Clinical Trials Disappointing - But Researchers Remain Optimistic
In the spring of 2014, Novartis announced that the company had decided to discontinue the development program for its main mGluR5 blocker, mavoglurant (AFQ056), following negative results in large international clinical trials for adults and adolescents with Fragile X syndrome. In both placebo-controlled trials, patients taking mavoglurant did not show improvement over placebo in any outcome measures. In September of 2014 Roche made a similar announcement regarding its international, multicentre clinical trial to evaluate the efficacy of its own mGluR5 blocker (RG7090) in the treatment of Fragile X. They too were unable to demonstrate any significant improvement over placebo in any of the outcome measures used.
In spite of this, the FXRFC and the research community are still optimistic that a targeted molecular treatment for Fragile X can work. Even as this article is being written, there are other potential treatments in various stages of development and testing, that are aimed at other “therapeutic targets”. One such drug is NNZ-2566, being developed by Neuren Pharmaceuticals. It has an entirely novel mechanism of action compared with other drugs that have been tested for Fragile X syndrome. Neuren Pharmaceuticals is the sponsor of a Phase II drug treatment clinical trial that is currently ongoing at 6 (soon to be 9) centres in the US. They have contacted the Fragile X Research Foundation of Canada and requested our assistance in recruiting Canadian participants into the study. They have several sites close to the Canadian border (Rush Medical Centre in Chicago, University of Massachusetts in Worcester, and Mount Sinai Hospital in Manhattan) and would be willing to support travel/accommodation for families committed to participating.See description below.
New Clinical Trial sponsored by Neuren
Description provided by Neuren Pharmaceuticals
Pharmaceuticals enrolling participants with
Fragile X Syndrome
Neuren Pharmaceuticals is pleased to inform you of an opportunity to participate in a clinical trial for adolescents and adults with Fragile X syndrome. This clinical trial is testing an investigational medication, NNZ-2566, as a targeted treatment for Fragile X syndrome (FXS). The purpose of this study is to assess the safety and efficacy of two doses of NNZ-2566 when compared to placeboin adolescent and adult males who have been diagnosed with Fragile X syndrome. This trial is currently enrolling participants and will include 60 participants between the ages of 14 - 40. Taking part in this study will involve 8 visits to the doctor’s office over a 10-week (about 2 ½ months) period. The study medication and all study-related evaluations will be provided at no cost to participants. Some support for travel will also be available. NNZ-2566 has an entirely novel mechanism of action compared with other drugs that have been tested for Fragile X syndrome. NNZ-2566 is a modified version of a biologically active part of Insulin-like Growth Factor (IGF-1). IGF-1 is a protein in the human body that helps cells grow and respond to stress or damage. In the brain, IGF-1 contributes to the growth of brain cells and the connections between them (synapses). The biologically active part of IGF-1 is called glypromate or GPE and supports the function of brain cells in a different way than IGF-1. GPE occurs naturally in the brain. NNZ-2566 is a version of GPE modified to make it available to take as an oral medication. NNZ-2566 may help improve brain function by enhancing functions normally performed by GPE and by increasing IGF-1 levels in the brain. NNZ-2566 has been shown in animal models of Fragile X to improve performance in tests of behavior and cognition.
The FDA has granted two special designations for Neuren’s development of NNZ-2566 in Fragile X: Fast Track Designation and Orphan Drug Designation. Both designations are important milestones in accelerating the development of viable treatments for Fragile X, and demonstrate a recognition of the critical unmet needs of individuals with Fragile X syndrome. Participating sites include: Rush University (Chicago), Icahn School of Medicine at Mt. Sinai (New York), University of Massachusetts Medical School (Worcester/Boston), Suburban Research Associates (Philadelphia), Emory University (Atlanta), and Children’s Hospital Colorado (Denver). Other sites will be added soon. More information and updated information on participating centers can be found at Clinicaltrials.gov at this link: http://www.clinicaltrials.gov/ct2/show/NCT01894958. For information about Neuren, please see their website: www.neurenpharma.com.
