Novartis Discontinues Development of mavoglurant (AFQ056) for Fragile X Syndrome
FRAXA Research Foundation Research Updates April 24, 2014July 11, 2018AFQ056, mGluR5, Novartis
Novartis Clinical Trials in Fragile X Ended
Novartis has announced that the company will be discontinuing its development program in Fragile X for its lead mGluR5 antagonist, mavoglurant (AFQ056), following negative results in a large international clinical trial in adults (reported in the Fall of 2013) and most recently, in a trial in adolescents. In both placebo-controlled trials, patients taking mavoglurant did not show improvement over placebo in any outcome measures.
Novartis has also announced that the current open-label extension phase of the trial will be closed, but patients will be allowed to continue on the medication until their next scheduled clinic visit, or August 29, whichever comes first. No more of the drug will be dispensed to trial participants, but mavoglurant which has already been dispensed will not be recalled.
We hope that we, and the greater Fragile X community, can learn from these trials both about why this drug was not effective overall in patients as well as about any issues with study design and outcome measures. Such information will be useful with future trials with other therapies for Fragile X. The fact that these particular trials did not succeed does not settle the question of whether the drug modifies Fragile X syndrome and does not rule out the validity of the mGluR5 theory.We at FRAXA are disappointed by the negative results, but wish to thank Novartis for conducting superb clinical trials (at great expense to the company). It is especially disappointing that a therapeutic strategy which showed such promise in preclinical studies did not translate to a broadly effective treatment in Fragile X patients. Nevertheless, many families have experienced wonderful effects during the course of these clinical trials, and the discontinuation of the Novartis program will be difficult for them.
FRAXA is planning a special “Science Update” teleconference on Wednesday April 30th, at 10:30am EDT, to discuss the implications of this latest news, as well as to discuss strategy and new initiatives.
________________________________________

Clinical Trial Success Probabilities – some “back of the envelope” calculations, optimistically assuming an 80% chance of making a correct choice at each step
by Mark Bear, PhD
Picower Professor of Neuroscience, MIT
Letter from Novartis CEO, Dr. Joe Jiminez, to a family, shared with permission
Date: April 24, 2014
Subject: RE: Novartis trial AFQ 056 showing real world results
Dear Dr. ___,
Thank you for your email, and for sharing your family’s very moving story about your experience on the AFQ056 trial.
First, let me share how touched and delighted I was to hear of Garrett’s progress in recent months. It’s great to hear of the progress he’s made at school and in his extra-curricular activities. As the father of three, I can imagine how proud you must feel.
I hear your concerns about the results of the unblinded data, in the face of your own personal experience and that of other parents you have spoken to. We too have heard several stories like this, and therefore I assure you that our decision to stop the ongoing development of the compound in Fragile X, which you may have seen announced today, was an extremely careful and considered one.
We took this decision in the face of the clinical evidence. Neither of the two Phase IIb/III studies in adults and adolescents met their primary endpoints. There were dramatic positive improvements in many patients in the trial, but those on AFQ056 did no better than those in the placebo arm. Many patients on placebo showed dramatic improvements during the course of the trial, which emphasizes the importance of continuous and sustained behavioral interventions in improving the long-term outcome of patients with such conditions.
Given the stories provided by many during the trial (while still blinded), we used additional qualitative scales to assess domains not captured by the primary endpoint, including communication, functional, cognitive and academic skills, such as the ones you mention improved in Garrett. In these areas too, AFQ conferred no benefits versus placebo.
I understand, as do all of my colleagues who have been deeply involved in the discovery and development of this compound, that this news will be disheartening to you and to other individuals, families and caregivers affected by Fragile X. I wish that we had had the success that this treatment for Fragile X had given us all hope for.
Kind regards
Joe
________________________________________
the following information was provided by Novartis
Key Points
• The Phase IIb/III studies with mavoglurant (AFQ056) in adolescents (CAFQ056B2214) and in adults (CAFQ056A2212) with FXS, did not meet the primary endpoint of showing significant improvement in abnormal behaviors in adults and adolescents with FXS compared to placebo.
• Mavoglurant was generally well tolerated and no safety concerns were identified in the studies.
• Novartis regrets to confirm that it will no longer be continuing development of mavoglurant in FXS. This decision was not taken lightly, and was based on the two phase II/III trials not meeting their primary and secondary endpoints.
• The studies were high quality with robust methodology and sufficient number of patients included (over 300 patients were randomized across the two studies).
• Novartis would like to acknowledge the collaborative efforts of the broader Fragile X community in the mavoglurant clinical study program in FXS. Importantly, the scientific community has gained important knowledge from the AFQ clinical trial program in FXS – including learnings about the science, the disease and how to conduct clinical trials of this magnitude in these rare patient populations.
Questions & Answers
1. Why is Novartis stopping the mavoglurant development program?

o The decision to discontinue the development program for mavoglurant in FXS was not taken lightly and was based on the two Phase IIb/III studies not meeting their primary and secondary endpoints.

2. What were the results of the Phase IIb/III studies of mavoglurant (AFQ056) in adolescents and in adults with FXS?
o Two Phase IIb/III studies with mavoglurant (AFQ056) – CAFQ056B2214 in adolescents with FXS and CAFQ056A2212 in adults with FXS – did not meet the primary endpoint of showing significant improvement in abnormal behaviors in adults and adolescents with FXS compared to placebo.
o Mavoglurant was generally well tolerated and no safety concerns were identified in the studies.

3. What is the status of the mavoglurant extension studies in Fragile X Syndrome?

o In view of the decision to no longer continue the development program for mavoglurant in FXS, the long-term extension studies of mavoglurant in Fragile X Syndrome will not be continuing.
o All extension studies will be discontinued before the end of August 2014.
o We understand that this news will be very disheartening for those involved in the management of FXS and for the individuals, families and caregivers affected by FXS.

4. Will mavoglurant be available for compassionate use in FXS?

o Per health authorities’ regulations, Novartis is not in a position to submit a request to health authorities for compassionate use for mavoglurant in FXS. We regret therefore that mavoglurant cannot be considered for compassionate use for the treatment of FXS.
o We understand that this news will be very disheartening for those involved in the management of FXS and for the individuals, families and caregivers affected by FXS.

Mavoglurant in Alcohol Drinking
Study Description
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Top of PageStudy DescriptionStudy DesignArms and InterventionsOutcome MeasuresEligibility CriteriaContacts and LocationsMore InformationBrief Summary:
The purpose of this alcohol-interaction pilot study is to provide information on the effect of mavoglurant on the pharmacokinetics of alcohol and on alcohol responses, including stimulation, sedation, intoxication, body sway and physiological responses. The investigators propose to test the effects of 200 mg mavoglurant versus placebo on alcohol related responses. This is a between subjects double blind randomized design in which the investigators plan to run 14 subjects to obtain 10 completers.

