[Posted 28/Aug/2025]

AUDIENCE: Neurology, Pediatric, Neurosurgery

KEY FINDINGS: Infants up to 6 weeks of age with genetically diagnosed SMA who were treated with risdiplam before the development of clinical signs or symptoms appeared to have better functional and survival outcomes at 12 and 24 months than untreated infants in natural history studies. Larger, controlled studies with longer follow-up are needed to further understand the relative efficacy and safety of presymptomatic treatment of SMA with risdiplam.

BACKGROUND: Risdiplam, an oral pre–messenger RNA splicing modifier, is an efficacious treatment for persons with symptomatic spinal muscular atrophy (SMA). The safety and efficacy of risdiplam in presymptomatic disease are unclear.

DETAILS: Authors conducted an open-label study of daily oral risdiplam (with the dose adjusted to 0.2 mg per kilogram of body weight) in infants 1 day (birth) to 42 days of age with genetically diagnosed SMA but without strongly suggestive clinical signs or symptoms. The primary outcome, assessed in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) amplitude of at least 1.5 mV, was the ability to sit without support at month 12. Natural history studies have shown that the majority of infants with two SMN2 copies who are untreated would have a severe SMA phenotype (type 1), would never sit independently, would receive permanent ventilation and feeding support, or would die by 13 months of age. Secondary outcomes that were assessed over a period of 24 months included survival, ventilatory support, motor milestones, the development of clinically manifested SMA, feeding, and growth. A total of 26 infants with two, three, or four or more copies of SMN2 were enrolled. After 12 months of treatment, 21 infants (81%) could sit unsupported for 30 seconds, 14 (54%) could stand alone, and 11 (42%) could walk alone. A total of 4 of 5 infants (80%; 95% confidence interval, 28 to 100) with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV were able to sit without support for at least 5 seconds. Three infants were withdrawn from the study by a parent or caregiver after the month 12 visit. Of 23 infants who completed 24 months of treatment, all were alive without the use of permanent ventilation or feeding support. Over a period of 24 months, nine treatment-related adverse events were reported in 7 infants; none of these events were serious.

Copyright © Massachusetts Medical Society. All rights reserved.

Source: Finkel, R. S., Servais, L., Vlodavets, D., et al. (2024). Risdiplam in Presymptomatic Spinal Muscular Atrophy. N Engl J Med. 2025; 393(7): 671-682. Published: August 13, 2025. DOI: 10.1056/NEJMoa2410120.

A Randomised, Open-Label, Multicentre, Phase 3 Trial

[Posted 28/Aug/2025]

AUDIENCE: Hematology, Oncology

KEY FINDINGS: With the limitation of a smaller sample size than planned due to the trial's early interruption, these results, to authors' knowledge, showed for the first-time high rates of MRD negativity with weekly carfilzomib added to lenalidomide-dexamethasone in patients with transplantation-ineligible newly diagnosed multiple myeloma. In the carfilzomib-lenalidomide-dexamethasone group, higher MRD negativity rates were associated with a progression-free survival advantage over lenalidomide-dexamethasone. Toxicities were predictable and generally manageable.

BACKGROUND: Before the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment for patients with newly diagnosed transplant-ineligible multiple myeloma, lenalidomide-dexamethasone was a standard of care. Authors aimed to explore whether addition of the second-generation proteasome inhibitor carfilzomib to lenalidomide-dexamethasone improved the rates of measurable residual disease (MRD) negativity and progression-free survival.

