Continuous Subcutaneous Apomorphine Infusion Sustains Efficacy in Phase 3 InfusON Trial

Responder rate data from the open-label, phase 3 InfusON trial (NCT02339064) presented at the 3rd Annual Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 22-25, 2024, demonstrated that continuous subcutaneous apomorphine infusion (CSAI) therapy significantly reduced OFF time in patients with Parkinson disease (PD), with benefits sustained through 52 weeks of the maintenance period.¹

Conducted by lead author Stuart Isaacson, MD, FAAN, director for the Parkinson’s Disease and Movement Disorders Center of Boca Raton in Florida, the study included outpatients with recurrent motor fluctuations despite optimized PD medications. Participants initiated CSAI with a 1-2 mg bolus, followed by a 1mg (0.2mL)/h infusion. CSAI was then titrated in 0.5-1 mg/h increments at clinic visits (1-10 days apart) to an optimal rate based on response and tolerability (maximum 8 mg/h). Other PD medications could be adjusted to manage dopaminergic adverse effects. Researchers defined responders as those with at least 2 hours of improvement in OFF time from baseline.

At the CSAl initiation dose, authors reported that reduction in OFF time was noted, with 27% meeting response criteria prior to the first titration visit. Notably, responder rates continued to improve with CSAI optimization, reaching 61% by the start of the maintenance period and sustained through 52 weeks of the maintenance period. Additionally, diary measures showed immediate improvement upon CSAI initiation, with reductions in OFF time and improvement in good ON time that increased with CSAI optimization in the titration period and was sustained throughout the maintenance period.

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Among 99 patients who were initiated on CSAI, 94 had post-baseline efficacy data and 85 completed the titration period. The patients enrolled typically required 3 to 5 titration visits (median = 4 visits) for CSAI optimization. The median duration of the titration period was 30 days. About 48 participants reduced concomitant PD medications during the titration period to manage dopaminergic AEs, with median time to first medication reduction of 9 days (range 2 to 44 days).

The adverse events (AEs) reported during CSAI titration were mainly mild to moderate in severity, with infusion site nodules and/or erythema, dyskinesia, and nausea as the most observed. The noted infusion site reactions were not severe, largely self-limiting, seldom led to discontinuation, and did not impact efficacy. Authors noted that dyskinesia was managed by lowering concomitant PD medications, as all patients had dyskinesia or history of dyskinesia at baseline. Nausea could be managed by slower titration; although patients received pretreatment with trimethobenzamide (Tigan), it is no longer available in the United States and its efficacy is not well-established.

At 2023 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held August 27-31, in Copenhagen, Denmark, data from the open-label extension of the phase 3 InfusON trial showed improvements in good ON and OFF time at the first titration visit of CSAI, with durable effects seen 1 year into the maintenance phase.² Following treatment, investigators recorded OFF time reductions of –0.9 h/day (n = 82) by the first titration visit and –1.7 h/day (n = 92) by the second visit. By the end of titration, mean daily OFF time was reduced by –2.8 h/day, or 39% (n = 80), compared with the 6.6 h/day (n = 94) coming into the study. In addition, treated patients demonstrated an improvement of 0.7 h/day in ON time without troublesome dyskinesia, which reached 3.0 h/day by the end of titration (43% increase).

In terms of safety, infusion site nodules was the most common treatment-related AE (63.6%), followed by dyskinesia (29.3%), nausea (24.2%), infusion site erythema (22.2%), dizziness (18.2%), and somnolence (17.2%). Titration was well-tolerated, as 86% of patients successfully entered the maintenance phase; however, 17 patients (17.2%) discontinued, mainly for infusion site nodules (4%) and nausea (3%).

The first prospective, randomized, placebo-controlled trial to assess the efficacy and safety of apomorphine infusion in patients with PD was the TOLEDO study (NCT02006121). Data from the open-label phase of the trial, published in 2021, continued to showcase the efficacy and safety of the therapy as a long-term option for persistent motor fluctuations. Pooled data from week 64 (n = 55) showed a mean change of –3.66 (SD, 2.72) hours in daily OFF time and increase of 3.31 (SD, 3.12) hours in ON time without troublesome dyskinesia.

Apomorphine infusion therapy was also found to allow substantial reductions in oral PD medication. Investigators from that trial concluded that apomorphine infusion represents a minimally invasive and easily reversible treatment option in comparison with intrajejunal levodopa/carbidopa gel and deep brain stimulation.³

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REFERENCES
1. Isaacson SH; Ceresoli-Borroni G, Espay AJ, et al. Continuous Subcutaneous Apomorphine Infusion (CSAI) Responder Rates During Titration: Observations from the Open-label Phase 3 InfusON Trial. Presented at: ATMRD; June 22-25, 2024; Washington, DC.
2. Isaacson S, Ceresoli-Borroni G, Espay A, et al. Early onset of efficacy during titration in US phase 3 open-label InfusON trial of apomorphine subcutaneous infusion for Parkinson’s disease motor fluctuations. Presented at: 2023 MDS Congress; August 27-31; Copenhagen, Denmark. Abstract 68.
3. Katzenschlager R, Poewe W, Rascol O, et al. Long-term safety and efficacy of apomorphine infusion in Parkinson’s disease patients with persistent motor fluctuations: results of the open-label phase of the TOLEDO study. Parkinsonism & Relat Disord. 2021;83:79-85. doi:10.1016/j.parkreldis.2020.12.024