David Liang, MD, PhD, Cardiologist at Hoag Hospital, discusses the diagnosis and management of Marfan syndrome.

Marfan syndrome is a rare genetic disorder characterized by problems in the development of connective tissue. This leads to changes in the strength and performance of tissues throughout the body including blood vessels, the heart, ligaments, tendons, and skin as well as overgrowth of bones. The largest concern in Marfan syndrome is its effect on the aorta, where aneurysm is common. Marfan syndrome is caused by mutations in the FBN1 gene.

Like most rare conditions, diagnosis of Marfan syndrome can be complex. Many patients can be identified through genetic screening when family history of the disease is known. However, about 1/3 of patients with the condition have spontaneous mutation or are not picked up through family screening. The most common diagnoses occur in early childhood when an ophthalmologist notices lenses are out of position, in teenage years when pectus abnormalities and scoliosis become apparent, or later in life in the case of aortic emergencies.

Current management of Marfan syndrome include medications that may slow the progression towards aorta aneurysm and aorta replacement surgery. Advancements in both of these treatment avenues has led to an increased life expectancy in patients with the condition.

The Marfan Foundation offers resources and support for patients, families, and healthcare providers through research and community. Learn more at https://marfan.org/

Chapters:
Introduction 00:00
Marfan Syndrome Overview 00:25
Current Management 2:01
Diagnostic Journey 3:52
The Marfan Foundation 6:05
The Marfan Foundation Gala 8:03
Take Home Message 9:23

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David Kuter, MD, DPhil, Director of Clinical Hematology at Massachusetts General Hospital, discusses recent results of a trial of mezagitamab in patients with immune thrombocytopenia (ITP).

ITP is an autoimmune bleeding disorder characterized by too few platelets in the blood. Symptoms may include bruising, nosebleed or bleeding in the mouth, bleeding into the skin, and abnormally heavy menstruation. Rarely, ITP may become a chronic ailment in adults and reappear, even after remission.

Mezagitamab is a fully human immunoglobulin IgG1 monoclonal antibody that targets and depletes CD38 expressing cells. Recent data from the phase 2 clinical trial evaluating mezagitamab was presented at the International Society on Thrombosis and Haemostasis (ISTH) 2025 Congress. Part A of the study enrolled 25 patients randomized to mezagitamab 100mg or 300mg or placebo while Part B enrolled 16 patients randomized to mezagitamab 600mg or placebo.

Results showed that through week 16 all groups experienced an increased duration of platelet response with a mean increase with mezagitamab over placebo of 4.9±1.6 weeks for 100mg, 6.9±2.1 for 300mg, and 9.6±1.7 for 600mg. Mean change from baseline in ITP patient assessment questionnaire scores illustrated a clinically meaningful improvement in health-related quality of life with mezagitamab versus placebo.

Chapters:
Introduction 00:00
ITP Overview 00:31
Current Management 1:39
Mezagitamab Overview 3:58
Phase 2 Clinical Trial 6:07
Take Home Message 9:45
Next Steps 12:34

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Erin Dunbar, MD, founding physician of the Brain Tumor Center and Director of Neuro-Oncology at Piedmont Atlanta Hospital, discusses the current landscape of glioblastoma.

Glioblastoma is a malignant brain tumor that develops from an astrocyte brain cell. These cells help support and nourish neurons and form scar tissue that helps repair brain damage in response to injury. Glioblastomas are often very aggressive and grow into surrounding brain tissue. Signs and symptoms (such as headache, nausea, vomiting and/or drowsiness) may develop when the tumor begins to put excess pressure on the brain. Affected people may also experience other features depending on the size and location of the tumor. In most cases, the exact underlying cause is unknown, however, they can rarely occur in people with certain genetic syndromes such as neurofibromatosis type 1, Turcot syndrome and Li Fraumeni syndrome.

Dr. Dunbar explains how the diagnosis process for glioblastoma can be lengthy and traumatizing. Due to the generic neurological symptoms common with early stages of the disease, glioblastoma often goes misdiagnosed. Additionally, emergency episodes caused by the tumor are often mistaken for a stroke, further prolonging accurate diagnosis.

Current management depends on a variety of individual tumor factors such as location, size, symptoms, and a patient’s personal health, etc. Treatment may include biopsy, surgery, radiation, tumor treating fields, and approved or investigational medications.

Dr. Dunbar describes how the treatment landscape has greatly improved in recent years, noting how historical medications were extremely toxic and hard to get. Advancements in technology and disease understanding have led to different surgery options as well as different administration methods and better targeted mechanisms of action to fundamental treatments.

