Why Did Fragile X Clinical Trials of mGluR Antagonists Fail?
by Michael Tranfaglia, MD. In my opinion, the Fragile X clinical trials of AFQ056 sponsored by Novartis failed because of a dose range that was inadequate for Fragile X, and because of the unexpected development of tolerance.
Fragile X Clinical Trial: Novartis Trial Results Are In, and They’re Not Pretty
This year’s Gordon Conference just finished, and Novartis presented their results for the first time (though advisors and advocates had been given a private peak months ago.) To say that the trial results for AFQ056 were disappointing would be the understatement of the century!
Novartis Discontinues Development of mavoglurant (AFQ056) for Fragile X Syndrome
Mavoglurant trials in Fragile X did not show improvement vs. placebo, leading Novartis to end the program and wind down the open-label extension.
New Clue to Fragile X and Autism Found Inside Brain Cells
FRAXA-funded research revealed that mGluR5 isn’t only on the cell surface. Drugs may need to reach internal receptors to be effective in Fragile X.
Social Behavior as an Outcome Measure for Fragile X Clinical Trials
FRAXA funding helped identify reliable social behavior tests in Fragile X mice and showed an mGluR5 treatment could improve sociability, guiding future trials.
Glycogen Synthase Kinase-3 (GSK3), Lithium and Fragile X
Dr. Jope found that lithium (at usual therapeutic doses) and investigational GSK3 inhibitors can reverse a number of cognitive deficits in FMR1 knockout mice.
Endocannabinoid Mediated Synaptic Plasticity in Fragile X Mice
FRAXA-funded studies found faulty endocannabinoid signaling in Fragile X brain circuits for reward and emotion, and boosting 2-AG restored normal function.
Targeting mGluR-LTD to Treat Fragile X Syndrome
With FRAXA support, Dr. Kimberly Huber uncovered how mGluR signaling contributes to Fragile X, laying the foundation for major clinical advances.
Small Rho GTPases, a Potential Therapeutic Target for Fragile X Syndrome
Dr. MariVi Tejada from the University of Houston tested several potential therapeutic compounds in an attempt to rescue function in the mouse model of Fragile X.
Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome
Disrupted mGluR5–Homer scaffolding in Fragile X is linked to excess CaMKII activity. Restoring this interaction could rebalance signaling and improve symptoms.
Ab-Mediated Translation in Fragile X Syndrome
This work found amyloid precursor protein (APP) overexpression and increased β-amyloid in Fragile X mice, implicating Alzheimer-related pathways in FXS pathology.
What Works, and What Doesn’t
Early on, no one knew which path would work. Now the results are clear, and they’re directing FRAXA toward the next major Fragile X treatment breakthrough.
Reward Function in Fragile X Syndrome
Loss of FMRP disrupts dopamine-driven reward function—Fragile X mice show impaired cocaine sensitization and place preference, revealing new plasticity defects.
A Metabolomic Drug Efficacy Index to Test Treatments in the Fragile X Mouse
This work revealed small-molecule metabolic changes in Fragile X brains and is using them to build a drug-efficacy index for screening therapies.
Compound that Inhibits mGluR5 Corrects Signs of Fragile X in Adult Mice
A Roche and MIT study published in Neuron finds that an mGlu5 inhibitor, CTEP, can reverse many Fragile X symptoms in adult mice.
Role of JNK in FMRP Regulated Translation in Fragile X Syndrome
JNK kinase is abnormally active in Fragile X model mice and directly regulates mGluR-dependent translation of FMRP targets, pointing to JNK as a therapeutic target.
Role of Excessive Protein Synthesis in the Ontogeny of FXS
Excessive neuronal protein synthesis is not just a symptom but appears to cause early synaptic wiring defects in Fragile X — highlighting translation control as a key target.
Clinical Trials Outcome Measures
In Fragile X participants, low-dose lithium showed benefits and helped refine biomarkers and behavioral assessments.
Manipulating Basal and mGluR-Stimulated cAMP Level in FXS Model Mice
Fragile X mice show reduced basal cAMP and exaggerated mGluR-LTD; boosting cAMP or blocking specific adenylyl cyclases rescues synaptic and behavioral defects.
Encouraging Results from First Trial of Minocycline in Fragile X
A clinical trial of minocycline in children with Fragile X found significantly better global improvement vs. placebo, supporting its safety and potential.
The Role of FMRP and Small, Non-Coding RNAs in Translation
Drs. Henri Tiedge and Jun Zhong investigated how BC1 RNA could restore balance in Fragile X brains, pointing toward RNA-targeted treatments.
Results of First Fenobam Trial in Adults with Fragile X Published
Fenobam showed positive results in a Phase IIa Fragile X trial. FRAXA supplied data that helped the drug earn Orphan status and move into clinical testing.
Role of the Cerebellum in the Dysfunction of Fragile X Syndrome
With FRAXA funding, Dr. Ben Oostra’s Dutch-Belgian team linked Fragile X to cerebellar motor learning deficits. Results published in Neuron (2008).
Imaging Synaptic Structure and Function in Fragile X Mice
With $150K from FRAXA, Dr. Carlos Portera-Cailliau studied Fragile X mouse brains to examine dendrite structure and mGluR5 treatment effects.