Experimental drug FRAX486 reverses signs of Fragile X in mice
An experimental new drug called FRAX486 has received a lot of press as being another potential future treatment for Fragile X. This compound is an enzyme known as a PAK inhibitor (p21-activated kinase) that has been shown to regulate the shape and function of the short branches found on neurons (called dendritic spines). Dr. Tonegawa’s lab has demonstrated that by reducing PAK by genetic manipulation they could rescue most signs of Fragile X in mice which had been genetically engineered to mimic the disorder.
This finding provided the necessary scientific basis to establish PAK inhibitors as potential treatments for Fragile X. However since there were no PAK inhibitors on the market at the time, a new company, called Afraxis, was created to develop the compound.
This work was reported In the March issue of the Proceedings of the National Academy of Science (PNAS) and demonstrated that a new compound called FRAX486 inhibits PAK activity in the brain and was able to reverse most of the cellular and behavioural abnormalities in the Fragile X mouse model with a single dose!
This is promising news for the Fragile X community because it adds another potential future drug candidate for the disorder-modifying treatment of Fragile X.
Cholesterol drug may treat Fragile X
In January 2013 a research team, led by Dr. Mark Bear at MIT, reported in the neuroscience journal Neuron that an available cholesterol-lowering drug may normalize the excessive production of proteins in the dendrites of neurons of Fragile X mice.
The mGluR theory of Fragile X postulates that there is an exaggerated response to activation of the signaling pathways which link the metabatropic glutamate receptors (mGluRs) to the protein manufacturing structures within neurons. Lovastatin is known to indirectly decrease the activity of these pathways (called ras-ERK signaling pathways) and has been used safely for many years as a cholesterol-lowering drug in both adults and children. The experiments described in this study show that lovastatin inhibits ras-ERK signaling sufficiently to have significant positive therapeutic effects in Fragile X animal models.
This preclinical work strongly suggests that lovastatin could have disorder-modifying effects in people with Fragile X. To prove its effectiveness in humans, clinical trials in Fragile X subjects are still necessary before lovastatin can be recommended as a new treatment.
Francois Corbin, MD, PhD at the Fragile X Clinic at University of Sherbrooke, Quebec is currently recruiting participants for an open trial of lovastatin. Canadian individuals aged 10 to 40 years who have Fragile X might be eligible to participate in this study and interested families can get more information by contacting the study coordinator, Sylvie Auger at firstname.lastname@example.org.
Novartis plans New Phase 2 Fragile X Clinical Trial in Canada
In April 2010, the Swiss pharmaceutical company Novartis announced that their experimental drug known as AFQ056 had succeeded in a small European clinical trial in showing improvements in several behavioural symptoms that are troublesome for people with fragile X syndrome and for their families. These exciting comments were disclosed in an interview with Novartis, and appeared in the April 29, 2010 issue of the New York Times Newspaper in the U.S.
While these are early results and further testing will be required to clearly demonstrate the safety and efficacy of the drug, the Fragile X Research Foundation of Canada is very excited to announce that Novartis will test their lead mGluR5 blocking drug, (known as AFQ056) to treat Fragile X in adult patients at several North American centres, including the Surrey Place Centre Fragile X Clinic in Toronto. The clinic is run by Dr. Carlo Paribello, President and Medical Director of the Fragile X Research Foundation of Canada. Recruitment of participants for this trial is expected to start in January 2011 and more details regarding this study will become available in the near future in our newsletters and on the clinicaltrials.gov website.
The preclinical work that this research is based is referred to as the “mGluR theory” of fragile X. It was first proposed by Mark Bear at Brown University in 2000, and immediately raised the possibility that this class of drugs (mGluR5 blockers) could be potential treatments for Fragile X.
