Diseases

João Gonçalves
Faculty of Pharmacy
University of Lisbon
Lisbon, Portugal

Paolo Caliceti
Department of Pharmaceutical and Pharmacological Sciences
University of Padova
Padova, Italy

What Is PEGylation and Why Is It Important?
We will begin by examining the clinical uses of therapeutic proteins, and their applications in healthcare. Next, we will discuss the inherent limitations of therapeutic proteins, including challenges such as pharmacokinetic (PK) profiles, protein aggregation during storage, and potential immune responses. The session will then delve into the process of PEGylation, where polyethylene glycol (PEG) is conjugated to functional amino acid groups on the protein surface. This modification may enhance the properties of therapeutic proteins, offering advantages in stability, half-life, and immunogenicity.

Biopharmaceutical and Immunological Properties of PEGylated Proteins
We will explore the biopharmaceutical and immunological properties of PEGylated proteins, focusing on how their unique structure and composition impact their function. We will discuss how each PEGylated protein has distinct properties based on PEG architecture, molecular weight and degree of conjugation that cannot be generalized across different pegylated molecules, highlighting the variability in pharmacokinetic (PK) characteristics such as half-life, absorption, distribution, and elimination. These factors can significantly influence clinical outcomes, including dosing intervals and overall therapeutic effectiveness. We will also address the potential clinical advantages and limitations of PEGylation, with real-world examples to illustrate how these proteins are used in practice.

Immunogenicity Considerations of PEGylated Proteins
We will explore the immunogenicity of PEGylated proteins, examining both the potential benefits and risks associated with PEG modification. While PEGylation can trigger immune responses against PEG itself or the PEGylated protein, it can also help mask epitopes and reduce anti-drug antibodies formation. Drug- and patient-related factors that influence immunogenicity risk will also be covered, along with the prevalence and impact of pre-existing anti-drug antibodies (ADAs).We will discuss the potential clinical consequences of immune reactions to PEG or PEGylated proteins, and how the risk of such responses can vary depending on the unique properties of each PEGylated protein. The session will also address strategies to mitigate anti-PEG immunogenicity, as well as approaches for monitoring immunogenicity across different stages of drug development—from preclinical studies to post-marketing surveillance. Additionally, we will explore tools that may help predict therapeutic responses to PEGylated proteins, touching on potential areas for future research.

Discussion and Conclusion
By the end of the session, participants will gain a comprehensive understanding of:
How PEGylation represents a major technological advancement in the development and optimization of therapeutic proteins.
How PEGylation affects both the biopharmaceutical properties and clinical applications of therapeutic proteins
Immunogenicity in the context of PEGylated proteins and the strategies used to manage and predict immune responses.
The role of PEGylation in therapeutic outcomes and the future opportunities for innovation in this field.


This educational webinar is based on the presenters’ manuscript titled “Optimizing Pharmacological and Immunological Properties of Therapeutic Proteins Through PEGylation: Investigating Key Parameters and Their Impact”, published in Drug Design, Development and Therapy.

Editorial support for the webinar was provided by Selene Medical Communications and funded by Chiesi Global Rare Diseases. The presenters have been compensated by Chiesi for their time presenting this webinar. All content is disease-state focused, and the presentation will not include information on specific products as treatment for any conditions.

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Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by abnormal bone development. Most babies with FOP appear normal and healthy at birth with one exception—the appearance of deformed big toes. Unfortunately, this common deformity can be attributed to other causes. This can result in a delay of years before a person is diagnosed with FOP properly. This educational webinar, hosted by Ellen Elias, MD, Professor, Pediatrics and Genetics, University of Colorado School of Medicine Christiaan Scott, MD Professor of Medicine at the University of Ottawa, examines best practices to suspect and diagnose this ultra-rare condition.

This educational program is made possible by an unrestricted grant from the International Fibrodysplasia Ossificans Progressiva Association (IFOPA).

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This educational program, hosted by Patrick McKiernan, MD, Pediatric Hepatologist at Birmingham Children's Hospital NHS Foundation Trust and Nadia Ovchinsky, MD, Professor of Medicine at NYU Grossman School of Medicine discuss the recently published guidance on best practices to diagnose, treat, and monitor patients with PFIC. It also explains why the new guidance recommends the early use of IBAT inhibitors in patients suspected of having progressive familial intrahepatic cholestasis (PFIC).

