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Sanofi Pasteur partners with the public health, medical and scientific communities to improve access to life-protecting vaccines and increase vaccination coverage, while striving to develop new and improved vaccines to enhance health and well-being.

Reference

Sanofi Pasteur at Glance

INFLUENZA

VACCINES

<h3>Your patients with diabetes are at increased risk of dangerous complications when diagnosed with influenza2-4:</h3>

Flu and Diabetes

<h3>Patients living with diabetes are at increased risk for influenza complications2-4:</h3>

<h3>~3x&nbsp;(95% CI: 2.04-4.71) 
 more likely to be&nbsp;hospitalized2</h3>
<h3>~4x&nbsp;(95% CI: 1.29-14.3) 
 more likely to be&nbsp;admitted tothe ICU2</h3>
Study design2 Subjects:162 patients aged &lt;1 to 85 years Study period:May 25–July 1, 2009 Study limitations:This study was limited to those with PCR-confirmed influenza A H1N1. Medical history was obtained solely by patient interview.

<h3>~2x&nbsp;(95% CI: 1.5-3.6) 
 more likely&nbsp;to die&nbsp;after influenza hospitalization</h3>
Study design4 Subjects:196 patients aged 18 and older Study period:April 29, 2009–March 31, 2010 Study limitations:Underreporting and misclassification of outcome or risk factors are possible and might conceal the real disease burden. Study period was during H1N1 pandemic.

<h3>74%&nbsp;(95% CI: 2.15-3.74, p &lt;0.05) 
 increase in abnormal glycemic events5</h3>
Study design:Patient generated health data and medical claims were analyzed for 167,672 patients aged 18 and older Study period:&nbsp;2016–2017 influenza season Study limitations:The analysis focused on adults with commercial insurance and does not fully represent older people with diabetes within the United States or at-risk underserved populations.

<h3>The American Diabetes Association® urges eligible individuals aged 6 months and older to get their annual flu shot6:</h3>
Protecting against influenza can help your patients with diabetes avoid influenza-related complications, such as hospitalization and death.2-4,7

References

Rattle is a global&nbsp;network of RSV experts&nbsp;that leverages up-to-date&nbsp;scientific content and evidence&nbsp;to engage in&nbsp;multichannel medical education&nbsp;and reinforce the need to&nbsp;protect all infants&nbsp;against RSV. Rattle is being developed to provide healthcare providers, or HCPs, the latest scientific and clinical information to challenge the status quo in RSV by:
<ul>
 <li>Increasing awareness of RSV</li>
 <li>Facilitating dialogue around RSV</li>
 <li>Deepening understanding of RSV</li>
 <li>Supporting knowledge exchange about the need for protection against RSV in all infants Rattle&nbsp;uses a sharing-best-practice philosophy for its programs, protagonized by a global network of RSV experts who guide the development of resources to support HCP educational needs regarding RSV for audiences worldwide.</li>
</ul>

RESPIRATORY-SYNCYTIAL-VIRUS

Rattle

<h2>RSV is a highly transmissible viral disease</h2>
<h3>Vision</h3>
A world-known medical education program that shattered the status quo and brought to life the need for an all-infant focus
<h3>Mission</h3>
Leverage high-quality medical evidence and global experts through a medical education program to reinforce the need to protect all infants

<ul>
 <li>
 <h3>RSV Epidemiology</h3></li>
 <li>
 <h3>RSV Burden&nbsp;of&nbsp;Disease</h3></li>
 <li>
 <h3>RSV Immunology&nbsp;&amp; Pathophysiology</h3></li>
 <li>
 <h3>RSV Prevention</h3></li>
 <li>
 <h3>RSV Clinical&nbsp;Management</h3></li>
</ul>

Learn more about the Rattle Education programme

black

<h2>HOW CAN THE TREATMENT PARADIGM OF cGVHD BE OPTIMIZED?</h2>
The lack of standardized treatment and response biomarkers, as well as the variability of the disease from person to person, impedes the goals of extending survival and improving QOL.1

with systemic corticosteroids, with or without CNIs, is well established in patients with chronic graft-versus-host disease.2-4

First-line therapy

Second-line therapy 
 may be required for approximately 70% 
 of patients with cGVHD.5

Second-line therapy

may be required for approximately 50% 
 of those patients, with many progressing to later lines of therapy.5

Third-line therapy

Both corticosteroids and CNIs may provide effective initial therapy for cGVHD. However, prolonged systemic use of either can cause significant toxicities.2
Toxicities associated with prolonged corticosteroid use include2

<ul>
 <li>Weight gain</li>
 <li>Bone loss&nbsp;</li>
</ul>

<ul>
 <li>Myopathy</li>
 <li>Diabetes&nbsp;</li>
</ul>

<ul>
 <li>Hypertension</li>
 <li>Mood swings</li>
</ul>

<ul>
 <li>Cataract formation</li>
 <li>Increased risk of infection</li>
</ul>

Toxicities associated with prolonged CNI use include6

<ul>
 <li>Metabolic abnormalities</li>
</ul>

Corticosteroids should be tapered to allow for the lowest dose that adequately controls cGVHD. Once cGVHD is controlled, corticosteroids should be withdrawn, followed by withdrawal of CNIs.2&nbsp;For these patients who are unable to tolerate prolonged exposure, a more targeted approach may be required.3,4,6,7
As patients progress to later lines of therapy, the focus of treatment becomes stabilizing the condition while limiting AEs and maintaining QOL.6,8

<div>
 A treatment paradigm that allows for the right treatment for the right patient at the right time may better address the manifestations of cGVHD.
</div>

Learn more about other treatment options

If initial therapy is not enough, what is the next step?

