Greg Palko, Vice President and Oncology Franchise Head of Kyowa Kirin North America, discusses a new cutaneous T-cell lymphoma (CTCL) Staging Tool.

CTCL is a rare group of malignancies that attack the body’s immune lymphatic system, affecting both B-cells and T-cells. The underlying cause of CTCL is not fully understood. Genetic causes are suspected but these issues appear to be sporadic mutations for the most common forms of CTCL. The most common subtypes of CTCL are Sézary syndrome and mycosis fungoides.

Common symptoms include widespread red rash that may cover most of the body, the presence of cancerous T cells in the blood, and abnormally enlarged lymph nodes. Other signs and symptoms may include intense itchiness, scaling and peeling of the skin; fever; weight loss; hair loss; ectropion; palmoplantar keratoderma; malformation of the nails; and hepatosplenomegaly.

As Mr. Palko explains, due to the variety of symptoms and many disease types, diagnosis of CTCL can be challenging. Many patients go two to seven years before getting an accurate diagnosis. Similarly, staging the severity of the disease can be fraught with uncertainty. However, properly staging patients can be crucial to developing and choosing accurate treatment plans.

The CTCL Staging Tool on PROBEinCTCL.com is a first-of-its kind tool aimed at guiding physicians on what to consider when staging patients with mycosis fungoides and Sézary syndrome. The tool takes physicians through a combination of questions and clinical case imagery evaluating the extent of disease across the TNMB system looking at skin, lymph nodes, visceral/metastasis, and blood. After completion, the tool shows a staging that best aligns with the individual patient case and additional information and guidance is provided for next steps.

The tool was developed from the National Comprehensive Cancer Network Guidelines and clinical trial design and staging recommendations from the International Society for Cutaneous Lymphoma, the U.S. Cutaneous Lymphoma Consortium, and the European Organisation for Research and Treatment of Cancer. The tool works to translate these complex guidelines into a more simple assessment with the goal of supporting more consistent and informed care.

Chapters:
Introduction 00:00
CTCL Overview 00:27
PROBE Staging Tool 1:36
Physician Use 3:22
Importance of Accurate Staging 4:55

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Clint Allen, MD, Senior Investigator, and Scott Norberg, DO, Associate Research Physician at Center for Cancer Research at the National Cancer Institute, discuss results from a study testing the safety and efficacy of zolapogene imadenovac to treat patients with recurrent respiratory papillomatosis (RRP).

RRP is a rare viral disease where tumors grow in the respiratory tract. The tumors can cause a hoarse voice, chronic cough, and difficulty breathing. These tumors rarely become cancerous, but can cause long-term airway and voice complications. RRP is caused by two types of human papillomaviruses (HPV), HPV 6 and HPV 11. There are currently no systemic treatments for this condition.

A recent study published in The Lancet Respiratory Medicine aimed to assess the safety and clinical activity of zolapogene imadenovac (PRGN 2012) in adult patients with RRP. Zolapogene imadenovac is a gorilla adenovirus vector-based gene therapy that targets robust T-cell immunity specific to HPV 6 or 11.

The study was a single-center, single-arm, phase 1/2 trial (NCT04724980) enrolling 38 patients who received a 12-week treatment course. The primary outcome measure was complete response rate, defined as the percentage of patients who did not require an intervention to control RRP in 12 months following treatment.

Of the 35 patients treated at the recommended phase 2 dose (5×1011 particle units), 51% demonstrated a complete response with the median duration of complete response yet to be reached. Complete responses were durable in 83% of those who achieved complete response, requiring no interventions in 12 months following treatment with a median follow up of 22 months.

Additionally, five patients had a partial response, defined as a 50% or greater reduction in clinically indicated interventions after treatment compared with before treatment. The objective response rate was 66%. Adverse events were mild and included grades 1-2 injection site reaction, fatigue, chills, and fever.

Based on these positive results, the U.S. Food and Drug Administration (FDA) approved zolapogene imadenovac in August 2025.

Chapters:
Introduction 00:00
RRP Overview 1:29
Pathophysiology and Natural History 2:46
Zolapogene Imadenovac Overview 4:28
Clinical Trial 6:15
Impact on Management 10:13

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Makayla Alger, patient advocate with TUBB4B, and her mother Joann Alger, discuss their experience with the condition and the need for awareness.

The TUBB4B gene is a gene believed to be involved in microtubule cytoskeleton organization and the mitotic cell cycle.

The condition initially presented in Makayla at the age of two when she first needed glasses. Soon thereafter, her hearing began to worsen. The back-to-back vision and hearing loss led Joann to push for genetic testing, where the TUBB4B mutation was identified.

