First fragile X test is approved, and Zynerba could benefit

The fragile X pipeline is strewn with failures, and crunch time is approaching for Zynerba’s cannabinoid.

Policy and regulation

Not all developers of in vitro diagnostics seek formal FDA approval for their assays – witness the rash of homebrew tests that have gone on sale for the new coronavirus over the past few weeks. Asuragen, however, likes to do things by the book, and its fragile X syndrome diagnostic is now the first test for this disorder to have gained the FDA’s authorisation.

The advent of a proven fragile X test – the FDA says the accuracy of the test is greater than 95% – could accelerate demand for therapies. This is already pressing, since nothing is yet approved specifically for the condition. Several projects are under development but only three are in active trials, and just one of these, Zynerba Pharmaceuticals’ Zygel, has made it to phase III. 

The US FDA says fragile X syndrome is the most common cause of inherited intellectual disability. Asuragen’s blood test, AmplideX, may now be used to diagnose the condition in combination with family history and clinical signs and symptoms. It may also be used to identify adults who carry alterations in the gene associated with fragile X – the FMR1 gene.

The diagnostic measures the number of repeats of the CGG segment in FMR1, and uses this to classify individuals into one of four categories: normal, intermediate, premutation or full mutation. The first two categories are not concerning. Patients with a full mutation typically have fragile X. Women with a premutation have an increased risk of having a child with fragile X, and men with a premutation are at an increased risk of passing the condition to their daughters. 

A delicate task

Phase II/III data likely coming this year could indicate whether Zygel becomes the first therapeutic specifically approved for fragile X. The Connect-FX study is testing two weight-based doses of the cannabinoid receptor agonist, administered as a transdermal gel every 12 hours, versus placebo.

The primary endpoint is change in score from baseline to week 14 on a subscale of the the aberrant behaviour checklist-community fragile X factor structure, a parent/caregiver reported behavioural outcome measure. 

Zygel’s open-label phase II Fab-C study hit its primary endpoint of reduction in the anxiety, depression, and mood scale (Adams) score from baseline to week 12, in 18 patients, with an average drop of 46%. 

Fab-C also showed a 55% improvement on the subscale used as the phase III endpoint. It is not known whether a similar showing in phase III will be good enough for approval – and Connect-FX incorporates a placebo group, further complicating matters. If Connect-FX does yield a convincing benefit, approval could come by mid-2021. 

Data on another candidate could come this summer, but this time only from phase II. The Rocket trial of OV101, a Gaba A receptor agonist licensed by Ovid Therapeutics from Lundbeck, is assessing three administration regimes, with adverse event rate at three months as the main outcome.  

The phase II study of BPN14770 in men with fragile X being undertaken by Tetra Therapeutics had a primary completion date of December 2019, according to clinicaltrials.gov, but no results have yet emerged. The placebo-controlled crossover study focuses on the project’s safety, but a raft of secondary endpoints could provide information on efficacy if and when the trial reports. 

Marinus Pharmaceuticals’ ganaxolone has demonstrated proof of concept in fragile X, and has appeared in prior Vantage analyses of this market (Novartis exit leaves fragile X pipeline in an even more frail state, May 1, 2014). For now the company is not developing the project in fragile X, stating in its 2018 10-K that it might pursue this in future. A possible trigger for this might come if Ovid’s Rocket trial hits, and reignites interest in Gaba A modulators as potential fragile X therapies.

The difficulty of treating fragile X pharmacologically should not be minimised: both Novartis and Roche have failed here in recent years. The de novo clearance of Asuragen’s test only raises the stakes, providing a ready population for whichever project first gains approval. The race appears to be Zynerba’s to lose. 

The fragile X files: upcoming therapies that might benefit from the AmplideX test
Project Company Mechanism Trials
Phase III
Zygel Zynerba Pharmaceuticals Cannabinoid receptor agonist 200-pt phase II/III trial, Connect-FX (NCT03614663), to report summer 2020
300-pt phase II/III extension trial (NCT03802799) to report 2022
SF-679/SF-775 Confluence Pharmaceuticals Gaba receptor agonist Assumed abandoned
Phase II
OV101 Ovid/ Lundbeck Gaba A receptor agonist 30-pt phase II trial, Rocket (NCT03697161), to report summer 2020
BPN14770 Tetra Therapeutics Phosphodiesterase 4D negative allosteric regulator 30-pt phase II trial in adult males (NCT03569631) concluded Dec 2019
Ganaxolone Marinus Pharmaceuticals Gaba A receptor regulator Not actively developing for FX
Trofinetide Oral Acadia/ Neuren Insulin-like growth factor 1 regulator Not actively developing for FX
AMO-01 Bellus Health/AMO Pharma Extracellular signal-related kinase inhibitor Trial yet to begin? 
FX = fragile X. Source: EvaluatePharma, clinicaltrials.gov & company websites.

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