Pamela Blair Allen, MD, MSc, Hematologist, discusses the new PROBE staging tool for cutaneous T-cell lymphoma (CTCL).

Cutaneous T-cell Lymphomas (CTCL) are rare, heterogeneous types of non-Hodgkin T-cell lymphoma that primarily manifest in the skin but can involve other disease compartments. CTCLs include a spectrum of variants. Mycosis Fungoides and Sézary Syndrome together are the most common CTCL subtypes.

Due to its challenging presentation, CTCL may be misdiagnosed, with some patients waiting 2 – 7 years for an accurate diagnosis. In an attempt to provide more information around the challenges of diagnosis and staging mycosis fungoides and Sezary Syndrome, the CTCL Staging Tool on PROBEinCTCL.com was developed help healthcare providers (HCPs) navigate the complicated process of accurately staging patients with Sézary syndrome and mycosis fungoides.

The tool takes physicians through a combination of up to 20 yes or no questions that are paired with real clinical case imagery. These questions bring physicians through the TNMB system, which evaluates the extent of disease across 4 compartments: skin (T), lymph nodes (N), visceral/metastasis (M), and blood (B). Upon completion, users are shown a staging which aligns most closely with the patient case provided and are directed to additional clinically relevant information for more guidance.

The tool draws from the National Comprehensive Cancer Network Guidelines and clinical trial design and staging recommendations from the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the European Organisation for Research and Treatment of Cancer (EORTC).

Learn more here: http://bit.ly/45kmTVz

Supported by Kyowa Kirin, Inc.

August 2025, COR-US-ONC-0115

4 0

Jacky Smith, MB, ChB, FRCP, PhD, Chair of Respiratory Medicine at the University of Manchester, discusses topline results from the phase 2a RIVER trial for patients with refractory chronic cough (RCC).

Topline results and a responder analysis from the RIVER clinical trial were presented at the 2025 European Respiratory Society conference. This study was a phase 2a, double-blind, placebo-controlled, crossover study of nalbuphine ER versus placebo in patients with RCC. The trial enrolled 66 patients with RCC stratified by 24-hour cough frequency at screening (10-19 coughs per hour and 20 or more coughs per hour).

Patients were randomly assigned to 1 of 2 21-day treatment sequences: nalbuphine ER to placebo or placebo to nalbuphine ER, with a 21-day washout between treatment. Nalbuphine ER was titrated every 7 days from 27 mg twice daily to 108 mg twice daily. The primary endpoint was relative change from baseline in 24-hour objective cough frequency at day 21 in all patients measured by an objective digital cough monitor.

Results illustrated that at day 21, there was a 56% placebo-adjusted reduction in cough frequency with nalbuphine ER 108 mg. The responder analysis showed that 87% of patients achieved a 30% or greater reduction in 24-hour cough frequency with nalbuphine ER 108 mg at day 21, which is considered a clinically meaningful improvement. More than half of patients achieved a 75% reduction in cough frequency at day 21 with nalbuphine ER 108 mg twice daily.

No serious treatment-emergent adverse events were observed. 10 patients discontinued treatment due to treatment-emergent adverse events. The most common of these were constipation, nausea, somnolence, headache, dizziness, and fatigue.

Topline data: https://www.trevitherapeutics.com/wp-content/uploads/2025/09/Smith-et-al.-ERS-Congress-2025-RIVER-Primary.pdf

Responder analysis: https://www.trevitherapeutics.com/wp-content/uploads/2025/09/Smith-et-al.-ERS-Congress-2025-RIVER-Responder-Analysis.pdf


This drug is investigational and its safety and effectiveness have not been established by the FDA.

0 0

Jill H. Simmons, MD, Endocrinologist at Vanderbilt University Medical Center in Nashville, Tennessee, provides an overview of the XLH Community Impact Survey and its results.

My name is Dr. Jill Simmons. I am a pediatric endocrinologist at Vanderbilt University Medical Center in Nashville, Tennessee. I am director of the Pediatric Metabolic Bone Disorders program here at Vanderbilt. I have been working in the field of rare metabolic bone disorders for about 20 years.

