Mavoglurant

Mechanism of action#

Selective, non-competitive antagonist (negative allosteric modulator) of the metabotropic glutamate receptor 5 (mGlu5, GRM5), a Gq-coupled class-C GPCR densely expressed on striatal medium spiny neurons. In Huntington's disease the rationale was two-fold: symptomatically, damping striatal mGlu5/glutamatergic signaling was hypothesized to reduce chorea; mechanistically, mGlu5 interacts with mutant-huntingtin-related excitotoxic NMDA signaling. The Phase 2 proof-of-concept tested the anti-choreatic (symptomatic) hypothesis and found no significant reduction in chorea versus placebo.

Formulations#

Mavoglurant for Cocaine use disorder#

Phase 2ActiveCocaine use disorder indication →

Mavoglurant (AFQ056/STP7), an oral mGlu5 negative allosteric modulator, for cocaine use disorder — an indication with no FDA-approved pharmacotherapy. Novartis ran the placebo-controlled Phase 2 (NCT03242928, n=68, sites in Switzerland/Spain/Argentina, completed December 2019): 98 days of mavoglurant bid versus placebo in adults with CUD, with reduced cocaine use versus placebo (also reduced concomitant alcohol use), published in Science Translational Medicine in April 2025. On the strength of these data Novartis licensed worldwide rights to Stalicla SA (January 2023; upfront + equity, up to $270M milestones plus royalties). Stalicla, under a Cooperative Research and Development Agreement with NIDA, completed the last Phase 3-enabling regulatory requirement — a Phase 1 double-blind cocaine/STP7 interaction safety study (NCT06273540, n=21, completed 2024-10-07). Stalicla guided US Phase 3 initiation in 2025 (funded by the US government per its DDI announcement), but as of 2026-08-14 no Phase 3 trial is registered on ClinicalTrials.gov and no Phase 3 start has been announced — the program is recorded at phase_2/active with that slippage explicitly noted, not assumed resolved.

Mavoglurant for Fragile X syndrome#

DiscontinuedDiscontinuedFragile X syndrome indication →

Novartis's fragile X syndrome program for mavoglurant (AFQ056) — the flagship clinical test of the mGluR5 theory of fragile X and, at the time, the largest fragile X drug program ever run. After an exploratory crossover Phase 2 (NCT00718341, 2008-2009) suggested benefit in patients with full FMR1-promoter methylation, Novartis ran two double-blind Phase 2b dose-ranging studies — adults (NCT01253629, n=175) and adolescents (NCT01357239, n=139) — plus long-term open-label extensions (NCT01348087, NCT01433354; the adolescent extension registered Phase 2/3). Both controlled studies missed their primary endpoints (no significant improvement in abnormal behaviors versus placebo in any stratum), and on 2014-04-24 Novartis announced it would stop development of mavoglurant in fragile X; both extensions were terminated for failure to demonstrate efficacy (September 2014). A final academic test — FXLEARN (NCT02920892, Berry-Kravis/Rush, NIH-funded, n=110 children age 3-6, AFQ056 vs placebo combined with parent-implemented language intervention, 2017-2022) — also found no significant effect on language outcomes (JCI 2023), closing out the indication. Stalicla's 2023 worldwide license covers neurodevelopmental disorders, but no fragile X trial or program has been announced since; the program is recorded as discontinued.

Mavoglurant for Obsessive-compulsive disorder#

DiscontinuedDiscontinuedObsessive-compulsive disorder indication →

Novartis's Phase 2 proof-of-concept of mavoglurant (AFQ056) as augmentation therapy in obsessive-compulsive disorder resistant to SSRI treatment (NCT01813019, CAFQ056A2225): randomized, double-blind, placebo-controlled, parallel-group, in patients who had failed an adequate SSRI course (12+ weeks at appropriate doses). Started November 2013, the study was prematurely terminated at the time of the first interim analysis (November 2014, n=50 of a planned ~60 randomized) because it did not meet its primary efficacy objective. The published report (Rutrick et al., Advances in Therapy 2017) confirmed that mavoglurant augmentation did not demonstrate efficacy over placebo in SSRI-resistant OCD. No further development in OCD by Novartis or by Stalicla (whose 2023 worldwide license is directed at substance-use and neurodevelopmental disorders); the program is discontinued.

Mavoglurant for Huntington's disease#

DiscontinuedDiscontinuedHuntington's disease indication →

Novartis's Phase 2 proof-of-concept of mavoglurant (AFQ056) for chorea in Huntington's disease (NCT01019473, CAFQ056A2207): a multi-centre, randomized, double-blind, placebo-controlled, parallel-group, multiple-oral-dose-titration study (n=44 actual, started November 2009, primary completion August 2011; registered TERMINATED without a stated reason). The peer-reviewed report (Reilmann et al., Movement Disorders 2015) found AFQ056 safe and tolerable in HD but with no significant reduction in chorea versus placebo — the symptomatic anti-choreatic hypothesis failed. No subsequent HD trial, publication of continued development, or sponsor statement exists; Novartis later discontinued mavoglurant development across all indications before out-licensing to Stalicla in 2023, whose license targets substance-use and neurodevelopmental disorders. The program is recorded as discontinued, with the date anchored to the trial's primary-completion month because Novartis never announced an HD-specific discontinuation.

Clinical trials#