PFIC encompasses a spectrum of autosomal recessive disorders characterized by impaired bile flow (cholestasis) due to defects in biliary epithelial transporters. These rare genetic conditions typically manifest in infancy or early childhood, leading to severe liver dysfunction and potentially life-threatening complications if left untreated. Common early symptoms observed in children with PFIC are jaundice, pruritus, elevated serum bile acid (SBA) values, malabsorption, and failure to thrive. PFIC can be a debilitating condition that significantly impacts the quality of life and can result in end-stage liver disease. As such, early detection and effective intervention are imperative for the prevention of disease progression.

Unfortunately, there are no relevant guidelines based on newly published research to help healthcare providers manage patients with PFIC. However, a recent opinion paper by leading experts in the management of PFIC provides evidence-based guidance on this subject and was recently published in JHEP Reports.

This educational program is made possible by an unrestricted grant from Ipsen.

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This educational program is made possible by an unrestricted grant from Takeda Pharmaceuticals.

Participants
Aleena Banerji, MD
Professor of Medicine, Harvard Medical School and Massachusetts General Hospital,
Boston, MA.

Timothy Craig, DO
Tenured Professor of Medicine, Pediatrics, Biomedical Sciences and OB/GYN, Penn State University, Hershey, PA.
Senior Medical Advisor Vinmec International Hospital, Times City, Hanoi, Vietnam

Marc Riedl, MD
Professor of Medicine, University of California, San Diego School of Medicine,
San Diego, CA.

Hereditary angioedema (HAE) is a rare genetic disease that results in immunologic attacks that can be life-threatening. HAE is the result of reduced levels of C1-inhibitor, a protein involved in various physiological processes in plasma, most notably with the complement system. C1-inhibitor also binds and inhibits plasma kallikrein and factor XIa, thereby affecting bradykinin production. It is believed that the disruptions of these processes lead to fluid leaking from the blood to connective tissue which leads to HAE attacks. [1,2] It is these HAE attacks that tend to put persons in the emergency department or unable to attend work or school. [3]

Numerous therapies are now available for patients with HAE to both treat acute attacks and prevent attacks via prophylactic treatment. [4-11].

With so many treatment options now available, is it disheartening to learn that not all patients with HAE are receiving equal care or access to care. Patients with HAE living in rural areas as patients from underrepresented racial or ethnic backgrounds are not provided the same level of care as patients, especially Caucasian patients, living in more affluent areas. [12-16]

This panel discussion by three clinical research leaders in HAE, Drs. Aleena Banerji, Timothy Craig, and Marc Riedl, provide an overview of the discrepancies in care observed in certain patient populations, as well as a discussion on best practices to reduce those inequalities moving forward.

References
1. Smith TD, Riedl MA. The future of therapeutic options for hereditary angioedema. Ann Allergy Asthma Immunol. 2024; doi: 10.1016/j.anai.2024.04.029 [online ahead of print]
2. Grumach AS et al. Current challenges and future opportunities in patient-focused management of hereditary angioedema: a narrative review. Clin Transl Allergy. 2023; 13: e12243.
3. Lumry WR. Hereditary angioedema: The economics of treatment of an orphan disease. Front Med. 2018;5:22.
4. Center Watch. Berinert (C1 Esterase Inhibitor (Human)). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3229-berinert-c1-esterase-inhibitor-human
5. Center Watch. Kalbitor (ecallantide). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3690-kalbitor-ecallantide
6. Center Watch. Firazyr (icatibant). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3534-firazyr-icatibant
7. Center Watch. Ruconest (C1 esterase inhibitor [recombinant]). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4155-ruconest-c1-esterase-inhibitor-recombinant
8. Center Watch. Cinryze (C1 Inhibitor (Human). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3317-cinryze-c1-inhibitor-human
9. Center Watch. Haegarda (C1 Esterase Inhibitor Subcutaneous [Human]). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3595-haegarda-c1-esterase-inhibitor-subcutaneous-human
10. Center Watch. Orladeyo (berotralstat). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4666-orladeyo-berotralstat
11. Center Watch. Takhzyro (lanadelumab-flyo). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4252-takhzyro-lanadelumab-flyo
12. Riedl MA et al. Optimization of care for patients with hereditary angioedema living in rural areas. Ann Allergy Asthma Immunol. 2022; 128: 526-533.
13. Meadow JA et al. Challenges in the management of hereditary angioedema in urban and rural settings: results of a United States survey. Ann Allergy Asthma Immunol. 2023; 130: 760-767.
14. Brouwer ES et al. Leveraging unstructured data to identify hereditary angioedema patients in electronic medical records. Allergy Asthma Clin Immunol. 2021; 17: 41.
15. Sylvestre S et al. Racial and ethnic disparities in the research and care of hereditary angioedema patients in the United States. J Allergy Clin Immunol Pract. 2021; 9: 4441-4449.
16. Craig TJ et al. Effectiveness and safety of lanadelumab in ethnic and racial minority subgroups of patients with hereditary angioedema: results from phase 3 studies. Allergy Asthma Clin Immunol. 2022; 18:845.