Abbreviations

Optimizing Treatment

CHRONIC-GRAFT-VERSUS-HOST-DISEASE-CGVHD

TRANSPLANT

<h2>What is the Pathogenesis of cGVHD?</h2>
Chronic graft-versus-host disease is a complex multisystem disorder caused by an immune imbalance following an allogeneic HCT, which leads to serious and potentially life-threatening complications from both inflammatory and fibrotic processes. cGVHD is mediated by multiple immune pathways and is characterized by1

Early inflammation due to tissue injury

Chronic inflammation and a dysregulated adaptive immune system

Chronic graft-versus-host disease presents multiple challenges for both clinicians and patients, specifically through manifestations of inflammation and fibrosis.
Although advances have been made in the understanding of cGVHD, many questions still remain.

Understanding the manifestations of cGVHD

What roles do the inflammatory and fibrotic processes play in cGVHD?

cGVHD is a significant burden on patients, affecting them physically, mentally, emotionally and financial

What is the full impact of cGVHD on patients' lives?

How targeting alternative molecular pathways may offer a different treatment approach

What is under clinical development?

cGVHD,chronicgraft-versus-hostdisease.
Although the understanding of the pathophysiology of cGVHD is improving, there is still much to be uncovered about the nature of the inflammatory cascade and the complex dynamics of the inflammatory and fibrotic processes.
Improving comprehension of these manifestations could help in the development of more targeted treatments.

Learn more about ROCK, BTK, JAK and IL-2

What molecular pathways are implicated in cGVHD?

Understandig cGVHD

<h2>cGVHD has a significant impact on the overall well-being of patients</h2>
cGVHD impacts patients' QOL
The&nbsp;inflammation and fibrosis&nbsp;associated with chronic graft-versus-host disease lead to multiple physical ailments, some of which include

Skin thickening or tightening, as well as painful rashes and lesions on the skin1-3

Joint stiffness and loss of mobility and dexterity2

Lung function impairment, which leads to significant 
 morbidity3-6

Results from multiple studies show that patients with cGVHD reported significantly worse QOL,&nbsp;as measured by various tools, such as the Lee Symptom Scale, the SF-36 and the FACT-BMT.7,8 
 A multicenter, prospective, observational cohort study evaluated 298 patients with cGVHD. When compared with age- and sex-matched US population normative data, patients with cGVHD had significantly lower scores, as measured by the SF-36 and the FACT-BMT, for8

When comparing mean SF-36 scores of patients with moderate to severe cGVHD with those of other chronic health conditions, patients with cGVHD had PCS comparable with8
✓ Systemic sclerosis ✓ Systemic lupus erythematosus ✓ Multiple sclerosis
Patients with moderate to severe cGVHD also showed greater impairment when compared with other conditions, including8
✓ Chronic lung disease ✓ Hypertension ✓ Diabetes ✓ Arthritis
Fibrosis, in particular, has a negative effect on QOL, especially when affecting the joints or extensive areas of the skin.2,9 This can lead to chronic disability and, in cases where fibrosis spreads to organs such as the lungs, significant mortality.4-6

Impact on Patients

<h2>WHAT ARE OTHER TREATMENT OPTIONS?</h2>
There are several adjunctive options for the treatment of patients with chronic graft-versus-host disease, including targeted therapies and ECP. However, there is currently limited guidance regarding when each should be considered and for which patients these treatments will be most effective.1-4

ECP is a nonpharmacologic immunomodulatory therapy that involves leukapheresis of patient peripheral blood mononuclear cells, exposure of the cellular product to UV-A light in the presence of 8-methoxypsoralen and reinfusion of the ex vivo–treated cells.1 
 The mechanisms of ECP are not completely understood, although it is believed that ECP suppresses alloimmune responses by altering the maturation and function of dendritic cells, as well as through the induction of Treg cells.1&nbsp;The procedure has shown benefit in patients with steroid-refractory cGVHD,1&nbsp;as well as in those with skin, oral, and liver cGVHD.5 
 ECP requires venous or central access and involves a variety of treatment schedules to identify the appropriate dose intensity and length of treatment.6