Condition or disease Intervention/treatment Phase
Alcohol Drinking Drug: MavoglurantDrug: Placebo Phase 1

Detailed Description:
The purpose of this alcohol-interaction pilot study is to provide information on the effect of mavoglurant on the pharmacokinetics of alcohol and on alcohol responses, including stimulation, sedation, intoxication, body sway and physiological responses. The investigators propose to test the effects of 200 mg mavoglurant versus placebo on alcohol related responses. This is a between subjects double blind randomized design in which the investigators plan to run 14 subjects to obtain 10 completers.
Subjects will participate in two lab sessions, one prior to taking medication and one following 8-11 days of mavoglurant/placebo. During each session, participants will receive successive doses of alcohol over a 90 min period designed to raise their blood alcohol levels to 80 mg/dl; this dose was chosen because this is close to the legal limit of intoxication and to the peak BAC the investigators have observed in prior research studies. Subjects will be monitored throughout the lab session and will receive a phone call two days following the 2nd lab session and a follow-up appointment one week after the 2nd lab session to assess any remaining side effects from the medication.
Official Title: A Pilot Study on the Safety and Efficacy of Mavoglurant in Alcohol Drinking

UNII: GT0I9SV4F6
Chemical Names: Mavoglurant
AFQ056
543906-09-8
UNII-GT0I9SV4F6
Mavoglurant racemate
More...

Molecular Weight: 313.397 g/mol
Dates: • Modify:
2019-03-30
• Create:
2006-10-25
Mavoglurant has been used in trials studying the treatment of Patient Diagnosed With OCD and and Resistant to SSRI Treatment (Failed SSRI Over 12 Weeks at Appropriate Doses).

CTID Title Phase Status Date
NCT03242928
Study to Investigate Whether AFQ056 Reduces Cocaine Use in Patients Diagnosed With Cocaine Use Disorder (CUD) 2 Recruiting 2018-08-29
NCT02920892
AFQ056 for Language Learning in Children With FXS 2 Recruiting 2018-08-27
NCT03327792
Mavoglurant in Alcohol Drinking 1 Recruiting 2018-02-08
NCT03341715
Metabotropic Glutamate Receptor-5 (mGlur5) Effects on Reward-Related fMRI-BOLD Activation in FHP and FHN 1 Not yet recruiting 2018-01-08
NCT01491932
Open-label, Long-term Safety Extension Study of AFQ056 in Parkinson's Patients With L-dopa Induced Dyskinesias
AFQ056 for Language Learning in Children With FXS
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT02920892
Recruitment Status : Recruiting
First Posted : September 30, 2016
Last Update Posted : August 29, 2018
See Contacts and Locations

Sponsor:
Elizabeth Berry-Kravis
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Elizabeth Berry-Kravis, Rush University Medical Center

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Study Description
Go to
Top of PageStudy DescriptionStudy DesignArms and InterventionsOutcome MeasuresEligibility CriteriaContacts and LocationsMore InformationBrief Summary:
The overall goals are to change the paradigm for development of mechanism targeted pharmacotherapy in neurodevelopmental disorders and provide a definitive test of the mGluR theory in humans by determining whether AFQ056, an mGluR5 negative modulator, can enhance neural plasticity in the form of language learning during an intensive language intervention in very young children with fragile X syndrome. This trial therefore will use an innovative but exploratory new trial design to develop a different way to examine efficacy of an agent with substantial support as a drug targeting CNS plasticity in preclinical models of a developmental disorder. If the design is successful, this trial can serve as a model for future trials of mechanistically-targeted treatments operating on neural plasticity in other neurodevelopmental disorders.

Condition or disease Intervention/treatment Phase
Fragile X Syndrome Drug: AFQ056Other: PlaceboOther: Language Intervention Phase 2

Detailed Description:
The trial will use a double blind placebo-controlled parallel-group flexible-dose forced titration design in which 100 subjects with FXS, age 32 months to 6 years of age will enter a 12-month blinded treatment phase during which they are randomized 1:1 to AFQ056 or placebo followed by an 8-month (open label) extension phase in which all participants will be treated with active drug. The flexible dose design will mimic practice, take into account differential responsiveness and the known inter-child variability in drug levels with AFQ056, and allow use of maximum tolerated dose (MTD) which is likely to be most effective.

Study Design
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Top of PageStudy DescriptionStudy DesignArms and InterventionsOutcome MeasuresEligibility CriteriaContacts and LocationsMore Information

Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of AFQ056 on Language Learning in Young Children With Fragile X Syndrome (FXS)
Actual Study Start Date : August 17, 2017
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 1, 2020
Experimental: AFQ056 group with language intervention
12 month treatment phase during which subjects are randomized to AFQ056. The initial dose of AFQ056 will be 25 mg BID. If the subject has no side effects the dose will be titrated (mandatory titration if no side effects) to the next level, 50 mg BID, 75 mg BID and 100 mg BID in order. A flexible dose design will mimic practice, and allow use of maximum tolerated dose (MTD) which is likely to be most effective. The dose can be adjusted weekly through week 7. After 7 weeks the dose will be fixed, and at the 2 month visit all subjects will initiate the language intervention, remaining on a stable AFQ056/placebo dose for the next 6 months. Drug: AFQ056
Oral suspension (liquid)
Other Name: Mavoglurant

Other: Language Intervention
The language intervention will be administered by a trained language specialist through a combination of in clinic visits and at home synchronous video conferencing sessions. The intervention will subsequently be delivered to the parent by a speech-language clinician through weekly clinician coaching, homework, and feedback sessions.

Placebo Comparator: Placebo group with language intervention
12-month treatment phase during which subjects are randomized to placebo. At the 2 month visit (language intervention baseline visit) all subjects will initiate the language intervention, remaining on placebo dose for the next 6 months. Other: Placebo
Oral suspension (liquid)

Other: Language Intervention
The language intervention will be administered by a trained language specialist through a combination of in clinic visits and at home synchronous video conferencing sessions. The intervention will subsequently be delivered to the parent by a speech-language clinician through weekly clinician coaching, homework, and feedback sessions.