Now 15 years of age, Makayla requires the use of hearing aids although her hearing has remained fairly stable. However, the vision component of the disease has been progressive, with her loss of night and peripheral vision.

As the family discusses, there are currently no treatments and advocacy groups/organizations for the TUBB4B disease. Joann highlights the frustration about the uncertainty of the disease; not knowing its progression, what symptoms may present, how bad Makayla’s vision might become. The family’s hope is that more awareness can be raised for the disease to stimulate further research and potential treatments.

Chapters:
Introduction 00:00
TUBB4B Overview and Diagnosis 00:10
Living With TUBB4B 2:41
Finding Other Patients 5:17
Advocacy Groups and Raising Awareness 6:38
What People Should Know 8:23

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Krista Casazza, PhD, co-author of the recent article “Biomarker Validation in NPC1: Foundations for Clinical Trials and Regulatory Alignment” in the Journal of Inherited and Metabolic Disease, discusses biomarker validation in Niemann-Pick disease type C (NPC1).

NPC1 is caused by genetic changes in the NPC1 gene. Symptoms may include lack of muscle coordination, brain degeneration, learning problems, loss of muscle tone, increased sensitivity to touch, spasticity, feeding and swallowing difficulties, slurred speech, and an enlarged liver and spleen.

Currently, the most reliable indicator of disease progression in NPC1 is the age at which neurological symptoms appear rather than age at diagnosis, which is often delayed due to phenotypic variability and limited awareness. Treatment options remain scarce, with miglustat approved for off-label use in some regions and 2-hydroxypropyl-β-cyclodextrin currently in clinical trials.

However, growing insights into disease mechanisms have fueled the development of pharmacodynamic, diagnostic, and prognostic biomarkers aimed at supporting earlier diagnosis and tracking therapeutic outcomes. Key areas of focus include cholesterol dysregulation, neuroinflammation, and neuronal loss, with promising biomarker candidates such as 24(S)-hydroxycholesterol, neurofilament light chain, bile acid derivatives, novel lipid species, and oxysterols.

Despite this progress, NPC1 remains a life-limiting disorder with significant diagnostic and therapeutic gaps. Continued translational research and clinical trial efforts will be critical to advancing biomarker validation, regulatory approval, and the development of disease-modifying therapies, moving the field closer to a precision medicine approach.

Chapters:
Introduction 00:00
NPC1 Overview 00:25
Biomarkers of NPC1 2:55

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Jamas LaFreniere, Founder of Sophie’s Hope Foundation and CURE GSD1b, and Blair Stone-Schneider, Executive Director of Sophie’s Hope Foundation, discuss their patient advocacy organization and starting a natural history study for glycogen storage disease type 1b (GSD1b).

GSD1b is an inherited condition characterized by the inability to break down glycogen. As a result, glycogen accumulates in cells throughout the body. In GSD1b, specifically, glycogen and fats build up within the liver and kidneys which can cause these organs to be enlarged and not function properly. Signs and symptoms of the condition generally develop at age 3 to 4 months and may include hypoglycemia, seizures, lactic acidosis, hyperuricemia, and hyperlipidemia. Affected people may also have short stature; thin arms and legs; a protruding abdomen; neutropenia (which may lead to frequent infections); inflammatory bowel disease and oral health problems. GSD1b is caused by changes in the SLC37A4 gene.

There are currently no approved treatments for this condition. Management of the disease includes a strict diet of corn starch every few hours, including overnight, to help regulate blood sugar levels. This places a high burden of disease on caregivers and patients with GSD1b.

Sophie’s Hope Foundation and CURE GSD1b are patient advocacy organizations founded by Jamas and Margot LaFreniere following their daughter Sophie’s diagnosis of GSD1b in 2019 at the age of two. Their mission is to find a cure for GSD1b through funding research and coordinating the collaboration of patients, caregivers, doctors, researchers, and pharmaceutical companies. Additionally, the organization focuses on raising awareness globally among the general population, governments, pharmaceutical industry, and regulatory bodies, as well as supporting patients and caregivers through community building and education.

Currently, a natural history study is underway for patients with GSD1b. The study is important in understanding disease progression and enabling future therapeutic development. Mr. LaFreniere and Ms. Stone-Schneider hope that this study is the first step in partnering with pharmaceutical companies to drive research and development of treatments for patients with GSD1b.