An emerging treatment that Dr. Dunbar is most excited about is berubicin, an anthracycline designed to induce DNA damage in targeted cancer cells by interfering with topoisomerase II enzyme that enables cell proliferation. In an international phase 3 trial, berubicin showed rapid imaging response as well as rapid clinical response. Tolerability was favorable and the known toxicities for the drug type were significantly less or nonexistent.

Additionally, Dr. Dunbar discussed the importance of awareness days, especially in the rare disease space. Not only are these days important to patients and families, but also to clinicians and researchers to be recognized and feel supported in the community and serve as motivation. These days are also important in bringing together all stakeholders, policymakers, legislative advocates, fundraisers, investors to focus on next steps in the disease space.

Chapters:
Introduction 00:00
Glioblastoma Overview 1:08
Diagnostic Journey 3:06
Current Management 6:09
Emerging Therapies and Clinical Trials 8:30
Importance of Awareness Days 16:49

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Surbhi Sidana, MD, Hematologist and Associate Professor at Stanford University, discusses effects of ciltacabtagene autoleucel (cilta-cel) in patients with multiple myeloma (MM).

MM is a bone marrow-based plasma cell neoplasm characterized by a serum monoclonal protein and skeletal destruction. Common symptoms include osteolytic lesions, pathological fractures, bone pain, hypercalcemia, and anemia. The exact underlying cause of multiple myeloma is currently unknown.

Cilta-cel is a B-cell maturation antigen-directed genetically modified autologous T cell immunotherapy. The CARTITUDE-4 clinical trial was a phase 3, randomized, open-label trial where patients were given cilta-cel plus standard of care or just effective standard of care.

As of May 1, 2024, with a median follow-up of 33.6 months, treatment with cilta-cel showed benefits in progression-free survival (PFS) and overall survival (OS) over standard of care, regardless of cytogenetic risk status. This benefit was consistent among patients with both standard-risk and high-risk cytogenetics, including those with del(17p), t(4;14), t(14;16), or gain/amp(1q). Among patients with extramedullary disease, cilta-cel demonstrated a median PFS of 13 months compared to 4 months with standard of care, while median OS was not reached with cilta-cel versus 16 months with standard of care.

Stratified by prior lines of therapy, patients treated with cilta-cel achieved a median PFS that was not reached across all groups, compared to 17 months, 12 months, and 8 months with standard of care, respectively. Similarly, median OS with cilta-cel remained unreached across all prior lines of therapy groups, whereas standard of care yielded unreached, unreached, and 34 months for patients with 1, 2, or 3 prior lines, respectively, with hazard ratios favoring cilta-cel.

Chapters:
Introduction 00:00
Multiple Myeloma Treatment Landscape 00:21
CARTITUDE-4 Clinical Trial 1:25
Take Home Message 4:29

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Michael J. Thorpy, MD, Professor of Neurology at Albert Einstein College of Medicine, discusses positive results in study of Lumryz (sodium oxybate) for hallucinations in patients with narcolepsy.

Narcolepsy is a chronic neurological disorder characterized by an inability of the brain to control sleep-wake cycles. Patients with narcolepsy typically enter REM sleep more quickly, causing the boundaries between wakefulness and sleep to blur. This causes fragmented sleep at night as well as muscle weakness and dream activity while awake. Common symptoms include excessive daytime sleepiness, cataplexy, sleep paralysis, and hallucinations.

Dr. Thorpy explains the prevalence of hypnagogic hallucinations in patients with narcolepsy as a result of entering REM sleep so quickly. Patients may experience REM dream phenomena while still awake or asleep. These dream hallucinations are often unpleasant and frightening and may include vivid dreams, lucid dreams, and out-of-body experiences.

Lumryz is an extended-release central nervous system depressant and new formula of sodium oxybate indicated for the treatment of cataplexy and excessive daytime sleepiness in patients ages 7 years and older with narcolepsy. The treatment may also help correct REM mechanisms that affect REM sleep phenomena.

Data was recently presented at the SLEEP 2025 meeting on the effects of Lumryz on hallucinations in patients with narcolepsy. The study was a 13-week, double-blind, placebo controlled trial and results were presented from a post-hoc analysis. Over 12,000 hallucination episodes were recorded throughout the study. Lumryz illustrated about a 50% reduction in hallucinations compared to placebo. The most improved hallucinations were those considered frightening and that occurred at sleep onset.

Chapters:
Introduction 00:00
Hallucinations in Narcolepsy 00:47
Treatment Strategies 3:14
Lumryz Overview 5:37
SLEEP 2025 Presentations 7:59
Take Home Message 10:40

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Fadi Fakhouri, MD, PhD, Professor of Nephrology at CHUV Lausanne, Switzerland, discusses new data on pegcetacoplan in patients with C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN).

