<h2>Understanding Tolebrutinib Fast Fact Series</h2>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td colspan="3" style="text-align: right; background-color: rgb(120, 62, 144);">Cell-based IC50&nbsp;1</td>
 </tr>
 <tr>
 <td style="text-align: center; background-color: rgb(244, 242, 246);">BTK</td>
 <td style="text-align: center; background-color: rgb(244, 242, 246);">Microglia-HMC cells</td>
 <td style="text-align: center; background-color: rgb(244, 242, 246);">0.7 nM</td>
 </tr>
 </tbody>
</table>

<ul>
 <li>Tolebrutinib shifted microglia from a disease-associated to a homeostatic phenotype in a mouse model3</li>
</ul>
<h3>Effect on microglial gene expression in vitro3</h3>

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="background-color: rgb(244, 242, 246);">
 BRaKe-MS Phase 2a study design4
 <ul>
 <li>N=7</li>
 <li>Switched to tolebrutinib from ocrelizumab</li>
 <li>CSF samples were obtained at baseline, and at 12 and 48 weeks after crossing over to tolebrutinib</li>
 </ul></td>
 </tr>
 </tbody>
</table>

<h3>At 48 weeks after crossing over to tolebrutinib, gene expression is altered in myeloid cells4</h3>

Tolebrutinib is an investigational agent and has not been approved for use by any regulatory authority.
Tolebrutinib is an investigational agent and has not been approved for use by any regulatory authority.
AIF1=allograft inflammatory factor 1; APOE=apolipoprotein E; BTK=Bruton’s tyrosine kinase; BTKi=BTK inhibitor; C1QC=complement C1Q C chain; CSF=cerebrospinal fluid; CSF1R=colony stimulating factor 1 receptor; HMC=human microglia clone; IC50=50% maximum drug inhibition; HLA=human leukocyte antigen; Ig=immunoglobulin; OPN=osteopontin; P2RY12=purinergic receptor P2Y12; P2RY13=purinergic receptor P2Y13; PwMS=people with MS; RGS1=regulator of G protein signalling 1; W=weeks.

References

Tolebrutinib Direct Effects on Myeloid Cells in PwMS

MULTIPLE-SCLEROSIS

NEUROLOGY

Inside MS: Explore how BTK drives immune cell activation and CNS damage

Discover the science behind Tolebrutinib: a BTK inhibitor designed to slow MS disability progression by modulating adaptive and innate immunity

Meet a Sanofi Specialist

OTHER-RARE-DISEASE-TOPICS

RARE-DISEASE

cGVHD has a&nbsp;high unmet need beyond 2L, as current treatments&nbsp;inadequately address diverse manifestations&nbsp;such as fibrosis and&nbsp;do not support long-term use, resulting in&nbsp;rapid disease progression.1

black

Guidelines clearly state that there are&nbsp;no standard therapies for SR patients2,3,5,7, limiting these patients to the following available therapies:

Currently, there is&nbsp;no consensus&nbsp;on the&nbsp;optimal choice of agents for 3L or further lines of therapy&nbsp;as per the major guidelines2
The need to investigate&nbsp;novel therapies&nbsp;to address the&nbsp;fibrotic manifestations&nbsp;of cGVHD in 2L and 3L has been recognized8,11
cGVHD progression is a key reason to modify or discontinue cGVHD therapy8

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="background-color: rgb(122, 0, 230); border-color: rgb(255, 255, 255);">
 1L</td>
 <td style="background-color: rgb(122, 0, 230); border-color: rgb(255, 255, 255);">
 2L</td>
 <td style="background-color: rgb(122, 0, 230); border-color: rgb(255, 255, 255);">
 3L</td>
 </tr>
 <tr>
 <td style="text-align: center; border-color: rgb(255, 255, 255);">3 to 7 months</td>
 <td style="text-align: center; border-color: rgb(255, 255, 255);">3 to 4 months</td>
 <td style="text-align: center; border-color: rgb(255, 255, 255);">4 to 5 months</td>
 </tr>
 <tr>
 <td style="text-align: center; border-color: rgb(255, 255, 255);">96%7</td>
 <td style="text-align: center; border-color: rgb(255, 255, 255);">71%7</td>
 <td style="text-align: center; border-color: rgb(255, 255, 255);">47%7</td>
 </tr>
 </tbody>
</table>

