Joan Smith, patient with systemic mastocytosis, discusses her diagnostic journey with systemic mastocytosis (SM).

SM is a rare disease, usually caused by mutations in the KIT D816V gene. The disorder is characterized by uncontrolled mast cell proliferation and activation across multiple organ systems. Indolent systemic mastocytosis accounts for approximately 90% of SM. Common symptoms may include anaphylaxis, maculopapular rash, pruritis, diarrhea, brain fog, fatigue and bone pain. Most adults present with skin lesions, usually in the form of urticaria pigmentosa.

Ms. Smith believes she’s had SM her entire life, citing symptoms sporadically appearing throughout childhood and early adulthood. However, it was not til her late 30s and early 40s that symptoms began to warrant her attention. That started when she awoke to an episode of gastrointestinal symptoms, flushing, rash, and tachycardia. That began a 16 year diagnostic journey.

SM can be difficult to diagnose due to the heterogeneity of symptoms that mimic many other conditions. After that first episode, Ms. Smith thought that she just had an allergic reaction. Following a second episode three weeks later, she went to her primary care physician where bloodwork came back normal and she was referred to a psychiatrist. Determined to figure out what was actually causing her symptoms, Ms. Smith went to St. Louis to see an endocrinologist and allergist, who tested her tryptase levels (a biomarker of SM). However, her levels came back as a false negative for SM and she tested positive for a variety of allergens.

For a period of time, Ms. Smith was placed on some medications for allergies that helped relieve some of her symptoms before beginning to worsen. Following a move to Colorado to see if an environment change would help, new symptoms began to appear and she again seeked out the guidance of an allergist/immunologist where she finally got a positive tryptase test and SM diagnosis. Ms. Smith was started on additional medications and higher doses of her previous medications and found a doctor who specializes in SM.

Eventually, these medications also began to stop working and her symptoms progressed, greatly impacting her quality of life. It was then that Ms. Smith was able to enroll in a clinical trial for, then investigational, Ayvakit (avapritinib). Following treatment with avapritinib, her symptoms greatly improved and she continued to use the medications to this day.

Ms. Smith notes the lasting mental burden of disease; overcoming the fear of having a severe reaction and not having medicine available and grieving the time that was lost due to undiagnosed disease and symptom burden.

Her advice for diagnosed patients is to find specialists in the disease to help with management and treatment plans, finding community and support groups, and becoming aware of personal triggers and doing your best to avoid them. For those who do not currently have a diagnosis, she stresses the importance of taking a break from the exhaustion and frustration of having an undiagnosed condition, but not to give up on finding a solution.

Ms. Smith wants doctors to know that it is important to listen to their patients and that just because they may not be able to figure out a diagnosis right away, they should not jump to the conclusion that someone is suffering from a mental or psychological disorder.

Chapters:
Introduction 00:00
Systemic Mastocytosis Overview 1:17
Diagnostic Journey 2:30
Signs and Symptoms 6:40
Treatment and Clinical Trial Involvement 8:38
Advice for Patients 13:13
Advice for Physicians 16:12

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Bernd Kasper, MD, PhD, University of Heidelberg Cancer Center, discusses results from the DeFi clinical trial of nirogacestat in patients with desmoid tumors.

Desmoid tumors are abnormal growths that arise from connective tissue. The tumors can occur anywhere in the body and are fibrous, much like scar tissue. They are generally not considered malignant because they do not metastasize, however, they can aggressively invade the surrounding tissue and can be very difficult to remove surgically. These tumors often recur, even after apparently complete removal. The most common symptom of desmoid tumors is pain. Other signs and symptoms, depending on the size and location of the tumor, may include constipation, limping, or difficulty moving the arms or legs.

