AFQ056 Archives • Fragile X Research - FRAXA Research Foundation

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.

FX-LEARN – Clinical Trial for Language Learning of AFQ056 in Children

FRAXA Research Foundation Berry-Kravis, Elizabeth • Clinical Trials • Recruiting • Rush University Medical Center February 1, 2018April 30, 2018AFQ056, Novartis

The purpose of this NeuroNEXT study is to find out if the drug AFQ056, made by the pharmaceutical company Novartis, is safe and has beneficial effects on language learning in children who have Fragile X syndrome (FXS). The study also aims to find out if a structured language intervention can help children with Fragile X syndrome communicate better.

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.

Fragile X Clinical Trial on Novartis’s AFQ056 Opens Enrollment

FRAXA Research Foundation Berry-Kravis, Elizabeth • Clinical • Recruiting • Rush University Medical Center August 30, 2017August 6, 2018AFQ056, mGluR5, Novartis

Elizabeth M. Berry-Kravis, MD, PhD has informed us that Rush University Medical Center in Chicago is enrolling the first patient in the NeuroNext learning trial for children ages 3-6 this week. This is the start of a large-scale Fragile X clinical trial of Novartis AFQ056 (an mGluR5 antagonist) with children.

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, 2016July 26, 2018AFQ056, mGluR5, Novartis

Rush University Medical Center Professor Elizabeth M. Berry-Kravis, MD, PhD, Begins a Large-Scale Clinical Trial to Study Effects of AFQ056, an mGluR5 Blocker, on Learning in Young Children BERRY tenacious! You can say a lot about Elizabeth M. Berry-Kravis, MD, PhD: • University of Notre Dame and University of Chicago educated. • Professor of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center. • Board certified in neurology with a special qualification in child neurology. • Expert in Fragile X syndrome and other neurogenetic diseases. You can also say she’ll talk your ears off. Literally! And much of it may go over your head. Yes, she often talks in industry jargon. Plenty of it. OK, we get it. She’s smart. Super smart. She’s caring. Super caring. She’s knowledgeable. Super knowledgeable. But did you know she’s tenacious? Incredibly, super-duper, berry tenacious? Good thing for us she’s on our side. No doubt herRead more

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

FRAXA’s 2014 Top Goals

FRAXA Research Foundation FRAXA Updates October 24, 2013March 11, 2018AFQ056, autism, FDA, lithium, lovastatin, mGluR5, minocycline, Neuren Pharmaceuticals, Novartis, Roche

Complete Phase II/III Clinical Trials of mGluR5 Antagonists – and learn results Currently two large pharmaceutical companies – Novartis and Roche – are conducting large-scale clinical trials of experimental new medications for Fragile X syndrome which target the mGluR5 pathway. The Novartis trial has finished enrolling adults and adolescents, while a pediatric trial is set to begin soon. The Roche trial is well on the way to completion as well, but is still enrolling some age groups. FRAXA has been working diligently to educate families about these trials in the hopes of getting them completed as quickly as possible. Our goal (of course) is to discover whether these new drugs could be effective treatments for Fragile X, and to see these trials through to marketing of mGluR5 antagonists for Fragile X. Accelerate Clinical Trials of Investigational Treatments, based on research already funded by FRAXA New treatment strategies have emerged and

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.

Luke Solotaroff – A Portrait

FRAXA Research Foundation Friend of FRAXA July 22, 2013February 24, 2018AFQ056, Novartis

Luke wakes up every morning with a smile on his face. And that joy stays in his heart all day long. Except when it’s time to turn the tv off, shut down the ipad, or close the dvd player. Then all hell breaks loose. He yells and screams and carries on until I either have to give him a time out or I hold the beloved device in my extended arm and promise to give it to him if he calms down and stays calm for a period of time. But as he continues to grow taller, stronger, and more clever, it gets harder to end the conflict with the desired outcome. He is a master jigsaw puzzle solver and sees patterns in the pieces rather than solving it by following the pictures. He often does puzzles upside down. I was explaining this to someone recently while we were watching

Andy Tranfaglia: an Adult with Fragile X Syndrome

Katie Clapp Friend of FRAXA June 13, 2013October 16, 2018AFQ056, Novartis

June 2017: Andy and his dad, Dr. Mike Tranfaglia Andy is 29 years old now. He lives at home with us, his mom and dad, two cats, and a dog. He can understand most of what people say, but is usually too anxious to let you know. He will cover his face whenever someone walks into the room - even his mom or dad! Andy attends a supported farm program most days, and the minute he is out of the house, we rush off to work at FRAXA. We don't know what the future holds, but we hope for great things for Andy. We try to teach him basic skills to increase his independence in the future, but realistically, we don't leave him alone for even 15 minutes at this point. What do you call a babysitter when you need care for a 29-year-old? There is an image of Andy I canRead more

