Sepsis signal could derail tozadenant – and perhaps even Acorda

Seven cases of sepsis, five of which were fatal, may have done for Acorda’s Parkinson’s candidate tozadenant. The patients affected were enrolled in a phase III programme and with no incidences of the condition seen in placebo patients toza looks to be toast.

Acorda insists that the fate of the asset has yet to be decided, but a side-effect this severe, even if it can be managed with closer patient monitoring, would at the very least drastically limit its sales potential. Acorda really needed a win with tozadenant following the refusal to file letter it got for Inbrija this summer and a number of prior setbacks. Instead its shares slumped 38%.

The phase III programme for tozadenant consists of an ongoing pivotal efficacy and safety study, CL05, and two long-term safety studies. Patient enrolment in the latter two has been paused.

CL05 but no cigar

On a conference call Acorda's chief executive Ron Cohen said four of the sepsis cases were associated with agranulocytosis – a severe, acute lowered white blood cell count – two had no white blood cell counts available at the time of the event, and one had a high white blood cell count.

The company is in discussions with the trials’ data safety monitoring boards and the FDA, but Mr Cohen could give no timing for when these groups might make recommendations about the future of the CL05 trial or indeed the drug. At the moment the study, which is fully enrolled, is continuing, with the patients’ blood cell count being monitored weekly. Previously this monitoring had occurred first at the two week point, then monthly for a few months, and then every three months.

Top-line data from the CL05 study are expected in the first quarter of 2018. Even if the remaining patients in this trial were to drop out immediately Mr Cohen believes Acorda would still have a good dataset with which to mount an approval application; over 90% of the intended patients have already completed follow-up, he said.

Whether such an application might meet with success is somewhat doubtful. Even a slam-dunk on efficacy seems unlikely to make up for this kind of safety signal.

In what will probably turn out to be an understatement, analysts from Leerink wrote that their most recent assumptions about toza, which gave it a 70% chance of eventual approval, “now seem overly optimistic”.

Vulnerable

No company would welcome this kind of safety snafu, but Acorda is particularly vulnerable as its recent clinical and regulatory history has been nothing short of woeful.

In May last year the group shelved Plumiaz, its intranasal diazepam, for seizure clusters in epilepsy patients after phase III data failed to show its bioequivalence to Diastat, a rectal gel formulation of the same drug.

A year ago, attempts to prove Ampyra’s usefulness in post-stroke walking difficulties ended in failure. The same project was hit by a ruling this March that invalidated four patents, causing Acorda’s shares to fall 21% (Patent rulings knock Acorda and Forward, April 3, 2017).

There was a brief uplift this February when positive phase III results for the inhaled levodopa Inbrija boosted Acorda's share price by 20% – but this was more than reversed in August when the FDA hit the project with a refusal to file letter over manufacturing issues (The regulatory news is good for Lilly and Abbott, but bad for Acorda, September 1, 2017).

Mr Cohen insists Inbrija is “a successful phase III drug”, which will be resubmitted to the FDA by the end of the year. The drug is “virtually a bird in the hand”, and once approved will be “at least the size of Ampyra” in terms of sales.

Neither is Acorda a company in any danger, Mr Cohen said. Even if the ongoing appeal against Ampyra’s patent invalidations is unsuccessful and the drug goes generic in July, the company will still have over $200m in cash at the end of next year.

Acorda might very well keep going. The future for tozadenant seems less certain.

To contact the writer of this story email Elizabeth Cairns or Jo Fagg in London at [email protected] or follow @EPVantage on Twitter

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