No outburst of opportunity in Tourette’s syndrome

Neurocrine Biosciences’ phase II stumble with its Tourette’s syndrome project Ingrezza should prompt sector observers to look towards the pipeline for the next opportunity for success in this varied disorder.

On the same day that Ingrezza came up short in reducing tic severity in adult patients, Psyadon Pharmaceuticals reported a significant improvement on the same measure in Tourette’s-affected children with ecopipam, an old molecule that has been tested in conditions ranging from movement disorders to cocaine abuse. These are the most advanced programmes in Tourette’s, although they are part of a pipeline that is exploring familiar mechanisms in central nervous system disease (see table below).

Not dead yet

Neurocrine has not killed Ingrezza in Tourette’s – the VMAT2 inhibitor still has a phase II trial in children due to read out in April that could yet yield significant difference over placebo in the Yale global tic severity scale, the primary endpoint on which the adult trial failed.

As HC Wainwright analyst Andrew Fein wrote today, “children are not little adults” when treating Tourette’s since many children grow out of the condition, and thus the adult population is harder to characterise. Nevertheless, Leerink’s Paul Matteis lowered his probability of success in Tourette’s from 70% to 30%.

Moreover, the group said a secondary endpoint, clinical global impression of change, did show a numerical benefit for patients taking Ingrezza. Investors appeared receptive to the positive message – shares were up 8% in early trading today following yesterday’s post-market announcement.

In addition to Tourette’s, Neurocrine has submitted Ingrezza to the US FDA to treat tardive dyskinesia, with a decision deadline of April 11. In this indication, the pill is forecast to have sales of $784m in 2022, according to EvaluatePharma. Today, the FDA said it would not be holding an advisory committee meeting for this submission, which for investors offset the negative news about a trial miss.

Tourette's syndrome pipeline (phase II unless stated)
Project Generic name Company Pharma class
Ingrezza valbenazine tosylate Neurocrine Biosciences VMAT2 inhibitor
Ecopipam ecopipam Psyadon/Merck & Co Dopamine D1 & D5 antagonist
SD-809* deutetrabenazine Teva Pharmaceutical Industries VMAT2 inhibitor
SNC-102 acamprosate calcium Synchroneuron GABA agonist
CPP-115 - Catalyst Pharmaceuticals GABA aminotransferase inhibitor
* Phase I

Source: EvaluatePharma

Seize the day

Privately held Psyadon, meanwhile, said ecopipam significantly reduced scores on the Yale scale compared with placebo in a study in children aged between seven and 17. It did not release specific numbers, including a p value, so it will be difficult to get a read on its clinical or commercial promise until data are published in a journal or released at a medical meeting.

Ecopipam is a dopamine D1 & D5 antagonist that blocks pathways similar to those in drugs used to treat schizophrenia and bipolar disorders, so the mechanism is familiar. It is the only dopamine antagonist in phase II for Tourette's.

On the other hand, Ingrezza is not alone in inhibiting VMAT2. Teva’s SD-809, which it acquired with the $3.5bn takeout of Auspex Pharmaceuticals, has been tested in Tourette’s in an open-label phase I trial that reported a reduction in tic severity on the Yale scale in 2015. Teva’s focus with this project has been largely in another movement disorder, chorea related to Huntington’s disease, although it has said that development in Tourette's will continue.

Two projects modulating GABA, another tried and tested CNS pathway, have been advanced. Synchroneuron has completed a phase II trial in 16 Tourette’s patients – this asset is also being studied in tardive dyskinesia – but does not appear to have released any data. Catalyst Pharmaceuticals, meanwhile, has been preparing CPP-115 for phase II in movement disorders after a phase I dosing trial in healthy volunteers.

It should be pointed out that Tourette’s today is treated with muscle relaxants and dopamine antagonists used primarily for other disorders. The R&D pipeline, meanwhile, is largely made up of projects being targeted for other movement disorders as the main indication, with Tourette’s representing another shot on goal.

Thus, any researcher able to identify a unique pathway in Tourette’s would open an opportunity to deliver a differentiated treatment to the market. Right now it does not look like there is much of a chance of this happening for many years.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @ByJonGardner on Twitter.

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