Alex Kowal – a Fragile X Portrait

FRAXA Research Foundation Fundraising Campaigns June 13, 2013June 18, 2018AFQ056, Novartis

My son Alex is almost 18 years old and has Fragile X Syndrome. I never thought that I would put my son on an experimental drug. I figured I’d wait until it came to market and be sure it was “safe”. My son was not going to be a lab rat. Almost two years ago, Alex became seriously ill from the medications he was taking. These were tried and true, “safe” non-experimental medications, and they nearly killed him. We needed to find a safer alternative – and quickly. After much thought and many discussions, we decided that the trial of AFQ056 from Novartis was our best option. At the time, the closest site was Rush University Medical Center in Chicago. To say I was afraid is the understatement of the year. But Alex had no quality of life. His anxiety level, even on meds, was through the roof! He was

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

FRAXA Research Outlook 2012 – Treatment Trials and the Next Wave of New Drugs

Michael Tranfaglia, MD Research Updates December 27, 2011July 14, 2018AFQ056, Alzheimer's, arbaclofen, autism, baclofen, basimglurant, FDA, glutamate, GSK3, lithium, mGluR5, minocycline, Novartis, PAK (p21-activated kinase), PDE4, Roche

Treatment Trials As you probably know, three pharmaceutical companies are conducting clinical trials in Fragile X. Two Swiss giants, Novartis and Roche, are racing to get their lead mGluR5 antagonists to market, and U.S. startup Seaside Therapeutics is pursuing a compound which targets the brain receptor, GABAB. Novartis has large-scale Phase IIb/III trials of the drug AFQ056 well underway. Sites worldwide are enrolling adolescents and adults, with 35 more adults needed and recruitment of adolescents planned through Fall 2012. At this point, some participants have already completed the placebo-controlled trial and are now taking AFQ056, with the option of continuing it until it reaches the market. Novartis is also working toward a trial of AFQ056 for younger children with Fragile X. Roche completed a Phase II trial of its mGluR5 antagonist (currently with the catchy name of RO4917523) last year and is about to commence a larger Phase II trialRead more

Letter from FRAXA’s Medical Director: State of the Science

Michael Tranfaglia, MD FRAXA Updates November 21, 2011July 5, 2018AFQ056, arbaclofen, autism, baclofen, Fragile X Meeting, lithium, mGluR5, minocycline, Novartis, Roche

On the eve of Thanksgiving, we want to thank everyone who has helped bring us so close to available treatments - and to take stock of where we are. by Michael R. Tranfaglia, MD Medical Director and Fragile X Parent Each year, we’ve described ever greater progress toward our ultimate goal: disease-modifying treatments and an ultimate cure for Fragile X. At times it must seem that this quest will take forever; however, the pace of research has truly moved into high gear in 2011! While FRAXA’s mission to find a cure for Fragile X is simple in concept, it is clearly a daunting task. To address the overwhelming complexity of this challenge, we have developed a plan of attack: • We fund high-quality basic research on the causes of Fragile X, which leads to possible treatment strategies (therapeutic targets). • We fund some of the finest neuroscientists in the worldRead more

Understanding the Mechanism of mGluR5

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • Completed Research Grant • de Vrij, Femke • Disease Mechanisms • Erasmus University Rotterdam • Oostra, Ben • Treatment Targets February 26, 2009May 16, 2018AFQ056, fenobam, fruit fly, LTD (Long-term depression), mGluR, mGluR5, miRNA, mRNAs, Novartis, prepulse inhibition, TAT (Trans-Activator of Transcription)

With a $304,000 grant from FRAXA Research Foundation from 1996-2009, Dr. Ben Oostra and his team at Erasmus University have done multiple studies related to Fragile X syndrome, the most recent being a study of spine morphology. Drs. Oostra and deVrij 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. Results published.

Involvement of the miRNA Pathway in Fragile X Syndrome

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • Completed Research Grant • de Vrij, Femke • Erasmus University Rotterdam • Oostra, Ben • Treatment Targets February 5, 2009August 2, 2018AFQ056, fenobam, fruit fly, LTD (Long-term depression), mGluR, mGluR5, miRNA, mRNAs, Novartis, prepulse inhibition, prepulse inhibition, TAT (Trans-Activator of Transcription)

With a $304,000 grant from FRAXA Research Foundation over several years, Drs. Oostra and deVrij from 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.