Dinesh Patel, PhD, CEO of Protagonist Therapeutics, discusses the New Drug Application (NDA) submission to the US Food and Drug Administration (FDA) for rusfertide to treat adults with polycythemia vera (PV). PV is characterized by excess red blood cells in the bloodstream, increasing the risk for blood clots. Most cases of PV are acquired and occur more frequently in men than in women. The condition has been associated with genetic changes in the JAK2 and TET2 genes. Rusfertide is an investigational first-in-class subcutaneously administered hepcidin mimetic peptide designed to regulate iron homeostasis and red blood cell production to control hematocrit levels in patients with PV. The NDA submission is based on positive 32-week primary analysis and 52-week results from the phase 3, global, randomized, placebo-controlled VERIFY clinical trial (NCT05210790). In this study, patients receiving rusfertide plus standard of care therapy demonstrated a substantially higher response rate compared to placebo plus standard of care, including durable hematocrit control, a reduction in phlebotomy requirements and improvement in pre-specified patient reported outcome endpoints.Rusfertide has received Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation from the FDA.

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Robert S. Ohgami, MD, PhD, Professor of Pathology, University of Utah, and Founding Vice President and Chief Medical Director, ARUP Institute for Research and Innovation, discusses the utilization of artificial intelligence (AI) to analyze Castleman disease (CD) histopathology.

CD is a heterogeneous group of rare lymphoproliferative disorders, affecting the lymph nodes and related tissues. There are two main forms: unicentric CD and multicentric CD. Unicentric CD is a localized condition that is generally confined to a single set of lymph nodes, while multicentric CD is a systemic disease that affects multiple sets of lymph nodes and other tissues throughout the body. The exact underlying cause of CD is currently unknown.

Diagnosis of CD requires histopathologic interpretation of lymph node biopsies where key histologic features, atretic germinal centers, follicular dendritic cell prominence, vascularity, hyperplastic germinal centers, and plasmacytosis, are graded on an ordinal scale from 0 to 3. This process often results in variability due to its subjective nature. A recent analysis, presented at the 2025 American Society of Hematology meeting, evaluated the use of AI computational pathology techniques (attention-based multiple instance learning; ABMIL) in automating CD grading reliability and accuracy as compared to hematopathology experts.

A proof-of-concept ABMIL model was developed to predict slide-level CD histology scores from whole-slide images of H&E-stained lymph node tissue. Each whole-slide image was divided into tiles and a pre-trained foundation model was used to extract embeddings, which were then aggregated by the ABMIL model into slide-level predictions across the five established histologic features and follicular twinning.

The dataset consisted of 154 whole-slide images featuring CD or CD-like histology that were annotated by eight hematopathologists for each feature. To evaluate model performance and interpretability, model predictions were compared to expert consensus and against the range of interobserver agreement among experts who were not CD specialists.

Significant inter-rater variability was confirmed with leave-one-out analysis of hematopathologist graders. Model disagreement was typically less than or equal to the average hematopathologist inter-rater spread and model predictions showed moderate concordance with expert ground-truth annotations within the range of inter-rater variability seen among hematopathologists.

Visualizations of tile-level attention weights confirmed that the model attends to diagnostically relevant regions and ignores irrelevant regions, supporting biological interpretability despite weak supervision. Dr. Ohgami explains that training such AI models allows for diagnostic histopathology that is reproducible, efficient, consistent, and gets patients into the right treatment quicker.

For more information, click here.

For more information on CD and other rare hematologic conditions, visit https://checkrare.com/diseases/hematologic-disorders/

Chapters:
Introduction 00:00
Castleman Disease Overview 00:56
Current Management 3:11
Artificial Intelligence in Disease Histopathology 5:27
Take Home Message 8:37

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Lynette Chee, PhD, Hematologist at The Royal Melbourne Hospital/ Peter MacCallum Cancer Centre, discusses elritercept’s effect on transfusion independence (TI) in patients with myelodysplastic syndromes (MDS),

MDS are a group of blood disorders characterized by abnormal development of blood cells within the bone marrow. People with MDS have abnormally low blood cell levels. Signs and symptoms may include dizziness, fatigue, weakness, shortness of breath, bruising and bleeding, frequent infections, and headaches. In some people with MDS, the condition progresses to bone marrow failure or develops into acute leukemia. MDS develops when a cell with a genetic change replicates, and the resulting copies begin to predominate in the bone marrow and suppress healthy stem cells. The genetic change may result from a genetic predisposition, or from injury to the DNA caused by an exposure such as chemotherapy or radiation. In many people with MDS there is no obvious exposure or cause.