Chapters:
Introduction 00:00
GSD1b Overview 1:31
Diagnostic Journey 2:16
Current Management 3:05
Ongoing Research 5:42
Natural History Study 8:03
Sophie’s Hope Foundation 11:33
What Physicians Should Know 17:45
Importance of Patient Organizations 20:40

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Phioanh Leia Nghiemphu, MD, Professor of Clinical Neurology at University of California Los Angeles, discusses the use of mirdametinib for neurofibromatosis type 1 with symptomatic plexiform neurofibromas (NF1-PN).


NF1 is a genetic condition that affects the skin, skeleton, and peripheral nervous system. The main signs and symptoms of NF1 include dark colored spots on the skin, neurofibromas, and freckles in the underarm and groin. Other symptoms may include colored spots in the eye, curvature of the spine, learning disabilities, and an increased risk for cancer. Plexiform neurofibromas are benign tumors that develop on or around neurons. The number of neurofibromas typically increases over time, and some can get large or turn cancerous and need to be removed. This condition is caused by genetic changes in the NF1 gene.

Earlier this year, the U.S. Food and Drug Administration (FDA) approved mirdametinib for the treatment of adult and pediatric patients ages 2 years and older with NF1 who have symptomatic plexiform neurofibromas (PN). Mirdametinib is an oral, small molecule, MEK inhibitor. It is the first and only FDA-approved therapy for this indication. Miradametinib received an accelerated approval based on results from the phase 2b ReNeu trial.

The study enrolled 114 patients with NF1-PN two years of age and older. Dr. Nghiemphu explains that the primary endpoint of the study, confirmed objective response rate (ORR), was met with a 41% ORR in adults and 52% in children. Tumor volume reductions were also significant and durable. Additionally, patients experienced reductions from baseline in pain and quality of life.

The safety and tolerability profile of mirdametinib was favorable with the most common adverse events in adults including rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. The most common adverse events in pediatric patients included rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.

Chapters:
Introduction 00:00
NF1-PN Overview 00:31
Presentation and Diagnosis 3:04
Mirdametinib Overview 4:04
Similarity to RASopathies 4:59
ReNeu Clinical Trial 5:24
Specialty Clinics 7:50
What Physicians Should Know 10:06

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Geoffrey Liu, MD, Senior Scientist at the Princess Margaret Cancer Centre at the University of Toronto, discusses new data on the treatment of ROS1-positive non-small cell lung cancer (NSCLC) with taletrectinib.

ROS1-positive NSCLC is a rare and aggressive lung cancer that typically occurs in patients aged 50 years and older and who have never smoked. Brain metastases are common in patients with this condition.

The U.S. Food and Drug Administration (FDA) approved taletrectinib for the treatment of adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) in June 2025. Taletrectinib is an oral, central nervous system-active, selective ROS1 tyrosine kinase inhibitor. The FDA approval followed positive results from the TRUST clinical trial program. Both TRUST-I and TRUST-II are phase 2, single-arm, pivotal studies evaluating taletrictinib in adults with advanced ROS1 positive NSCLC. The TRUST-I trial enrolled 173 patients in China and TRUST-II enrolled 164 patients globally.

New data from the TRUST clinical trial program was recently presented at the IASLC 2025 World Conference on Lung Cancer.

Updated TRUST-II Study Results
For TKI-naïve patients, the confirmed objective response rate (cORR) was 85.2% at a median follow-up of 20.5 months. Median progression-free survival (PFS) was not yet reached; the longest PFS was observed at 31.6 months and ongoing. Median duration of response (DOR) was also not yet reached; the longest DOR was observed at 30.4 months and ongoing. A DOR of at least 12 months was achieved by 74.0% of patients and of at least 18 months by 68% of patients. An intracranial response was achieved by 66.7% of patients with brain metastases.
In TKI-pretreated patients, cORR was 61.7% at a median follow-up of 20.4 months. Median PFS was 11.8 months, and median DOR was 19.4 months. An intracranial response was achieved by 56.3% of patients with brain metastases.

Updated TRUST-I Study Results
For TKI-naïve patients in TRUST-I, cORR was 90.3% at a median follow-up of 40.9 months. Median PFS was 44.6 months. Median DOR was not yet reached; the longest DOR was observed at 46.9 months and ongoing. An intracranial response was achieved by 87.5% of patients with brain metastases.

In TKI-pretreated patients, cORR was 51.5% at a median follow-up of 35.1 months. Median PFS was 7.6 months, and median DOR was 13.2 months. An intracranial response was achieved by 75.0% of patients with brain metastases.

