Effectiveness (Case Controlled) 
 RSV-Hospitalization Reduction (compared to previous years)

<h2>Countries that have implemented nirsevimab</h2>

<h3>Implementation of&nbsp;nirsevimab&nbsp;to reach infants in US</h3>

*Can adjust administration schedules based on local epidemiology (e.g. Alaska and Hawaii) 
 **Children with chronic lung disease of prematurity who required medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) any time during the 6-month period before the start of the second RSV season, Children with severe immunocompromise, Children with cystic fibrosis who have either 1) manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest imaging that persist when stable) or 2) weight-for-length &lt;10th percentile, American Indian or Alaska Native children

<h4>Reference</h4>
<ol>
 <li>
 Jones JM et al, Morb Mortal Wkly Rep 2023;72:920–925. 2. Flemin-Dutra KE et al, Morb Mortal Wkly Rep 2023;72:1115-1122.</li>
</ol>

<h4>Reference</h4>
<ol>
 <li>
 Moline HL, et al. MMWR Morb Mortal Wkly Rep 2024;73:209–214.&nbsp;</li>
</ol>

<h3>Nirsevimab Receipt and Intent for Infants Survey - US</h3>
Monthly Nirsevimab Receipt and Intent Among Females Aged 18-49 Years, United States

<h4>References</h4>
<ol>
 <li>
 NIS Adult COVID Module (NIS-ACM) Hard Copy Questionnair https://www.cdc.gov/vaccines/imz-managers/nis/downloads/NIS-ACM-Questionnaire-Q1-2024-508.pdf Published Q1 2024(Accessed 05 Feb 2024)</li>
 <li>
 Nirsevimab Receipt and Intent for Infants, United States https://www.cdc.gov/vaccines/imz-managers/coverage/rsvvaxview/nirsevimab-coverage.html (Published January 10/2024 Accessed 08 Mar 2024)</li>
</ol>

<h3>Implementation of&nbsp;nirsevimab&nbsp;to reach infants in France</h3>

<h4>Parents acceptance were higher than previously estimated by French authorities</h4>

<h4>Reference</h4>
<ol>
 <li>
 DGS-URGENT N°2023_14&nbsp;<a href="https://sante.gouv.fr/IMG/pdf/dgs-urgent_2023-14_-_traitement_preventif_vrs.pdf" target="_blank">https://sante.gouv.fr/IMG/pdf/dgs-urgent_2023-14_-_traitement_preventif_vrs.pdf</a>&nbsp;(Published: 24/08/2023 Accessed 12 of March 2024)</li>
</ol>

<h3>Bronchiolitis Decline Continues; 
 Nirsevimab’s Impact Uncertain in France without specific data</h3>
Compared to previous seasons, and at this stage of the epidemic, bronchiolitis-related activities are:
&lt;3 months old: lower&nbsp;than those of the seasons before&nbsp;the emergence of Covid-19; close to or slightly lower&nbsp;than those in&nbsp;the 2021-2022 season lower&nbsp;than those in&nbsp;the 2022-2023 season.
3-11 months: 
 generally close to the activities observed during the 2021-2022 and 2022-2023 seasons (ER visits and hospitalization) lower or comparable to those in the seasons before the emergence of Covid-19, except for hospitalization rates after ER remain within the values).
Differences in terms of the impact of the bronchiolitis epidemic observed between infants &lt;3 months of age and infants 3 - 11 months&nbsp;cannot be certainly directly linked to the deployment of nirsevimab treatment on national territory,&nbsp;even if it is the youngest infants who have preferentially been able to benefit from maternity treatment.
The syndromic data of the&nbsp;Oscour network do not make it possible&nbsp;to identify infants who have been able to benefit from this preventive treatment, or to identify infants with RSV bronchiolitis.

<h4>References</h4>
<ol>
 <li>
 <a href="https://www.santepubliquefrance.fr/maladies-et-traumatismes/maladies-et-infections-respiratoires/grippe/documents/bulletin-national/infections-respiratoires-aigues-grippe-bronchiolite-covid-19-.-bulletin-du-31-janvier-2024" target="_blank">https://www.santepubliquefrance.fr/maladies-et-traumatismes/maladies-et-infections-respiratoires/grippe/documents/bulletin-national/infections-respiratoires-aigues-grippe-bronchiolite-covid-19-.-bulletin-du-31-janvier-2024</a>&nbsp;(Published 31 January 2024, Accessed in March 14th 2024)</li>
 <li>
 <a href="https://www.santepubliquefrance.fr/media/files/01-maladies-et-traumatismes/maladies-et-infections-respiratoires/infections-respiratoires-aigues/annexe_bronchio_france_1-12_mois_20240131" target="_blank">https://www.santepubliquefrance.fr/media/files/01-maladies-et-traumatismes/maladies-et-infections-respiratoires/infections-respiratoires-aigues/annexe_bronchio_france_1-12_mois_20240131</a>&nbsp;(Published 31 January 2024, Accessed in March 14th 2024)</li>
</ol>