Outcome Measures
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Top of PageStudy DescriptionStudy DesignArms and InterventionsOutcome MeasuresEligibility CriteriaContacts and LocationsMore Information
Primary Outcome Measures :
1. Language - Weighted Child Intentional Communication Score [ Time Frame: up to 21 months ]
Weighted Communication Score is coded from a 15 minute semi-structured examiner/child play session and reflects child initiated communication that involves the child's use of gestures, eye contact, vocalizations, and/or words and word combinations to communicate a message to a listener. The Weighted Communication Score coded from a standardized play session has been used in cohorts with autism spectrum disorder (ASD) and has been able to measure change in language skills with age and change in language skills in response to an intervention. Goal is to demonstrate greater improvement in language learning in young children with FXS treated with AFQ056 in combination with an intensive standardized parent-implemented language intervention, relative to those treated with the language intervention and placebo, after 6 months of intervention, as a marker of drug effect on neural plasticity, the core problem in the disorder

Novartis Announces Results of Mavoglurant (mGluR5) (AFQ056) Clinical Trials and the Conclusion of the Long-Term Extension Study
Earlier this month Novartis released results of the Phase IIb/III studies with mavoglurant (AFQ056) in adolescents with Fragile X syndrome (FXS). The trial results from the study of adults were released late last year. Both studies did not meet the primary endpoint of showing significant improvement in abnormal behaviors compared to placebo. Earlier today the company announced that it will no longer continue development of mavoglurant in FXS, nor will it continue the long-term extension studies of mavoglurant in FXS. The company did however make clear that given the significant unmet medical need, they remain committed to continuing their search for new treatments for rare conditions.
Company representatives acknowledged that this news will be disheartening for those affected by and involved in the management of FXS and have assured us that this decision was not taken lightly. They also acknowledged the collaborative efforts of the broader Fragile X community in the studies and noted the scientific community has gained important knowledge from the AFQ clinical trial program in FXS – including learning about the science, the condition and how to conduct clinical trials of this magnitude in our patient population.
All study participants will be contacted by their individual clinic. Please remember there are many people for each site to contact and this could take some time. Many of you will read about this development here before hearing it from your clinic. We are assured that participants will be given instructions on the process of stopping AFQ056. All participants will then need to work with their own doctor to determine the next, best step in treatment. If caregivers and participants involved in the extension studies wish to seek immediate information they are instructed to contact their investigator and study site.
In the short time since learning of this we have reached out to prominent members of the research community for their initial perspective on this news. One message we’ve been asked to pass-on is that it is important for the community to understand that the fact that these particular trials did not show benefit does not address the question of whether the drug modifies FXS and does not rule out the validity of the mGluR5 theory. Other feedback we’ve received is that these studies did not address whether it is possible to modify FXS in much younger individuals (as only adolescents and adults were studied), and with regard to the older individuals studied, three months of treatment could not be reasonably expected to reverse 12-45 years of altered signaling in the brain.
All of us at the National Fragile X Foundation (NFXF) know that the news that your family member will need to soon stop taking AFQ056 is very upsetting. We have heard your descriptions of the improvements you have observed in your family members during the trial, or the extension, and we know how worried you will likely be about the change.
Over the past few months I have had the opportunity to meet with Novartis and monitor the course of these trials and all of us at the NFXF are committed to helping our community cope and make the transition to the next chapter in the quest for safe and effective treatments for FXS.
Please, stayed tuned, check back for updates at novartis.fragilex.org often, work closely with your doctor and remain hopeful and optimistic that new and better treatments are still forthcoming. It is only through our participation in the process that science moves forward.
Lastly, this is sure to be a hot topic at the NFXF conference in July. Novartis will be presenting their results and the top docs in-the-know will be there to share their perspective. As always, you’ll learn about what’s really happening well in advance of any official publication and get perspective from the experts themselves that you can’t get anywhere else. We hope you can join us.