Results from the phase 2 trial of elritercept treatment in lower risk- (LR) MDS (NCT04419649) were recently presented at the 2025 American Society of Hematology (ASH) meeting. Elritercept is an investigational modified activin receptor type IIA/IgG1 fusion protein designed to bind and block select TGF-β superfamily ligands.

As of April 3, 2025, 79 patients treated with elritercept starting at the recommended part 2 dose of 3.75 mg/kg were evaluable for the modified intention-to-treat-24 analysis of transfusion independence (TI) and median exposure was 11.9 months. In the first 24 weeks of treatment, 38.5% of patients achieved TI of 8 or more weeks. In the first 48 weeks, 26.9% achieved TI of 24 or more weeks, with 75.9% maintaining TI at 48 weeks.

Sustained TI of 24 weeks or more was observed in 67.3% of patients with TI of 8 weeks or more. TI of 48 weeks or more was achieved in 20.5% of patients over the course of the entire study. Median duration of response was 110.9 weeks among patients who had TI of 8 weeks or more in the first 24 weeks.

Median time to TI of 8 weeks or more was 0.4 weeks. Hematologic improvement-erythroid response was measured in 96 patients at the recommended part 2 dose and achieved in 61.5% with median time to response of 3.1 weeks. SF3B1 was the most frequently mutated gene and found in 91% of RS positive patients. Among the modified intention-to-treat 24-week population, TI of 8 weeks or more responses were observed in 52% of patients with and 25% without SF3B1 mutations.

For more information on MDS and other rare hematologic conditions, visit https://checkrare.com/diseases/hematologic-disorders/

Chapters:
Introduction 00:00
MDS Overview 00:39
Elritercept Clinical Trial 3:19
Take Home Message 7:53

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Tsewang Tashi, MD, Hematologist at the Huntsman Cancer Institute at the University of Utah, discusses long-term data from the PIONEER clinical trial examining the use of avapritinib in patients with indolent systemic mastocytosis (ISM).

Systemic mastocytosis (SM) is a rare disease usually caused by mutations of the KIT D816V gene. The disorder is characterized by uncontrolled mast cell proliferation and activation across multiple organ systems. ISM accounts for approximately 90% of systemic mastocytosis. 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.

Avapritinib is an oral, potent, selective KIT D816V inhibitor, and the first and only approved targeted therapy for adult patients with ISM in the USA and the EU. Approval was based on results from the phase 2 PIONEER (NCT03731260) trial, a randomized, double-blind, placebo-controlled study evaluating comparing the safety and efficacy of avapritinib plus best supportive care with placebo plus best supportive care in patients with ISM.

Recently, data from approximately 3.5 years of long-term follow-up was presented at the 2025 American Society of Hematology (ASH) meeting. Overall, 226 patients initiated avapritinib 25mg once daily across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg once daily in Part 3. Median treatment duration was 40.0 months as of February 21, 2025.

Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change in total symptom score was −19.80 at week 144 and −20.43 at week 168 from a baseline of 48.08. Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms per ISM-Symptom Assessment Form. Sustained responses were observed across all individual symptom domains with mean changes at month 33 and month 39 of −3.77 and −3.84 for the gastrointestinal domain, −8.21 and −8.20 for the skin domain, and −4.66 and −4.87 for the neurocognitive domain. The mean percent change in Mastocytosis Quality-of-Life Questionnaire was −34.67 at month 33 and −40.72 at month 39 from a baseline of 54.24.