<h3>Comparing bronchiolitis episodes before and after nirsevimab implementation (Infovac Sentinel)</h3>
RSV cases reduction observed in the target group of immunization
Over 70% of infants born since mid-Sep 2023 til 31st December have been immunized with nirsevimab

No RDT done in the first half of September

Data as of 31st of December, 2023. IRAP Network (ACTIV/AFPA)

<h3>Impact of Nirsevimab in bronchiolitis episodes (Infovac Sentinel)</h3>
Jan 2024
“The key change is the efficacy of Nirsevimab (confirmed above 80%) in France, with the very significant decrease in the number of cases before the age of 3 months.”

<h4>Reference</h4>
Infovac France Newsletter Newsletter N°10 - November 2023 | Infovac France (Published 28th of November 2023, accessed 12 of March 2024)

France

<h3>Implementation of&nbsp;nirsevimab&nbsp;to reach infants in Spain</h3>

*- Preterm infants below 35 weeks gestational age. - Infants with bronchopulmonary dysplasia64. - Infants with congenital heart disease with significant hemodynamic impairment (those being treated for congestive heart failure, those with moderate or severe pulmonary hypertension, and children with cyanotic heart disease). - Infants with severe immunosuppression due to oncohaematological processes, primary immunodeficiencies (especially combined immunodeficiencies and congenital agammaglobulinemia). ‡ Castilla y Leon:Under 7 months: From 1st March 2023;Pais Vasco: Under 3 months: From 1st July 2023,Navarra: In season

<h4>References</h4>
<ol>
 <li>
 Martinon-Torres et al. Euro Surveill 2023, 28:pii=2300606</li>
 <li>
 Calendario de inmunizaciones.&nbsp;<a href="https://vacunasaep.org/profesionales/calendario-de-inmunizaciones-aep-2024" target="_blank">https://vacunasaep.org/profesionales/calendario-de-inmunizaciones-aep-2024</a>&nbsp;published January 1st 2024, accessed 12 March 2024 43. Recomendaciones de utilización de nirsevimab&nbsp;<a href="https://www.sanidad.gob.es/areas/promocionPrevencion/vacunaciones/comoTrabajamos/docs/Nirsevimab.pdf" target="_blank">https://www.sanidad.gob.es/areas/promocionPrevencion/vacunaciones/comoTrabajamos/docs/Nirsevimab.pdf</a>, published July 2023,accessed 12 of March 2024</li>
</ol>

<h3>The deployment of Nirsevimab capitalized on existent immunization frameworks, facilitating its assimilation into routine vaccine administration practices.</h3>
1. Burden of Disease 
 Evidence of RSV burden in all infants and surveillance generated1,5
2. Regulatory &amp; scientific societies endorsement 
 EMA approved2&nbsp;and pediatric society (AEP)3recommended nirsevimab for prevention of RSV in all infants during their first RSV season
3. NIP inclusion 
 As for any vaccine-like product, a NITAG4&nbsp;multidisciplinary working group evaluated and recommended nirsevimab based on :
<ul>
 <li>Scientific</li>
 <li>Epidemiological</li>
 <li>Ethical</li>
 <li>Political</li>
 <li>Economical</li>
</ul>

<h4>Abbreviations</h4>
AEP: Spanish Academy of Pediatrics,&nbsp;EMA: European Medicines Agency ,&nbsp;NIP: National Immunization Program

<h4>References</h4>
<ol>
 <li>
 Wildenbeest JG et al. Lancet Respir Med. 2023 Apr;11(4):341-353. doi: 10.1016/S2213-2600(22)00414-3. Epub 2022 Nov 10.</li>
 <li>
 EMA New medicine to protect babies and infants from respiratory syncytial virus (RSV) infection&nbsp;<a href="https://www.ema.europa.eu/en/news/new-medicine-protect-babies-and-infants-respiratory-syncytial-virus-rsv-infection" target="_blank">https://www.ema.europa.eu/en/news/new-medicine-protect-babies-and-infants-respiratory-syncytial-virus-rsv-infection</a>&nbsp;published 16 September 2022, accesse 12 of March 2024</li>
 <li>
 Calendario de inmunizaciones.&nbsp;<a href="https://vacunasaep.org/profesionales/calendario-de-inmunizaciones-aep-2024" target="_blank">https://vacunasaep.org/profesionales/calendario-de-inmunizaciones-aep-2024</a>&nbsp;published January 1st 2024, accessed 12 March 2024</li>
 <li>
 Recomendaciones de utilización de nirsevimab&nbsp;<a href="https://www.sanidad.gob.es/areas/promocionPrevencion/vacunaciones/comoTrabajamos/docs/Nirsevimab.pdf" target="_blank">https://www.sanidad.gob.es/areas/promocionPrevencion/vacunaciones/comoTrabajamos/docs/Nirsevimab.pdf</a>, published July 2023. accessed 12 of March 2024</li>
 <li>
 Martinón-Torres, Fet al. BMC Infect Dis&nbsp;23, 385 (2023).&nbsp;</li>
</ol>