DETAILS: EMN20 is a randomised, open-label, multicentre, phase 3 trial comparing weekly carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma, conducted in 27 centres in Italy. Key inclusion criteria included fit or intermediate-fit status according to the International Myeloma Working Group (IMWG) frailty score, measurable disease according to IMWG criteria, and Eastern Cooperative Oncology Group performance status lower than 3. Patients randomly assigned to the carfilzomib-lenalidomide-dexamethasone group received 28-day carfilzomib-lenalidomide-dexamethasone cycles (carfilzomib 20 mg/m² intravenously on day 1 for cycle 1, followed by 56 mg/m² intravenously on days 8 and 15 for cycle 1, then 56 mg/m² intravenously on days 1, 8, and 15 for cycles 2-12, and 56 mg/m² intravenously on days 1 and 15 from cycle 13 until 5 years after randomisation; lenalidomide 25 mg orally on days 1-21 until disease progression or intolerance; dexamethasone 40 mg orally on days 1, 8, 15, and 22 until disease progression or intolerance). Patients assigned to the lenalidomide-dexamethasone group received 28-day cycles with lenalidomide-dexamethasone (same dosing and schedule used in the carfilzomib-lenalidomide-dexamethasone group). Primary endpoints were MRD negativity by next-generation sequencing (sensitivity 10-5) after 2 years of treatment and progression-free survival; and were assessed in the intention-to-treat (ITT) population (all patients who were eligible to receive treatment and who were randomly assigned to one of the treatment groups). On Nov 23, 2021, after enrolling 30% of planned patients (101/340), the trial was prematurely stopped due to the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment in Italy, which caused the lenalidomide-dexamethasone control group to no longer be considered a standard treatment. This trial is registered with ClinicalTrials.gov, NCT04096066, and study recruitment is complete. Between Nov 14, 2019, and Nov 23, 2021, 82 of 101 enrolled patients were assessed for eligibility and were randomised to receive carfilzomib-lenalidomide-dexamethasone (n=42) or lenalidomide-dexamethasone (n=40). In the ITT population, 35 (43%) of 82 patients were female and 47 (57%) were male. At data cutoff (March 29, 2024), the median follow-up was 35.2 months (IQR 30.3-38.7). The 2-year MRD negativity rates were 25 (60% 95% CI 43-74) of 42 patients with carfilzomib-lenalidomide-dexamethasone versus 0 (0%; 0-9) of 40 patients with lenalidomide-dexamethasone (p<0.0001). Median progression-free survival was not reached (not reached-not reached) with carfilzomib-lenalidomide-dexamethasone versus 20.9 months (15.7-not reached) with lenalidomide-dexamethasone (hazard ratio 0.24 [95% CI 0.11-0.56], p=0.00084). One patient was excluded from the safety analysis because they died before starting treatment. The most frequent grade 3 or worse adverse events were neutropenia (nine [22%] of 41 patients), thrombocytopenia (four [10%]), diarrhoea (four [10%]), cardiac events (three [7%]), infections (three [7%]), and arterial hypertension (two [5%]) with carfilzomib-lenalidomide-dexamethasone, and neutropenia (six [15%] of 40) and skin rash (four [10%]) with lenalidomide-dexamethasone. The most common serious adverse event was SARS-CoV-2-related pneumonia in both the carfilzomib-lenalidomide-dexamethasone group (two [5%] of 41 patients) and lenalidomide-dexamethasone group (three [7%] of 40 patients). Treatment-emergent adverse events leading to death were observed in two patients in the carfilzomib-lenalidomide-dexamethasone (two SARS-CoV-2 infections) and four patients in the lenalidomide-dexamethasone group (one acute myocardial infraction, one heart failure, one septic shock, and one SARS-CoV-2 infection).

Copyright © Elsevier Ltd. All rights reserved.

Source: Bringhen, S., Cani, L., Antonioli, E., et al. (2024). Carfilzomib-Lenalidomide-Dexamethasone Versus Lenalidomide-Dexamethasone in Patients With Newly Diagnosed Myeloma Ineligible for Autologous Stem-Cell Transplantation (EMN20): A Randomised, Open-Label, Multicentre, Phase 3 Trial. The Lancet Haematology. 2025; 12(8): e621-e634. Published: August, 2025. DOI: 10.1016/S2352-3026(25)00162-0.

[Posted 22/Aug/2025]

AUDIENCE: All Healthcare Professionals

KEY FINDINGS:

BACKGROUND: Recurrent Respiratory Papillomatosis (RRP) is a rare and chronic condition caused by human papillomavirus (HPV) types 6 and 11. The disease leads to the formation of benign tumors in the respiratory tract, most often in the larynx, which can cause significant symptoms like voice changes and difficulty breathing. Historically, the primary treatment for RRP has been repeated surgical removal of the tumors, as there have been no approved medical therapies to address the underlying cause.

