Aman Chauhan, MD, Oncologist at the University of Miami, discusses details of a phase 3 study testing paltusotine in patients with carcinoid syndrome due to neuroendocrine tumors (NETs).

NETs are rare tumors that usually develop in the GI tract or lungs, but may develop in other parts of the body, such as the pancreas, testicle, or ovary. In later stages, symptoms may vary depending on where the tumor is located. The tumor may produce hormone-like substances that spread to the body and cause symptoms of carcinoid syndrome, such as flushing of the face and chest, diarrhea, and trouble breathing. The cause of neuroendocrine neoplasms is unknown.

Paltusotine is a selectively-targeted somatostatin receptor type 2(SST2) nonpeptide. The treatment is currently approved by the U.S. Food and Drug Administration (FDA) for patients with acromegaly.

The phase 3 CAREFNDR (NCT07087054) clinical trial is a randomized, international, multicenter, placebo-controlled, double-blind study evaluating paltusotine in carcinoid syndrome due to NET. Patients will be treated for 16 weeks with a primary endpoint of change from baseline in flushing frequency at week 12. A second phase 3 trial is also in development, testing the nonpeptide drug candidate, CRN09682, in patients with somatostatin receptor 2-expressing tumors. The CAREFNDR study is currently enrolling patients. For more information, visit carefndr.com.

This study builds on a phase 2 study previously presented. Results from this study in carcinoid syndrome demonstrated rapid and sustained reductions in flushing episodes and bowel movement frequency. A preliminary analysis of phase 2 data from the open-label trial of paltusotine in the treatment of patients with carcinoid syndrome due to NETs showed an overall investigator-assessed progression free survival rate of 74% following one year of treatment.

Chapters:
Introduction 00:00
Carcinoid Syndrome 00:58
Current Management 2:49
Ongoing Phase 3 Clinical Trials 4:52
Next Steps 7:57

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Alexandra C. Bayer Wildberger, PhD, Post-Doctoral Associate at Yale School of Medicine, discusses the shift to precision medicine in myasthenia gravis (MG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. The condition results from a defect in the transmission of nerve impulses to muscles, which in the majority of patients is due to the presence of antibodies against acetylcholine receptor (AChR). The exact reason this occurs is not known.

As Dr. Bayer explains, the therapeutic landscape for MG has greatly evolved past traditional immunosuppressants over the last few years. The advent of mechanism-based therapies, such as FcRn inhibitors, complement inhibitors, and the potential for isotype-specific proteases, are providing patients with more tailored treatment options.

Due to the heterogeneity of MG, the biggest challenge at present is identifying the most effective treatment for a patient’s specific underlying mechanism of disease. Dr. Bayer explains how this will help to optimize the usage of resources in disease treatment and reduce unnecessary side effects and exposure to treatments that are not beneficial to individual patients.

Current research is striving to better understand the complexities behind MG, such as the exact presence of immunoglobulin classes and the roles they play in the disease, to move towards a precision medicine approach. Recently, Yale has published work describing a previously unrecognized subset of patients with IgM-AChR specific autoantibodies. Next steps involve understanding the role of these autoantibodies in vivo.

Dr. Bayer notes the key role that the RDCRN’s MGNet has played in their research. Through scientific and clinical resources, such as clinical samples and data from the network’s biorepository and funding for further research, the consortium is helping to accelerate the understanding and more effective treatment of MG.

Chapters:
Introduction 00:00
AChR-Positive Myasthenia Gravis 00:26
Need for Tailored Therapeutics 1:37
Ongoing Research 3:23
RDCRN MG Consortium 4:38

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Naomi Patel, MD, MPH, Rheumatologist at Massachusetts General Hospital, discusses long-term data from the AQUARIUS study of avacopan in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

GPA is a type of vasculitis causing swelling of the blood vessels anywhere in the body. The condition mainly impacts the sinuses, nose, trachea, lungs, and kidneys. The swelling can limit the flow of blood to these body parts, causing damage. Symptoms of the disease can include sinus pain, recurrent respiratory infections, joint pain, fatigue, and skin lesions. The exact cause of GPA is unknown, but it is a type of autoimmune disease. MPA is also a type of vasculitis. The kidneys, lungs, nerves, skin, and joints are the most commonly affected areas of the body. The cause of this disorder is unknown.

