Abstract Details

Title Development of eIF2B Activator ABBV-CLS-7262 as a Novel Treatment for Vanishing White Matter Disease

Topic Child Neurology and Developmental Neurology

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 8-001

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 () 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.

Authors/Disclosures
Amos Baruch (Calico) PRESENTER	Dr. Baruch has received personal compensation for serving as an employee of Calico Life Science.
Paul R. Malik, PhD (Ionis Pharmaceuticals)	Dr. Malik has received personal compensation for serving as an employee of AbbVie. Dr. Malik has received personal compensation for serving as an employee of Calico Life Sciences.
ANU GOPATHI (Calico)	ANU GOPATHI has nothing to disclose.
Ellen Ingalla (Calico)	Ellen Ingalla has received personal compensation for serving as an employee of Calico.
Matthew Rosebraugh, PhD (AbbVie)	Dr. Rosebraugh has received personal compensation for serving as an employee of AbbVie Inc. Dr. Rosebraugh has stock in AbbVie Inc..
Yi Rang Han, PhD (AbbVie)	Dr. Han has received personal compensation for serving as an employee of AbbVie.
Emmanuelle Bellemin (Calico Life Science LLC)	No disclosure on file
Adrian Serone (Calico Life Sciences)	Adrian Serone has received personal compensation for serving as an employee of Calico Life Sciences, LLC.
Steven Fausch (Abbvie)	Steven Fausch has received personal compensation for serving as an employee of Abbvie. Steven Fausch has stock in Abbvie.
Jyoti Asundi (Calico life Sciences)	Jyoti Asundi has received personal compensation for serving as an employee of Calico Life Sciences.
Ganesh Kolumam (Calico labs)	No disclosure on file
Chunlian Zhang (Calico Labs)	Chunlian Zhang has nothing to disclose.
Jose Zavala-Solorio (Calico Life Sciences)	Jose Zavala-Solorio has nothing to disclose.
Diana Donnelly-Roberts (AbbVie Inc)	No disclosure on file
Malleswari Challagundla (AbbVie Deutschland GmbH & Co. KG)	Malleswari Challagundla has received personal compensation for serving as an employee of AbbVie Deutschland GmbH & Co. KG. Malleswari Challagundla has stock in AbbVie Deutschland GmbH & Co. KG.
Christina Boch (AbbVie Deutschland GmbH & Co. KG)	Christina Boch has received personal compensation for serving as an employee of AbbVie. Christina Boch has stock in AbbVie.
Charlie Cao (Calico Life Sciences)	Charlie Cao has received personal compensation for serving as an employee of Calico Life Sciences.
Eric Mohler	Eric Mohler has received personal compensation for serving as an employee of AbbVie. Eric Mohler has stock in AbbVie.
Carmela Sidrauski (Calico Life Sciences LLC)	Carmela Sidrauski has received personal compensation for serving as an employee of Calicolabs. Carmela Sidrauski has received intellectual property interests from a discovery or technology relating to health care.
Joshua Bonkowsky, MD, PhD	Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Denali. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Passage Bio. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Bonkowsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Dr. Bonkowsky has stock in Orchard. The institution of Dr. Bonkowsky has received research support from NIH. The institution of Dr. Bonkowsky has received research support from ELA. An immediate family member of Dr. Bonkowsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Bonkowsky has received publishing royalties from a publication relating to health care. Dr. Bonkowsky has received publishing royalties from a publication relating to health care.
Anna Jeong, MD (AbbVie)	Dr. Jeong has received personal compensation for serving as an employee of AbbVie. An immediate family member of Dr. Jeong has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for Stryker. Dr. Jeong has stock in AbbVie.
Bill Cho, MD, PhD (Calico)	Dr. Cho has received personal compensation for serving as an employee of Calico. Dr. Cho has stock in Roche.

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