Novartis exit leaves Fragile X pipeline in an even more frail state

Sufferers of genetic disorder fragile X syndrome last week saw another once-promising candidate struck from the already painfully slender pipeline of potential drug therapies. Novartis confirmed that it would end development of AFQ056, after the mGluR5 antagonist failed in two phase IIb/III trials.

What appears to be the exit of a major pharma player from this space is a big blow. This is particularly so because the news comes less than a year after Seaside Therapeutics pulled down the shutters on research into its hopeful candidate, STX209 (Seaside setback in autism and Fragile X leave few therapeutic hopes, May 24, 2013).

Fragile X is one of the most common causes of inherited learning disabilities and is caused by a mutation preventing expression of the fragile X mental retardation protein (FMRP). FMRP regulates the processes in cells that generate functional proteins in the brain. Symptoms of the disorder, which occurs in both girls and boys, include moderate to severe mental retardation, seizures and behavioural problems.

At present there are no approved disease modifying medications and the only available treatments are antidepressants and mood stabilisers, which are used to control symptoms, rather than reverse the effects of the disorder (Therapeutic focus – Turning point ahead for Fragile X syndrome, February 28, 2012).

Narrow field

With Novartis now out of the race, a search of clinical trials databases reveals very few active clinical studies ongoing, many of which are being conducted by academic institutions. A scan of shows that more than 90% of active research in Fragile X is now being carried out by institutions or universities.

One of the most substantial trials on-going is a 48 patient study being conducted by the Children's Hospital Medical Center in Cincinnati and Rush University Medical Center, of acamprosate calcium.

Initially approved for alcohol dependency, the drug is a GABA B agonist and also works as an mGluR5 antagonist, as well as inhibiting the N-methyl-D-aspartate receptors. This triple action on neural pathways might give the drug an advantage over AFQ056 and STX09, which both focused solely on the mGluR5 pathway. states the trial will complete in 2016. However, other institutions have previously tested the drug, seemingly with little notable success.

Aside from this study, several academic centres are running imaging and biomarker studies in an attempt to elucidate the condition’s pathophysiology. Research into novel agents remains the territory of commercial companies.

Big pharma

Roche is the only big pharma company to have a compound in clinical testing, but even its commitment to the disorder is unclear.

RG7090 (previously known as RO4917523), is currently in phase II studies and the Swiss group states it is “expected to play an important therapeutic role” in fragile X. But the development focus of the drug appears to have shifted to treatment resistant depression rather than fragile X.

It has just completed a 185 patient 12 week study to evaluate whether the mGluR5 antagonist can make improvements on anxiety and depression scores, is safe and can change fragile X patients’ social responsiveness and aberrant behaviour.

Results from the study, one of the largest conducted in the space, could come in the second half of the year

Smaller companies

New Zealand based Neuren Pharmaceuticals started its phase II trial in Fragile X in January, and expects the results in the first half of next year. The trial is testing NNZ-2566, an insulin-like growth factor 1 (IGF-1) analogue, in adolescent and adult males and is looking to recruit 60 patients.

Primary outcomes will measure the incidence of adverse events, while physiological and behavioural changes are included in the secondary measures. NNZ-2566 received orphan drug designation and fast track designation from the FDA. It is also being testing in traumatic brain injury and Rett Syndrome.

Meanwhile privately held Marinus Pharmaceuticals is testing ganaxolone, a neurosteroid that has a high affinity for GABA receptors. The phase II trial is looking to recruit 60 patients aged 6- 17 years old and compares ganaxolone to placebo.

The primary outcome is the measure of clinical behaviours such as anxiety and attention using the clinician's global impression-improvement (CGI-I) scale. The primary completion date, according to, is September 2015. It is also being tested in seizure disorders.

With Novartis having abandoned the most advanced novel agent in the space, these three agents represent the best near-term hopes that a pharmaceutical agent might be able to improve the lives of Fragile X sufferers.

Fragile X pipeline – active drug trials  
Phase Product Company Pharmacological Class Trial ID
Phase III AFQ056 (mavoglurant) Novartis mGluR5 antagonist NCT01357239
recently abandoned
Acamprosate calcium Children's Hospital Medical Center, Cincinnati;
Rush University Medical Center
GABA agonist NCT01911455
Phase II RG7090/RO4917523 Roche mGluR5 antagonist NCT01750957
Ganaxolone Marinus Pharmaceuticals GABA A receptor modulator NCT01725152
NNZ-2566 IV/oral Neuren Pharmaceuticals Limited IGF-1 analogue NCT01894958

To contact the writer of this story email Lisa Urquhart in London at or follow @LisaEPVantage on Twitter

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