Journal of Pharmacokinetics and Pharmacodynamics
December 2015, Volume 42, Issue 6, pp 639–657 | Cite as
Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics
• Authors
• Authors and affiliations
• Thierry Wendling
• Swati Dumitras
• Kayode Ogungbenro
• Leon Aarons
• Thierry Wendling
o 1
o 2
• Swati Dumitras
o 2
• Kayode Ogungbenro
o 1
• Leon Aarons
o 1
Email author
1. 1.Manchester Pharmacy SchoolThe University of ManchesterManchesterUK
2. 2.Drug Metabolism and PharmacokineticsNovartis Institutes for Biomedical ResearchBaselSwitzerland
Original Paper
First Online: 01 August 2015
• 476Downloads
• 7Citations
Abstract
Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug–drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanistic absorption model for exploratory Monte Carlo simulations. The ability of the model to predict MVG pharmacokinetics when orally co-administered with ketoconazole in adults or administered alone in 3–11 year-old children was evaluated using data from three other clinical studies. The population model provided a good description of both the median trend and variability in MVG plasma pharmacokinetics following IV administration in adults. The Bayesian approach offered a continuous flow of information from pre-clinical to clinical studies. Prediction of the DDI with ketoconazole was consistent with the results of a non-compartmental analysis of the clinical data (threefold increase in systemic exposure). Scaling of the WBPBPK model allowed reasonable extrapolation of MVG pharmacokinetics from adults to children. The model can be used to predict plasma and brain (target site) concentration–time profiles following oral administration of various immediate-release formulations of MVG alone or when co-administered with other drugs, in adults as well as in children.
Keywords
Mavoglurant Population pharmacokinetics Physiologically-based pharmacokinetic models Bayesian analysis Drug–drug interactions Paediatrics
Electronic supplementary material
The online version of this article (doi: 10.1007/s10928-015-9430-4) contains supplementary material, which is available to authorized users.
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Notes
Acknowledgments
The authors would like to thank Nikolaos Tsamandouras and Andres Olivares-Morales (Manchester Pharmacy School, The University of Manchester, Manchester, United-Kingdom) for fruitful discussions.
Compliance with ethical standards
Conflict of interest
Thierry Wending is an employee of Novartis Pharma AG and a Ph.D. student at the University of Manchester.
Supplementary material
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References
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Wendling T, Ogungbenro K, Pigeolet E, Dumitras S, Woessner R, Aarons L (2015) Model-based evaluation of the impact of formulation and food intake on the complex oral absorption of mavoglurant in healthy subjects. Pharm Res 32(5):1764–1778. doi: 10.1007/s11095-014-1574-1 CrossRefPubMedGoogle Scholar
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Fragile X-Associated Disorders
Reymundo Lozano, ... Randi J. Hagerman, in Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015
Therapies Under Investigation
A number of new, targeted treatments are currently under investigation for FXS. AFQ056, an mGluR5 antagonist made by Novartis, completed a controlled trial in adolescents and adults in Europe demonstrating efficacy in those who had a full mutation that was completely methylated but not in those with incomplete methylation.88 These results have stimulated multicenter trials in adolescents and adults with FXS utilizing more complete testing of the methylation status, but the results have not yet been published. Roche also has an mGluR5 antagonist, RO4917523, which is currently in multicenter trials for children through adulthood with FXS, and the results are pending.
A number of new treatments are also being studied in clinical trials after promising efficacy studies in the animal models of FXS. These include lovastatin, which lowers extracellular-signal-regulated kinase (ERK) phosphorylation in the mTOR pathway and an insulin-like growth factor-1 (IGF1) analog made by Neuren. Other treatment trials are in the pipeline but have yet to come to clinical trials.
Read full chapter
Annual Reports in Medicinal Chemistry
Sylvain Célanire, ... Jean-Philippe Rocher, in Annual Reports in Medicinal Chemistry, 2012
3.4.2 Other CNS disorders
FXS is an X-linked condition associated with intellectual disability and behavioral problems. AFQ056 has recently demonstrated a beneficial effect on the behavioral symptoms of fully methylated FXS patients versus partially methylated patients in a crossover study of 30 male FXS patients.89 RO4917523 (undisclosed structure; Roche) entered a Phase II clinical trial in early 2012.90 STX107 (undisclosed structure; Seaside Therapeutics) has completed Phase I trials.91
RO4917523 is currently being studied in patients with major depressive disorders, who show inadequate response to ongoing antidepressant therapies. Phase II studies have been completed, but no data have yet been released.92
ADX10059 (38) has shown the first clinical evidence for analgesic effects of mGluR5 NAMs. Data from a proof-of-concept study in episodic migraine patients demonstrated a significant improvement following acute treatment of ADX10059.93
Read full chapter
Pathophysiology, Pharmacology, and Biochemistry of Dyskinesia
L.K. Prashanth, ... Wassilios G. Meissner, in International Review of Neurobiology, 2011
F New Agents and Targets for The Treatment of Dyskinesia
Research of recent years has focused on the development of non-dopaminergic drugs including molecules acting on serotonin, glutamate, and adrenergic receptors.
Agonists of 5-HT1A and 5-HT1B as well as antagonists of 5-HT2A and 5-HT2C receptors are in development for motor fluctuations and dyskinesia. The most advanced compound is the 5-HT1A agonist sarizotan which failed to demonstrate effective for dyskinesia in two late stage trials (Goetz et al., 2007). Reasons may have included prominent placebo effect (Goetz et al., 2007) and dose limitations due to lower potency dopamine D2 receptor antagonism. The current status of late development for sarizotan is uncertain at present.
Of all other targets, mGlu5 receptor negative allosteric modulators (NAM) are most advanced in clinical development for dyskinesia. In this view, AFQ056 has shown antidyskinetic effects in parkinsonian non-human primates and in a phase Ib/II clinical trial in PD patients (Berg et al., 2010; Grégoire et al., 2011). AFQ056 decreased AIMS scores by 50% compared to placebo. UPDRS motor scores were also improved by more than three points versus placebo, but the study was underpowered to reach statistical significance. A large RCT is ongoing and ADX10059, another mGlu5 NAM is entering early stage assessments for dyskinesias.
The selective NMDA receptor 2B (NR2B) antagonist taxoprodil has shown antidyskinetic properties while abnormal thinking, depersonalization, and amnesia were frequent side effects (Nutt et al., 2008). Selective AMPA receptor antagonists such as perampanel have also been evaluated in PD patients. However, the drug failed to demonstrate a significant effect on wearing-off, dyskinesia, and cognition (Eggert et al., 2010).
Safinamide, a sodium channel inhibitor with MAO-B inhibitory activity initially developed as an antiepileptic, has been shown to inhibit glutamate release (Schapira, 2010). Safinamide is currently in late stage RCTs for motor control, and is also being explored for potential efficacy against dyskinesia and cognitive impairment in PD.
The effect of fipamezole, an α-2-adrenergic antagonist, on dyskinesia has been assessed in a phase II trial (Lewitt et al., 2010). The overall results displayed no differences between drug and placebo probably because of an important heterogeneity between the enrolling centers. When only looking at US subjects, fipamezole showed a significant decrease in dyskinesia ratings without worsening parkinsonism (Lewitt et al., 2010). Another α-2-adrenergic antagonist, idazoxan, has been tested in two small clinical studies. Results were conflicting (Manson et al., 2000a; Rascol et al., 2001) and the development of this drug for dyskinesia was finally stopped.
Novel approaches to dyskinesia therapy will be more detailed in a specific chapter of this issue.
Read full chapter
Fragile X Syndrome and Autism Spectrum Disorders
W. Ted Brown, Ira L. Cohen, in The Neuroscience of Autism Spectrum Disorders, 2013
New Drug Trials in FXS
This is an exciting time for research in FXS. We are seeing the beginnings of targeted treatment trials of drugs for the syndrome. MPEP is not suitable for humans due to its short half-life and potential toxic effects, but derivative mGluR5 antagonists have been developed by at least three pharmaceutical companies. Jacquemont et al. (2011) reported an early phase II double-blind placebo-controlled trial with the Novartis compound AFQ056 in 30 subjects with FXS. Of the subjects that completed the protocol, 7, with full FMR1 promoter methylation as assayed by a bisulfate method and with no detectable FMR1 mRNA, showed improved behavior, as measured with the ABC-C, after AFQ056 treatment as compared with placebo (P < 0.001). The authors detected no response in 18 patients with partial promoter methylation. The reasons why only those with full methylation would show improvements are unclear at this time. A large follow-up trail is now underway (see http://www.ClinicalTrials.gov). Trials are also underway with the Hoffmann-La Roche mGluR5 inhibitor, RO4917523, and the Seaside Therapeutics compound STX107. Results of these exciting studies should be known within a one-year time frame.