The DeFi clinical trial (NCT03785964) is a phase 3 global, randomized, multicenter, double-blind, placebo-controlled trial evaluating the efficacy, safety, and tolerability of nirogacestat in adult patients with progressing desmoid tumors. Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor approved by the U.S. Food and Drug Adminsitration (FDA) as monotherapy for the treatment of adults with progressing desmoid tumors. Long-term safety and efficacy data from the DeFi clinical trial was recently published in the Journal of Clinical Oncology.

With a data cutoff date of December 2024, new results showed that median best percent reduction from baseline in target tumor size with continuous nirogacestat treatment was -32.3% at year 1 and -75.8% for patients completing at least 4 years of treatment. Objective response rate increased from 34.3% in year 1 to 45.7% in patients who received nirogacestat for up to 4 years. There were also three additional partial responses since the primary analysis, yielding 24 partial responses and 8 complete responses in total.

Improvements in patient-reported outcomes of pain, desmoid tumor-specific symptom severity and physical functioning, and global health status/quality of life and role functioning occurred early and were sustained up to 45 months of treatment. Overall, the incidence and severity of frequently reported treatment-emergent adverse events decreased through years two, three, and four of treatment. The most common adverse events were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea.

Chapters:
Introduction 00:00
Current Management 00:35
DeFi Clinical Trial 1:41
Next Steps 2:42
Take Home Message 4:15

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Alaa Hamed, MD, Global Head of Medical Affairs Rare Diseases at Sanofi, discusses results from the ElevAATe clinical trial of efdoralprin alfa for the treatment of patients with alpha-1 antitrypsin deficiency (AATD).

AATD is an inherited disease that causes an increased risk of having chronic obstructive pulmonary disease (COPD), liver disease, skin problems, and vasculitis. Pulmonary problems almost always occur in adults, whereas liver and skin problems may occur in adults and children. Symptoms may include shortness of breath and wheezing, repeated infections of the lungs and liver, yellow skin, fatigue, rapid heartbeat when standing, vision problems, and weight loss. However, some people with AATD do not have any problems. AATD is caused by genetic changes in the SERPINA1 gene. The genetic changes cause too little or no working alpha-1 antitrypsin protein (AAT) to be made. AAT is made in the liver cells and sent through the bloodstream to the lungs where it helps protect the lungs from damage. Having low levels of AAT (or no AAT) may lead the lungs to become damaged. A build-up of abnormal AAT may cause liver damage.

Efdoralprin alfa is a recombinant human AAT-Fc fusion protein being investigated for treatment of adults with AATD emphysema. The treatment is designed to restore functional AAT levels to the normal range and inhibit neutrophil elastase.

The ElevAATe clinical trial is a phase 2 double-blind, randomized study evaluating efdoralprin alfa versus standard-of-care plasma-derived augmentation therapy in patients with AATD emphysema. The trial has enrolled 97 patients who receive the treatment every three weeks, every four weeks, or standard-of-care once weekly.

Results were recently announced showing that efdoralprin alfa demonstrated a statistically significant greater mean increase in functional AAT levels within normal range as measured by trough concentrations at steady state compared to patients on standard-of-care at week 32. Key secondary endpoints were also met, demonstrating superior mean increase in fAAT average concentration as well as higher percentage of days above the lower limit of normal range for both 3-week and 4-week dosing groups.

Additionally, efdoralrpin alfa was well-tolerated and had a similar adverse event profile to standard-of-care. Additionally safety follow-up will be assessed in the ElevAATe open-label extensions study.

Chapters:
Introduction 00:00
AATD Overview 00:33
Diagnosis Journey 1:02
Current Management 2:28
Efdoralprin Overview 3:17
ElevAATe Clinical Trial 3:59
Next Steps 4:59

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Xiaohui Niu, Director of the Bone and Soft Tissue Tumour Diagnosis and Research Centre at Beijing Jishuitan Hospital, discusses a long-term analysis of the MANEUVER clinical trial of pimicotinib for the treatment of patients with tenosynovial giant cell tumor (TGCT).