Treatment with avapritinib was well tolerated and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events were grades 1 or 2, and 7% of patients experienced grade 3 or greater adverse events of which diarrhea, neutrophil count decrease, and weight increase occurred in one or more patients. No grade 3 or greater adverse events of increase in transaminases were observed. Edema (peripheral and periorbital) was the most frequently reported adverse event, and was mostly grade 1 and occurred most frequently during the first 3 to 4 months of treatment. Three patients experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed.

A second analysis aimed to assess bone health in patients with ISM receiving avapritinib. A total of 79 patients receiving avapritinib had baseline and 1 or more post-baseline DXA scans. Of these patients, 16% used anti-osteoporosis therapy while receiving avapritinib.

The mean bone mineral density (BMD) at baseline for the lumbar spine, left hip, and left femoral neck was 1.02 g/cm^2, 0.93 g/cm^2, and 0.84 g/cm^2, respectively. Mean percent change in lumbar spine BMD was 1.66% at year 1 and 4.05% at year 3. Mean percent change in left hip BMD at year 1 and year 3 was 2.19% and 3.31%, respectively. Corresponding value for the left femoral neck at year 1 was 1.62% and year 3 was 2.08%. Increases in BMD were seen regardless of concomitant anti-osteoporosis therapy with avapritinib. Mean lumbar BMD at year 3 was 3.0% in 6 patients taking anti-osteoporosis medications and 4.4% in 20 patients not receiving such therapy.

Tartrate-resistant acid phosphatase 5b (TRAcP-5b), a biomarker for bone reabsorption, was measured in 20 age- and sex-matched healthy donors and 131 patients with ISM. Of these, 90 patients had paired baseline and treatment samples tested. Baseline TRAcP-5b concentration was significantly lower in patients receiving avapritinib, compared to healthy donors. This was observed with and without concomitant anti-osteoporosis therapy: 1.55 U/L and 1.68 U/L, respectively. By Week 48, TRAcP-5b concentration significantly increased above baseline toward the normal range in patients receiving avapritinib, including those not receiving concomitant anti-osteoporosis therapy.

Chapters:
Introduction 00:00
ISM Overview 00:18
Diagnostic Journey 1:22
Need for Awareness 2:17
PIONEER Clinical Trial 3:44
Bone Health in PIONEER 5:42
Clonal Evolution in ISM 8:49

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Andrew T. Kuykendall, MD, VERIFY Lead Investigator and Associate Member in the Department of Hematology at Moffitt Cancer Center, discusses 52-week results from the VERIFY clinical trial testing rusfertide in patients with polycythemia vera (PV).

PV is a condition characterized by an increased number of red blood cells. Affected people may also have excess white blood cells and platelets. The excess cell levels leads to thicker blood and increased risk for blood clots. PV occurs more frequently in men than it does in women. The condition has been associated with genetic changes in the JAK2 and TET2 genes.

At the 2025 American Society of Hematology (ASH) meeting, 52-week results from the phase 3 VERIFY (NCT05210790) clinical trial evaluating rusfertide in patients with PV were presented. The study was designed to evaluate the safety and efficacy of rusfertide in patients with uncontrolled hematocrit who are phlebotomy-dependent despite current standard of care.

During Part 1a of the study, 293 patients were randomized to receive either rusfertide or placebo, as an add-on to their current treatment. During Part 1b, all participants were eligible to receive open-label rusfertide to evaluate the durability of the treatment response. 274 patients continued into Part 1b, and 267 patients remained in the study through week 52, with 254 continuing to receive rusfertide in part 2.

Phlebotomy Eligibility

At week 52, 61.9% of patients treated with rusfertide plus standard of care throughout parts 1a and 1b experienced a durable clinical response, defined as absence of phlebotomy eligibility. Additionally, 84.1% of patients treated with rusfertide who experienced a clinical response in the part 1a assessment window maintained their response and 77.9% of patients who crossed over from placebo to rusfertide at week 32 for part 1b experienced a clinical response during the part 1b assessment window. Median time to first phlebotomy was 16 weeks in the placebo group but was not reached in the rusfertide group in part 1a or 1b, or the placebo to rusfertide crossover group in part 1b.