<h3>Successful implementation demonstrated by high coverage</h3>
Galicia, Spain is conducting an impact study on nirsevimab and RSV
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td>Group</td>
 <td>Number of Immunized 
 (as of Feb 25th, 2024)</td>
 <td>% Coverage Rate</td>
 </tr>
 <tr>
 <td>At birth</td>
 <td style="text-align: center;">5,638</td>
 <td style="text-align: center;">92.7%</td>
 </tr>
 <tr>
 <td>Catch-up</td>
 <td style="text-align: center;">6,234</td>
 <td style="text-align: center;">85.3%</td>
 </tr>
 <tr>
 <td>Increased Risk</td>
 <td style="text-align: center;">349</td>
 <td style="text-align: center;">100%</td>
 </tr>
 <tr>
 <td>Total</td>
 <td style="text-align: center;">12,221</td>
 <td>&nbsp;</td>
 </tr>
 </tbody>
</table>

<h4>References</h4>
<ol>
 <li>
 Martinon-Torres et al. ESWI Respiratory Virus Summit 2024 | ESWI 5th of March 2024 Brussels &amp; online</li>
</ol>

<h3>Impact of Nirsevimab implementation in Galicia</h3>

Cumulative weekly RSV hospitalization rate in Galicia by season, up to Feb 4th 2024 (week 5/24)

<h4>References</h4>
<ol>
 <li>
 Results of implementation of Nirsevimab in Galicia Nirsegal.com published February 2024 accessed march 2024</li>
 <li>
 Martinon-Torres et al. ESWI Respiratory Virus Summit 2024 | ESWI 5th of March 2024 Brussels &amp; online</li>
</ol>

<h3>Cumulative cases in other age groups not lower than previous seasons in children 1 to 4 years old and older than 60 years, not targeted for nirsevimab immunization</h3>

Higher cumulative case number than median of previous seasons
Weekly RSV hospitalization rate in Galicia by season, week 8 2024

<h4>Reference</h4>
<ol>
 <li>
 Results of implementation of Nirsevimab in Galicia Nirsegal.com published February 2024 accessed March 2024 2. Martinon-Torres et al. ESWI Respiratory Virus Summit 2024 | ESWI 5th of March 2024 Brussels &amp; online</li>
</ol>

<h3>Effectiveness of Nirsevimab Against RSV-Related Outcomes in Hospital and Primary Care Settings</h3>
A Retrospective Cohort Study in Infants in Catalonia (Spain)
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td>Outcome</td>
 <td style="width: 9%;">N</td>
 <td>Rate per 100,000 person days</td>
 <td style="width: 9%;">N</td>
 <td>Rate per 100,00 person days</td>
 <td>Adjusted hazard ratio (95% CI)</td>
 <td>Effectiveness</td>
 </tr>
 <tr>
 <td>ICU admission</td>
 <td style="text-align: center; width: 9%;">17</td>
 <td style="text-align: center;">2.13</td>
 <td style="text-align: center; width: 9%;">8</td>
 <td style="text-align: center;">0.33</td>
 <td style="text-align: center;">0.099 (0.041 to 0.237)</td>
 <td style="text-align: center;">90.1% (76.3% to 95.9%)</td>
 </tr>
 <tr>
 <td>Hospital admission</td>
 <td style="text-align: center; width: 9%;">76</td>
 <td style="text-align: center;">9.55</td>
 <td style="text-align: center; width: 9%;">52</td>
 <td style="text-align: center;">2.16</td>
 <td style="text-align: center;">0.124 (0.086 to 0.179)</td>
 <td style="text-align: center;">87.6% (82.1% to 91.4%)</td>
 </tr>
 <tr>
 <td>Viral pneumonia</td>
 <td style="text-align: center; width: 9%;">14</td>
 <td style="text-align: center;">2.06</td>
 <td style="text-align: center; width: 9%;">42</td>
 <td style="text-align: center;">1.79</td>
 <td style="text-align: center;">0.393 (0.203 to 0.758)</td>
 <td style="text-align: center;">60.7% (24.2% to 79.7%)</td>
 </tr>
 <tr>
 <td>Hospital emergency visits</td>
 <td style="text-align: center; width: 9%;">354</td>
 <td style="text-align: center;">45.1</td>
 <td style="text-align: center; width: 9%;">604</td>
 <td style="text-align: center;">25.5</td>
 <td style="text-align: center;">0.446 (0.385 to 0.516)</td>
 <td style="text-align: center;">55.4% (48.4% to 61.5%)</td>
 </tr>
 <tr>
 <td>Primary care attended bronchiolitis</td>
 <td style="text-align: center; width: 9%;">617</td>
 <td style="text-align: center;">93.9</td>
 <td style="text-align: center; width: 9%;">1,560</td>
 <td style="text-align: center;">69.7</td>
 <td style="text-align: center;">0.519 (0.467 to 0.576)</td>
 <td style="text-align: center;">48.1% (42.4% to 53.3%)</td>
 </tr>
 <tr>
 <td>RSV infection</td>
 <td style="text-align: center; width: 9%;">31</td>
 <td style="text-align: center;">4.57</td>
 <td style="text-align: center; width: 9%;">71</td>
 <td style="text-align: center;">3.04</td>
 <td style="text-align: center;">0.311 (0.200 to 0.483)</td>
 <td style="text-align: center;">68.9% (51.7% to 80.0%)</td>
 </tr>
 </tbody>
</table>

