Nuplazid’s schizophrenia flop provides Advance warning

Acadia has tried to see the positives after a pivotal trial failure with Nuplazid in schizophrenia, but the data bode ill for other label-expansion studies.

The chances of Acadia’s Nuplazid in schizophrenia had always looked like a long shot, and so it proved when the pivotal Enhance trial failed yesterday, leading the company to write off the drug's prospects in this specific setting.

Acadia still hopes that it can salvage something in the disease, with another important trial readout looming in a slightly different schizophrenia use. But this and other Nuplazid label-expansion efforts now look shaky, and the group has little else in its pipeline.

Acadia's catalysts
Project Study Setting  Trial ID Data due
Nuplazid Enhance Adjunctive treatment of schizophrenia, largely positive symptoms NCT02970292 Failed July 2019
Nuplazid Advance Adjunctive treatment of schizophrenia patients with negative symptoms NCT02970305 Year-end 2019
Nuplazid Harmony Dementia-related psychosis NCT03325556 Interim analysis H2 2019
Nuplazid Clarity-2 Major depressive disorder NCT03968159 2021
Trofinetide N/A Rett syndrome N/A Phase III to start Q4 2019

Source: Company presentation, EvaluatePharma, clinicaltrials.gov.

Nuplazid is approved in the US for Parkinson’s disease psychosis, and brought in $224m last year, despite questions over a high number of deaths with the drug. Acadia has so far avoided the worst-case scenario of Nuplazid being pulled from the market, but the latest data are another blow to the company, which opened down 12% this morning.

Nuplazid sales are forecast to hit $1.7bn by 2024, according to EvaluatePharma sellside consensus; much of this is to come in Parkinson’s disease, though other indications like schizophrenia, Alzheimer’s and depression are expected to make a sizeable contribution.

Not Enhanced

Now Nuplazid’s prospects in schizophrenia look dimmer after the failure of Enhance, which did not show a difference between the drug and placebo on the primary endpoint, change in the positive and negative syndrome scale (PANSS) at six weeks.

Enhance tested Nuplazid as an add-on in patients with an inadequate response to existing antipsychotics. It required patients to have so-called “positive” symptoms, such as hallucinations and delusions, but it also allowed for enrolment of those with “negative” symptoms, like withdrawal and lack of emotion. Around half of the patients in Enhance had prominent negative symptoms too.

The ongoing Advance trial, which is due to yield data in the fourth quarter, also tests adjunctive Nuplazid, but is focused squarely on patients with negative symptoms, and in fact excludes subjects with positive symptoms, Acadia’s president, Serge Stankovic, said during a conference call yesterday.

Though Enhance's headline result was a fail, the detail might be important: Enhance found what Acadia termed a significant benefit on a secondary endpoint, the PANSS negative symptoms scale subscore, with an unadjusted p value of 0.0474.

The caveat is that, as the primary endpoint was not met, this finding can only be considered exploratory. And the numerical benefit over placebo was small, around half a point or less, and it is unclear whether this is clinically meaningful.

Another reason for caution with read-across is that Advance is much longer, at 26 weeks. And Advance tests a different endpoint, the negative symptom assessment-16 (NSA-16) score.

On the other hand, the company is claiming that European sites in Enhance produced better results than US centres. While this could favour Advance, which has an even greater bias towards European centres than Enhance did, many of the European sites are in central and eastern Europe and Russia, raising questions about data reliability.

Either way, investors were not convinced by Acadia’s spin, and the company’s stock dropped 14% this morning.

Bad omen?

As well as raising questions about the Advance study’s eventual outcome, the Enhance flop also looks like a bad omen for the ongoing Harmony study in dementia-related psychosis. An interim analysis of this trial is due in the second half, at which point it could either be stopped for efficacy or continue until completion next year.

Stifel analysts noted that dementia-related psychosis was more similar to schizophrenia than to Parkinson’s disease psychosis, with the latter at least partly driven by levodopa therapy.

And Acadia recently started a phase III trial of Nuplazid in major depressive disorder, which is also a big if after questionable phase II results (Chalk up a fail for Nuplazid, Acadia’s spin notwithstanding, 31 October 2018).

Perhaps the company’s focus on its sole approved drug is understandable – the only other asset in its pipeline is trofinetide, soon to go into phase III in Rett syndrome. But if Nuplazid’s label expansion studies continue to fall flat, which now seems more likely, Acadia might need to look elsewhere for growth.

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