Zorevunersen in Children and Adolescents with Dravet Syndrome
The safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome.
KEY FINDINGS: The safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome.
BACKGROUND: Enrolled patients 2 to 18 years of age with Dravet syndrome who were receiving standard antiseizure medications in two phase 1-2a, open-label, multicenter studies (MONARCH and ADMIRAL). Patients were included in either a single-ascending-dose cohort, in which zorevunersen (10 to 70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period. Patients eligible for rollover to the two open-label extension studies (SWALLOWTAIL and LONGWING) continued to receive zorevunersen (<=45 mg) every 4 months. The safety and pharmacokinetics of zorevunersen were assessed in the primary analysis; clinical effects were also evaluated.
DETAILS: Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels, in patients with Dravet syndrome are not known. A total of 81 patients were enrolled in the phase 1-2a studies. As of May 30, 2025, a total of 75 patients had entered the extension studies. Most adverse events were mild or moderate. The most common adverse event was post-lumbar puncture syndrome (in 25% of patients) in the phase 1-2a studies and was an elevated protein level in cerebrospinal fluid (in 45%) in the extension studies. One patient had suspected unexpected serious adverse reactions, 1 had an adverse event that led to study withdrawal, 2 died from sudden unexpected death in epilepsy, and 1 died from malnutrition. Patients who received 70 mg of zorevunersen (one, two, or three doses) in the phase 1-2a studies, followed by up to 45 mg in the extension studies, had a median change from baseline in convulsive-seizure frequency ranging from -58.82% to -90.91% across 1-month intervals during the first 20 months of the extension studies. The data supported improvements in overall clinical status, quality of life, and adaptive behavior with continued treatment for up to 36 months in the extension studies.
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A Pragmatic SMART Study of Medication and CBT Sequencing in Pediatric Anxiety Disorders
Fluoxetine and exposure-based CBT showed broadly comparable improvement over 24 weeks. Among those remaining symptomatic, CBT followed by combination therapy showed the strongest overall improvement pattern.
KEY FINDINGS: In this pragmatic study of clinically complex and demographically diverse youths, fluoxetine and exposure-based CBT produced broadly comparable improvement in anxiety symptoms over 24 weeks. For patients who remained symptomatic after 12 weeks, adding the alternate treatment generally showed a tendency toward greater improvement than optimizing monotherapy, although the overall differences were small and did not establish combination therapy as superior on the primary outcome. The CBT→combination sequence produced the strongest overall pattern of improvement across anxiety severity and functional impairment measures. Treatment response also varied across racial and ethnic groups, with Non-Hispanic White youths showing greater benefit from fluoxetine-based treatment sequences on some parent- and youth-reported secondary outcomes, whereas racial and ethnic minority youths showed greater benefit from transition to combination therapy on selected measures.
BACKGROUND: Choosing between medication and cognitive-behavioral therapy (CBT) as the initial treatment for pediatric anxiety disorders, and determining how to proceed when symptoms persist, remains clinically challenging. This pragmatic randomized trial evaluated whether initiating treatment with fluoxetine or exposure-based CBT produced better outcomes and whether adding the alternate treatment was more effective than continuing the initial therapy when remission was not achieved after 12 weeks.
DETAILS: This 24-week, single-blind sequential multiple assignment randomized trial included 316 youths aged 8-17 years with DSM-5 anxiety disorders, significant anxiety symptoms, and functional impairment. Participants were initially randomized to 12 weeks of fluoxetine or weekly exposure-based "Coping Cat" CBT. Fluoxetine dosing ranged from 10 to 80 mg/day. Youths who did not achieve remission after 12 weeks were subsequently randomized to either optimization of their initial treatment or optimization plus addition of the other modality. Outcomes included youth- and parent-reported 41-item Screen for Child Anxiety Related Emotional Disorders (SCARED) scores and Childhood Anxiety Impact Scale (CAIS) scores. The study was conducted in primary care and community mental health settings and included youths with substantial sociodemographic disadvantage and co-occurring mental health conditions.
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Youth-reported SCARED scores decreased by 31.7% over 24 weeks, from 42.9 at baseline to 29.31 at study endpoint. Improvement did not differ significantly between initial fluoxetine and CBT, although CBT showed a nonsignificant numerical advantage, with a 24-week difference in mean group change of 1.45 (95% CI=-2.25, 5.16). Among participants who did not remit by week 12, combination treatment was not significantly superior to continued optimized monotherapy for youth-reported anxiety at week 24 (group difference in mean change from baseline: -2.74, 95% CI=-6.53, 1.05).
