AFQ056 · program

Mavoglurant for Fragile X syndrome

DiscontinuedDiscontinuedNovartis Pharma AG (NVS)

Indications for AFQ056: Cocaine use disorder · Phase 2 Huntington's disease · Discontinued Obsessive-compulsive disorder · Discontinued Fragile X syndrome · Discontinued

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.

Data current as of

Development timeline

DiscontinuedApr 2014
  1. Novartis announced it would discontinue mavoglurant development in fragile X after both Phase 2b studies (CAFQ056A2212 adults; CAFQ056B2214 adolescents) failed to meet primary endpoints — no significant improvement in abnormal behaviors versus placebo in adults or adolescents, in any methylation stratum. The open-label extensions were subsequently terminated (September 2014); NCT01348087's registry reason: 'Study treatment AFQ056 failed to demonstrate efficacy in the adult patient'; NCT01433354's: 'The study treatment failed to demonstrate efficacy in target population'. The later academic FXLEARN study (completed 2022; JCI 2023) was independent of Novartis's decision and also negative.↗
Phase 2Jun 2008 – Nov 2010
  1. Confirmatory Phase 2b program began: double-blind dose-ranging study in adults (NCT01253629, 25/50/100 mg bid vs placebo, n=175, stratified by FMR1 methylation), followed by the adolescent study NCT01357239 (May 2011, n=139) and open-label extensions NCT01348087 (adults) and NCT01433354 (adolescents; registered Phase 2/3). CT.gov gives month precision.
  2. Exploratory Phase 2 crossover study NCT00718341 started (n=30 adult males with FXS). Post-hoc analysis suggested behavioral improvement confined to the subgroup with fully methylated FMR1 promoters — the stratification hypothesis the Phase 2b program was built to confirm. CT.gov gives month precision (June 2008); day is an anchor.

Clinical trials in Fragile X syndrome

NCT02920892FXLEARNPhase 2Completedn=110

AFQ056 for Language Learning in Children With FXS (FXLEARN; investigator-initiated, NIH-funded, Novartis-supplied drug)

Started Aug 2017· Primary completion May 2022· 📍 14 sites across 1 country (United States)

missedprimaryLanguage outcomes after AFQ056 vs placebo combined with parent-implemented language intervention in children aged 3-6

No significant benefit of AFQ056 over placebo on language learning (Berry-Kravis E, et al. J Clin Invest. 2023) — the last clinical test of mGlu5 NAM therapy in fragile X; the negative result closed out the indication rather than reviving it.

NCT01482143CAFQ056A2223Phase 1Completedn=21

Clinical Study to Assess the Pharmacokinetics, Safety and Tolerability of Single and Multiple Doses of AFQ056 in Pediatric Patients With Fragile X Syndrome

Started Mar 2012· Primary completion Oct 2013· 📍 4 sites across 2 countries (United States, Spain)

NCT01433354CAFQ056B2214E1Phase 2/3Discontinuedn=119

Long-term, Safety and Tolerability Study of AFQ056 in Adolescent Patients With Fragile X Syndrome (open-label extension, registered Phase 2/3; terminated for lack of efficacy)

Started Nov 2011· Primary completion Sept 2014· 📍 28 sites across 13 countries (United States, Germany, Spain, Switzerland)

NCT01348087CAFQ056A2212E1Phase 2Discontinuedn=148

Long-term, Safety, Tolerability and Efficacy Study of AFQ056 in Adult Patients With Fragile X Syndrome (open-label extension; terminated for lack of efficacy)

Started Aug 2011· Primary completion Sept 2014· 📍 28 sites across 10 countries (United States, Germany, Australia, France)

NCT01357239CAFQ056B2214Phase 2Completedn=139

A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of AFQ056 in Adolescent Patients With Fragile X Syndrome

Started May 2011· Primary completion Jan 2014· 📍 38 sites across 16 countries (United States, Germany, Spain, Italy)

missedprimaryBehavioral improvement at 12 weeks vs placebo (ABC-C, FXS-adapted)

Did not meet the primary endpoint in adolescents with FXS; together with the adult study's miss this triggered the 2014-04-24 discontinuation.

NCT01253629CAFQ056A2212Phase 2Completedn=175

A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate AFQ056 in Adult Patients With Fragile X Syndrome

Started Nov 2010· Primary completion Aug 2013· 📍 31 sites across 10 countries (United States, Germany, Australia, France)

missedprimaryChange in aberrant behaviors (ABC-C, FXS-adapted) at 12 weeks vs placebo

Did not meet the primary endpoint: no significant improvement in abnormal behaviors versus placebo in adults with FXS, including the fully methylated stratum the program was designed around.

NCT00718341CAFQ056A2204Phase 2Completedn=30

Efficacy, Safety and Tolerability of AFQ056 in Fragile X Patients (exploratory double-blind crossover, adult males)

Started Jun 2008· Primary completion Feb 2009· 📍 3 sites across 3 countries (Switzerland, Italy, France)

Formulations

FormulationRouteRegimenPharmacokinetics
Mavoglurant immediate-release oral capsule (twice daily)
The HD proof-of-concept (NCT01019473, 2009-2011) used multiple oral dose titration of AFQ056 twice daily over 32 days of treatment (titrated up to 100 mg bid per the published report's design description). Same immediate-release oral capsule line as the contemporaneous fragile X program.
OralTwice daily—

Mechanism of action (compound-wide)

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.

TargetActionAffinity
mGlu5primaryGRM5NAM—ⓘ

← Full AFQ056 compound page (identity, identifiers, all indications)

Sources

  1. Berry-Kravis E, et al. Effects of AFQ056 on language learning in fragile X syndrome. J Clin Invest. 2023 — FXLEARN primary result (no significant benefit) — Journal of Clinical Investigation / PubMed
  2. Mavoglurant (AFQ-056), GtoPdb ligand 7586 — mGlu5 negative allosteric modulator — IUPHAR/BPS Guide to PHARMACOLOGY
  3. NCT00718341 (CAFQ056A2204) — Efficacy, Safety and Tolerability of AFQ056 in Fragile X Patients (exploratory Phase 2, n=30) — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT01019473 (CAFQ056A2207) — Phase 2 proof-of-concept of AFQ056 to reduce chorea in Huntington's disease (n=44; TERMINATED, no registry reason given) — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT01253629 (CAFQ056A2212) — AFQ056 in Adult Patients With Fragile X Syndrome (Phase 2b, n=175, 25/50/100 mg bid arms) — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT01348087 — Long-term extension in adults; TERMINATED: 'Study treatment AFQ056 failed to demonstrate efficacy in the adult patient' — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT01357239 (CAFQ056B2214) — AFQ056 in Adolescent Patients With Fragile X Syndrome (Phase 2b, n=139) — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT01433354 — Long-term extension in adolescents (registered Phase 2/3); TERMINATED: 'The study treatment failed to demonstrate efficacy in target population' — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT01482143 (CAFQ056A2223) — Pediatric PK/safety study of AFQ056 in fragile X (Phase 1, n=21) — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT02920892 (FXLEARN) — AFQ056 for Language Learning in Children With FXS (sponsor Elizabeth Berry-Kravis; Phase 2, n=110, completed 2022) — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. Novartis Discontinues Development of mavoglurant (AFQ056) for Fragile X Syndrome (2014 community update coverage; both Phase 2b studies CAFQ056A2212 and CAFQ056B2214 missed primary endpoints) — FRAXA Research Foundation