Pooled Safety Data from TRUST-I and TRUST-II

The safety and tolerability profile in the integrated analysis from across trials was favorable, with manageable adverse events. Adverse events of clinical interest, including diarrhea, nausea, vomiting and dizziness, were transient and resolved quickly with a median resolution range of 1-3 days. No treatment discontinuations occurred due to these adverse events of clinical interest. AST and ALT elevations occurred in 76% of patients and led to one patient discontinuing treatment.

Chapters:
Introduction 00:00
NSCLC Treatment Landscape 00:34
TRUST Clinical Trials 1:19
Take Home Message 7:08

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Scott Baver, PhD, Vice President of Medical Affairs at ITF Therapeutics, discusses long-term safety and efficacy data on givinostat for patients with Duchenne muscular dystrophy (DMD).

DMD is a rare neuromuscular disorder characterized by progressive muscle wasting. DMD occurs primarily in males, though in rare cases may affect females. The symptoms of DMD include progressive weakness and atrophy of both skeletal and heart muscle. Early signs may include delayed ability to sit, stand, or walk and difficulties learning to speak. Muscle weakness is usually noticeable in early childhood. DMD is caused by genetic changes in the DMD gene.

Recently, positive long-term safety and efficacy data from the phase 2 and phase 3 EPIDYS clinical trials of givinostat in patients with DMD was published in Annals of Clinical and Translational Neurology.

Givinostat is an orally administered histone deacetylase (HDAC) inhibitor that regulates excessive HDAC activity that occurs in muscles affected by DMD. This helps restore expression of key genes and biological processes necessary for muscle maintenance and repair. Givinostat was approved by the U.S. Food and Drug Administration (FDA) in March 2024 for the treatment of patients with DMD ages six years and older.

The analysis from the EPIDYS trials included multiple cohorts of boys with DMD who received givinostat over various durations. Using propensity matching methods, 142 patients receiving givinostat and 142 from the natural history cohort were included in the analyses. Results indicated that long-term treatment with givinostat, in combination with corticosteroids, delayed disease progression in ambulant patients ages six years and older with DMD.

Clinical benefit was also observed in key mobility functions such as ability to rise from floor, where givinostat may delay loss of ability by a median of 2 years. Loss of ability to climb four stairs was delayed by 3.3 years and loss of ability to walk was delayed by 2.9 years. Additionally, givinostat was generally well-tolerated across all cohorts and no new safety signals emerged during long-term treatment.

Chapters:
Introduction 00:00
DMD Landscape Overview 00:34
EPIDYS Clinical Trial 2:25
Givinostat Indication 3:50
Take Home Message 4:46

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Sharon Halperin, Research Director for Lipodystrophy United and patient, discusses her diagnostic journey with lipodystrophy.

Lipodystrophies are rare metabolic disorders characterized by the loss of adipose tissue. This leads to complications such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver. Lipodystrophies generally begin in childhood and have an underlying autoimmunity. The disorder can be genetic or acquired. Symptoms that may indicate a should be evaluated for lipodystrophy include thin arms and legs, prominent muscular veins, cutaneous fat around abdomen, and difficult to treat diabetes. Current management of patients includes cosmetic surgery, diet, and drug therapy for control of diabetes and dyslipidemia. Leptin replacement therapy is the only lipodystrophy-specific treatment.

Ms. Halperin shares her diagnostic journey, starting with signs and symptoms of insulin resistance and lipodystrophy at 6 years old. While searching for a diagnosis, she went to 11 different endocrinologists who all tested her for Cushing’s, each test coming back normal. She was diagnosed with type 2 diabetes at 28 years old which accelerated her path to a lipodystrophy diagnosis. A year and a half ago while searching for an endocrinologist to write up her diagnostic history for disability, a doctor conducted a physical examination and finally gave a diagnosis of lipodystrophy.

Ms. Halperin wants physicians to know that patients are compliant and treatment and trying their best, even when it may not seem like it. She highlights the multisystemic nature of the disease as a challenge to adequately managing the disease. She also wants doctors to understand the high burden of disease on patients and how their symptoms affect their daily life and mental health. While testing for metabolic function and other disease components is important, mental health check ins and asking about how symptoms are making patients feel are essential as well.

Finally, Ms, Halperin advises patients who have been newly diagnosed with lipodystrophy to find community. Networking with patients who have been through similar experiences and can help patients cope with their diagnosis and treatment. Additionally, she stresses the importance of education, noting that the more knowledge one has on the disease, the easier it is to manage.

Chapters:
Introduction 00:00
Diagnostic Journey 00:47
What Physicians Should Know 2:22
Advice for Newly Diagnosed Patients 4:13

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