AFQ056 Archives • Fragile X Research - FRAXA Research Foundation

FX-Learn Clinical Trial is Enrolling Children with Fragile X

FRAXA Research Foundation Berry-Kravis, Elizabeth • Clinical • Recruiting • Rush University Medical Center May 9, 2019May 10, 2019AFQ056, mGluR5, Novartis

The NeuroNext learning trial for children with Fragile X syndrome ages 3-6 is open for enrollment. This clinical trial of Novartis AFQ056 (an mGluR5 antagonist) is recruiting at 13 clinical sites across the U.S.

Pharmacological Tolerance in the Treatment of Fragile X Syndrome

FRAXA Research Foundation 2018 Grants • Bear, Mark • Current Research Grants • Massachusetts Institute of Technology (MIT) • McCamphill, Patrick • Treatment Targets May 9, 2018May 9, 2018AFQ056, arbaclofen, drug tolerance, GABA, GSK3, lithium, mGluR5, Novartis, Roche

With a $90,000 grant from FRAXA Research Foundation, Dr. Patrick McCamphill and Dr. Mark Bear at Massachusetts Institute of Technology (MIT) will further investigate drug tolerance and ways to overcome it.

Mechanisms of Tolerance to Chronic mGluR5 Inhibition

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Bear, Mark • Disease Mechanisms • Massachusetts Institute of Technology (MIT) • Osterweil, Emily • Research Grant with Results • Senter, Rebecca • Treatment Targets September 19, 2017August 29, 2018AFQ056, drug tolerance, glutamate, lovastatin, mGluR5, Novartis, Roche

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.

Did Tolerance Result in Fragile X mGluR5 Clinical Trial Failures?

Theodore Coutilish Bear, Mark • Massachusetts Institute of Technology (MIT) • Research Updates • Senter, Rebecca March 15, 2017June 14, 2018AFQ056, drug tolerance, glutamate, mGluR, mGluR5, Novartis, Roche

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.

New Fragile X Clinical Trial for Children Launching in June 2017

Theodore Coutilish Berry-Kravis, Elizabeth • Clinical Trials • Research Updates • Rush University Medical Center October 31, 2016February 25, 2019AFQ056, mGluR5, Novartis

Rush University Medical Center Professor Elizabeth M. Berry-Kravis, MD, PhD, has launched and is recruiting participants for a large-scale clinical trial to study effects of AFQ056, an mGluR5 blocker, on learning in young children.

Employer Matching Gift List

FRAXA Research Foundation FRAXA Updates March 11, 2016June 18, 2018AFQ056, Novartis

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

Why Did Fragile X Clinical Trials of mGluR Antagonists Fail?

Michael Tranfaglia, MD Clinical Trials • Research Updates August 15, 2014July 9, 2018AFQ056, arbaclofen, baclofen, drug tolerance, lithium, mGluR, mGluR5, minocycline, Novartis

Drug Tolerance and Dose Range Problems May Have Been the CulpritsAndy Tranfaglia and his dad, Mike Tranfaglia 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. Dosage problems are relatively easy to correct, but tolerance to the degree we observed may be a kind of fatal flaw, at least if we're talking about mGluR5 antagonists. The mGluR Theory of Fragile X is still probably correct; it's just that no one (least of all Novartis) expected tolerance to this drug -- indeed, I'm not sure they would agree that's what happened. I think we saw a much better response than most people because our son, Andy, was also on minocycline, effectively augmenting the response, and perhaps delaying the development of tolerance. This may be a clue to understanding the mechanism of tolerance,Read more

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

Michael Tranfaglia, MD Clinical Trials • Research Updates June 26, 2014August 6, 2018AFQ056, Fragile X Meeting, mGluR5, minocycline, Novartis, Roche

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

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 drugRead more

Social Behavior as an Outcome Measure for Fragile X Clinical Trials

FRAXA Research Foundation 2012 Grants • 2013 Grants • Clinical • Completed Research Grant • Drug Repurposing • Erasmus University Rotterdam • FRAXA Research Grants • Treatment Targets • Willemsen, Rob September 13, 2013April 25, 2018AFQ056, AMPA, AMPAkines, autism, baclofen, ERK, mGluR5, minocycline, NMDA, Novartis

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.

Clinical Trials FAQ ← Frequently Asked Questions

FRAXA Research Foundation Clinical Trials • Research Updates January 11, 2013July 11, 2018AFQ056, arbaclofen, autism, basimglurant, FDA, minocycline, Novartis, Roche

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

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • Completed Research Grant • Disease Mechanisms • Erasmus University Rotterdam • Oostra, Ben • Treatment Targets February 26, 2009January 21, 2019AFQ056, fenobam, fruit fly, LTD (Long-term depression), mGluR, mGluR5, miRNA, mRNAs, Novartis, prepulse inhibition, TAT (Trans-Activator of Transcription)

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.

The miRNA Pathway in Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Completed Research Grant • de Vrij, Femke • Erasmus University Rotterdam • Oostra, Ben • Research Grant with Results • Treatment Targets February 5, 2009March 21, 2019AFQ056, fenobam, fruit fly, LTD (Long-term depression), mGluR, mGluR5, miRNA, mRNAs, Novartis, prepulse inhibition, prepulse inhibition, TAT (Trans-Activator of Transcription)

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.