Avacopan is a selective oral C5a receptor antagonist that was approved by the U.S. Food and Drug Administration (FDA) for the treatment of GPA/MPA in 2021. Data was recently presented at ACR and Kidney Week (ASN) from the AQUARIUS clinical trial of avacopan in patients with GPA/MPA.

Data From ACR Presentation (AQUARIUS Part 1) One-Year Real-World Effectiveness with Avacopan in GPA and MPA

This ongoing retrospective cohort study describes 12-month effectiveness and safety outcomes for avacopan in patients with GPA/MPA.

Among the 95 patients with available 12 month follow-up data, 64% were in remission at month 6, while at month 12, 95% had a BVAS v3 equal to zero, 87% were glucocorticoid-free, and 61% had sustained remission. The median discontinuation time was three months and the majority of patients experienced no worsening of glucocorticoid toxicity.

Sustained remission was similar in those with baseline kidney, lung, or ENT involvement. The most common GTI-MD domain with net worsening was blood pressure, followed by body mass index, lipid metabolism, and glucose tolerance. The majority had no net worsening of metabolic GC toxicity over 12 months, indicating either net improvement or no change.

Data From ASN Presentation of AQUARIUS Real-World Clinical Outcomes in a Large Health Care System After Avacopan Initiation for Granulomatosis with Polyangiitis (GPA) or Microscopic Polyangiitis (MPA) Involving the Kidneys

This is a retrospective cohort study of patients prescribed avacopan for GPA/MPA from December 1, 2021 to April 1, 2024, reporting 12-month outcomes in those with baseline kidney involvement.

Among 58 patients with kidney involvement treated with avacopan, 16% received dialysis less than or equal to 1 month following initiation. Of 54 patients with 12 month follow-up, 69% had sustained remission. Median estimated glomerular filtration rate (eGFR) among those not on dialysis at baseline and 12 months was 35 and 44, respectively. 4% of patients newly initiated dialysis greater than 1 month after avacopan initiation. Of 7 patients on dialysis at baseline with complete follow-up, 86% discontinued dialysis by 12 months. Among those with baseline urine protein:creatinine ratio (UPCR) greater than 2 g/g, median UPCR declined from 1.4 at baseline to 0.3 g/g at 12 months.

Chapters:
Introduction 00:00
GPA/MPA Overview 00:16
AQUARIUS Clinical Trial 1:01
Prior Treatment 2:54
Results of Trial 4:24
Take Home Message 9:00

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Michael Weiss, MD, Neurologist at the University of Washington, discusses data on the RAISE and RAISE-XT clinical trials of zilucoplan for the treatment of generalized myasthenia gravis (gMG).

gMG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known.

Zilucoplan and the RAISE Clinical Trial Program

Data on the RAISE and RAISE-XT clinical trials of zilucoplan for the treatment of generalized MG was recently presented at the 2025 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting and Myasthenia Gravis Foundation of American (MDFA) Scientific Session.

Zilucoplan is a once-daily SC injection, self-administered peptide inhibitor of complement component 5 (C5 inhibitor). Zilucoplan may inhibit complement-mediated damage to the neuromuscular junction through its targeted mechanism of action. The treatment was approved by the U.S. Food and Drug Administration in October 2023 for the treatment of adult patients with AChR-positive gMG.

The RAISE clinical trial (NCT04115293) was a multicenter, randomized, double-blind, placebo-controlled, study evaluating the safety, efficacy, and tolerability of zilucoplan in patients with generalized MG. RAISE-XT (NCT04225871) is a phase 3, multicenter, open-label extension study of zilucoplan in patients with generalized MG.

Effect of Zilucoplan on Fatigue in Patients With gMG: RAISE-XT 120-Week Follow-Up

The RAISE clinical trial demonstrated that treatment with zilucoplan resulted in clinically meaningful and nominally significant improvement in fatigue versus placebo in patients with gMG. The objective of this post hoc analysis was to assess the long term effect of zilucoplan in the ongoing RAISE-XT extension study up to week 120.