DETAILS: The U.S. Food and Drug Administration (FDA) has approved Papzimeos (zopapogene imadenovec-drba), a groundbreaking immunotherapy, for the treatment of adult patients with RRP. This therapy is a non-replicating adenoviral vector that works by stimulating a targeted immune response against the HPV-infected cells. It is administered via a subcutaneous injection and represents the first non-surgical therapeutic option for this rare disease, offering a new approach beyond traditional surgical management.

The approval of Papzimeos was based on data from a single-arm, open-label trial. The study demonstrated that 51.4% of patients who received the treatment achieved a complete response, defined as not needing any further surgical intervention for 12 months following the treatment. The clinical benefits were shown to be durable for most patients over a two-year period and correlated with the development of specific T-cells targeting HPV 6 and 11. The therapy had a favorable safety profile with no serious treatment-related adverse events.

Key information:

• First-of-its-kind Approval: Papzimeos is the first approved medical therapy for RRP.
• Novel Mechanism: It is an immunotherapy that targets the root cause of the disease, HPV-infected cells.
• Approval Pathway: The product received Orphan Drug and Breakthrough Therapy designations and was approved under Priority Review, reflecting the significant unmet medical need for RRP patients.

Source: FDA Approves First Immunotherapy for Recurrent Respiratory Papillomatosis. FDA. 2025; Published: August 14, 2025.

[Posted 19/Aug/2025]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: GSS correlates with other validated reflux questionnaires and discriminates abnormal from normal reflux burden in patients with reflux symptoms. GSS change also reflects reflux treatment outcome and satisfaction. GSS is a useful addition to patient symptom assessment before and after GERD treatment.

BACKGROUND: Visual Analog Scales (VAS) are simple, easy for patients to comprehend, and require limited translation. Authors evaluated the value of esophageal global symptom severity (GSS) measured using VAS in assessing initial reflux symptom burden as compared with other validated questionnaires, esophageal symptom burden, and outcome after reflux management.

DETAILS: Authors analyzed pooled data from published historical cohorts of patients undergoing pH-impedance testing for reflux symptoms from 3 continents (North America, Europe, Asia). Univariate (Spearman correlation), multivariable (general linear regression), and receiver operating characteristic analyses were performed to compare GSS with validated symptom instruments including gastroesophageal reflux disease questionnaire (GERDQ), GERD health-related quality of life (GERD-HRQL), Reflux Symptom Index (RSI), and metrics from pH-impedance monitoring per Lyon Consensus 2.0. One thousand two hundred ninety-six patients (mean age 52.0 years, 61.9% female) were included: 937, 197, and 162 from North America, Europe, and Asia, respectively. GSS significantly correlated with GERDQ (R = 0.455), GERD-HRQL (R = 0.440), RSI (R = 0.491), acid exposure time (AET) (R = 0.158), and total reflux episodes (R = 0.161) (P < 0.0001 for each comparison). The mean GSS was higher with abnormal GERDQ, GERD-HRQL, RSI, pathologic AET, and conclusive GERD per Lyon Consensus (P < 0.0001 each comparison). On receiver operating characteristic analyses, GSS was noninferior to GERDQ, GERD-HRQL, and RSI in predicting pathologic AET and total reflux episodes, and conclusive GERD. Percentage improvement in GSS after antireflux treatment significantly correlated with change in GERDQ (R = 0.536, P < 0.0001) and treatment satisfaction (R = 0.532 P = 0.0002). On multivariable linear regression analyses, percentage change in GSS remained an independent predictor of both change in GERDQ (ß = 0.813, P < 0.0001) and satisfaction with antireflux therapy (ß = 1.90, P = 0.0006).

Copyright © The American College of Gastroenterology. All rights reserved.

Source: Chan, W. W., Schroeder, M., Richardson, A., et al. Validation of Esophageal Global Symptom Severity as a Patient-Reported Outcome for Evaluation of Reflux Symptoms. The American Journal of Gastroenterology. 2025; 120(8): 1760-1769. Published: August, 2025. DOI: 10.14309/ajg.0000000000003499.

FDA Safety Communication

[Posted 12/Aug/2025]

AUDIENCE: Patient, Health Care Professional, Pharmacy, Cardiology, Neurology, Internal Medicine, Family Practice, Travel Clinics

KEY FINDINGS: FDA Removes Recommended Pause in Use and Approves Required Updated Labeling of Ixchiq (Chikungunya Vaccine, Live).