Exploratory analyses of treatment sequences found that CBT followed by combination therapy produced the greatest overall improvement across the primary and secondary outcomes, although youth-reported SCARED scores did not differ significantly between individual sequences at week 24. Parent-reported SCARED scores declined by 37.8%, from 38.9 to 24.2, over 24 weeks. Parent ratings showed faster improvement with initial fluoxetine at weeks 6 and 12, while youth-reported CAIS scores favored initial CBT by week 24. Reduced appetite was more frequent with medication during both treatment stages, occurring in 43.7% versus 32.3% during stage 1 (p<0.05) and in 17.3% with med→med, 3.6% with CBT→CBT, and 12.1% with combination treatment during stage 2 (p=0.013). Serious or unexpected adverse events were rare.
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Source: Peterson, B. S., West, A. E., Weersing, V. R., et al. A Pragmatic SMART Study of Medication and CBT Sequencing in Pediatric Anxiety Disorders: A Randomized Clinical Trial. American Journal of Psychiatry. 2026; 183(9): 668-681. Published: September, 2026. DOI: 10.1176/appi.ajp.20251037.
Irregularly Shaped Microplastics May Compromise the Kidney’s Glomerular Filtration Barrier
In a mouse study, irregularly shaped microplastic particles persisted in circulation, accumulated in the kidneys, and were detected in urine despite more than 99% of administered particles being excreted in feces. Irregular particles caused renal vascular and tubular lesions, capillary flow disturbances, and changes suggesting disruption of the glomerular filtration barrier. They also produced glomerular albumin hyperfiltration and increased proximal tubular albumin uptake. These effects were not observed with spherical microplastic particles, highlighting particle shape as a potentially important determinant of renal toxicity.
KEY FINDINGS: In this experimental mouse study, irregularly shaped microplastic particles demonstrated a different biological distribution and renal effect profile from spherical particles. Despite >99% of administered particles being excreted in feces, irregular fragments persisted in the circulation, accumulated in the kidneys, and were detected in urine. Renal exposure was associated with vascular and tubular lesions, capillary flow disturbances, and changes suggesting disruption of the glomerular filtration barrier. The findings indicate that microplastic morphology may be an important determinant of biological effects, although the clinical relevance to human kidney health remains to be established.
BACKGROUND: Human exposure to microplastics is widespread, but the biological effects of particle shape remain incompletely understood. Most experimental studies have used spherical particles, despite environmental microplastics commonly occurring as irregular fragments. This study compared spherical and irregularly shaped microplastic particles to determine whether particle morphology influences their distribution in the body and their effects on renal function.
DETAILS: Investigators administered labeled spherical and irregular microplastic particles to mice by oral gavage, either as a single dose or daily for 7 days. Microplastic distribution was evaluated in multiple organs, while renal effects were assessed using histochemistry and intravital multiphoton microscopy. Additional functional experiments were performed using isolated perfused mouse kidneys. Overall intestinal absorption was limited, with >99% of administered microplastic particles being eliminated in feces. However, irregular fragments remained detectable in the circulation for several days and accumulated in multiple organs following oral exposure.
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Irregular microplastic particles were detected in the urine as well as within renal blood vessels, glomeruli, and tubules. Their presence in the urine suggested that these particles could cross the glomerular filtration barrier. Within the kidney, irregular particles were associated with phagocytic cells. Functional studies demonstrated that irregular microplastics caused disturbances in capillary flow and produced lesions involving renal blood vessels and the tubular system. They also resulted in glomerular albumin hyperfiltration and increased proximal tubular albumin uptake, findings consistent with impairment of the glomerular filtration barrier. These effects were not observed following ingestion of spherical microplastic particles.
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Source: Triebel, H., De Luca, F., Baumann, S. J., et al. Irregularly Shaped Microplastic Particles Compromise the Integrity of the Glomerular Filtration Barrier of the Kidney. Kidney360. 2026; 7(8): 1750-1762. Published: May 12, 2026. DOI: 10.34067/KID.0000001215.
Next-Generation Phenotyping May Strengthen Variant Interpretation in Mowat-Wilson Syndrome
In a proof-of-concept study, GestaltMatcher ranked Mowat-Wilson syndrome as the leading diagnosis in a 4-year-old child with a de novo ZEB2 variant. Three of 4 facial images met the PP4 moderate threshold and 1 met the supporting threshold. Integration of facial, HPO, and molecular data through PEDIA ranked ZEB2 as the most likely disease-causing gene. The findings suggest that AI-assisted phenotyping may provide quantitative support for variant interpretation while complementing expert clinical genetics assessment.