At week 120, the mean change from baseline in the Neuro-QoL Short Form Fatigue T-score was 12.65. Of patients with available data at baseline and week 120, 77% showed clinicallt meaningful improvements in their T-score at week 120 compared to baseline. Additionally, 60.7% transitioned to a lower fatigue severity level. At week 120, 60.7% of patients had mild or no fatigue compared with 19.7% at baseline.

Long-Term Effectiveness of Zilucoplan in MG: Predictive Modeling in a United States Real-World Database

The objective of this study was to estimate the long-term effect of zilucoplan on the risk of severe exacerbations using predictive modeling based on clinical trial data and a U.S. real-world database. It assessed the medical benefit of zilucoplan on top of standard of care and its impact across different gMG therapy scenarios.

Step one included replication of most RAISE inclusion/exclusion criteria in the external control arm and weighting it with the zilucoplan arm. This resulted in a strong similarity in baseline patient characteristics. The adjusted hazard ratio of zilucoplan, compared to standard of care, on severe exacerbations over two years was 0.14.

Additionally, simulations showed 8.6%-15.1% reduction in severe exacerbations risk at two years when using zilucoplan in addition to standard of care versus standard of care alone in different scenarios. This suggests that zilucoplan significantly reduces the long-term risk of severe exacerbations with benefit across different gMG real-world standard of care therapy.

Interpreting Patient Quality of Life Experience With Zilucoplan in gMG in RAISE and RAISE-XT

In the RAISE clinical trial, treatment with zilucoplan resulted in statistically significant improvements in the Myasthenia Gravis Quality of Life 15-item revised (MG-QoL15r) versus placebo in patients with gMG. The objective of this study was to interpret the meaningfulness of MG-QoL15r improvements.

At Week 12, patients on zilucoplan were more likely than those on placebo to answer “not at all” for all items, including for the most severe symptoms (e.g., for “difficulty speaking”, placebo: 41.9%; zilucoplan: 63.9%). For the total population, this likelihood increased at Week 60.

Chapters:
Introduction 00:00
RAISE-XT Clinical Trial 00:12
Fatigue Versus Muscle Weakness 3:08
Patient Quality of Life Study 4:57

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James Howard, Jr., MD, Professor of Neurology at the University of North Carolina, discusses new data on the safety and efficacy of Vyvgart (efgartigimod alfa) for patients with AChR-Ab seronegative generalized myasthenia gravis (gMG).

gMG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known.

New data on the efficacy and safety of efgartigimod alfa was recently presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting and the Myasthenia Gravis Foundation of America (MGFA) Scientific Session.

Efgartigimod alfa is a first-in-class human IgG1 antibody fragment that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG autoantibodies. The ADAPT SERON clinical trial was a phase 3 randomized, double-blind, placebo-controlled, multicenter study evaluating the safety and efficacy of efgartigimod in adults with AChR-Ab seronegative gMG.

The study met its primary endpoint, demonstrating that AChR-Ab seronegative gMG patients treated with efgartigimod achieved a statistically significant improvement in MG Activities of Daily Living (MG-ADL) total score compared to placebo after four weeks.

In the overall population, mean change from baseline in patients treated with efgartigimod was a clinically meaningful 3.35 point improvement in MG-ADL total score at week four. These results illustrate significant improvements in one or a combination of their abilities in breathing, eating, eyesight, and motor functions. Improvements in MG-ADL and Quantitative MG (QMG) scores among patients treated with efgartigimod were increasingly pronounced across subsequent treatment cycles in the overall population and in all patient subgroups.

Efgartigimod was well tolerated across AChR-Ab seronegative subtypes and consistent with the established safety profile in patients with AChR-Ab seropositive gMG and other indications. No new safety concerns were identified.

Chapters:
Introduction 00:00
FcRn Inhibitors Versus Complement Inhibitors 00:12
ADAPT SERON Clinical Trial 4:29
Patients Without a Specific Antibody 8:31
Take Home Message 9:26

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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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