The research results in the animal models for Fragile X have been so dramatic, that it has now prompted three pharmaceutical companies to conduct clinical trials using mGluR5 blockers as possible treatments for this disorder. While it takes several years of rigorous testing before Health Canada will approve a new drug for use on the market, this class of drugs is also being developed for Parkinson’s disease, so it is likely that at least one mGluR5 blocker will be available in the near future.
Canadian clinical trial of minocycline in Fragile X shows promise for future treatment!
Results of the first clinical trial of minocycline in Fragile X patients were recently published in BMC Neurology, and they suggest that this medication can improve many of the challenging behaviours commonly seen in Fragile X syndrome.
The trial was entitled “Open-label add-on treatment trial of minocycline in fragile X syndrome” and was published in BMC Neurology 2010, 10:91.
The study included twenty males and females with Fragile X, aged 13-32, and was conducted by Dr. Carlo Paribello at the Surrey Place Centre Fragile X clinic in Toronto. The trial was funded by the FRAXA Research Foundation and the FXRFC. Patients received either 100 mg or 200 mg of minocycline daily, and their behaviours were evaluated prior to treatment and again 8 weeks after daily minocycline.
Behavioural scores showed striking improvement and the drug was generally well tolerated. The most significant side effect noted was, in blood tests, an asymptomatic conversion to a positive ANA (Antinuclear Antibody) in two people. This is a nonspecific marker of immunoinflammatory connective tissue diseases, so physicians who prescribe minocycline should be aware of its risk for inducing potentially serious autoimmune reactions.
Minocycline belongs to a group of antibiotics called synthetic tetracyclines, and it has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections. In 2008 Dr. Iryna Ethell of the University of California at Riverside showed that minocycline, which inhibits MMP-9 activity, reverses behavioural and neuronal abnormalities in mice bred to mimic Fragile X.
This study suggests that minocycline can provide significant benefits to Fragile X patients.These findings are also consistent with the Ethell team’s results in mice, suggesting that minocycline modifies underlying neural defects that characterize Fragile X.
Dr. Paribello is continuing his study at the Surrey Place Centre Fragile X Clinic, with an extended treatment phase to investigate whether there is developmental or cognitive improvement with long term minocycline treatment.
There is growing excitement in the Fragile X research community and among the families of people that have Fragile X syndrome. The progress that researchers have made over the past few years has allowed us to finally start moving potential treatments out of the lab and into the clinics. The Fragile X Research Foundation of Canada has spearheaded this progress by partnering with Surrey Place Centre to establish the first FX Clinic and initiating the first Canadian clinical trial to test a new treatment for Fragile X.
The FXRFC has also expanded its international collaboration by participating in the Fragile X Clinic and Research Consortium organized by the National Fragile X Foundation in the U.S. It currently consists of 20 clinics in the U.S. and one in Canada. By being part of this consortium, the FX Clinic in Toronto will be able to participate in a number of multicentre clinical drug trials that are in various stages of planning.
Minocycline - In 2009, the FXRFC initiated the first clinical trial using minocycline to treat Fragile X. This trial is based on the recent discovery that this drug can reverse structural abnormalities seen in the brain cells of Fragile X mice. Minocycline belongs to a group of antibiotics called synthetic tetracyclines, and it has been used by people for more than fifty years to treat Lyme disease, acne, and other skin infections.
With funding from FRAXA, the Feigelson Foundation, and the FXRFC, our research team at the Surrey Place Centre Fragile X clinic in Toronto Ontario is running an open label trial to see if minocycline can improve learning and reduce anxiety and behavioral problems in people with Fragile X syndrome.
It has been known for some time that minocycline inhibits a protein called matrix metalloproteinase-9, (MMP-9). MMPs are involved in normal development and physiological processes such as wound repair and tissue remodeling, as well as in disease processes such as arthritis. Recent studies have shown that MMP-9 levels are abnormally high in the brains of Fragile X mice. In the mouse studies, minocycline reduced MMP-9 levels in the brain, corrected brain abnormalities in dendritic spines, and reduced anxiety, all while improving cognitive function. This trial is nearing completion and the results should be ready for release in 2010.