TGCT is a rare condition characterized by the abnormal growth of tissue lining the joints and tendons throughout the body (synovium), resulting in a noncancerous tumor. There are two types of TGCT: the local or nodular form (where the tumor involves the tendons that support the joint, or in one area of the joint) and the diffuse form (where the entire lining of the joint is involved). Symptoms might include pain, limitation of movement, and locking of the joint. The knee is most commonly affected by this condition, though it can occur in other joints. The underlying cause of TGCT is unknown.

Pimicotinib is an orally administered, highly selective and potent small molecule inhibitor of CSF-1R. The MANEUVER clinical trial is a phase 3, three-part, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of pimicotinib in patients with TGCT who require systemic therapy and have not received prior anti-CSF-1/CSF-1R therapy. Longer-term results from the MANEUVER clinical trial were recently presented at European Society for Medical Oncology (ASMO).

The presented analysis showed that at a median follow-up of 14.3 months, the objective response rate for patients treated with pimicotinib from the beginning of the study increased to 76.2% from 54% at week 25. Additionally, objective response rate per BIRC based on tumor volume score increased to 74.6% from 61.9% at week 25. At the time of data cutoff, the median duration of response was not reached, with 93.7% of pimicotinib-treated patients experiencing a reduction in tumor size by BIRC per Response Evaluation Criteria in Solid Tumors v1.1 at longer-term follow-up.

Pimicotinib also demonstrated clinically meaningful improvements with longer-term follow-up up to week 73 in key patient-reported measures including range of motion, pain, stiffness, and physical function that significantly impacted patients living with TGCT. Additionally, patients who were initially randomized to placebo and then switched to pimicotinib in the open-label phase experienced an objective response rate of 64.5% with a median follow-up of 8.5 months after switching.

At longer-term follow-up there were no new safety concerns and no evidence of cholestatic hepatotoxicity, drug-induced liver injury, or hair/skin hypopigmentation. The majority of treatment-emergent adverse events were of mild severity and manageable.

Chapters:
Introduction 00:00
TGCT Overview 1:03
Pimicotinib and the MANEUVER Clinical Trial 4:24
Take Home Message and Next Steps 8:07

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Philip J. Ferrone, MD, Vitreoretinal Consultants of New York, discusses results from the TEASE-2 clinical trial of gildeuretinol in patients with Stargardt disease.


Stargardt disease is a genetic eye disorder that causes progressive vision loss. It affects the macula, an area of the retina responsible for sharp, central vision. Vision loss is due to abnormal accumulation of lipofuscin in the cells within the macula. Patients with Stargardt disease also have problems with night vision, and some have problems with color vision. It is most commonly caused by genetic changes in the ABCA4 gene. There are currently no available treatments for this condition.

Gildeuretinol is an investigational compound designed to reduce the dimerization of vitamin A without modulating the visual cycle. TEASE-2 was a randomized, double-masked, placebo-controlled study in 79 patients with moderate Stargardt disease. Results from the TEASE-2 clinical trial (NCT02402660) of gildeuretinol for the treatment of moderate Stargardt disease were recently presented at the 2025 American Academy of Ophthalmology (AAO) meeting.

Of those treated with gildeuretinol, there was a 28% reduction in progression of disease. However, due to the heterogeneity of the patient population enrolled, the p-value was not statistically significant. As Dr. Ferrone notes, these results still show great promise in the potential of this treatment in Stargardt disease. Additionally, the safety profile of gildeuretinol is favorable with limited side effects and adverse events.

Next steps include further analysis of the TEASE-2 population and ongoing TEASE-3 and TEASE-4 studies hope to bring data to the U.S. Food and Drug Administration.

Chapters:
Introduction 00:00
Diagnostic Journey 1:46
Red Flag Symptoms 2:59
Current Management 3:24
Gildeuretinol Overview 3:36
TEASE-2 Clinical Trial 4:56
Next Steps 8:57

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Isabella Herman, MD, PhD, Pediatric Neurologist and Neurogeneticist at Boys Town National Research Hospital, discusses the role of genetic testing in epilepsy care.