Certainly, as part of that, I work with patients with XLH, primarily in the pediatric age range, but also some young adults as we think about some of the transition burdens that we have. I provide clinical care, also participate in clinical research and clinical trials, as well as this particular patient survey that we're going to be discussing today.

XLH Overview
XLH is short, I should say, for X-linked hypophosphatemia, or what we will often call it in pediatrics is X-linked hypophosphatemic rickets, because in the patient population that I care for, often it causes some specific skeletal findings that manifest as rickets on X-ray.

It's a genetic disorder, it's considered a rare genetic disorder, probably occurring in somewhere around 1 in 20,000 to 1 in 50,000 patients in the world. It's caused by variants in a gene called the PHEX gene, which is short for Phosphate-Regulating Endopeptidase Homolog X-linked gene. I will call that PHEX from here on out.

That gene defect causes chronic inappropriate elevation of something called FGF23, which is the phosphate-regulating hormone, Fibroblast Growth Factor 23, which works to regulate phosphate metabolism, particularly in the renal tubules.

If you have too much FGF23, what essentially happens is the phosphate transporter in the renal tubule will essentially stay wide open so that what's coming in from a dietary standpoint from phosphorus intake essentially immediately is released in the urine, leading to low serum phosphate.

When you have low serum phosphate, that causes a variety of manifestations that we can get into as we continue to talk. But again, the primary problem is an elevated FGF23 that needs to be managed in order to keep the serum phosphorus levels normal.

0 0

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.

4 0

Al Freedman, PhD, Rare Disease Psychologist and Rare Dad, discusses the XLH impact survey and mental health in rare diseases.

My name is Dr. Al Freedman. I'm a practicing clinical psychologist and I specialize in supporting the psychological and emotional needs of patients and families affected by rare disease. I'm also a dad. The reason that I'm focused on rare disease is because of my son, Jack, who was born in 1995 and diagnosed with SMA or Spinal Muscular Atrophy. Jack was given one year to live when he was a baby and thankfully, he didn't fully cooperate with his prognosis. He lived to the age of 26. I learned a lot from my son and I learned a lot every day from other patients and families affected by rare diseases all around the world.

I provide one-on-one counseling services to patients and families. I provide group facilitation service for rare disease advocacy organizations. I provide facilitation for many rare disease support groups around the world. I consult with rare disease advocacy leaders on how to build support programs for their communities and I consult with industry partners on how to support the communities they serve with treatments and treatments that are in development. I'm very busy because there are very few of us at the intersection of mental health and rare disease. I'm happy to share what I know about my work and also specifically about the XLH community.

XLH Impact Survey

Not surprisingly to me, as someone familiar with many rare disease communities. The XLH
community has a significant mental health challenges and the survey the community conducted revealed 83% of adults and 90% of children reported at least one mental health issue. But not surprisingly, a small minority of these patients are seeing a mental health professional. Not surprisingly, anxiety is at the core of many of the concerns.

Those of us in the rare disease community deal with a lot of uncertainty and living with
uncertainty is anxiety-provoking. It came as no surprise to me to see that the most common mental health issue reported was anxiety. Depression was also reported. High rate of depression and also social isolation. Many rare disease patients in this community and others experience social isolation, which is a great challenge and was a challenge during the pandemic and continues to be a challenge for rare disease patients.

Addressing Mental Health in Rare Diseases

It comes as no surprise that attention to mental health would lag behind attention to physical health and medical issues when it comes to rare disease. I'd like to say as a dad that for 26 years, I didn't have time to talk about how I felt about my son's situation. I was busy literally keeping him alive. We have to attend to rare disease. If our physical condition and our medical status to keep stable is a primary need that takes up a lot of time. It takes up a lot of bandwidth. The attention to mental health lags behind.

Secondly, as importantly, access to mental health services is very difficult in the United States. Our mental health system doesn't work very well. It's pretty broken. Access to mental health services for people without rare disease is a challenge. With rare disease, to find person who can help us who has expertise in the unusual situation we're in, is very hard to find. Having insurance cover the cost is hard to find and there are very few mental health practitioners available. Part of this is practical challenge related to time and priorities. Part of this is our health care system just doesn't work very well when it comes to mental health.

0 0

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).

2 0

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.

1 0

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

1 0