Fenobam - This is an experimental drug that partially blocks the mGluR5 receptors on the surface of brain cells. In Fragile X, the signalling pathway that is triggered by stimulation of this receptor is overactive. This causes overproduction of a number of other proteins that are involved in maintaining normal synaptic structure and function. Experiments using animal models for Fragile X have shown that drugs that partially block the mGluR5 receptors, like Fenobam, can reverse the abnormalities seen in animal brain cells.
In 2008 Fenobam was granted “orphan drug” status by the FDA in the U.S. in order to speed up the process of bringing this drug to market. Unfortunately, at that time the FDA in the U.S. would only approve a “single-dose” trial so few conclusions could be drawn from that trial. While there is still much interest in developing Fenobam as a possible treatment for Fragile X, its future is still uncertain, though not due to clinical or scientific problems, but for economic reasons. Neuropharm, the British Pharmaceutical company that has been developing Fenobam, was hit particularly hard by the economic downturn that started in the Fall of 2008. As a result, the future development of Fenobam is still unknown at this time.
STX 107 - This is another mGluR5 blocker that is currently a more likely candidate for early testing in patients with Fragile X. It is being developed by Seaside Therapeutics, a small pharmaceutical company in Massachusetts. They are currently running a Phase I clinical trial in normal volunteers to determine if there are any side effects. Once this phase is completed, some time in 2010, preparations can start on planning a Phase II clinical trial in patients with Fragile X.
AFQ56 - This is a version of an mGluR blocker that belongs to Novartis, and a trial using this drug is currently being run at centres in France, Italy and Switzerland. The results of this trial will determine if AFQ56 will be considered for testing in North America in the future.
RO4917523 - This is yet another version of an mGluR5 antagonist (blocker) being developed by the Swiss pharmaceutical giant Hoffmann-LaRoche (“Roche”). They have begun U.S. trials of their lead mGluR5 antagonist, RO4917523, for Fragile X. The FXRFC will be meeting with representatives of both Roche and Seaside Therapeutics in May 2010 to discuss plans to expand these trials to Canada.
STX209 - This is also known as Arbaclofen and is not currently available on the market but is actually a purified version of Baclofen. Baclofen is currently approved for use in treating muscle spasticity in adults and children. However, in 2006, researchers working with the Fragile X knockout mouse showed that drugs such as Arbaclofen, that block a particular neuron receptor known as GABA-B, may actually have beneficial effects for Fragile X as well.
The absence of FMRP in Fragile X syndrome, is associated with hyper-activity and heightened sensory sensitivity. The hyperactivity is similar to the behavioral abnormality seen in attention deficit disorders. The sensory hyper-reactivity is manifested as anxiety and sensory defensiveness to visual, tactile and auditory stimuli. Abnormal auditory processing in Fragile X can underlie inattention, poor listening skill and difficulty in understanding speech.
Some of the symptoms of Fragile X can be reproduced in the FMRP deficient mouse strain. These FMRP deficient mice exhibit hyper-activity and sensory hyper-reactivity manifested as abnormal sound induced reflexes and even seizures. Both the hyperactivity and the sensory hyper-reactivity are thought to be due to an imbalance between the inhibitory and excitatory brain circuits. In other words, underactive inhibitory pathways in Fragile X result in too much activity in the excitatory pathways. Since we know that the inhibitory pathways are regulated by the GABA(B) receptor (gamma-aminobutyric acid receptor) , researchers were able to alleviate these behavioral abnormalities when they activated the GABA(B) receptor with Arbaclofen. An additional benefit of this class of drugs is that they also reduce anxiety, a frequent symptom in Fragile X.
Clinical trials using Arbaclofen (developed by Seaside Therapeutics)
are currently being conducted at several U.S. centres, and will likely be extended to Canada in the near future.