Development of eIF2B Activator ABBV-CLS-7262 as a Novel Treatment for Vanishing White Matter Disease
Amos Baruch1, Paul Malik1, Anu Gopathi1, Ellen Ingalla1, Matthew Rosebraugh2, Yi Rang Han2, Emmanuelle Bellemin1, Adrian Serone1, Steven Fausch2, Jyoti Asundi1, Ganesh Kolumam1, Chunlian Zhang1, Jose Zavala-Solorio1, Diana Donnelly-Roberts2, Malleswari Challagundla3, Christina Boch3, Charlie Cao1, Eric Mohler2, Carmela Sidrauski1, Joshua Bonkowsky4, Anna Jeong2, William Cho1
1Calico Life Sciences, 2Abbvie, 3AbbVie Deutschland GmbH & Co. KG, 4University of Utah
Objective:
Provide scientific rationale and clinical approach to test ABBV-CLS-7262 as a novel therapy for Vanishing White Matter disease
Background:
Vanishing White Matter (VWM) disease is a rare, progressive leukodystrophy. VWM disease is caused by recessive partial loss-of-function mutations in any of the five genes encoding eIF2B, a guanine nucleotide exchange factor for the eukaryotic translation initiation factor eIF2 which is essential for protein synthesis and is an effector of the integrated stress response (ISR). ABBV-CLS-7262 is a brain-penetrant, small molecule activator of eIF2B that stabilizes the eIF2B complex and boosts its activity, including that of complexes carrying pathogenic VWM mutations.
Design/Methods:
Studies in a preclinical model of VWM were performed to determine the therapeutic potential of eIF2B activators. ABBV-CLS-7262 was tested in a healthy volunteer Phase 1 study and more recently in an open-label Phase 1b study (
NCT05757141) enrolling participants with VWM disease.
Results:
An eIF2B activator rescued motor deficits in a mouse model of VWM. Concomitant changes were observed in ISR gene expression and pharmacodynamic biomarkers. In addition, NfL was markedly reduced following treatment in VWM mice, highlighting a link between ISR attenuation and neurodegeneration. In a Phase 1 study in healthy volunteers, ABBV-CLS-7262 was well-tolerated following dosing for up to 14 days. ABBV-CLS-7262 increased eIF2B enzyme activity and suppressed the ISR in blood cells. A Phase 1b/2 study was initiated to assess safety, tolerability, pharmacokinetics and pharmacodynamics of ABBV-CLS-7262 in participants with VWM disease. Baseline CSF and plasma biomarkers will be presented.
Conclusions:
ABBV-CLS-7262 is being developed as a potential first-in-class treatment for VWM, supported by preclinical studies and Phase 1 healthy volunteer data. A Phase 1b/2 study in people with VWM has been initiated which may enable future studies.