Findings: Among 26,525 infants, a dose of nirsevimab led to an adjusted HR for hospital admission due to RSV bronchiolitis of 0·124 (0·086 to 0·179) and an adjusted HR for ICU admission of 0·099 (0·041 to 0·237). Additionally, the adjusted HR observed for emergency visits was 0·446 (95% CI: 0·385 to 0·516), 0·393 (95% CI: 0·203 to 0·758) for viral pneumonia, 0·519 (95% CI: 0·467 to 0·576) for bronchiolitis attended in primary care, and 0·311 (95% CI: 0·200 to 0·483) for RSV infection. Sensitivity and negative control outcome analyses supported these findings.

<h4>Reference</h4>
<ol>
 <li>
 Coma E. et al, Preprints with the Lancet, available at SSRN:&nbsp;<a href="https://ssrn.com/abstract=4749763" target="_blank">https://ssrn.com/abstract=4749763</a></li>
</ol>

Spain

<h3>Implementation of&nbsp;nirsevimab&nbsp;to reach infants in Luxembourg</h3>

<h4>Reference</h4>
Recommandations du Conseil supérieur des maladies infectieuses concernant l’immunisation passive contre le RSV par des nouveaux anticorps CONSEIL SUPERIEUR D’HYGIENE (public.lu) published July 2023; accessed 14th of March 2024

<h3>Luxembourg</h3>
<ul>
 <li>The&nbsp;length of hospital stay&nbsp;was significantly&nbsp;reduced&nbsp;from a mean&nbsp;of 5.1 days&nbsp;(SD: 5.4) in 2022 compared to&nbsp;3.2 days&nbsp;(SD: 2.5) in 2023 (p &lt; 0.001).</li>
 <li>Infants &lt; 6 months old (5.6&nbsp;days in 2022 vs&nbsp;3.4&nbsp;days in 2023, p &lt; 0.001)</li>
 <li>78.5%&nbsp;(22/28) of infants up to 6 months of age needing oxygen supplementation were not immunised.</li>
 <li>69.2%&nbsp;(9/13) received Nasal high flow therapy were not immunized.</li>
 <li>66.6%&nbsp;(6/9) admitted to PICU were not immunized.</li>
</ul>

The majority of severe RSV LRTI cases were on non-immunized infants
<ul>
 <li>Coverage in Maternity wards October to mid-December 2023 was estimated at 84% (from 66% to 94%).</li>
 <li>A decrease of 69% RSV lab-confirmed hospitalizations among infants under 6 months old.</li>
 <li>With a 38% decrease in children under 5 years of age 65.3% of infants under 6 months were not immunized.</li>
</ul>

<h4>Reference</h4>
Ernst C et al. Euro Surveill.&nbsp;2024;29(4):pii=2400033.

Luxembourg

RESPIRATORY-SYNCYTIAL-VIRUS

VACCINES

Real World Evidence Impact of universal immunization with Nirsevimab

<h2>By the time pompe disease slows them down, the damage has already begun2–4</h2>
Diagnose and manage Pompe disease early to help your patients stay ahead of their disease2–4
<h3>Pompe disease is a life-threatening, progressive neuromuscular disorder that causes irreversible muscle damage1–4</h3>
Pompe disease, also referred to as acid maltase deficiency or glycogen storage disease type II (GSDII), is an underrecognized, inherited multisystemic disorder that causes progressive muscle damage, profound disability and premature death.1,4,5 
 For patients, Pompe disease means progressive respiratory and muscle complications, as well as life-limiting burden.4
Pompe disease is heterogeneous, with varying ages of onset and rates of progression4,6