C3G is a rare kidney disease characterized by damage to kidney glomeruli due to abnormal activation of the complement system. When C3 proteins get lodged in the kidney, glomeruli get injured and buildup of toxins and reduced urine production occur. This can ultimately lead to declined kidney function. Common signs and symptoms include hematuria, proteinuria, reduced glomerular filtration rate and increased creatinine levels, fatigue, and edema of the hands, feet, and ankles.

Pegcetacoplan is a targeted C3 therapy designed to regulate excessive activation of the complement cascade. It is currently approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

The VALIANT (NCT05067127) clinical trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study evaluating the safety and efficacy of pegcetacoplan in patients ages 12 years and older with C3G or primary IC-MPGN. A total of 124 patients were enrolled and randomized to pegcetacoplan or placebo twice weekly for 26 weeks. Following the 26-week period, an open-label phase was open to all patients. The primary endpoint was log transformed ratio of urine protein-to-creatinine (UPCR) at week 26 compared to baseline.

Recently, new data from this trial was presented at the 2025 European Renal Association (ERA) Congress. Pegcetacoplan demonstrated a statistically significant proteinuria reduction of 68% at week 26 versus placebo. This reduction was sustained at one year. Patients also achieved stabilization of kidney function measured by estimated glomerular filtration rate (eGFR). For patients that switched to pegcetacoplan from placebo during the open-label extension, similar results were seen in proteinuria reduction and kidney function stabilization. Additionally, the safety profile of pegcegtacoplan was favorable.

Chapters:
Introduction 00:00
C3G Overview 00:40
Current Management 2:00
Pegcetacoplan Overview 3:02
VALIANT Clinical Trial 3:43
Take Home Message 7:57
Kidney Transplantation 8:57

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Mike Flanagan, PhD, Chief Scientific Officer at Avidity Biosciences, discusses topline results from study testing delpacibart braxlosiran (del-brax) in patients with facioscapulohumeral muscular dystrophy and the newly initiated phase 3 trial.

FSHD is a rare disorder characterized by muscle weakness and atrophy. This condition gets its name from the areas of the body that are affected most often: muscles in the face, around the shoulder blades, and in the upper arms. The signs and symptoms of FSHD usually appear in adolescence and include loss of muscle function, pain, and fatigue. The condition is caused by abnormal expression of the DUX4 gene.

Del-brax is a monoclonal transferrin receptor 1 (TfR1) antibody conjugated with a siRNA targeting DUX4 mRNA, designed to target the underlying cause of abnormal DUX4 gene expression.

The FORTITUDE clinical trial program includes a phase 1/2, randomized, placebo-controlled, double-blind study evaluating multiple doses of del-brax in patients with FSHD. In total, the two dose escalation cohorts evaluated 39 patients on either 2 mg/kg or 4 mg/kg of del-brax versus placebo over 12 months.

Top line data from this trial showed consistent improvement of functional mobility and muscle strength measured by the 10-Meter Walk-Run test, Timed Up and Go, and quantitative muscle testing compared to placebo. There was also an observed consistent improvement in multiple measures of quality of life with del-brax versus placebo measured by patient reported outcomes. Additionally, rapid and significant reductions in KHDC1L and creatine kinase levels were observed. Del-brax is illustrating a favorable long-term safety and tolerability profile with most adverse events mild to moderate.

Based on these results, del-brax has been granted access to the Accelerated Approval Program for the treatment of FSHD by the U.S. Food and Drug Administration (FDA). To move forward with a full approval, the global, confirmatory, randomized, placebo-controlled, double-blind, 18-month, phase 3 FORWARD study has been initiated. The study will evaluate 2 mg/kg of del-brax every six weeks in approximately 200 patients with FSHD.

Chapters:
Introduction 00:00
FSHD Overview 00:48
Current Management 4:11
Del-brax Overview 4:38
FORTITUDE Clinical Trial Data 5:43
Next Steps 6:56
Other Programs 8:14

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Paolo Ghia, MD, PhD, Professor of Medical Oncology at Università Vita-Salute San Raffaele in Milan, Italy, discusses results from clinical trial testing ibrutinib plus venetoclax in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL).

CLL/SLL are rare cancers that affect the white blood cells, specifically B cells. The conditions are similar but differ primarily in location of the disease. In patients with CLL, the cancer mainly manifests in the bloodstream, while in patients with SLL, the cancer manifests mainly in the lymph nodes and lymphoid tissue. Early signs and symptoms may include swollen lymph nodes, fatigue, weight loss, fever, night sweats and/or frequent infections. The underlying cause is thought to be a combination of genetic and other unknown factors.