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Alan Percy, MD, Pediatric Neurologist at the University of Alabama at Birmingham, discusses results from the DAFFODIL study evaluating long-term safety of trofinetide in girls ages two to four years with Rett syndrome.

Rett syndrome is a neurodevelopmental condition primarily affecting girls. Patients with the disease appear to have normal psychomotor development during the first 6 to 18 months of life. This is followed by a developmental "plateau," and then rapid regression in language and motor skills. Additional signs and symptoms may include:

- Repetitive, stereotypic hand movements
- Fits of screaming and inconsolable crying
- Autistic features
- Panic-like attacks
- Teeth grinding
- Episodic apnea and/or hyperpnea
- Gait ataxia and apraxia
- Tremors
- Seizures
- Slowed head growth

Classic Rett syndrome is most commonly caused by genetic changes in the MECP2 gene and is usually inherited in an X-linked dominant manner.

The DAFFODIL study (NCT04988867) is an open-label study evaluating the long-term safety of trofinetide in girls ages two to four years with Rett syndrome. Trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1. It was approved by the U.S. Food and Drug Administration for the treatment of Rett syndrome in patients 2 years and older in 2023.

The key finding from this study was a safety profile in children ages two to four years of age similar to that observed in patients ages five years of age and older in the LAVENDER, LILAC-1, and LILAC-2 trials. Diarrhea and vomiting were the most common treatment-emergent adverse events, but were of mild to moderate severity. Additionally, the use of a diarrhea management plan (discontinuation of laxatives and initiation of increased fiber) led to a lower discontinuation rate caused by diarrhea, with only one discontinuation.

Other endpoints supported symptom improvement as observed in scores of CGI-I scale, CaGI-I scale, and change from baseline in ICND-QoL. Caregivers also noted significant improvement in patients’ ability to say new words, make eye contact, and use of hands.

Chapters:
Introduction 00:00
Trofinetide Overview 00:43
DAFFODIL Study 1:22
Symptom Improvement 4:04
New Learnings 5:14

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Jean Donadieu, MD Service d'Hémato-Oncologie Pédiatrique, Hopital, Paris, provides an overview of WHIM syndrome.

WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with neutropenia that typically presents in childhood or adolescence. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, recognition and diagnosis is often delayed, sometimes even into adulthood. Consequently, WHIM syndrome may be misdiagnosed and underdiagnosed.

To an extent, the name WHIM syndrome is a misnomer. The symptoms listed in the acronym (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis do not describe the most common manifestations of the disorder, and only 23% of patients present with all four symptoms comprising WHIM.

In fact, the most common symptoms in patients diagnosed with WHIM syndrome are the laboratory findings of neutropenia (98%) and lymphopenia (88%).[3] Warts were seen in only 42% of one 66-patient cohort (though in more than half in another study), hypogammaglobulinemia in 65%, and recurrent infections in 92%. Myelokathexis, revealed via bone marrow biopsy, is often used to confirm the diagnosis, along with genetic testing.

The initial clinical sign of WHIM syndrome is recurrent infection. In a survey of patients with WHIM syndrome, Geier and colleagues[3] found that recurrent infection was the first recognizable symptom in 88% of patients (most commonly bacterial respiratory infections [49%] or otitis media [23%]). Skin infections were seen initially in 13%, and HPV-related infections (including warts) were the first recognized symptom in only 2% of patients. In this survey, 96% of patients with WHIM syndrome presented their initial symptom by age 5 years; 70% presented by 1 year of age.

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