<div>
 <table border="1" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <td style="background-color: rgb(244, 242, 246);">IOPD</td>
 <td style="background-color: rgb(244, 242, 246);">&nbsp;</td>
 <td style="background-color: rgb(244, 242, 246);">LOPD</td>
 </tr>
 <tr>
 <td>Infantile-onset Pompe disease&nbsp;1 in 138,000 people7*</td>
 <td>Prevalence 1 in 40,000 
 for all forms 
 of Pompe disease1†</td>
 <td>Late-onset Pompe disease&nbsp;1 in 57,000 people7*</td>
 </tr>
 <tr>
 <td>Within the first year of life5</td>
 <td>Presentation</td>
 <td>At any point during childhood or adulthood5</td>
 </tr>
 <tr>
 <td>Rapidly progressive and, if left unmanaged, results in death by 2 years of age, most commonly due to cardiorespiratory failure3</td>
 <td>Progression</td>
 <td>Steadily progressive and can result in premature death, most commonly due to respiratory failure5</td>
 </tr>
 </tbody>
 </table>
</div>

<h2>Diagnose and manage Pompe disease early to help reduce patient burden4,6,8</h2>
*Estimates based on studies from The Netherlands. No prevalence studies have been performed in Canada. †Based on one study in a New York population.

Pathophysiology behind the Burden of Disease
Pompe disease is caused by a deficiency of acid α-glucosidase (GAA) enzyme activity, resulting in uncontrolled and progressive lysosomal glycogen accumulation in muscle cells throughout the body1,3,4
<ul>
 <li>In patients that present with Pompe disease before 1 year of age (infantile-onset), GAA enzyme activity may be completely missing; and if some activity remains, it is usually &lt;1% of normal5</li>
</ul>

Uncontrolled glycogen accumulation causes lysosomes to swell and rupture, resulting in1
<ul>
 <li>Irreversible cellular damage6,10</li>
 <li>Progressive destruction of skeletal muscle (including respiratory musculature), cardiac muscle and smooth muscle9,10</li>
 <li>Debilitating respiratory, motor, musculoskeletal, cardiac, bulbar, and gastrointestinal (GI) muscular manifestations3,9,13–15</li>
</ul>

<h2>Diagnostic and treatment delays result in unchecked disease progression leading to respiratory complications, muscle damage, life-altering burden and/or death2,16</h2>
<h3>Patients with Pompe Disease often Face Delayed Diagnosis1</h3>
<ul>
 <li>
 Delayed diagnosis can lead to significant muscle tissue deterioration, diminished physical function and premature death2,17</li>
 <li>The median delay to definitive diagnosis for patients with LOPD can be as much as 7 years18,19</li>
</ul>

<h2>Deficient GAA enzyme activity leads to progressive muscle damage and multisystemic manifestations1,3-5</h2>
<h3>Patients with Pompe disease most often present with signs of motor and Respiratory Impairment&nbsp;4,14,15</h3>
<ul>
 <li>77%&nbsp;of patients with LOPD present with both exercise intolerance and limb-girdle muscle weakness15</li>
 <li>55%&nbsp;of patients with LOPD present with both respiratory insufficiency and limb-girdle muscle weakness15</li>
</ul>
IOPD&nbsp;Symptoms present in early infancy and progress rapidly, typically leading to death by 2 years of age. Manifestations most commonly include cardiomyopathy, hypotonia, muscle weakness, respiratory distress, feeding difficulties, and failure to thrive4,5,20

<h3>LOPD can manifest in many different parts of the body</h3>

<h2>Test early for Pompe disease if you spot these common signs or symptoms in your practice1</h2>
<h3>Proximal Muscle weakness, the most common presentation in LOPD, makes everyday activities a Challenge for Patients&nbsp;30</h3>

80% of patients with LOPD report experiencing problems with daily tasks due to loss of muscle strength and function22*‡ 
 In patients with LOPD, ongoing and progressive loss of muscle function can lead to life-limiting consequences. At the time of diagnosis:16*
<ul>
 <li>50% of patients have difficulty getting up from a chair</li>
 <li>Nearly 50% of patients experience limitations in their ability to work or study</li>
 <li>More than 20% of patients are wheelchair bound and/or require respiratory support</li>
</ul>

<h3>Respiratory Insufficiency is a Cardinal feature of LOPD and the Primary cause of mortality&nbsp;31</h3>
Patients with LOPD who experienced difficulty with tasks at the time of diagnosis&nbsp;16*†
<ul>
 <li>Respiratory dysfunction can be the first symptom and may present without overt motor symptoms25
 <ul>
 <li>Symptoms of respiratory insufficiency are the primary presenting symptom in about one-third of LOPD cases25</li>
 <li>Respiratory failure can occur while patients with Pompe disease are still ambulatory4</li>
 </ul></li>
</ul>
<ul>
 <li>Respiratory dysfunction can be present early in the disease course, even when respiratory symptoms are not the initial symptom25,32
 <ul>
 <li>A decrease in FVC is an early sign of respiratory impairment in Pompe disease25</li>
 <li>4 of 6 patients (67%) showed reduced FVC at diagnosis despite lack of respiratory symptoms32</li>
 </ul></li>
</ul>
<ul>
 <li>Progressive diaphragm weakness is the major cause of respiratory dysfunction in LOPD31</li>
</ul>
FVC=forced vital capacity.