Abbreviations
1L:&nbsp;First Line;&nbsp;2L:&nbsp;Second Line;&nbsp;3L:&nbsp;Third Line;&nbsp;SR:&nbsp;Steroid-resistant;&nbsp;NCCN :&nbsp;National Comprehensive Cancer Network;&nbsp;ASH:&nbsp;American Society of Hematology;&nbsp;ANZTCT:&nbsp;Australia and New Zealand Transplant &amp; Cellular Therapies;&nbsp;EBMT: European Society for Blood and Marrow Transplantation;&nbsp;ECP:&nbsp;Extracorporeal photopheresis;&nbsp;cGVHD:&nbsp;Chronic graft-versus-host disease.

Unmet Need

PAYOR

OUT-OF-TAXONOMY

Belumosudil is the&nbsp;first and best-in-class ROCK2 inhibitor, specifically designed as an immunomodulator to target both the inflammatory and fibrotic/sclerotic manifestations of cGVHD.1

Belumosudil&nbsp;decreases activation of STAT3, triggering the significant&nbsp;downregulation of both Th17 and Tfh cells, leading to the&nbsp;downregulation of pro-inflammatory cytokines (IL-21, IL-17).2,5

↓&nbsp;Inflammation
Belumosudil&nbsp;increases phosphorylation of STAT5, causing the&nbsp;upregulation of Treg cells.3&nbsp;Overall, this has an&nbsp;immunomodulatory effect&nbsp;on STAT3 and STAT5 phosphorylation,&nbsp;reducing inflammation.1,4

200 mg once daily administered orally7

REZUROCK® (belumosudil) is indicated for the treatment of adult and pediatric patients 12 years and older with cGVHD after failure of at least two prior lines of systemic therapy.7

Belumosudil&nbsp;prevents the polymerization of G-actin to F-actin, including the&nbsp;downregulation of MRTF-related profibrotic gene expression.6
↓&nbsp;Fibrosis

Belumosudil&nbsp;downregulates fibrosis, as demonstrated by&nbsp;decreased collagen deposition around the bronchioles&nbsp;and the&nbsp;delayed progression of scleroderma&nbsp;in animal cGVHD models.3

Abbreviations
ROCK2:&nbsp;Rho associated coiled-coil containing protein kinase 2;&nbsp;STAT3:&nbsp;Signal transducer and activator of transcription 3;&nbsp;Th:&nbsp;&nbsp;helper cells;&nbsp;Tfh:&nbsp;T follicular helper cells;&nbsp;IL-21 :&nbsp;Interleukin-21;&nbsp;IL-17:&nbsp;Interleukin-17;&nbsp;Treg:&nbsp;Regulatory&nbsp; ;&nbsp;STAT5: Signal transducer and activator of transcription 5;&nbsp;G-actin:&nbsp;Globular protein;&nbsp;F-actin:&nbsp;Filamentous protein;&nbsp;MRTF:&nbsp;Myocardin-related transcription factor;&nbsp;cGVHD:&nbsp;Chronic graft-versus-host disease.

Rezurock Dosage

cGVHD is the&nbsp;most common complication of alloHSCT, leading to significant multi-organ damage and affecting&nbsp;~54%&nbsp;of patients annually and increasing both premature mortality and healthcare costs.1

Among patients undergoing alloHSCT, approximately 54% develop cGVHD, out of which ~35% experience a moderate form and ~30% a severe form of the disease.2

A substantial proportion of patients with cGVHD present with concomitant inflammatory and fibrotic manifestations.3
<ul>
 <li>Up to 50% of patients with moderate cGVHD and 60% with severe disease may exhibit lung involvement, which can manifest as bronchiolitis obliterans, a fibrotic manifestation that can be especially difficult to treat.4</li>
</ul>

Non-relapse mortality continues to increase over time in patients with cGVHD reaching 22% after 5 years.15

Direct costs increase by 1.5 times in mild cGVHD and 4 times in moderate to severe cGVHD, compared with patients post-alloHSCT without cGVHD.16

Social functioning, physical functioning, general health, and other QoL components are worsened with cGVHD progression.17-18

