Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome

Dragana Protic; Elizabeth Breeze; Guadalupe Mendoza; Marwa Zafarullah; Leonard Abbeduto; Randi Hagerman; Christopher Coffey; Merit Cudkowicz; Blythe Durbin-Johnson; Paul Ashwood; Elizabeth Berry-Kravis; Craig A Erickson; Robin Filipink; Andrea Gropman; Lenora Lehwald; Angela Maxwell-Horn; Stephanie Morris; Amanda Palladino Bennett; Lisa Prock; Amy Talboy; Nicole Tartaglia; Jeremy Veenstra-VanderWeele; Flora Tassone

doi:10.1177/20503121241282401

Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome

SAGE Open Med. 2024 Sep 29:12:20503121241282401. doi: 10.1177/20503121241282401. eCollection 2024.

Authors

Dragana Protic^{1

2}, Elizabeth Breeze^{3

4}, Guadalupe Mendoza⁵, Marwa Zafarullah⁵, Leonard Abbeduto^{4

6}, Randi Hagerman^{4

7}, Christopher Coffey⁸, Merit Cudkowicz⁹, Blythe Durbin-Johnson¹⁰, Paul Ashwood³, Elizabeth Berry-Kravis¹¹, Craig A Erickson¹², Robin Filipink¹³, Andrea Gropman¹⁴, Lenora Lehwald¹⁵, Angela Maxwell-Horn¹⁶, Stephanie Morris¹⁷, Amanda Palladino Bennett¹⁸, Lisa Prock¹⁹, Amy Talboy²⁰, Nicole Tartaglia²¹, Jeremy Veenstra-VanderWeele^{22

23

24}, Flora Tassone^{4

5}

Affiliations

¹ Faculty of Medicine, Department of Pharmacology, Clinical Pharmacology, and Toxicology, University of Belgrade, Belgrade, Serbia.
² Fragile X Clinic, Special Hospital for Cerebral Palsy and Developmental Neurology, Belgrade, Serbia.
³ Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA.
⁴ MIND Institute, University of California Davis, Sacramento, CA, USA.
⁵ Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, USA.
⁶ Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, CA, USA.
⁷ Department of Pediatrics, University of California Davis, Sacramento, CA, USA.
⁸ Department of Biostatistics, University of Iowa, Iowa City, IA, USA.
⁹ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, USA.
¹¹ Department of Pediatrics, Neurological Sciences, Anatomy, and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
¹² Cincinnati Hospital and Medical Center, Cincinnati, OH, USA.
¹³ Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ Children's National Medical Center, Washington, DC, USA.
¹⁵ Nationwide Children's Hospital, Columbus, OH, USA.
¹⁶ Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Washington University Medical Center, Saint Louis Children's Hospital, St. Louis, MO, USA.
¹⁸ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁹ Boston Children's Hospital, Boston, MA, USA.
²⁰ Emory University Medical Center, Atlanta, GA, USA.
²¹ Children's Hospital of Colorado, Denver, CO, USA.
²² Center for Autism and the Developing Brain, New York-Presbyterian, New York, NY, USA.
²³ Department of Psychiatry, Columbia University, New York, NY, USA.
²⁴ New York State Psychiatric Institute, New York, NY, USA.

Abstract

Background: Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3-6 years.

Objectives: The current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome.

Design: A double-blind placebo-controlled parallel-group flexible-dose forced titration design.

Methods: Blood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels' detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected.

Results: This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome.

Conclusion: Our findings of the lack of association between clinical improvement and biomarkers' levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints.

Registration: ClincalTrials.gov NCT02920892.

Keywords: AFQ056; Fragile X syndrome; MMP-9; biomarkers; mTOR pathway.

Associated data

ClinicalTrials.gov/NCT02920892