HCT Control

Mean hematocrit remained less than 43% through week 52 in patients treated with rusfertide throughout Part 1a and Part 1b and those who switched from placebo to rusfertide for Part 1b. Median time to first hematocrit 45% or greater was 8.3 weeks in the placebo group in part 1a, but was not reached in the rusfertide group during parts 1a or 1b.

Quality of Life Endpoints

Patients treated with rusfertide in parts 1a and 1b maintained improvements in patient reported outcomes as measured by PROMIS Fatigue SF-8a and MFSAF TSS7.

Safety and Tolerability

Rusfertide was generally well tolerated through 52 weeks of treatment with the most common treatment-emergent adverse events including injection site reactions, anemia, and fatigue, all of which were primarily grade 1 or 2. Serious adverse events occurred in 8.1% of patients treated with rusfertide.

To learn more about PV and other rare hematologic conditions, visit https://checkrare.com/diseases/hematologic-disorders/

Chapters:
Introduction 00:00
Polycythemia Vera Overview 00:37
Current Management 2:06
VERIFY Clinical Trial 3:50
Next Steps 7:25

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Leonard L. Dragone, MD, PhD, Disease Area Leader in Autoantibody and Rheumatology, Johnson & Johnson Innovative Medicine, discusses positive topline results from a study of nipocalimab in patients with systemic lupus erythematosus (SLE).

SLE is an autoimmune disease characterized by inflammation in the connective tissues, leading to multisystem involvement and potentially significant morbidity and mortality. Genetic, immunological, endocrine, and environmental factors influence the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms. Common signs and symptoms include severe fatigue, malaise, fever, loss of appetite, weight loss, joint pain and swelling, butterfly rash, and muscle pain and weakness.

Recently, positive topline results from the phase 2b JASMINE clinical trial were announced. JASMINE (NCT04882878) is a 52-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study evaluating nipocalimab in 228 adult patients with active SLE. Nipocalimab is an investigational monoclonal antibody designed to bind with high affinity to block FcRn and reduce levels of circulating IgG antibodies.

The study met its primary endpoint of percentage of patients in the nipocalimab group achieving SLE Responder Index composite response at week 24 with statistical significance compared with the placebo group. It also met key secondary and exploratory endpoints. Its safety and tolerability profile was consistent with previous phase 2 studies, with no new safety concerns identified.

This study marks the first positive study of an FcRn blocker for the treatment of SLE. Based on these results, there are plans to initiate a phase 3 program. Nipocalimab is currently approved to treat another autoimmune disease, myasthenia gravis.

Full results from the JASMINE study are expected to be presented at a future medical congress.

To learn more about SLE and other rare autoimmune disorders, visit https://checkrare.com/diseases/autoimmune-autoinflammatory-disorders/

Chapters:
Introduction 00:00
SLE Overview 00:24
Current Management 1:26
JASMINE Clinical Trial 2:23
Next Steps 3:42
Take Home Message 4:38

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Shervin Assassi, MD, Director, Division of Rheumatology at McGovern Medical School, discusses the approval of Jascayd (nerandomilast) tablets for treatment of patients with progressive pulmonary fibrosis (PPF).

PPF is a subcategory of interstitial lung disease (ILD) characterized by progressive scarring of the walls of the air sacs in the lung. PPF is not a specific diagnosis, but a disease behavior that can occur in many types of ILD. Signs and symptoms include shortness of breath, cough, fatigue, depression, and anxiety.

The U.S. Food and Drug Administration (FDA) has approved nerandomilast tablets for the treatment of adults with PPF. Nerandomilast is the first preferential PDE4B inhibitor with immunomodulatory and antifibrotic effects. The approval is based on results from the pivotal phase III FIBRONEER-ILD clinical trial.

The primary endpoint of the trial was the absolute change from baseline in Forced Vital Capacity (FVC) at week 52. Nerandomilast demonstrated significantly smaller reduction in FVC from baseline compared to placebo. The adjusted mean decline in absolute change from baseline in FVC in patients receiving nerandomilast 18 mg or 9 mg was -86 mL and -69 mL, respectively, compared to -152 mL in the placebo group.