Abbreviations
alloHSCT:&nbsp;Allogeneic hematopoietic stem cell transplantation;&nbsp;cGVHD:&nbsp;Chronic graft-versus-host disease;&nbsp;QoL:&nbsp;Quality of life.

cGVHD Burden

Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung condition characterized by breathing difficulties, with&nbsp;significant impacts on patients' quality of life.
Global Impact

Global Death Toll:
<ul>
 <li>Globally, COPD is the&nbsp;third leading cause of death,&nbsp;following ischemic heart disease and stroke1</li>
 <li>In 2019 alone, it caused&nbsp;3.23 Million deaths worldwide,&nbsp;representing&nbsp;6% of total global deaths1,2.</li>
</ul>

Widespread Prevalence:
<ul>
 <li>Approximately&nbsp;299.4 Million cases&nbsp;were reported globally in 2017, showing a&nbsp;24%&nbsp;increase since 20073.</li>
 <li>The&nbsp;prevalence of COPD is projected to increase, with an estimated&nbsp;5.4 Million deaths by 20604.</li>
</ul>

DALYs:
<ul>
 <li>COPD accounts for the majority of Disability-Adjusted Life Years (DALYs) among chronic respiratory diseases5, causing 2.6% of global DALYs in 20156.</li>
</ul>

<h3>COPD Burden in United Arab Emirates</h3>
COPD presents a significant health challenge with&nbsp;rising prevalence rates and economic impact:
<ul>
 <li>
 COPD prevalence&nbsp;was estimated to be between&nbsp;3.7%&nbsp;and&nbsp;5.3%&nbsp;in 20247 
 &nbsp;</li>
 <li>
 Mortality Impact:&nbsp;COPD accounts for about 2% of all-cause deaths7. 
 &nbsp;</li>
 <li>
 Macroeconomic Impact:&nbsp;According to the World Bank, the estimated economic loss attributed to COPD in 2017 was approximately&nbsp;$12.726 Billion, reflecting the long-term economic consequences of unmanaged COPD in the region&nbsp;8.</li>
</ul>

Direct Costs of Treatment and Care:
Hospitalizations and Medications:&nbsp;The direct costs of COPD are largely driven by hospitalizations, outpatient visits, and prescription drugs. Severe exacerbations significantly increase these costs, with hospitalizations accounting for a major portion of the expenses9-10
Exacerbations:&nbsp;Costs related to exacerbations are a significant component of direct healthcare expenses. Moderate exacerbations cost approximately €888 (US $1045.17), while severe exacerbations cost about €7091 (US $8346.04) per event9.
Healthcare Services:&nbsp;Direct costs also include general practitioner visits, laboratory tests, and rehabilitation programs. These services are essential for managing COPD but contribute to the overall financial burden9-10.

Indirect Costs
Productivity Losses:&nbsp;Indirect costs primarily arise from loss of productivity due to COPD-related disability, premature death, and work absences9-10.
Premature Retirement:&nbsp;COPD often leads to early retirement, which further contributes to indirect costs by reducing the workforce participation and increasing social transfer payments&nbsp;10.

Productivity claims associated with COPD were responsible for 10% of the overall COPD cost burden for working patients&nbsp;11:

Productivity Losses:
<ul>
 <li>Frequent exacerbators experience the highest productivity loss:&nbsp;456.5</li>
 <li>Infrequent exacerbators have a significant loss as well:&nbsp;361.8</li>
 <li>Non-exacerbators show the lowest productivity loss:&nbsp;255.</li>
</ul>
→ Exacerbations directly correlate with increasing productivity losses.

Lost Work Time (sick leave):
<ul>
 <li>Frequent exacerbators also show the highest amount of lost work time:&nbsp;60.0</li>
 <li>Non-exacerbators experience less time away from work:&nbsp;49.8</li>
 <li>Infrequent exacerbators fall in between:&nbsp;60.0</li>
</ul>
→ Exacerbations are key drivers of absenteeism in COPD patients.

Decreased Productivity (Presenteeism)
<ul>
 <li>Frequent exacerbators suffer a higher loss in productivity while at work:&nbsp;29.3</li>
 <li>Non-exacerbators:&nbsp;11.4</li>
</ul>
→ Exacerbations are key drivers of absenteeism in COPD patients.