Ibrutinib is a tyrosine kinase inhibitor and venetoclax is a B-cell lymphoma 2 protein inhibitor, both approved for the treatment of CLL. The combination Ibr+Ven is an oral, once-daily, chemotherapy-free first-line treatment for CLL/SLL. The CAPTIVATE clinical trial (NCT02910583) was a phase 2, multicenter, 2-cohort study evaluating ibrutinib plus venetoclax (Ibr+Ven) for the treatment of treatment-naïve patients with CLL/SLL. The trial specifically looked at minimal residual disease (MRD)-guided discontinuation and fixed duration therapy.

A total of 202 patients enrolled in this clinical trial and completed dosing with Ibr+Ven with a median follow-up of 68.9 months. The 5.5-year progression-free survival (PFS) rate was 66% and the overall survival (OS) rate was 97%. The 5.5-year PFS rates in patients without and with del(17p)/mutated TP53 were 70% and 36%, respectively. In patients with unmutated IGHV, 5.5-year PFS was 55%; 63% in patients without, and 44% in patients with concomitant del(17p)/mutated TP53/complex karyotype.For those with mutated IGHV, PFS was 79%, 85% in patients without, and 62% in patients with concomitant del(17p)/mutated TP53/complex karyotype.

Undetactable MRD (uMRD) was achieved in peripheral blood in 54% of patients at cycle 7 and 69% at end of treatment. This was also achieved in bone marrow in 69% of patients at the end of treatment. In patients with uMRD in peripheral blood at the end of treatment, 5.5-year PFS rates were higher than in those with MRD. A total of 64 patients had progressive disease following treatment with Ibr+Ven, while freedom from next-line treatment was 73%.
Of the 40 patients with available samples at disease progression, only one was found to have an acquired subclonal mutation in BCL2, a finding of unclear clinical significance. Importantly, no acquired resistance-associated mutations were observed in BTK or PLCG2. A total of 36 patients went on to receive retreatment, with 25 receiving ibrutinib alone and 11 receiving Ibr+Ven. Among those retreated with Ibr alone, the overall response rate (ORR) was 76% following a median follow-up of 28.4 months. The two-year PFS and OS rates in this group were 91% and 96%, respectively. For those retreated with Ibr+Ven, the ORR was 82% after a median follow-up of 15.2 months. Notably, both one-year PFS and OS rates in this group were 100%, highlighting the promising activity and tolerability of Ibr-based retreatment strategies in patients with CLL who experience disease progression.

Chapters:
Introduction 00:00
Current Treatment Options 00:38
CAPTIVATE Clinical Trial 1:46
Take Home Message 5:56

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Krish Patel, MD, Medical Oncologist at Sarah Cannon Research Institute, discusses first results from a study evaluating CAR-T cell therapy for large B cell lymphoma (LBCL).

LBCL is a form of non-Hodgkin lymphoma. Lymphomas occur when cells of the immune system, B lymphocytes, grow and multiply uncontrollably. It can start in the lymph nodes or outside of the lymphatic system in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Often, the first sign of is a painless rapid swelling in the neck, armpit, abdomen, or groin caused by enlarged lymph nodes. Other symptoms include night sweats, unexplained fevers, and weight loss.

First results from a global phase 1b study (NCT05421663) evaluating JNJ-90014496, a CD19/CD20 bispecific CAR-T cell therapy, in adult patients with relapsed/refractory LBCL was recently presented at the European Hematology Association 2025 meeting. Primary endpoints of the study are recommended phase 2 dose and safety. Secondary endpoints include objective response rate (ORR), complete response rate (CRR), time to first response, and pharmacokinetics.

As of February 2025, 48 patients with CAR-T naïve, heavily pretreated R/R LBCL were treated with JNJ-90014496. At a median follow-up of six months across all doses, 79% of patients cytokine release syndrome with median time to onset of three days and median duration of eight days. In 42 evaluable patients across all doses, ORR was 90.5% and CRR was 76.2%. Median time to first response was one month.

Grade 3/4 treatment emergent adverse events (TEAEs) were observed in 83% and 25% of patients, respectively. The most common grade 3/4 TEAEs were neutropenia, leukopenia, anemia, and thrombocytopenia.

The identified recommended phase 2 dose was 75M CAR+ T-cells. At this dose, in 20 evaluable patients with a median follow-up of three months, ORR was 95% and CRR was 80%.

At the identified recommended phase 2 dose, there were no grade 3/4 cytokine release syndrome, however 86% of patients had grade 1/2 cytokine release syndrome. Additionally, there were no grade 3/4 ICANS and only 5% of patients had grade 1 ICANS. At this dose, 77% had grade 3/4 TEAEs and 23% had serious TEAEs. The most common grade 3/4 TEAEs were neutropenia and lymphopenia.

Chapters:
Introduction 00:00
Large B Cell Lymphoma Landscape 00:32
CD19 Overview 1:28
Clinical Trial Overview 1:50
Take Home Message 6:02

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