Did tolerance result in Fragile X mGluR5 clinical trial failures?

Did tolerance result in Fragile X mGluR5 clinical trial failures?

Remember the Novartis and Roche large-scale clinical trials that failed a few years ago?

Who could forget?

Certainly not Rebecca Senter, PhD, FRAXA postdoctoral fellow, Massachusetts Institute of Technology.

Although the 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, Picower Professor of Neuroscience, Department of Brain and Cognitive Sciences, MIT, to carefully review parent observations during the trials. Those caregiver reports suggested tolerance to metabotropic glutamate receptor 5 (mGluR5) antagonists developed quickly, consistent with some preclinical findings in the mouse model.

Recognizing the importance of these findings, FRAXA last year funded a two-year MIT project to explore if mGluR5 antagonists dosed chronically causes tolerance, and if so, how it develops and to probe new avenues to prevent or circumvent it.

During the first year, Dr. Senter and Dr. Bear showed there is indeed tolerance after just three doses of an mGluR5 antagonist in mice that have been bred to mimic fragile X syndrome. They are now investigating how and why the tolerance occurs and — most importantly — how to combat it.

Impacting Future Fragile X Clinical Trials

Dr. Senter’s research goal is to understand how and why tolerance develops to chronic dosing with mGluR5 antagonists in fragile X patients.

"We can design the best therapy possible, but if it can’t be dosed chronically in patients, then it isn’t going to work for fragile X," said Dr. Senter, who is moving to a position at a pharmaceutical company. "Fragile X is a lifelong disorder, and thus it is worthwhile to understand why this tolerance is developing. Is it specific to the mGlu5 mechanism? Is it specific to fragile X?"

"Because there is so much hope in the field for mGluR5 antagonists as a viable therapeutic mechanism to treat fragile X, it’s worthwhile to understand what’s going on mechanistically to understand why this tolerance develops with the hope of being able to take our findings into consideration when designing future clinical trials. Not only will our results provide a possible mechanism for why tolerance develops to chronic mGluR5 antagonism and how to circumvent it, it may also provide insight into other therapeutic mechanisms in the future."

Understanding Tolerance

Tolerance is an enormous problem in many drugs, and particularly in drugs that impact the brain. Through the FRAXA-funded study, the MIT researchers have learned several interesting things about tolerance.

"First, we’ve been able to observe tolerance reliably in the mouse model of fragile X," Dr. Senter said. "This finding is important because it builds upon the parent reports from the clinical trials and previous external research. The second observation is the tolerance pathway is due to alterations in the signaling from mGluR5 to protein synthesis, which has been well characterized by several labs in the field. Because of this, we are excited and hopeful to be able to understand what is happening in the mouse model with the goal of being able to figure out if there are ways to circumvent the development of tolerance."

FRAXA Is ‘Amazing’

Dr. Senter said her work on this project would not have been possible without the support of FRAXA.

"FRAXA’s commitment to funding research that directly addresses the difficult questions in the field is amazing," she said. "I was interested in working on fragile X because we understand so much about the underlying biology, yet we have not been successful in finding a therapeutic intervention that lasts in patients. Investigating tolerance dovetails nicely with my training from graduate school and allows me to continue working in the field of neurodevelopmental disorders."

 

Mark Bear's goal: disease-modifying treatments for fragile X

 

FRAXA Grants to Robert Bauchwitz, MD, PhD — Columbia University