GABA is the major inhibitory neurotransmitter in the brain and abnormally low levels of GABA-mediated transmission have been found in Fmr1 knockout mice (D'Hulst et al., 2006; El Idrissi et al., 2005). Administration of the GABAergic drug (R)-baclofen (arbaclofen) decreases mGluR signaling and was found to reduce seizure susceptibility in Fmr1 knockout mice (Pacey et al., 2009). A double-blind placebo-controlled crossover trial was performed at 12 sites in the United States using the Seaside Therapeutics drug STX209 (arbaclofen) (Brown et al., 2010). A total of 49 subjects with a full mutation of FMR1, and who met the severity criteria on the Aberrant Behavior Checklist – Irritability (ABC-I) subscale, completed the study. Significantly more subjects showed improved behavior and socialization while on the studied drug, indicating a significant potential for the treatment of behavioral symptoms in FXS. Larger, phase III, double-blind trials are now under way with this GABAergic drug to determine the potential benefits in children and adults with FXS. A large trial is also under way to test this drug in children and adolescents with ASD (http://www.ClinicalTrials.gov).
Several other drugs are also in various stages of development and in preliminary trials having shown potential beneficial effects in Fmr1 knockout animals. These include minocycline, lithium, memantine, ampakines, inhibitors of PI3K/ERK signaling, and inhibitors of p21 kinase (Gross et al., 2011). It is anticipated that many of these targeted treatments, if found beneficial for FXS, may also be useful for at least a subset of individuals with ASD.
Read full chapter
Fragile X Syndrome and X-linked Intellectual Disability
Kathryn B. Garber, ... Jeannie Visootsak, in Emery and Rimoin's Principles and Practice of Medical Genetics, 2013
107.2.11.4 Future Pharmacotherapies for FXS
Although current therapies for FXS are aimed at symptom management, the future of psychopharmacology treatment in FXS is promising, as it is specifically directed at preventing and/or improving some of the cognitive and behavioral features in FXS. The enhanced mGluR5-dependent hippocampal and cerebellar LTD, exaggerated synaptic weakening, and increased internalization of AMPA receptors associated with loss of FMRP, as described above, are believed to underlie the cognitive deficits in FXS (89). Thus, therapeutic strategies that incorporate mGluR5 antagonists might reduce excess mGluR5-mediated dendritic translation and its downstream effects and thus be useful in treating some of the symptoms of FXS (111). Selective mGluR5 antagonists, including the prototype of the class, 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been studied in animal models of FXS (112). It rescues hyperactivity and audiogenic seizures in knockout mice, and cognitive and neuroanatomical phenotypes in a Drosophila fruit fly model of FXS (113).
Clinical trials in individuals with FXS are currently being conducted with several compounds that target the mGluR5 pathway. Fenobam, a high potency and selective mGluR5 antagonist, is comparable to MPEP (114). Fenobam was previously investigated as an anxiolytic in several phase II studies in the early 1980s with reported central nervous system-related side effects including hallucinations, vertigo, paraethesias, and insomnia, especially in higher doses (115). In a pilot open-label, single-dose trial of Fenobam in 12 adults with FXS, no significant adverse events were identified (116). Decreases in hyperactivity and anxiety were reported, and improvement of the prepulse inhibition was seen in 50% of the subjects. Phase I and II clinical studies in FXS are presently underway for several other mGluR5 antagonists: R04917523 (Roche, Basel, Switzerland), AFQ056 (Novartis, Basel, Switzerland), and STX107 (Seaside Therapeutics, Boston, MA). In a double-blind, crossover study of AFQ056 in 30 males with FXS, aged 18–35 years, adverse events were reported by 80% of the subjects, mostly fatigue and headache. No significant effects were noted between AFQ056 and placebo groups in the Aberrant Behavior Checklist scores. However, the study data suggested that the response in AFQ506 treatment might be predicted by the methylation status of the FMR1 promoter. Seven subjects with full methylation showed significant effects of AFQ506 treatment in the ABC and Repetitive Behavior Scale, whereas, subjects with partial methylation did not show any significant improvements with AFQ056 treatment when compared to placebo (117).
Lithium is an alternative strategy to target the excessive signaling through the mGluR pathway and may potentially correct the overactive dendritic protein synthesis in FXS (118). Lithium reduces mGluR-activated translation and reverses phenotypes in the Drosphilia FXS fly model and FMR1 knockout mouse. In an open-label trial of lithium in 15 males with FXS (6–23 years of age), improvements in behavioral functioning, adaptive skills, and verbal memory were reported (119). Results were not as positive for the Ampakine compound CX516. This class of compounds facilitates the activity of AMPA receptors, thereby targeting a downstream effect of excess mGluR activity. A Phase II double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of CX516 in individuals with FXS found no significant improvement in memory, language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo (120).
Targeting the GABA system may provide an alternative treatment strategy in FXS. GABA is a key inhibitory neurotransmitter system in the brain and works in opposition to the excitatory glutamate pathways. The expression of various subunits of the GABA-A receptor is reduced in knockout FXS mice and in Drosophila dFMR1 knockout flies (121). This appears to render these organisms more sensitive to excess glutamate signaling and may be responsible for the observation that high levels of glutamate in food are lethal to dFMR1-deficient flies (122). This lethality provided the impetus for a screen of 2000 compounds to identify those that rescue this glutamate-induced lethality and lead to the identification of three that implicate the GABA inhibitory pathway as a counter-effect to the lethality. One of these was the GABA-B agonist baclofen. Baclofen has since been found to ameliorate the abnormal phenotypes in several animal models of FXS, including audiogenic seizures and hyperactivity in the FXS mice (123). In both human and animal studies, arbaclofen, which is the active isomer of racemic baclofen, appears better-tolerated and more efficacious than racemic baclofen. Studies are now being conducted to explore the efficacy, safety, and tolerability of arbaclofen, STX209, (Seaside Therapeutics, Boston, MA) in adolescents and adults with FXS.
Minocycline, a tetracycline antibiotic, inhibits the activity of matrix metallo-proteinase-9 (MMP-9), which is elevated in the hippocampus of FMR1 knockout mice and may be partially responsible for the immature dendritic spine profile of hippocampal neurons (124). In an open-label, add-on trial of 20 adults with FXS (13–32 years of age), behavioral improvements were noted (125). Two subjects sero-converted to a positive antinuclear antibody test, which is suggestive of a lupus-like reaction likely induced by the drug. Additionally, minocycline can cause graying of teeth in children younger than 7 years of age if their permanent teeth have not erupted. Of note, with long-term use minocycline can cause graying of other tissues and increased sensitivity to sunlight.
It is hoped that the targeting of therapeutics to ameliorate the underlying pathophysiologic mechanism of FXS will result in improved outcomes for affected individuals. Many FXS clinical trials are currently underway and we await the results with eagerness. These medications could perhaps also be effective in the treatment of more common forms of autism or other neurodevelopmental disorders, which may overlap FXS in terms of the underlying molecular mechanisms.
Read full chapter
Neurodevelopmental Disorders
Harald Sontheimer, in Diseases of the Nervous System, 2015
5.2 Emerging Treatments
Known disease-modifying treatments are currently not available, and therefore treatments are largely supportive and focused on comorbidities. In light of the successes in correcting the FXS symptoms in mouse models by targeting mGLUR5, however, pilot clinical studies have begun to pursue this strategy in patients. Fortunately, one mGLUR5 inhibitor, fenobam, was already approved as a safe anxiolytic and showed promise in an open label, phase II study. More potent novel drugs targeting mGLUR5, including STX107, AFQ056, and RO4917523, are now at various stages of clinical testing.14
An alternative approach to changing the activity of mGLUR5 is limiting the presynaptic release of Glu. This can be accomplished using the GABA agonist baclofen, a strategy that was effective in FMR1 knockout mice; it restores spine morphology, reverses AMPA internalization, and corrects many of the cognitive symptoms. This prompted the use of the active baclofen enantiomer arbaclofen in clinical studies of patients with FXS. Although successful in a phase II, double-blind, placebo-controlled study, a subsequent phase III study showed no improvement above placebo. Another GABA agonist approved to aid the treatment of alcohol withdrawal, acamprosate, showed promise in a small, open-label study in children with FXS, and a larger-scale, placebo-controlled study is now on its way.