Average respiratory function—measured by FVC—at study entry was 61%, reflecting moderate restrictive lung disease33
<ul>
 <li>Respiratory function declined consistently, including a 2.3% decline after 12 months and a 6.2% decline after 48 months33</li>
 <li>Respiratory function is often diminished in the early stages of LOPD, prior to diagnosis, and continues to decline over time4,33</li>
</ul>

<h2>The most common cause of death among patients with symptom onset at &gt;12 months of age, reported in the Pompe registry, was respiratory in nature (40.9%)&nbsp;34</h2>
*Based on a meta-analysis of 19 studies of patients with LOPD. Continuous outcomes were modeled using fractional polynomial meta-analysis, which estimates the development of outcomes over time.33

<h3>The Differential Diagnosis for Pompe Disease4</h3>
Include Pompe disease in your differential alongside these other diseases

<table border="1" cellpadding="10" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="width: 20%;">&nbsp;</td>
 <td style="width: 13%;">Muscle weakness</td>
 <td style="width: 13%;">Abnormal gait or difficulty walking</td>
 <td style="width: 12%;">Elevated creatine kinase (CK)</td>
 <td style="width: 15%;">Respiratory insufficiency</td>
 <td style="width: 13%;">Difficulty swallowing</td>
 <td style="width: 14%;">Exercise intolerance</td>
 </tr>
 <tr>
 <td style="width: 20%;">Pompe disease4 
 2.5 per 100,000</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 12%;">●</td>
 <td style="text-align: center; width: 15%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 14%;">●</td>
 </tr>
 <tr>
 <td style="width: 20%;">General myopathy35–39</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 12%;">●</td>
 <td style="text-align: center; width: 15%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 14%;">●</td>
 </tr>
 <tr>
 <td style="width: 20%;">Duchenne muscular dystrophy35,40–43 
 1.7–8.2 per 100,000</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 12%;">●</td>
 <td style="text-align: center; width: 15%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 14%;">●</td>
 </tr>
 <tr>
 <td style="width: 20%;">Limb-girdle muscular dystrophy43–46 
 0.8–6.9 per 100,000</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 12%;">●</td>
 <td style="text-align: center; width: 15%;">&nbsp;</td>
 <td style="text-align: center; width: 13%;">&nbsp;</td>
 <td style="text-align: center; width: 14%;">●</td>
 </tr>
 <tr>
 <td style="width: 20%;">Myasthenia gravis40,47,48 
 20 per 100,000</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 12%;">●</td>
 <td style="text-align: center; width: 15%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 14%;">●</td>
 </tr>
 <tr>
 <td style="width: 20%;">Inflammatory myopathy49–52 
 14–25 per 100,000</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 13%;">&nbsp;</td>
 <td style="text-align: center; width: 12%;">●</td>
 <td style="text-align: center; width: 15%;">&nbsp;</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 14%;">●</td>
 </tr>
 <tr>
 <td style="width: 20%;">Polymyositis52–54 
 2.7–70 per 100,000</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 12%;">●</td>
 <td style="text-align: center; width: 15%;">&nbsp;</td>
 <td style="text-align: center; width: 13%;">●</td>
 <td style="text-align: center; width: 14%;">●</td>
 </tr>
 </tbody>
</table>

Consider testing for Pompe disease when you see these high-risk signs3,23,55–57
<ul>
 <li>Presymptomatic, persistent or unexplained sustained elevation of serum creatine kinase (CK) levels: ranging from 1.5 to 15 times the upper limit of normal (~300–2000 U/L)</li>
 <li>Muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW)</li>
 <li>HyperCKemia+LGMW</li>
</ul>

<h2>The median delay to definitive diagnosis for patients with LOPD can be as much as 7 years18,19</h2>

Adapted from: Toscano A et al. Acta Myologica 2013;32:78–81

Abbreviations

<h3>Sign and Symptoms in LOPD Patients</h3>

<h3>Sign and Symptoms in IOPD Patients</h3>

<h3>Diagnose Pompe disease using a s imple Dried blood spot (Dbs) Test or Genetic Testing21</h3>
GAA enzyme activity testing can identify patients who have Pompe disease21
Testing for Pompe disease

