Researchers have studied potential corrected QT interval (QTc) prolongation from drug–drug interactions (DDIs), raising unresolved questions about their real‐world impact. This retrospective case‐crossover study investigated the effects of QT‐prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT‐prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95–3.02)). The risk was higher with drugs of “known risks” (OR: 3.78 (2.91–4.90)) and “conditional risk” (OR: 2.08 (1.65–2.62)). DDIs, particularly involving multiple “known risk” drugs (OR: 7.86 (4.96–12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75–11.30)), or the concurrent use of ≥4 QT‐prolonging drugs with any risk (OR: 5.28 (3.96–7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care.

01 Jan 2025·Journal of Clinical Oncology

Menin Inhibition With Revumenib for KMT2A -Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)

Article

Author: Byrd, John ; Heiblig, Mael ; Sabins, Himalee ; Patel, Manish ; Kovacsovics, Tibor ; Cuglievan, Branko ; Whitlock, James ; Thirman, Michael ; Chen, Jing ; DiPersio, John ; Schuh, Andre ; Shukla, Neerav ; Chudnovsky, Yakov ; Aldoss, Ibrahim ; Bajel, Ashish ; Stein, Eytan M. ; Perl, Alexander ; McNeer, Nicole ; Fleming, Shaun ; Stone, Richard ; Wolach, Ofir ; Shami, Paul J. ; Arnan-Sangerman, Montserrat ; Zwaan, C. Michel ; Mantzaris, Ioannis ; Marconi, Giovanni ; Grove, Carolyn S. ; Gu, Yu ; McMahon, Christine M. ; Thirman, Michael J. ; Zwaan, C. Michael ; Blachly, James S. ; Wei, Andrew ; Fernandez, Pau Montesios ; Traer, Elie ; Issa, Ghayas C. ; Nachmias, Boaz ; Arellano, Martha ; Madigan, Kate ; Talati, Chetasi ; Dickens, David S. ; Greenwood, Matthew ; Bagley, Rebecca G. ; Nguyen, Huy Van ; Mannis, Gabriel N.

PURPOSE Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A -rearranged ( KMT2Ar ) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. METHODS AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399 ). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 ( NPM1 ) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m 2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar . The separate NPM1 cohort of the trial is ongoing. RESULTS From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% ( P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. CONCLUSION Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

01 Jan 2025·Journal of Infection and Chemotherapy

Disproportionality analysis of amenamevir-induced encephalopathy using the Japanese adverse drug event report database

Article

Author: Ashida, Akira ; Ogawa, Taku ; Nishihara, Masami ; Yamada, Tomoyuki ; Kusaka, Yusuke ; Tanaka, Tomoko

INTRODUCTIONAnti-herpesvirus drug-induced encephalopathy can complicate herpes zoster treatment; however, the association between the recently developed anti-herpesvirus drug amenamevir and encephalopathy development remains unknown. Determining the characteristics of amenamevir-induced encephalopathy is essential for potentially improving patient outcomes in the treatment of herpes zoster. The aim of this study is to identify the association between amenamevir treatment and encephalopathy and to determine the risk factors for amenamevir-induced encephalopathy via disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database.METHODWe conducted a retrospective observational study using anonymized data from the JADER database. Encephalopathy was defined according to the Standardized Medical Dictionary for Regulatory Activities Queries specific to "Noninfectious encephalopathy/delirium." Disproportionality analysis was used to calculate the reporting odds ratios (RORs) and 95 % confidence intervals (CIs) to assess associations between amenamevir and encephalopathy. Multivariable logistic regression considered age, gender, chronic kidney disease, and cytochrome P450 3A inhibitor use as potential risk factors.RESULTSOut of 713,316 patients, 246 were prescribed amenamevir. The median onset of encephalopathy in these patients was 3 days. Disproportionality of encephalopathy was observed in patients treated with amenamevir (ROR, 3.44; 95 % CI, 2.48-4.78). Furthermore, multivariable logistic regression analysis suggested that an age of ≥70 years was associated with amenamevir-induced encephalopathy (ROR, 7.63; 95 % CI, 2.25-25.9).CONCLUSIONThese results suggest that amenamevir treatment may be associated with encephalopathy, particularly in patients aged ≥70 years. Healthcare providers should be aware of this potential risk, especially in elderly patients, to prevent severe central nervous system complications.

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Fibrosis	Preclinical	US	Angion Biomedica Corp.	-

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