The key secondary composite endpoint was the time to the first occurrence of any of the components of the composite endpoint over the blinded duration of the trial: acute ILD exacerbation, hospitalization for respiratory cause, or death. Overall, there was no statistically significant treatment difference in the hazard ratio for the nerandomilast 18 mg or 9 mg groups compared to placebo for the key secondary composite endpoint.

Further results for nerandomilast 18 mg in respect to the key secondary endpoint components, from an exploratory analysis, were also published. Treatment showed a significant reduction in risk of acute ILD exacerbations over the blinded trial duration compared to placebo and a reduction in the risk of hospitalization for respiratory cause over the blinded trial duration compared to placebo.

Additionally, a prespecified analysis of overall survival at the end of the trial showed a trend in favor of nerandomilast. The hazard ratios for all-cause mortality until the end of the trial for nerandomilast 18 mg and 9 mg compared to placebo were 0.51 and 0.51, respectively.

Overall, nerandomilast was well-tolerated in patients with PPF. Diarrhea was the most common adverse reaction associated with treatment and treatment discontinuation and occurred most frequently in patients treated with 18 mg or 9 mg nerandomilast with background antifibrotic therapy, versus patients receiving placebo and background antifibrotic therapy. In most patients treated with nerandomilast, diarrhea was of mild to moderate intensity and generally occurred within the first 3 months of treatment.

To learn more about PPF, ILD, and other rare lung conditions, visit https://checkrare.com/diseases/lung-diseases/

Chapters:
Introduction 00:00
Progressive Pulmonary Fibrosis Overview 00:50
PPF Diagnosis 2:01
Current Management 2:56
Nerandomilast Overview 4:57
FIBRONEER-ILD Clinical Trial 6:42
Take Home Message 9:48

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Lynn Malec, MD, Versiti Blood Research Institute and Medical College of Wisconsin, discusses results from the XTEND-ed clinical trial evaluating efanesoctocog alfa for the treatment of patients with hemophilia A.

Hemophilia A is an inherited bleeding disorder in which the blood does not clot normally. People with hemophilia A will bleed more than normal after an injury, surgery, or dental procedure. Bleeding into the joints, muscles, brain, or organs can cause pain and other serious complications. Hemophilia A is caused by changes in the F8 gene that results in low levels of factor VIII, needed to form blood clots. .

Efanesoctocog alfa is a first-in-class high-sustained factor VIII replacement therapy designed to decouple recombinant factor VIII from endogenous von Willebrand factor. A third interim analysis of the XTEND-ed (NCT04644575) long-term extension study examining the safety and efficacy of efanesoctocog alfa prophylaxis in patients with severe hemophilia A was presented at the 2025 American Society of Hematology meeting.

In the extension study. patients who completed XTEND-1 (patients 12 years or older) and XTEND-Kids (patients younger than 12 years) were given the option to continue once-weekly 50 IU/kg efanesoctocog alfa prophylaxis in the ongoing, multicenter, open-label, long-term XTEND-ed study.

XTEND-1 to XTEND-ed

A total of 146 adults rolled over from XTEND-1 to XTEND-ed baseline. The median treatment duration in XTEND-ed was 166 weeks. No factor VIII inhibitor development was observed. During XTEND-ed, the mean annualized bleed rate (ABR) for day 1 to month 12 was 0.70, months 12 to 24 was 0.62 and months 24 to 36 was 0.45, with 65.8%, 68.1%, and 78.0% of participants with zero bleeds, respectively. The mean model-based ABR for the efficacy period was 0.60 for overall treated bleeds, and 0.20 and 0.29 for spontaneous and traumatic bleeds, respectively. Of 252 treated bleeding episodes, 94.0% were resolved with 1 efanesoctocog alfa injection and participants rated the response excellent/good for 87.8% bleeds. The median weekly efanesoctocog alfa consumption was 51.6 IU/kg.