NGS can be used to confirm or test for a number of neuromuscular diseases. 
 Neuromuscular specialists may have access to NGS to identify the genetic variants involved in the clinical manifestations of Pompe disease. Specifically, the SGM panel examines&nbsp;multiple genes&nbsp;simultaneously, shortening time to diagnosis when you have a large differential consisting of muscular dystrophies, myopathies and myasthenia syndromes.
Consider testing if you suspect Pompe disease or other genetic neuromuscular disorders

<h2>GAA enzyme activity testing via DBS is a simple and reliable way to screen for Pompe disease in your symptomatic patients&nbsp;21</h2>

<h3>Patient case: 39-year-old woman with progressive respiratory insufficiency&nbsp;60</h3>
Patient presented with a 3-year history of progressive shortness of breath*
Characteristics:
<ul>
 <li>Progressive shortness of breath</li>
 <li>Shortness of breath upon exertion or within minutes of lying down</li>
 <li>Excessive breathlessness when swimming</li>
 <li>Hypersomnolence during the day with associated morning headaches that developed over the last 2 months</li>
</ul>
Medical history:
<ul>
 <li>Epworth score: 21 (out of 24)†</li>
 <li>Unprovoked pulmonary emboli 6 years prior</li>
 <li>Pelvic venous congestion syndrome</li>
 <li>Undergoing persistent anticoagulation therapy</li>
</ul>

<h2>In patients with Pompe disease, ongoing muscle damage can lead to progressive respiratory insufficiency and a variety of other debilitating and potentially life-threatening symptoms1,4,5</h2>

Clinical assessment:
<ul>
 <li>Lab results 
 <ul>
 <li>Oxygen saturation on room air: 97%</li>
 <li>Full blood count: normal</li>
 <li>C-reactive protein: normal</li>
 <li>CK: mildly elevated (624 U/L)</li>
 </ul></li>
</ul>
<ul>
 <li>Mobility assessment 
 <ul>
 <li>Mildly waddling gait</li>
 <li>Limited weakness on hip flexion</li>
 </ul></li>
</ul>
<ul>
 <li>Pulmonary function test results 
 <ul>
 <li>FVC sitting: 2.29 L; 82% predicted</li>
 <li>FVC supine: 0.92 L; 33% predicted</li>
 </ul></li>
</ul>
<ul>
 <li>Daytime arterial blood gas evaluation 
 <ul>
 <li>Partial pressure of CO2: 54 mm Hg (upper limit of normal: 45 mm Hg)63</li>
 <li>Partial pressure of oxygen: 85 mm Hg (normal range: 75 to 100 mm Hg)64</li>
 </ul></li>
</ul>
<ul>
 <li>Overnight polysomnogram 
 <ul>
 <li>Severe desaturation during rapid eye movement sleep (nadir 68% room air)</li>
 </ul></li>
</ul>
Diagnostic screening results:
<ul>
 <li>Blood spot testing—acid alpha-glucosidase enzyme level activity: &lt;0.1 L (normal range, 0.3-3.0)</li>
</ul>
Therapeutic interventions:
<ul>
 <li>Bilevel ventilation on spontaneous-timed mode</li>
 <li>Awaiting start of disease-specific therapy</li>
</ul>

F/V ex=expiratory portion of flow volume loop; F/V in=inspiratory portion of flow volume loop.
*Not actual patient. †The Epworth sleepiness scale measures daytime sleepiness via 8 questions on a 4-point scale, from 0 (“would never doze”) to 3 (“high chance of dozing”), that assesses a patient’s propensity to doze or fall asleep during common daily activities.61

<h3>Ongoing Management Goals in Pompe Disease</h3>
LOPD and IOPD
<ul>
 <li>Stabilize or improve motor function and muscle strength4,66
 <ul>
 <li>LOPD: ability to stand, sit, walk, and climb stairs</li>
 <li>IOPD: ability to crawl, sit up, and feed</li>
 </ul></li>
</ul>
<ul>
 <li>Stabilize or improve respiratory function65,66
 <ul>
 <li>FVC in upright and supine positions4,9</li>
 </ul></li>
</ul>
<ul>
 <li>Delay the need for respiratory assistance65,66</li>
</ul>
LOPD
<ul>
 <li>Delay the need for walking assistance2,65,66</li>
 <li>Maintain or improve quality of life65,66</li>
 <li>Enhance patient independence65,66</li>
</ul>
IOPD
<ul>
 <li>Stabilize or improve cardiac health4</li>
 <li>Promote motor development and growth4</li>
</ul>

<h2>In patients with Pompe disease, early and ongoing multidisciplinary care is key to managing symptoms and improving outcomes1,4</h2>