BTK inhibitors form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. Nonclinical studies have shown that this class of drug inhibits the proliferation and survival of malignant B cells in vivo, as well as cell migration and substrate adhesion in vitro.3&nbsp;Some BTK inhibitors also inhibit IL-2–ITK, which is highly expressed in T cells and is closely related to BTK.1 
 Both B and T cells play important roles in the pathogenesis of cGVHD,7&nbsp;and the inhibition of BTK and ITK has shown clinical benefit.1,7 
 Warnings and precautions associated with BTK inhibitors include infections and cytopenias, which include thrombocytopenia, neutropenia and anemia.3

BTK inhibitors

JAK1 and JAK2 mediate receptor signaling for a variety of pro-inflammatory cytokines, which are elevated in cGVHD.1 
 Inhibitors of this pathway have been shown to decrease expression of inflammatory cytokines and reduce GVHD in murine models,1,2&nbsp;as well as suppress activation and differentiation of dendritic cells and T cells.1&nbsp;This approach has shown promising results in patients with steroid-refractory cGVHD.1,8 
 Safety considerations associated with JAK inhibitors include monitoring for pruritus, infections, thrombocytopenia and leukopenia.8

JAK inhibitors

A greater number of treatments that address both the inflammatory and fibrotic processes of cGVHD are needed.

Learn more about potential targeted options

Are there new approaches to the treatment of cGVHD under clinical development?

Other Treatment Options

<h2>WHAT ROLES DO THE INFLAMMATORY AND FIBROTIC PROCESSES PLAY IN cGVHD?</h2>
Chronic graft-versus-host disease is characterized by a combination of tissue inflammation and fibrosis, which manifest across multiple organ systems.1-4 
 The relationship between these 2 processes in cGVHD is complex and not fully understood.3&nbsp;Fibrosis may be viewed as a natural consequence of inflammation, as an independent process or as interrelated with inflammation in some ways but not completely dependent on it.5

Because of chronic inflammatory changes, cGVHD can present with collagen-producing fibroblasts,2 resulting in fibrotic lesions.2,4
Fibrotic lesions can develop across multiple organs4

SKIN

MOUTH

JOINTS

EYES

GI TRACT

ESOPHAGUS

LIVER

LUNGS

Fibrosis is a major contributor to life-threatening complications and significant morbidity.6

<h3>Patients develop multiorgan manifestations, including skin, mouth, joint/fascia, eye, upper and lower GI tract, esophagus, liver, genitourinary and/or lung manifestations.4,7,8</h3>

Skin manifestations are the most common, occurring in

Approximately half of patients have lung involvement,

which can manifest as bronchiolitis obliterans, a fibrotic manifestation that can be especially difficult to treat.

<div>
 Although the inflammation associated with cGVHD can be addressed, there is limited evidence regarding the impact of current treatments on fibrosis.10-15
</div>

Learn more about patient quality of life

How do inflammation and fibrosis affect patients’ lives?

Learn more about current treatment options

What treatments are currently available for cGVHD?

Inflammation and Fibrosis Role

<h2>WHAT TREATMENTS ARE UNDER CLINICAL DEVELOPMENT?</h2>
There are multiple novel therapies currently being investigated for the treatment of chronic graft-versus-host disease with the hopes of improving patient outcomes.

Selective rho-associated coiled-coil–containing protein kinase (ROCK) 2 inhibitors have been studied as a potential treatment option for cGVHD, given that this molecular pathway&nbsp;mediates both the inflammatory and fibrotic components&nbsp;of the disease.1,2 
 Selective ROCK2 inhibition has been shown to help resolve immune dysregulation by downregulating pro-inflammatory T helper (Th) 17 cells and increasing regulatory T (Treg) cells. Furthermore, selective ROCK2 inhibition has been shown to downregulate key fibrotic processes, such as TGF-β and LPA, leading to a decrease in fibrosis and collagen deposition.1-4 
 Clinical studies are currently ongoing to evaluate the potential benefifits of selective ROCK2 inhibition in cGVHD.

Selective ROCK2 inhibitors

The involvement of JAKs in the signaling of pro-inflammatory cytokines involved in cGVHD pathogenesis has been a large area of interest. The potential use of JAK1 selective inhibitors in the treatment of cGVHD is currently being explored.

Selective JAK1 inhibitors5

The important role that IL-2 plays in Treg cell development, expansion, activity and survival has led to interest in its use for the treatment of cGVHD. Clinical studies in patients with cGVHD have shown that low-dose subcutaneous IL-2 has increased Treg cells, with minimal effect on CD4+&nbsp;T cells. Clinical studies are currently ongoing to explore the potential benefits of IL-2 therapy.

IL-26

Combination therapy that is intended to disrupt each phase of the GVHD cascade is another area in which research is underway. This approach to therapy would ideally use synergistic agents with different mechanisms of action and nonoverlapping toxicities

Combination therapy7

As research continues, promising targets in cGVHD are being uncovered, with the possibility of offering patients more comprehensive and optimized treatments in the near future.

Learn more about inflammation and fibrosis

What are the manifestations of cGVHD that need to be addressed?

Abbreviation

Treatment under Clinical Development

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