Citations

Abstract Background: Ivosidenib (IVO) is a first-in-class oral inhibitor of the IDH1 mutant (mIDH) enzyme. In the ClarIDHy phase 3 study of previously treated patients with mIDH cholangiocarcinoma (CCA), IVO treatment led to improved progression-free survival (PFS) and overall survival (OS) vs placebo (median PFS: 2.7 vs. 1.4 months and OS 10.3 vs. 5.1 months, when adjusted for the 70% crossover rate; HR, 0.49 [95% CI, 0.34-0.70]; 1-sided P<0.001. Here, we studied the dynamics of mutations emerging after 6 months of IVO treatment using ctDNA analyses. Methods: Prior to enrollment, all subjects in ClarIDHy had IDH1 R132 mutations confirmed by a central NGS panel utilizing tumor biopsy tissue. Since post-progression tissue samples were unavailable, discovery of emerging mutations was limited to plasma ctDNA assessments. To explore molecular changes associated with acquired resistance, an analysis was performed on 18 subjects treated with IVO for ≥6 months (4 partial response; 12 stable disease, 2 NA) using matched baseline and end of treatment (EOT) samples (PGDx elioTM plasma complete, 521 gene panel). A subset of the oncogenic alterations identified were selected for confirmation by ddPCR analysis in ctDNA samples collected longitudinally. Longitudinal plasma 2HG levels were also evaluated. Results: This analysis identified several EOT mutations not present at baseline. The most common mutations were in the MAPK pathway, including activating KRAS, NRAS, and MAP2K1 mutations and loss-of-function NF1 mutations (6/18 patients, 33%). In 2/6 patients, multiple MAPK pathway mutations were detected. There was a range of variant allele frequencies (VAFs) of RAS alterations, including some that had comparable levels to the truncal mIDH, suggesting that MAPK activation may have made a major contribution to the burden of resistant disease. ddPCR analyses from longitudinal plasma samples from selected cases confirmed these findings. In addition, 2 patients had mutations affecting transcription/epigenetics (WT1 and KMT2C). Finally, only 1 patient had acquired mutations in IDH genes (IDH2-R172K and IDH1-G131V). The WT1, KMT2C, and IDH variants had a low VAF. Accordingly, EOT plasma 2HG levels were reduced vs pre-treatment levels in the patient with secondary mIDH, indicating a limited role in the overall emergence of resistance. Conclusion: Analyses of paired baseline/EOT samples suggest that multiple acquired mutations could contribute to IVO resistance, with oncogenic MAPK pathway alterations being the most common. Consistent with previous clinical studies conducted in AML, IDH1 second site mutations and isotype switching to IDH2, rarely emerge during IVO treatment. The lack of detectable mutations in the majority of patients could reflect the sensitivity of the NGS assay or a role for non-genetic mechanisms of resistance. Citation Format: Hatice Duygu Saatcioglu, Haley Ellis, Jinkai Wan, Sam Lubner, Milind Javle, Ghassan K. Abou-Alfa, James M. Cleary, Robin Kate Kelley, Mitesh J. Borad, Teresa Macarulla, Do Youn Oh, Camelia Gliser, Susan Pandya, Sung Chloe, Nabeel Bardeesy, Adriana Tron. Circulating tumor DNA analysis demonstrates newly emerging alterations in previously treated IDH1 mutated cholangiocarcinoma patients enrolled in the ClarIDHy study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4648.

Abstract Purpose To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2025 in the United States, with a focus on the nonfederal hospital and clinic sectors. Methods Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2025 were reviewed—including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, endocrine drugs, generics, specialty drugs and vaccines. For nonfederal hospitals, clinics, and overall (all sectors), estimates of growth of pharmaceutical expenditures in 2024 were made based on a combination of quantitative analyses and expert opinion. Results In 2024, overall pharmaceutical expenditures in the US grew 10.2% compared to 2023, for a total of $805.9 billion. Utilization (a 7.9% increase) and new drugs (a 2.5% increase) drove this increase, while prices remained flat (a 0.2% decrease). Semaglutide was the top drug in 2024, followed by tirzepatide and adalimumab. Drug expenditures were $39.0 billion (a 4.9% increase) and $158.2 billion (a 14.4% increase) in nonfederal hospitals and clinics, respectively. In clinics, increased utilization drove growth, with a small contribution from new products, while prices remained flat. In nonfederal hospitals, new products, price, and new volume each contributed modestly to growth in spend. Several new drugs that will influence spending are expected to be approved in 2025. Specialty, endocrine, and cancer drugs will continue to drive expenditures. Conclusion For 2025, we expect overall prescription drug spending to rise by 9.0 to 11.0%, whereas in clinics and hospitals we anticipate an 11.0% to 13.0% increase and a 2.0% to 4.0% increase, respectively, compared to 2024. These national estimates of future pharmaceutical expenditure growth may not be representative of any health system because of the myriad of local factors that influence actual spending.

AbstractEpilepsy syndromes are distinct electroclinical entities which have been recently defined by the International League Against Epilepsy Nosology and Definitions Task Force. Each syndrome is associated with “a characteristic cluster of clinical and EEG features, often supported by specific etiologic findings”. Syndromes often present in an age‐dependent manner, carry both prognostic and treatment implications, and are associated with a specific range of comorbidities. Syndromes are most commonly identified in young children and are less frequent in adults. Syndrome identification assists clinicians in selecting the highest yield investigations, the most effective therapies, and allows them to give more accurate prognoses both with regards to seizure control and potential remission as well as expected, associated comorbidities. This review outlines how syndromes are organized and defined, highlighting the characteristic features of the more common entities.Plain Language SummaryEpilepsy syndromes are identifiable entities that are characterized by specific seizure type(s) and EEG findings. Identification of an epilepsy syndrome often provides a clue to the underlying cause, helps clinicians select the most effective treatments, and provides information on the likely outcome.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683