<h2>Diagnose and Manage Pompe Disease early to help Reduce Patient Burden</h2>
<ul>
 <li>In patients with Pompe disease, symptoms of motor impairment are often most pronounced while early respiratory manifestations of diaphragmatic muscle weakness may present with more subtle signs9,14,15</li>
 <li>The leading causes of death are cardiorespiratory failure (IOPD) and respiratory failure (LOPD)4,5,18</li>
 <li>Rapid and definitive diagnostic testing can be done through a DBS GAA enzyme assay combined with a genetic analysis such as NGS21—consider testing for Pompe disease when you see:</li>
 <li>Progressive proximal muscle weakness with or without respiratory insufficiency or unexplained persistent hyperCKemia (1.5 to 15x normal levels; ~300–2000 U/L)1,21-24</li>
 <li>Unspecified limb-girdle myopathy22</li>
 <li>A family member who has Pompe disease5</li>
</ul>
Connect with Sanofi Genzyme associates for help facilitating discussions around implementing testing protocols for your practice, or for more information, by calling medical information at 1-800-589-6215.

Pompe

POMPE

RARE-DISEASE

ACID-SPHINGOMYLENASE-DEFICIENCY-NIEMANN-PICK

Management of ASMD - Expert opinion: Professor Moeen Al Sayed

Professor Moeen gives a detailed explanation on how Olipudase Alfa acts in the body once administered.

Management of ASMD - Expert opinion: Professor Fatma Al- Jasmi

Professor Fatma explains the effect of Olipudase Alfa on the symptoms presented in patients with ASMD.

Navigating the Pompe Disease Journey

Recognizing key signs and symptoms along the way

<h2>Consensus based on literature supporting clinical presentation and recommendations</h2>
Literature Analysis on LOPD Symptoms (Rheumatology): Hierarchy of Evidence

<ul>
 <li>Systemic review and meta-analysis</li>
 <li>Randomized controlled trials</li>
 <li>Observational studies (cohort studies/screening studies)</li>
 <li>Case series studies</li>
 <li>Case series, case reports</li>
 <li>Expert Opinion</li>
</ul>

<ul>
 <li>&nbsp;11 studies for adult#&nbsp;LOPD</li>
</ul>

<h3 style="text-align: center;">Rheumatology-Specific</h3>
Clinical Presentation for Adult#&nbsp;LOPD Proposed During the First Meeting

<ul>
 <li>Unexplained general/inflammatory myopathy</li>
 <li>Asymptomatic hyperCKemia/paucisymptomatic</li>
 <li>Unexplained LGMW</li>
 <li>Polymyositis non-responding to steroids</li>
</ul>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center;">High CK/elevated 
 LDH, ALT, and AST</td>
 </tr>
 </tbody>
</table>

<h3 style="text-align: center;">Rheumatology-Specific Diagnostic Algorithm Proposed During the Second Meeting</h3>

<h2>Conclusion</h2>
A consensus-based diagnostic algorithm simplifies LOPD diagnosis across specialties

Recommendation
Testing for Pompe disease must be done if any one specialty-specific symptom plus elevated CK/LDH/ALT/AST or a family history of unexplained muscle weakness are present.
*The age of patients with pediatric/juvenile LOPD ranges from 1 to 17 years; #The age of patients with adult LOPD is usually 18 years and above.

Reference

Expert Group Consensus From the Arabian Peninsula On the Diagnosis of Lopd

OTHER-RARE-DISEASE-TOPICS

Legacy Video for Rare Disease Academy

Recap video for Rare Disease academy over the years including save the date for the 6th&nbsp;Rare Disease academy.

A survey was conducted to quantify:

Object case:&nbsp;BWS&nbsp;was used to explore 15&nbsp;ASMD symptoms/risks.

<h2>Results</h2>
<h3>Baseline characteristics</h3>

Median age
<ul>
 <li>5 years&nbsp;for patients in the US</li>
 <li>3 years&nbsp;for children of parents from the US and the UK</li>
</ul>

Symptoms
<ul>
 <li>Abdominal enlargement</li>
 <li>Abdominal pain</li>
 <li>Fatigue</li>
 <li>Shortness of breath</li>
</ul>

<h2>Cognitive pretesting interviews</h2>
<ul>
 <li>
 Parents and patients reported difficulty in identifying ASMD-associated symptoms.</li>
 <li>Parents were unaware of their child experiencing ASMD symptoms unless indicated by the child.</li>
</ul>

<h3>Patients and parents</h3>
The largest differences in severity levels were observed for:
<ul>
 <li>Fatigue</li>
 <li>Joint pain</li>
 <li>Abdominal pain</li>
</ul>

<ul>
 <li>Patients and parents had similar preferences for ranking symptoms/risks.</li>
 <li>A wide range of symptoms displayed heterogeneity in samples.</li>
</ul>

black

*Severe fatigue: Fatigue so severe that the respondent might need help taking care of themselves and doing daily activities.

Impact of symptoms and risk of ASMD on patients and caregivers

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