Welcome to your weekly digest of approaching regulatory and clinical readouts. Acadia’s antipsychotic Nuplazid seems to have just about weathered the storm of safety concerns that sprang up around a year ago, with first-quarter 2019 sales of $63m, a jump of 29% year-on-year. Now Acadia’s attention is turning to expanding the indications for which Nuplazid may be used.
Nuplazid, a 5-HT2A inverse agonist currently approved for Parkinson’s disease psychosis, is in two crucial phase III trials both due to read out in the coming months. First up is the Enhance study in patients with an inadequate response to schizophrenia drugs, top-line data from which are expected mid-year.
The 380 patients in this study will take a background antipsychotic plus either Nuplazid – 10, 20 or 34mg per day, taken as two pills – or placebo. The primary endpoint is the change from baseline score on the positive and negative syndrome scale at six weeks. The company has said that approved schizophrenia drugs have shown an effect size of 0.25-0.5, so this could be a benchmark for approval, provided safety is clean.
The drug’s performance in phase II was mixed. In 423 patients with schizophrenia who had responded to earlier treatment, Nuplazid significantly enhanced the efficacy of Risperdal but actually lowered the efficacy of Haldol. At least safety was fairly benign, with no significant changes in treatment-emergent adverse events when Nuplazid was added to the other drugs.
If Nuplazid defies its phase II track record and scores a hit in Enhance, it probably stands a good chance of approval owing to the significant unmet need among patients who respond inadequately to other antipsychotics. Nothing is approved for this particular niche – it is separate to treatment-resistant schizophrenia, for which clozapine is approved.
But the risk that a confirmatory trial will be required even in the event that Enhance is a success is a sizeable one.
Hallucinations and delusions
Another schizophrenia study of Nuplazid, the phase II Advance in negative symptoms, ought to yield top-line data at the end of 2019. Before that, interim data from the phase III Harmony study in dementia-related psychosis will emerge.
Harmony is testing Nuplazid’s ability to prevent relapse in 356 patients with hallucinations and delusions associated with dementia-related psychosis. All patients were given 34mg of the drug for 12 weeks after which the non-responders were kicked off the trial. The responders were then randomly assigned to placebo or Nuplazid dosed at 20 or 34mg per day; the primary outcome is the time from randomisation to relapse in this latter, 26-week double-blind period.
According to Stifel analysts there is a slim chance that if positive, the interim data could be considered pivotal by the FDA. If the interim readout is not a total knockout Harmony will continue until its scheduled conclusion in 2020.
A look at Acadia’s pipeline, and the corresponding consensus forecasts compiled by EvaluatePharma, shows how enormously reliant on Nuplazid the company is. Schizophrenia is forecast to bring in $249m in 2024, though this primarily comes from the inadequate response indication, so a result in negative symptoms would be a boost.
Nuplazid’s use in dementia-related psychosis could add $267m to the group’s 2024 revenues. Acadia’s only other asset is the insulin-like growth factor 1 regulator trofinetide, which the sellside sees making just $57m in 2024 in the neurological condition Rett syndrome – peanuts compared with a forecast total of $1.7bn for Nuplazid.
|Annual WW indication sales ($m)|
|Product||Indication||Indication status||2018||2020e||2022e||2024e||Indication launch|
|Nuplazid||Parkinson's disease||Marketed||224||453||783||950||May 2016|
|Nuplazid||Schizophrenia||Phase III||-||15||101||249||Dec 2020|
|Nuplazid||Alzheimer's disease||Phase III||-||11||100||267||Dec 2020|
|Nuplazid||Psychosis, acute||Phase III||-||-||-||-||-|
|Nuplazid||Other neurological indications||Phase III||-||-||-||-||-|
|Nuplazid||Depression||Phase II||-||-||41||170||Dec 2021|
|Trofinetide Oral||Rett syndrome||Phase II||-||-||8||57||Dec 2022|
|Trofinetide Oral||Fragile X syndrome||Phase II||-||-||-||-||-|