BACKGROUND: Ixchiq contains a live, weakened version of the chikungunya virus and may cause symptoms similar to those of chikungunya disease. Some of the postmarketing reports include adverse events that are consistent with severe complications of chikungunya disease, resulting in hospitalization; one person died from encephalitis. Continuous monitoring and assessment of the safety of all vaccines remains an FDA priority. Suspected adverse events may be reported to the Vaccine Adverse Event Reporting System (VAERS), which is co-managed by FDA and CDC.

DETAILS: On May 9, 2025, FDA issued a safety communication informing the public that the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) jointly recommended a pause in the use of Ixchiq (Chikungunya Vaccine, Live) in individuals 60 years of age and older while the Agencies undertook an investigation of postmarketing reports of serious adverse events, including neurologic and cardiac events, in individuals who have received the vaccine. At the time of the May 9, 2025, recommended pause, FDA conveyed its intention to conduct an updated benefit-risk assessment for the use of Ixchiq in individuals 60 years of age and older. FDA has completed an updated benefit-risk assessment of Ixchiq, including for use in individuals 18 years of age and older. Based on the available data, and its benefit-risk assessment, FDA has removed the recommended pause in the use of Ixchiq in individuals 60 years of age and older and has approved updates to the Prescribing Information and Patient Information that it required of the company, Valneva Austria GmbH.

Source: FDA Update on the Safety of Ixchiq (Chikungunya Vaccine, Live): FDA Safety Communication. FDA. Published: 7th August, 2025.

[Posted 1/Jul/2025]

AUDIENCE: Neurology, Internal Medicine, Ob/Gyn

KEY FINDINGS: This population-based study on dementia biomarkers found that P-tau181 was dependent on age and APOEe4; NfL on age and sex; and GFAP on age, sex, APOEe4, and menopause status. GFAP levels and rate of increase were higher in women, especially in premenopausal participants. Future research should confirm these findings and further explore the role of menopause in dementia pathogenesis among women.

BACKGROUND: Dementia-related blood biomarkers are the future of large-scale dementia risk stratification; however, the extent to which phosphorylated tau (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are associated with nonmodifiable risk factors has yet to be confirmed in the community, and the role of menopause has yet to be investigated. Therefore, the aim of this study was to examine the association of age, sex, APOEe4 status, and menopause, with dementia-related blood biomarker levels (P-tau181, NfL, and GFAP) and rate of change over 11 years in longitudinal biomarker measurements in community-dwelling adults.

DETAILS: Within this German population-based Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung cohort study (n = 9,940), a nested case-control study of 1,026 participants (1:1, without dementia during follow-up: incident dementia during follow-up) aged 50-75 years at baseline followed over 17 years was conducted. Blood biomarker measurements (P-tau181, NfL, and GFAP) were completed in blood from baseline, 8-year, and 11-year follow-ups, and cross-sectional and longitudinal regression analyses were used to assess the association with age, sex, APOEe4, and menopause. The mean age of participants was 64 years, and women accounted for slightly over half (54%) of the sample. Age was cross-sectionally and longitudinally significantly associated with all dementia-related biomarkers (p < 0.001). NfL and GFAP levels more strongly correlated (Spearman R = 0.55 and 0.49) with age at baseline than P-tau181 levels (Spearman R = 0.21). Women experienced significantly higher levels and rates of increase in GFAP (p < 0.001) while men experienced higher levels of NfL after adjusting for age and APOEe4 (p < 0.01). APOEe4 status was significantly associated with baseline and longitudinal levels of P-tau181 (baseline ß = 0.30, p < 0.05) and GFAP (baseline ß = 15.84, p < 0.001). Of interest, premenopausal status was significantly associated with higher GFAP levels after adjusting for age, sex, and APOEe4 (ß = 19.09, p < 0.05).

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Stocker, H., Beyer, L., Trares, K., et al. Association of Nonmodifiable Risk Factors With Alzheimer Disease Blood Biomarkers in Community-Dwelling Adults in the ESTHER Study. American Academy of Neurology. 2025; 104(9): 213500. Published: May 27, 2025. DOI: 10.1212/WNL.000000000021350.