Preclinical studies with FMR1 transgenic mice showing promising reversal of symptoms by targeting pathways downstream of mGLUR5, prompted some trials using already approved drugs. For example, minocycline is an antibiotic that inhibits matrix metalloproteinase-9, and in animal models the drug normalized dendritic spine morphology. In a small, placebo-controlled study it improved some but not all symptoms in children 5–17 years of age. Lithium is a known mood stabilizer used in patients with bipolar disorder and depression. It targets GSK3, an enzyme that is upregulated in FXS. A small, 15-patient study found that lithium significantly improves the behavior of patients with FXS.
These examples are elegant illustrations of how basic research can drive translational medicine. The principal findings resulted from basic studies of learning and memory, which identified a cellular defect in a mouse model that subsequently elucidated a complex disease mechanism that is now pharmacologically altered. The monogenetic nature of the disease allowed for the development of a robust, clinically relevant mouse model of disease with excellent predictive value. As we have learned throughout this book, inadequate preclinical models are often a major obstacle for translational science.
Read full chapter
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Mavoglurant
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• 2 Methyl 6 (Phenylethynyl)pyridine
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Fragile X-Associated Disorders
Reymundo Lozano, ... Randi J. Hagerman, in Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015
Therapies Under Investigation
A number of new, targeted treatments are currently under investigation for FXS. AFQ056, an mGluR5 antagonist made by Novartis, completed a controlled trial in adolescents and adults in Europe demonstrating efficacy in those who had a full mutation that was completely methylated but not in those with incomplete methylation.88 These results have stimulated multicenter trials in adolescents and adults with FXS utilizing more complete testing of the methylation status, but the results have not yet been published. Roche also has an mGluR5 antagonist, RO4917523, which is currently in multicenter trials for children through adulthood with FXS, and the results are pending.
A number of new treatments are also being studied in clinical trials after promising efficacy studies in the animal models of FXS. These include lovastatin, which lowers extracellular-signal-regulated kinase (ERK) phosphorylation in the mTOR pathway and an insulin-like growth factor-1 (IGF1) analog made by Neuren. Other treatment trials are in the pipeline but have yet to come to clinical trials.
Read full chapter
Annual Reports in Medicinal Chemistry
Sylvain Célanire, ... Jean-Philippe Rocher, in Annual Reports in Medicinal Chemistry, 2012
3.4.2 Other CNS disorders
FXS is an X-linked condition associated with intellectual disability and behavioral problems. AFQ056 has recently demonstrated a beneficial effect on the behavioral symptoms of fully methylated FXS patients versus partially methylated patients in a crossover study of 30 male FXS patients.89 RO4917523 (undisclosed structure; Roche) entered a Phase II clinical trial in early 2012.90 STX107 (undisclosed structure; Seaside Therapeutics) has completed Phase I trials.91
RO4917523 is currently being studied in patients with major depressive disorders, who show inadequate response to ongoing antidepressant therapies. Phase II studies have been completed, but no data have yet been released.92
ADX10059 (38) has shown the first clinical evidence for analgesic effects of mGluR5 NAMs. Data from a proof-of-concept study in episodic migraine patients demonstrated a significant improvement following acute treatment of ADX10059.93
Read full chapter
Pathophysiology, Pharmacology, and Biochemistry of Dyskinesia
L.K. Prashanth, ... Wassilios G. Meissner, in International Review of Neurobiology, 2011
F New Agents and Targets for The Treatment of Dyskinesia
Research of recent years has focused on the development of non-dopaminergic drugs including molecules acting on serotonin, glutamate, and adrenergic receptors.
Agonists of 5-HT1A and 5-HT1B as well as antagonists of 5-HT2A and 5-HT2C receptors are in development for motor fluctuations and dyskinesia. The most advanced compound is the 5-HT1A agonist sarizotan which failed to demonstrate effective for dyskinesia in two late stage trials (Goetz et al., 2007). Reasons may have included prominent placebo effect (Goetz et al., 2007) and dose limitations due to lower potency dopamine D2 receptor antagonism. The current status of late development for sarizotan is uncertain at present.
Of all other targets, mGlu5 receptor negative allosteric modulators (NAM) are most advanced in clinical development for dyskinesia. In this view, AFQ056 has shown antidyskinetic effects in parkinsonian non-human primates and in a phase Ib/II clinical trial in PD patients (Berg et al., 2010; Grégoire et al., 2011). AFQ056 decreased AIMS scores by 50% compared to placebo. UPDRS motor scores were also improved by more than three points versus placebo, but the study was underpowered to reach statistical significance. A large RCT is ongoing and ADX10059, another mGlu5 NAM is entering early stage assessments for dyskinesias.
The selective NMDA receptor 2B (NR2B) antagonist taxoprodil has shown antidyskinetic properties while abnormal thinking, depersonalization, and amnesia were frequent side effects (Nutt et al., 2008). Selective AMPA receptor antagonists such as perampanel have also been evaluated in PD patients. However, the drug failed to demonstrate a significant effect on wearing-off, dyskinesia, and cognition (Eggert et al., 2010).
Safinamide, a sodium channel inhibitor with MAO-B inhibitory activity initially developed as an antiepileptic, has been shown to inhibit glutamate release (Schapira, 2010). Safinamide is currently in late stage RCTs for motor control, and is also being explored for potential efficacy against dyskinesia and cognitive impairment in PD.
The effect of fipamezole, an α-2-adrenergic antagonist, on dyskinesia has been assessed in a phase II trial (Lewitt et al., 2010). The overall results displayed no differences between drug and placebo probably because of an important heterogeneity between the enrolling centers. When only looking at US subjects, fipamezole showed a significant decrease in dyskinesia ratings without worsening parkinsonism (Lewitt et al., 2010). Another α-2-adrenergic antagonist, idazoxan, has been tested in two small clinical studies. Results were conflicting (Manson et al., 2000a; Rascol et al., 2001) and the development of this drug for dyskinesia was finally stopped.
Novel approaches to dyskinesia therapy will be more detailed in a specific chapter of this issue.
Read full chapter
Fragile X Syndrome and Autism Spectrum Disorders
W. Ted Brown, Ira L. Cohen, in The Neuroscience of Autism Spectrum Disorders, 2013
New Drug Trials in FXS
This is an exciting time for research in FXS. We are seeing the beginnings of targeted treatment trials of drugs for the syndrome. MPEP is not suitable for humans due to its short half-life and potential toxic effects, but derivative mGluR5 antagonists have been developed by at least three pharmaceutical companies. Jacquemont et al. (2011) reported an early phase II double-blind placebo-controlled trial with the Novartis compound AFQ056 in 30 subjects with FXS. Of the subjects that completed the protocol, 7, with full FMR1 promoter methylation as assayed by a bisulfate method and with no detectable FMR1 mRNA, showed improved behavior, as measured with the ABC-C, after AFQ056 treatment as compared with placebo (P < 0.001). The authors detected no response in 18 patients with partial promoter methylation. The reasons why only those with full methylation would show improvements are unclear at this time. A large follow-up trail is now underway (see http://www.ClinicalTrials.gov). Trials are also underway with the Hoffmann-La Roche mGluR5 inhibitor, RO4917523, and the Seaside Therapeutics compound STX107. Results of these exciting studies should be known within a one-year time frame.
GABA is the major inhibitory neurotransmitter in the brain and abnormally low levels of GABA-mediated transmission have been found in Fmr1 knockout mice (D'Hulst et al., 2006; El Idrissi et al., 2005). Administration of the GABAergic drug (R)-baclofen (arbaclofen) decreases mGluR signaling and was found to reduce seizure susceptibility in Fmr1 knockout mice (Pacey et al., 2009). A double-blind placebo-controlled crossover trial was performed at 12 sites in the United States using the Seaside Therapeutics drug STX209 (arbaclofen) (Brown et al., 2010). A total of 49 subjects with a full mutation of FMR1, and who met the severity criteria on the Aberrant Behavior Checklist – Irritability (ABC-I) subscale, completed the study. Significantly more subjects showed improved behavior and socialization while on the studied drug, indicating a significant potential for the treatment of behavioral symptoms in FXS. Larger, phase III, double-blind trials are now under way with this GABAergic drug to determine the potential benefits in children and adults with FXS. A large trial is also under way to test this drug in children and adolescents with ASD (http://www.ClinicalTrials.gov).
Several other drugs are also in various stages of development and in preliminary trials having shown potential beneficial effects in Fmr1 knockout animals. These include minocycline, lithium, memantine, ampakines, inhibitors of PI3K/ERK signaling, and inhibitors of p21 kinase (Gross et al., 2011). It is anticipated that many of these targeted treatments, if found beneficial for FXS, may also be useful for at least a subset of individuals with ASD.