In total, 86.3% experienced 1 or more treatment-emergent adverse event, most commonly COVID-19, arthralgia, influenza, and nasopharyngitis. Two participants had 1 or more treatment-related adverse event (facial paralysis and reduced factor VIII levels); no treatment-related serious adverse events were reported. Treatment-emergent adverse events unrelated to efanesoctocog alfa led to the death of two participants and treatment discontinuation in three participants.

XTEND-Kids to XTEND-ed

Among children, 71 rolled over from XTEND-Kids to XTEND-ed, with the median treatment duration of 116.7 weeks. No factor VIII inhibitors were observed. During XTEND-ed, the mean ABR evaluated for day 1 to month 12 was 0.68 and months 12 to 24 was 0.49, with 64.8% and 66.1% participants with zero bleeds, respectively. The mean model-based aABR was 0.64 for overall treated bleeds, and 0.08 and 0.44 for spontaneous and traumatic bleeds, respectively. Of 89 treated bleeding episodes, 91.0% were resolved with 1 efanesoctocog alfa injection and participants rated the response excellent/good for 94.1% bleeds. The median weekly efanesoctocog alfa consumption was 54.0 IU/kg.

Overall, 84.5% participants experienced 1 or more treatment-emergent adverse event, most commonly pyrexia, upper respiratory tract infection, arthralgia, and cough. Two participants had 1 or more treatment-related adverse event (asthma and post infusion pain and headache); no treatment-related serious adverse event or treatment discontinuations were reported.

To learn more about hemophilia and other rare hematologic conditions, visit https://checkrare.com/diseases/hematologic-disorders/

Chapters:
Introduction 00:00
Hemophilia Overview 00:49
XTEND-ed Clinical Trial 1:37
Take Home Message 5:21

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Richard Nowak, MD, Director of the Myasthenia Gravis Clinic at Yale University, discusses the recent U.S. Food and Drug Administration (FDA)approval of Uplizna (inebilizumab) for the treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor antibody positive (AChR-Ab+) or anti-muscle specific tyrosine kinase antibody positive (MuSK- Ab+).

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 that bind or disrupt the function of acetylcholine receptors in the neuromuscular junction. The reason this occurs is not known.

Inebilizumab is a first-in-class approach to gMG treatment, targeting CD19+ B cells. The approval offers patients deep and durable symptom control with just two doses a year after two initial doses.The approval was supported by data from the MINT clinical trial (NCT04524273), a randomized, double-blind, placebo-controlled, parallel-group study evaluating the safety and efficacy of inebilizumab in adults with gMG. The trial enrolled 238 participants, including 190 patients who are AChR-Ab+ and 48 patients who are MuSK-Ab+.

Patients on steroids at baseline began tapering at week 4 to reach prednisone 5 mg per day by week 24. By week 26, 87.4% of patients taking inebilizumab and 84.6% of those taking placebo had reduced their steroid dose to 5 mg or less per day.

Additionally, at week 26, inebilizumab demonstrated a 1.9-point difference in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared with placebo. Benefits in the AChR-Ab+ patient subgroup continued through week 52, with an exploratory analysis of AChR-Ab+ patients showing a 2.8-point difference in MG-ADL for inebilizumab compared with placebo. The most common adverse events were headache and infusion-related reactions

As Dr. Nowak explains, this approval is important to the MG community, where diverse treatment options are needed to address unique patient needs. Focusing on new mechanisms of action in treatment options can help in the development of treatments for patients with certain MG antibodies.

This approval marks the third indication for inebilizumab, which was previously approved by the FDA to treat adults with AQP4 antibody positive neuromyelitis optica spectrum disorder and adults with immunoglobulin G4-related disease.

To learn more about gMG and other rare neurological conditions, visit https://checkrare.com/diseases/neurology-nervous-system-diseases/

Chapters:
Introduction 00:00
gMG Landscape 00:22
Inebilizumab Overview 1:36
MINT Clinical Trial 2:35
Importance of Treatment Options 4:15
Take Home Message 6:32

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