KEY FINDINGS: Computational facial phenotyping using GestaltMatcher identified MWS as the leading diagnosis in a child with a suspected de novo ZEB2 variant and provided quantitative evidence that supported variant interpretation. Three of 4 facial images reached the PP4 moderate threshold, while 1 reached the supporting threshold. Integration of facial phenotype, HPO information, and molecular data through PEDIA ranked ZEB2 first and contributed to classification of the variant as likely pathogenic. The findings provide a proof of concept for incorporating NGP into rare-disease diagnostic and variant-interpretation workflows, although larger, multicenter studies are needed to establish reproducibility and generalizability.
BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene and characterized by developmental impairment, epilepsy, congenital anomalies, and distinctive craniofacial features. Although next-generation phenotyping (NGP) tools such as GestaltMatcher can assist in recognizing rare genetic disorders, their use as quantitative evidence for variant interpretation within the American College of Medical Genetics and Genomics (ACMG) framework remains less established. This study evaluated whether computational facial phenotyping and multimodal clinical data could support variant prioritization and the ACMG PP4 phenotype-specificity criterion in MWS.
DETAILS: The investigators applied GestaltMatcher to a 4-year-old child with an undiagnosed neurodevelopmental disorder, suspected MWS, and a de novo ZEB2 variant. Facial photographs were analyzed alongside Human Phenotype Ontology (HPO) terms and simulated exome data using the PEDIA framework. Bayesian likelihood modeling was used to establish Gestalt score thresholds corresponding to supporting, moderate, strong, and very strong PP4 evidence. Brain MRI was also analyzed for structural abnormalities associated with MWS. The GestaltMatcher model had been trained using 9,671 images from 7,294 patients representing 275 disorders. For the MWS analysis, the dataset included 11 individuals with MWS and 14 age-matched controls.
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GestaltMatcher ranked MWS as the leading diagnosis, while integration through PEDIA also ranked ZEB2 as the most likely disease-causing gene. Across the 4 facial images from the proband, 3 achieved the PP4 moderate threshold and 1 achieved the PP4 supporting threshold. The established Gestalt score thresholds were 0.5111 for supporting, 0.5672 for moderate, 0.6609 for strong, and 0.7632 for very strong evidence.
Using the NGP-derived PP4 moderate evidence together with the original ACMG evidence, the ZEB2 variant was classified as likely pathogenic. Brain MRI demonstrated subtle thinning of the corpus callosum, a finding consistent with previously reported MWS-associated neuroimaging abnormalities. MRI-derived features also differentiated individuals with MWS from age-matched controls in exploratory analysis.
An additional exploratory case involving an infant with molecularly confirmed MWS showed that GestaltMatcher could prioritize MWS based solely on infant facial characteristics. The authors emphasize that NGP is intended to complement, rather than replace, expert clinical genetic assessment.
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Source: Hsieh, T. C., Todd, D., Warner, T., et al. Leveraging Next-Generation Phenotyping in Dysmorphology to Support Variant Interpretation in Mowat-Wilson Syndrome. Neurology Genetics. 2026; 12(4): e200384. Published: July 1, 2026. DOI: 10.1212/NXG.0000000000200384
Long-Term Outcomes of Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia
In a phase II study of 30 patients with newly diagnosed FLT3-mutated AML, azacitidine, venetoclax, and gilteritinib produced a 96% CR/CRi rate. At a median follow-up of 41.5 months, median RFS and OS were 23.4 and 29.7 months, with 3-year rates of 43% and 46%, respectively. Baseline RAS pathway mutations were associated with poorer outcomes, while 67% of evaluable relapses lacked detectable FLT3 mutations. The triplet produced durable remissions but frequently required treatment dose or duration reductions because of myelosuppression.
KEY FINDINGS: In this phase II study, azacitidine, venetoclax, and gilteritinib produced high remission rates and encouraging long-term survival in patients with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. The 3-year RFS and OS rates were 43% and 46%, respectively, although outcomes were less favorable in patients with FLT3-ITD mutations and baseline RAS pathway mutations. Most evaluable relapses were FLT3-negative, suggesting that resistance may involve mechanisms beyond persistent FLT3-mutated disease. Dose or duration reductions were frequently required during consolidation, primarily reflecting the challenge of managing myelosuppression. Randomized studies are needed to establish the role of this triplet regimen relative to current standard approaches.
