Research Highlights Safety and Potential New Formulation of Aripiprazole Lauroxil

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On Monday, May 7, during a poster session at the 2018 Annual Meeting of the American Psychiatric Association, held in New York, New York, researchers presented new data on the injectable antipsychotic treatment aripiprazole lauroxil (AL; Aristada), which is indicated for the treatment of schizophrenia.

David Walling, PhD, presented findings¹ from a phase 1 pharmacokinetic, safety, and tolerability study of a potential 1-day initiation regimen for AL. Currently, AL injection requires 21 days of orally administered aripiprazole supplementation to achieve therapeutic levels. For patients who initiate their treatment with AL in a hospital setting, a 1-day initiation regimen would provide an alternative to oral supplementation that could assure therapeutic levels of the drug at the time that they are discharged form inpatient treatment.

The proposed 1-day regimen uses a nano-crystalline milled dispersion of AL; the small particle size allows the drug to dissolve more quickly, and is intended to result in therapeutic levels when it is given together with the first oral dose of AL.

The blinded, randomized, phase 1 study compared the 1-day initiation regimen (injection of the nano-crystalline milled dispersion plus a 30 mg dose of oral aripiprazole) with the standard approach (injection of AL at a dose of either 441 or 882 mg plus 21 daily 15 mg doses of oral aripiprazole). Patients—of whom 161 were enrolled and 133 completed the study—were randomized to either the 1-day initiation regimen or the standard regimen.

The researchers found that the 1-day initiation group had comparable aripiprazole concentrations to the 21-day initiation group. Reported adverse events were injection-site pain, headache, increased weight, insomnia, dyspepsia, and anxiety. A total of 9 akathisia events occurred (4 events in 4 patients in the 1-day group and 5 events in 2 patients in the 21-day group). Eight of these events were mild, and none led to discontinuation of treatment.

Walling and his team concluded that the combination of the of the nano-crystalline milled dispersion with 30 mg of oral aripiprazole was well tolerated, and an adequate alternative to a standard initiation regimen. The 1-day regimen, said the researchers, is currently under review by the FDA.

Also presenting research² on AL was Leslie L Citrome, MD, MPH. Citrome and his team sought to translate data from clinical trials into Number Needed to Treat (NNT) metrics for the benefits of medications (the number of patients who would need to be treated with a therapy in order to prevent 1 negative outcome) and Number Needed to Harm (NNH) metrics (the number of patients who would need to be exposed to a therapy in order to cause harm in 1 patient), an approach that they say can provide clinicians with guidance for using AL to treat patients with schizophrenia.

The researchers drew efficacy and tolerability data from the pivotal, double-blind, placebo-controlled study of AL in patients with acute episodes of schizophrenia, and calculated NNT and NNH values using those data.

They found that, pooling the 2 doses of AL (441 mg and 882 mg every 4 weeks), the percentage of patients who improved by 30% or more on the Positive and Negative Syndrome Scale (PANSS) were 35.3% for patients receiving AL and 18.4% for those receiving placebo, yielding a NNT of 6 (95% CI, 5-12). At a lower threshold for response (a 20% improvement in PANSS), the NNT was 4.

Akathisia was the only AE that both had an incidence of 5% or greater in patients receiving AL and was twice the rate of the group receiving the placebo, yielding a NNH of 14 (95% CI, 9-33). AL, say the researchers, was 2.3 times more likely to produce a therapeutic response than an incident of akathisia.

“Using the metrics of NNT and NNH, efficacy and safety results were consistent with prior aripiprazole clinical trials for the treatment of patients with an acute exacerbation of schizophrenia,” concluded the authors.

References

1. Walling D, Hard M, Wehr A, Du Y, Weiden PJ, von Moltke L. Aripiprazole lauroxil NanoCrystal dipsersion: a potential 1-day initiation regimen for long-acting aripiprazole lauroxil. Presented at the American Psychiatric Association 2018 meeting, May 7, 2018; New York, New York. Abstract 142.

2. Citrome LL, Du Y, Weiden PJ. Translating trial endpoint to NTT, NNH, and LHH: a re-analysis of the pivotal trial of aripiprazole lauroxil for the treatment of schizophrenia. Presented at the American Psychiatric Association 2018 meeting, May 7, 2018; New York, New York. Abstract 159.