Read full chapter
Fragile X Syndrome and X-linked Intellectual Disability
Kathryn B. Garber, ... Jeannie Visootsak, in Emery and Rimoin's Principles and Practice of Medical Genetics, 2013
107.2.11.4 Future Pharmacotherapies for FXS
Although current therapies for FXS are aimed at symptom management, the future of psychopharmacology treatment in FXS is promising, as it is specifically directed at preventing and/or improving some of the cognitive and behavioral features in FXS. The enhanced mGluR5-dependent hippocampal and cerebellar LTD, exaggerated synaptic weakening, and increased internalization of AMPA receptors associated with loss of FMRP, as described above, are believed to underlie the cognitive deficits in FXS (89). Thus, therapeutic strategies that incorporate mGluR5 antagonists might reduce excess mGluR5-mediated dendritic translation and its downstream effects and thus be useful in treating some of the symptoms of FXS (111). Selective mGluR5 antagonists, including the prototype of the class, 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been studied in animal models of FXS (112). It rescues hyperactivity and audiogenic seizures in knockout mice, and cognitive and neuroanatomical phenotypes in a Drosophila fruit fly model of FXS (113).
Clinical trials in individuals with FXS are currently being conducted with several compounds that target the mGluR5 pathway. Fenobam, a high potency and selective mGluR5 antagonist, is comparable to MPEP (114). Fenobam was previously investigated as an anxiolytic in several phase II studies in the early 1980s with reported central nervous system-related side effects including hallucinations, vertigo, paraethesias, and insomnia, especially in higher doses (115). In a pilot open-label, single-dose trial of Fenobam in 12 adults with FXS, no significant adverse events were identified (116). Decreases in hyperactivity and anxiety were reported, and improvement of the prepulse inhibition was seen in 50% of the subjects. Phase I and II clinical studies in FXS are presently underway for several other mGluR5 antagonists: R04917523 (Roche, Basel, Switzerland), AFQ056 (Novartis, Basel, Switzerland), and STX107 (Seaside Therapeutics, Boston, MA). In a double-blind, crossover study of AFQ056 in 30 males with FXS, aged 18–35 years, adverse events were reported by 80% of the subjects, mostly fatigue and headache. No significant effects were noted between AFQ056 and placebo groups in the Aberrant Behavior Checklist scores. However, the study data suggested that the response in AFQ506 treatment might be predicted by the methylation status of the FMR1 promoter. Seven subjects with full methylation showed significant effects of AFQ506 treatment in the ABC and Repetitive Behavior Scale, whereas, subjects with partial methylation did not show any significant improvements with AFQ056 treatment when compared to placebo (117).
Lithium is an alternative strategy to target the excessive signaling through the mGluR pathway and may potentially correct the overactive dendritic protein synthesis in FXS (118). Lithium reduces mGluR-activated translation and reverses phenotypes in the Drosphilia FXS fly model and FMR1 knockout mouse. In an open-label trial of lithium in 15 males with FXS (6–23 years of age), improvements in behavioral functioning, adaptive skills, and verbal memory were reported (119). Results were not as positive for the Ampakine compound CX516. This class of compounds facilitates the activity of AMPA receptors, thereby targeting a downstream effect of excess mGluR activity. A Phase II double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of CX516 in individuals with FXS found no significant improvement in memory, language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo (120).
Targeting the GABA system may provide an alternative treatment strategy in FXS. GABA is a key inhibitory neurotransmitter system in the brain and works in opposition to the excitatory glutamate pathways. The expression of various subunits of the GABA-A receptor is reduced in knockout FXS mice and in Drosophila dFMR1 knockout flies (121). This appears to render these organisms more sensitive to excess glutamate signaling and may be responsible for the observation that high levels of glutamate in food are lethal to dFMR1-deficient flies (122). This lethality provided the impetus for a screen of 2000 compounds to identify those that rescue this glutamate-induced lethality and lead to the identification of three that implicate the GABA inhibitory pathway as a counter-effect to the lethality. One of these was the GABA-B agonist baclofen. Baclofen has since been found to ameliorate the abnormal phenotypes in several animal models of FXS, including audiogenic seizures and hyperactivity in the FXS mice (123). In both human and animal studies, arbaclofen, which is the active isomer of racemic baclofen, appears better-tolerated and more efficacious than racemic baclofen. Studies are now being conducted to explore the efficacy, safety, and tolerability of arbaclofen, STX209, (Seaside Therapeutics, Boston, MA) in adolescents and adults with FXS.
Minocycline, a tetracycline antibiotic, inhibits the activity of matrix metallo-proteinase-9 (MMP-9), which is elevated in the hippocampus of FMR1 knockout mice and may be partially responsible for the immature dendritic spine profile of hippocampal neurons (124). In an open-label, add-on trial of 20 adults with FXS (13–32 years of age), behavioral improvements were noted (125). Two subjects sero-converted to a positive antinuclear antibody test, which is suggestive of a lupus-like reaction likely induced by the drug. Additionally, minocycline can cause graying of teeth in children younger than 7 years of age if their permanent teeth have not erupted. Of note, with long-term use minocycline can cause graying of other tissues and increased sensitivity to sunlight.
It is hoped that the targeting of therapeutics to ameliorate the underlying pathophysiologic mechanism of FXS will result in improved outcomes for affected individuals. Many FXS clinical trials are currently underway and we await the results with eagerness. These medications could perhaps also be effective in the treatment of more common forms of autism or other neurodevelopmental disorders, which may overlap FXS in terms of the underlying molecular mechanisms.
Read full chapter
Neurodevelopmental Disorders
Harald Sontheimer, in Diseases of the Nervous System, 2015
5.2 Emerging Treatments
Known disease-modifying treatments are currently not available, and therefore treatments are largely supportive and focused on comorbidities. In light of the successes in correcting the FXS symptoms in mouse models by targeting mGLUR5, however, pilot clinical studies have begun to pursue this strategy in patients. Fortunately, one mGLUR5 inhibitor, fenobam, was already approved as a safe anxiolytic and showed promise in an open label, phase II study. More potent novel drugs targeting mGLUR5, including STX107, AFQ056, and RO4917523, are now at various stages of clinical testing.14
An alternative approach to changing the activity of mGLUR5 is limiting the presynaptic release of Glu. This can be accomplished using the GABA agonist baclofen, a strategy that was effective in FMR1 knockout mice; it restores spine morphology, reverses AMPA internalization, and corrects many of the cognitive symptoms. This prompted the use of the active baclofen enantiomer arbaclofen in clinical studies of patients with FXS. Although successful in a phase II, double-blind, placebo-controlled study, a subsequent phase III study showed no improvement above placebo. Another GABA agonist approved to aid the treatment of alcohol withdrawal, acamprosate, showed promise in a small, open-label study in children with FXS, and a larger-scale, placebo-controlled study is now on its way.
Preclinical studies with FMR1 transgenic mice showing promising reversal of symptoms by targeting pathways downstream of mGLUR5, prompted some trials using already approved drugs. For example, minocycline is an antibiotic that inhibits matrix metalloproteinase-9, and in animal models the drug normalized dendritic spine morphology. In a small, placebo-controlled study it improved some but not all symptoms in children 5–17 years of age. Lithium is a known mood stabilizer used in patients with bipolar disorder and depression. It targets GSK3, an enzyme that is upregulated in FXS. A small, 15-patient study found that lithium significantly improves the behavior of patients with FXS.
These examples are elegant illustrations of how basic research can drive translational medicine. The principal findings resulted from basic studies of learning and memory, which identified a cellular defect in a mouse model that subsequently elucidated a complex disease mechanism that is now pharmacologically altered. The monogenetic nature of the disease allowed for the development of a robust, clinically relevant mouse model of disease with excellent predictive value. As we have learned throughout this book, inadequate preclinical models are often a major obstacle for translational science.
Read full chapter
About ScienceDirectRemote accessShopping cartContact and supportTerms and conditionsPrivacy policy
We use cookies to help provide and enhance our service and tailor content and ads. By continuing you agree to the use of cookies.
Copyright © 2019 Elsevier B.V. or its licensors or contributors. ScienceDirect ® is a registered trademark of Elsevier B.V.