COPD treatment not only affects productivity of patients, but also of the caregivers:
A Spanish study analyzed the burden borne by informal caregivers (n=220,892) of patients with COPD12.

% of informal caregivers (of COPD patients) with health-,professional-,and leisure/social-related problems

% of informal caregivers of COPD patients having problems vs. caregivers of patients with other chronic diseases

Caregivers face severe challenges:
<ol>
 <li>83%&nbsp;of caregivers report leisure/social-related problems, followed by&nbsp;38%&nbsp;experiencing professional-related problems and&nbsp;35%&nbsp;facing health issues.</li>
 <li>COPD caregivers, more than those of other chronic diseases like stroke or myocardial infarction, face&nbsp;greater deterioration of health and a marked decrease in leisure time.</li>
 <li>The comparison with caregivers of other chronic diseases further emphasizes the unique burden COPD imposes, showing&nbsp;higher rates of decreased leisure time and overall strain on caregivers.</li>
</ol>

Economic Burden of COPD in UAE

Long term data on Rezurock demonstrates efficacy without compromising safety, establishing it as a well-tolerated 3L therapy for patients with cGVHD1

Clinical Trial (ROCKstar 36-month follow-up)2

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(229, 199, 255);">Category</td>
 <td style="text-align: center; background-color: rgb(229, 199, 255);">Patients, n (%) 
 (n=152*)</td>
 </tr>
 <tr>
 <td>Any AE</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">151 (99)</td>
 </tr>
 <tr>
 <td>Grade ≥3 AEs</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">94 (62)</td>
 </tr>
 <tr>
 <td>Drug-related AEs</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">109 (72)</td>
 </tr>
 <tr>
 <td>Drug related SAEs, n(%)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">12 (8)</td>
 </tr>
 <tr>
 <td>On study death</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">28 (18)</td>
 </tr>
 <tr>
 <td>AE leading to deaths</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">10 (7)</td>
 </tr>
 </tbody>
</table>

*152 patients include 77 patients on belumosudil 200 mg QD treatment and 75 patients on belumosudil 200 mg BID treatment

RWE3

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td colspan="1" rowspan="2" style="text-align: center; background-color: rgb(229, 199, 255);">Category</td>
 <td style="text-align: center; background-color: rgb(229, 199, 255);">belumosudil 
 LOT-episodes (n=113)</td>
 <td style="text-align: center; background-color: rgb(253, 243, 217);">BAT LOT-episodes 
 (n=245)</td>
 </tr>
 <tr>
 <td style="text-align: center; background-color: rgb(229, 199, 255);">Patients, n (ratea)</td>
 <td style="text-align: center; background-color: rgb(253, 243, 217);">Patients, n (ratea)</td>
 </tr>
 <tr>
 <td style="background-color: rgb(242, 242, 242);">Any AE</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">52&nbsp;(41.2)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">175 (51.3)</td>
 </tr>
 <tr>
 <td style="background-color: rgb(242, 242, 242);">Moderate, n (rate3)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">17 (13.5)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">67 (19.7)</td>
 </tr>
 <tr>
 <td style="background-color: rgb(242, 242, 242);">Severe, n (rate3)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">30 (23.8)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">80 (23.5)</td>
 </tr>
 <tr>
 <td style="background-color: rgb(242, 242, 242);">AE attributed to background cGVHD medication, n (rate3)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">12 (9.5)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">47 (13.8)</td>
 </tr>
 <tr>
 <td style="background-color: rgb(242, 242, 242);">AE led to death, n (rate3)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">5 (16)</td>
 <td style="text-align: center; background-color: rgb(242, 242, 242);">11 (16)</td>
 </tr>
 </tbody>
</table>

a: Rate is the incidence rate per 100 episode-years (rate = count / ( total exposure time in years / 100))

Abbreviations
3L:&nbsp;Third line;&nbsp;AE:&nbsp;Adverse event;&nbsp;QoL:&nbsp;&nbsp;Quality of life;&nbsp;RWE:&nbsp;Real-world evidence;&nbsp;n:&nbsp;Sample size;&nbsp;LOT: Line of therapy;&nbsp;BAT:&nbsp;Best available therapies;&nbsp;cGVHD:&nbsp;Chronic graft-versus-host disease.

Rezurock Safety

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