Acadia can’t shake off its Nuplazid nightmare

Questions about hallucination and deaths continue to swirl around Acadia's Nuplazid.

Whether Acadia has a future will not become clear until the US FDA concludes a review into the safety of the group’s controversial antipsychotic, Nuplazid. While no further evidence might emerge in the meantime, investors need to be braced for volatility all the same.

Yesterday Acadia fell 7% with the entry into the Nuplazid fray of a new entity – the Southern Investigative Reporting Foundation – even though this non-profit group’s long report about the drug reveals little new beyond what CNN unearthed in March. That said, separate data have at last shed some light on Nuplazid-related deaths and other adverse events (see table below).

Advera Health Analytics, which specialises in compiling and curating US adverse event reports, lists 920 deaths in patients where Nuplazid is “primary suspect” between its US launch, in mid-2016, and the end of this year's first quarter. Nuplazid is approved for psychosis in Parkinson’s disease patients.

The Advera data corroborate numbers cited by CNN: that report, which appeared to be taken straight from the FDA Adverse Events Reporting System, cited about 500 deaths at June 2017, and a total of 700 by the year end. Advera’s numbers are more accurate, since they are derived from FDA Adverse Event Reporting System quarterly data files, whose results are then cleaned to eliminate duplicates and other inaccuracies.

Of course, this still says nothing about whether the deaths are actually due to Nuplazid – that remains subject to medical confirmation. Neither can conclusions be drawn as to whether 920 is out of the ordinary for this type of drug in this patient population.

Controversial

Still, it cannot be denied that Nuplazid is highly controversial: the 5-HT2A inverse agonist had flunked one phase III trial, whereupon a second was halted early. The FDA then permitted a third study with various changes, and this read out positively.

Despite a medical reviewer’s objections approval was granted after a 12-to-two adcom vote in favour of Nuplazid’s benefits outweighing its risks. Particularly contentious was the fact the FDA had given a green light on the basis of one redesigned study, rather than the normal two pivotal trials.

Yesterday’s Southern Investigative Reporting Foundation (SIRF) report repeated many of these concerns, adding allegations about how Acadia had incentivised doctors to prescribe Nuplazid. The drug sold $125m last year – the low end of expectations – and EvaluatePharma 2024 sellside consensus sees revenue beating $2bn, though much will depend on broader use, such as in Alzheimer’s disease psychosis.

Acadia stock had slid 22% in April when the FDA confirmed that it was reviewing Nuplazid’s safety after the problems highlighted by CNN and the Institute for Safe Medication Practices (ISMP), another non-profit organisation.

The ISMP had also highlighted Nuplazid’s association with hallucination, citing 487 reports (21.8% of all adverse events) at March 2017. Advera’s curated figures are more up to date, going to the end of the first quarter and giving a total of 1,646 cases of hallucination where Nuplazid is “primary suspect”.

Selected Nuplazid adverse events
  Hallucination* Death*
Jul-Dec 2016 200 108
Jan-Dec 2017 1,068 569
Jan-Mar 2018 378 243
Note: *cases where Nuplazid is listed as "primary suspect"; numbers are duplicated if hallucination and death occurred in the same patient. Source: Advera Health Analytics.

The SIRF also claims that the total patients experiencing hallucination or a confused state since launch now stands at 2,320; again, these totals look like they are taken directly from the FDA database, so should be treated with some caution.

Acadia has consistently defended Nuplazid’s safety and efficacy, and this stance is unlikely to change until the FDA’s review is completed. Meanwhile, the company has lost 30% of its value since March, and unless it can allay the fears its share price might continue to haemorrhage.

This story has been updated to add numbers for the 2018 first quarter. Advera Health Analytics is partly financed through venture capital provided by Evaluate Ltd, the parent company of EP Vantage.

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