Novartis Announces Results of Mavoglurant (mGluR5) (AFQ056) Clinical Trials and the Conclusion of the Long-Term Extension Study
Earlier this month Novartis released results of the Phase IIb/III studies with mavoglurant (AFQ056) in adolescents with Fragile X syndrome (FXS). The trial results from the study of adults were released late last year. Both studies did not meet the primary endpoint of showing significant improvement in abnormal behaviors compared to placebo. Earlier today the company announced that it will no longer continue development of mavoglurant in FXS, nor will it continue the long-term extension studies of mavoglurant in FXS. The company did however make clear that given the significant unmet medical need, they remain committed to continuing their search for new treatments for rare conditions.
Company representatives acknowledged that this news will be disheartening for those affected by and involved in the management of FXS and have assured us that this decision was not taken lightly. They also acknowledged the collaborative efforts of the broader Fragile X community in the studies and noted the scientific community has gained important knowledge from the AFQ clinical trial program in FXS – including learning about the science, the condition and how to conduct clinical trials of this magnitude in our patient population.
All study participants will be contacted by their individual clinic. Please remember there are many people for each site to contact and this could take some time. Many of you will read about this development here before hearing it from your clinic. We are assured that participants will be given instructions on the process of stopping AFQ056. All participants will then need to work with their own doctor to determine the next, best step in treatment. If caregivers and participants involved in the extension studies wish to seek immediate information they are instructed to contact their investigator and study site.
In the short time since learning of this we have reached out to prominent members of the research community for their initial perspective on this news. One message we’ve been asked to pass-on is that it is important for the community to understand that the fact that these particular trials did not show benefit does not address the question of whether the drug modifies FXS and does not rule out the validity of the mGluR5 theory. Other feedback we’ve received is that these studies did not address whether it is possible to modify FXS in much younger individuals (as only adolescents and adults were studied), and with regard to the older individuals studied, three months of treatment could not be reasonably expected to reverse 12-45 years of altered signaling in the brain.
All of us at the National Fragile X Foundation (NFXF) know that the news that your family member will need to soon stop taking AFQ056 is very upsetting. We have heard your descriptions of the improvements you have observed in your family members during the trial, or the extension, and we know how worried you will likely be about the change.
Over the past few months I have had the opportunity to meet with Novartis and monitor the course of these trials and all of us at the NFXF are committed to helping our community cope and make the transition to the next chapter in the quest for safe and effective treatments for FXS.
Please, stayed tuned, check back for updates at novartis.fragilex.org often, work closely with your doctor and remain hopeful and optimistic that new and better treatments are still forthcoming. It is only through our participation in the process that science moves forward.
Lastly, this is sure to be a hot topic at the NFXF conference in July. Novartis will be presenting their results and the top docs in-the-know will be there to share their perspective. As always, you’ll learn about what’s really happening well in advance of any official publication and get perspective from the experts themselves that you can’t get anywhere else. We hope you can join us.

Jeffrey Cohen
Interim Executive Director
National Fragile X Foundation
By NFXF| 2014-04-24T10:51:28+00:00 Apr 24, 2014|News Reports and Commentaries, Novartis AFQ056|Comments Off
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