BACKGROUND: Relapse after frontline azacitidine and venetoclax remains a major challenge in patients with FLT3-mutated acute myeloid leukemia (AML), with relapse often associated with expansion of FLT3-mutated clones. This phase II study evaluated the long-term efficacy and safety of adding the FLT3 inhibitor gilteritinib to azacitidine and venetoclax in adults with newly diagnosed FLT3-mutated AML who were considered unfit for intensive chemotherapy.
DETAILS: Thirty patients with newly diagnosed FLT3-mutated AML were treated with the azacitidine, venetoclax, and gilteritinib triplet regimen. The median age was 71 years, and 22 (73%) patients had FLT3-ITD mutations. Fourteen patients (47%) proceeded to allogeneic hematopoietic stem cell transplantation in first remission. The median follow-up was 41.5 months.
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The complete remission or complete remission with incomplete hematologic recovery rate was 96%. Eleven patients (37%) subsequently relapsed, and among evaluable relapses, the FLT3 mutation was no longer detectable in 67%, indicating that relapse mechanisms were not necessarily driven by persistent FLT3-mutated disease.
The median relapse-free survival (RFS) was 23.4 months and median overall survival (OS) was 29.7 months. At 3 years, RFS was 43% and OS was 46%. Among patients with FLT3-ITD-mutated AML, median RFS and OS were 17.0 months and 21.8 months, respectively, with 3-year RFS and OS rates of 32% and 36%. Baseline RAS pathway mutations were associated with poorer outcomes.
Survival outcomes were similar regardless of whether patients underwent allogeneic hematopoietic stem cell transplantation in first remission. Among patients receiving at least one consolidation cycle, 68% required a reduction in the dose or duration of at least one study drug, highlighting the need to manage treatment-related myelosuppression during prolonged therapy.
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Source: Short, N. J., Kantarjian, H. M., Daver, N., et al. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML. Blood Advances.. 2026; 10(17): 5743–5750. Published: May 27, 2026. DOI: 10.1182/bloodadvances.2026019841.
[Posted 2/Sep/2026]
AUDIENCE: Hematology, Oncology
KEY FINDINGS: In this phase II study, azacitidine, venetoclax, and gilteritinib produced high remission rates and encouraging long-term survival in patients with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. The 3-year RFS and OS rates were 43% and 46%, respectively, although outcomes were less favorable in patients with FLT3-ITD mutations and baseline RAS pathway mutations. Most evaluable relapses were FLT3-negative, suggesting that resistance may involve mechanisms beyond persistent FLT3-mutated disease. Dose or duration reductions were frequently required during consolidation, primarily reflecting the challenge of managing myelosuppression. Randomized studies are needed to establish the role of this triplet regimen relative to current standard approaches.
BACKGROUND: Relapse after frontline azacitidine and venetoclax remains a major challenge in patients with FLT3-mutated acute myeloid leukemia (AML), with relapse often associated with expansion of FLT3-mutated clones. This phase II study evaluated the long-term efficacy and safety of adding the FLT3 inhibitor gilteritinib to azacitidine and venetoclax in adults with newly diagnosed FLT3-mutated AML who were considered unfit for intensive chemotherapy.
DETAILS: Thirty patients with newly diagnosed FLT3-mutated AML were treated with the azacitidine, venetoclax, and gilteritinib triplet regimen. The median age was 71 years, and 22 (73%) patients had FLT3-ITD mutations. Fourteen patients (47%) proceeded to allogeneic hematopoietic stem cell transplantation in first remission. The median follow-up was 41.5 months.
The complete remission or complete remission with incomplete hematologic recovery rate was 96%. Eleven patients (37%) subsequently relapsed, and among evaluable relapses, the FLT3 mutation was no longer detectable in 67%, indicating that relapse mechanisms were not necessarily driven by persistent FLT3-mutated disease.
The median relapse-free survival (RFS) was 23.4 months and median overall survival (OS) was 29.7 months. At 3 years, RFS was 43% and OS was 46%. Among patients with FLT3-ITD-mutated AML, median RFS and OS were 17.0 months and 21.8 months, respectively, with 3-year RFS and OS rates of 32% and 36%. Baseline RAS pathway mutations were associated with poorer outcomes.
Survival outcomes were similar regardless of whether patients underwent allogeneic hematopoietic stem cell transplantation in first remission. Among patients receiving at least one consolidation cycle, 68% required a reduction in the dose or duration of at least one study drug, highlighting the need to manage treatment-related myelosuppression during prolonged therapy.
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Source: Short, N. J., Kantarjian, H. M., Daver, N., et al. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML. Blood Advances.. 2026; 10(17): 5743–5750. Published: May 27, 2026. DOI: 10.1182/bloodadvances.2026019841.
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