Drug Tolerance is Likely Culprit Behind the Failure of MGluR5 Clinical Trials

Drug Tolerance is Likely Culprit Behind the Failure of MGluR5 Clinical Trials

We have long suspected that the clinical trials of mGluR5 blockers from Novartis and Roche failed because the drug triggered tolerance, losing effect over time. With a $90,000 grant from FRAXA, Dr. Patrick McCamphill, a Postdoctoral Fellow in the MIT lab of Dr. Mark Bear, is investigating. He does indeed find tolerance, and now he is looking for ways to overcome it.

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Pharmacological Tolerance in the Treatment of Fragile X Syndrome

Pharmacological Tolerance in the Treatment of Fragile X Syndrome

With a $90,000 grant from FRAXA Research Foundation over 2018-2019, Dr. Patrick McCamphill, postdoctoral fellow in Dr. Mark Bear’s lab at Massachusetts Institute of Technology (MIT), is investigating drug tolerance to mGluR5 antagonists, arbaclofen, and other potential Fragile X treatments. He is also exploring ways to overcome it.

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Mechanisms of Tolerance to Chronic mGluR5 Inhibition

Mechanisms of Tolerance to Chronic mGluR5 Inhibition

Over the past few years, both Novartis and Roche sponsored large-scale clinical trials of metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) to treat Fragile X syndrome (FXS). With a $90,000 grant from FRAXA Research Foundation in 2015-2017, Dr. Mark Bear’s team will explore if mGlu5 NAMs dosed chronically causes tolerance, and if so, how it develops and to probe new avenues to prevent or circumvent it.

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Did Tolerance Result in Fragile X mGluR5 Clinical Trial Failures?

Did Tolerance Result in Fragile X mGluR5 Clinical Trial Failures?

Although the clinical trials failed to show efficacy in the patient population and Novartis and Roche discontinued their Fragile X development programs, Dr. Senter has worked with Mark Bear, PhD to carefully review parent observations. Those caregiver reports suggested tolerance to mGlu5 antagonists antagonists developed quickly, consistent with some preclinical findings in the mouse model.

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Employer Matching Gift List

Matching Gift Companies YOU CAN MAKE YOUR GIFT WORTH EVEN MORE! Many companies sponsor matching gift programs and will match your gift to FRAXA. To find out if your company has a matching gift policy, check the list below or contact your company’s HR office. If your company is eligible, request a matching gift form and send it completed and signed with your contribution. Some companies will match gifts made by retirees and/or spouses. For companies that require FRAXA’s full legal name, it is FRAXA Research Foundation, Inc. THE IMPACT OF YOUR GIFT MAY BE DOUBLED OR EVEN TRIPLED! A Abbott Laboratories Acadian Asset Management Inc. Adage Capital Management Adobe Systems Inc. ADP AEP Aetna Inc. Aetna Life and Casualty Foundation The Air Products Foundation Allegro Microsystems Inc. Allstate Foundation Altria Group Inc. Anheuser Busch AMD American Electric Power American Express American Fidelity Corp. American International Group Inc. Ameritech Amgen

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Fragile X Clinical Trial: Novartis Trial Results Are In, and They’re Not Pretty

AFQ056 Fragile X Clinical Trial showed Negative Results 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! While the company has already announced that the adult and adolescent trials failed to meet their pre-designated endpoints, the numbers looked really bad. This wasn't a case of the drug working, but placebo effects leading to an outcome that wasn't statistically significant; in this case, the effect of the drug was statistically significant, but in the wrong direction! So, what went wrong? The evidence for using mGluR5 antagonists in Fragile X was really strong going into these trials---in fact, about as good as it ever gets. The drug itself was an advanced compound that had been studied extensively.Read more

Novartis Discontinues Development of mavoglurant (AFQ056) for Fragile X Syndrome

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 drugRead more

Social Behavior as an Outcome Measure for Fragile X Clinical Trials

Social Behavior as an Outcome Measure for Fragile X Clinical Trials

One of the features of the Fragile X mouse model which is relevant to the human Fragile X syndrome (and autism) is social behavior. Several tests show consistent social behavioral abnormalities in the Fragile X mouse model. With a $140,000 grant from FRAXA Research Foundation in 2012-2013, Dr. Willemsen at Erasmus University used social behavior tests to measure the effectiveness of several drug strategies.

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Clinical Trials FAQ ← Frequently Asked Questions

Question: How Do Families Decide Which Trial is Best for Them? Answer: Each of the trials has different requirements for joining, so many – if not most – people will only be eligible for one trial after screening. The best way to approach this is to call the clinic contact closest to your area and discuss this with him/her. Age, weight, current medications, behavior, and IQ are all factors. When will the Trials be Finished? It all depends on enrollment. Trials need to have a certain number of people (a number determined before the trial starts) complete the trial before they can analyze the data and present results to the FDA. It all depends on how many people sign up to participate. Is There Assistance for Travel? Many trials provide financial assistance for travel expenses. The amount depends on how far you have to travel. Please check with the coordinatorRead more

Understanding the Mechanism of mGluR5 in Fragile X Mouse Models

Understanding the Mechanism of mGluR5 in Fragile X Mouse Models

With $184,000 in funding from FRAXA Research Foundation from 1996-2005, Dr. Ben Oostra and his team at Erasmus University have done multiple studies related to Fragile X syndrome. This lab created the first Fragile X mouse models and went on to perform many critical studies in Fragile X mouse models. Results published.

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The miRNA Pathway in Fragile X Syndrome

With a $120,000 grant from FRAXA Research Foundation over 2008-2009, Drs. Oostra and deVrij at Erasmus University studied miRNA and Fragile X. miRNAs are RNAs that can repress the translation of target mRNAs – therefore they can play a role in protein synthesis within the neuron. Preliminary results showed large differences in miRNA expression in the Fragile X mouse brain compared to the wild type. This lab investigated the effect of mGluR5 antagonists on the levels of these specific miRNAs.

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