Chapters:
Introduction 00:00
Clinical Implications of Gene Testing 00:46
Benefits of Genetic Diagnosis 2:17
Genetic Diagnosis' Effect on Treatment 3:38
Genome and Exome Sequencing 5:19
Importance of Identifying Underlying Causes 6:29
Genetic Causes of Adult Onset Epilepsy 7:50
Genetic Epilepsy and Comorbid Conditions 9:42
Genetic Testing Recommendations 10:56

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Tara Adams, a mother to two daughters with epilepsy, describes how genetic testing impacted diagnosis, treatment, and management.

Chapters:
Introduction 00:00
Diagnostic Journey 00:20
Advice for Patients and Families 2:37
Importance of Genetic Testing 3:28
Benefits of Identifying Genetic Causes 4:41
Finding a Community 6:21
Take Home Message 7:25

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Wildon Farwell, MD, Chief Medical Officer at Satellos, discusses the safety and efficacy of SAT-3247 to treat adults with Duchenne muscular dystrophy (DMD).

DMD is a genetic 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. DMD is caused by mutations in the DMD gene that codes for dystrophin.

Recent data presented at the 30th Annual Congress of the World Muscle Society shows promising clinical data demonstrating initial efficacy of once-daily oral SAT-3247 in adults with DMD. SAT-3247 is an oral, small molecule drug being developed to regenerate skeletal muscle lost due to DMD, independent of dystrophin and regardless of exon mutation status. A phase 1a/b study looked at effects of SAT-3247 in five patients ages 20 to 27 years of age over a 28-day period.

As Dr. Farwell explains, the data presented demonstrated that SAT-3247 was safe and well-tolerated across the study with a desirable pharmacokinetic profile. Individuals treated with SAT-3247 also demonstrated a 118.6% mean improvement in maximum grip strength in the dominant hand and a 97.9% mean improvement in the non-dominant hand. This represents an approximate doubling of grip strength from around 2 kg to around 4 kg, far greater than seen in published natural history data for this age group.

Additionally, patients exhibited a 5.8% mean improvement of predicted forced vital capacity, also inconsistent with natural history. All other measures remained stable over the study period and no drug-related adverse events of moderate severity or higher were observed and no dose-limiting toxicities occurred.

The five patients who participated in the phase 1b study were invited to enroll in an 11-month open-label follow-up study which is also looking to enroll additional male patients ages 16-25 years. The primary endpoints of this study are to evaluate long-term safety and tolerability, as well as the effect of SAT-3247 on fat fraction in biceps brachii muscle. Secondary endpoints include the effect of SAT-3247 on fat fraction and impact on muscle force and function.

Based on this initial data, there are also plans for a phase 2 randomized, double-blind, placebo-controlled, global, proof-of-concept study of SAT-3247 in ambulatory children with DMD. Primary endpoints will evaluate safety and tolerability of SAT-3247 and effect on muscle force. Secondary endpoints will evaluate SAT-3247’s impact on muscle quality, function, and regeneration.

Chapters:
Introduction 00:00
Satellite Cells 1:11
SAT-3247 Overview 2:37
Possible Use in Other Indications 5:18
Clinical Trial Data 5:59
Next Steps 10:38
Take Home Message 12:18

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Dale Colorado, DO, Vice Chair of Education and Program Director of UAB Rehabilitation Pavilion, discusses the importance and impact of the new Merz Therapeutics Training Room at the University of Alabama Rehabilitation Pavilion.

The new training room will provide specialized, hands-on education for medical students, residents, fellows and faculty in advanced, evidence-based techniques for treating neuromusculoskeletal disorders. The training room will be equipped with learning technologies such as a virtual anatomy dissection table, diagnostic ultrasound systems, injection simulation models, electromyography (EMG) training tools and audiovisual equipment for live demonstrations.

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