Objective: Evaluate if dose optimization (DO) of apomorphine sublingual film (APL-130277; APL) can achieve improved FULL “ON” response in patients with Parkinson’s disease (PD) and “OFF” episodes vs the initially efficacious therapeutic dose (TD).

Background: In a pivotal study, APL at doses of 10–35 mg was efficacious and generally well tolerated for on-demand treatment of “OFF” episodes in patients with PD.

Method: A Phase 2 study (NCT03187301) enrolled patients on stable PD medications who were able to have drug-withdrawal–induced “OFF” episodes. Patients underwent APL dose titration (5-mg increments from 10–40 mg; 10-mg increments from 40–60 mg) in a confirmed “OFF” state until a TD achieving FULL “ON” was confirmed. Next, subjects were up-titrated to 2 dose levels (DLs) above the TD up to 60 mg, if tolerated. Changes from predose MDS-UPDRS Part III scores at 30, 60, and 90 min postdose were evaluated post hoc. In addition, an exposure–response (ER) nonlinear mixed‑effects model was developed with apomorphine concentration and clinical response data from up to 9 clinical studies.

Results: 79% of patients were titrated within the first 3 doses (10–20 mg). In the efficacy population, 16 received DO 1 DL higher than TD; 19 received DO 2 DLs higher. Mean (SE) predose MDS-UPDRS Part III scores were similar between TD and DO 1 DL (59.2 [3.90] and 57.8 [3.50], respectively) and 2 DLs higher (50.2 [4.02] and 50.7 [3.79]). Mean postdose reductions in MDS-UPDRS Part III scores were greater with DO vs TD at all timepoints; the greatest improvement (DO-TD) was at 30 min postdose with DO 2 DLs higher (–8.2 [3.23]). For all timepoints, ~3- to 6-fold greater improvement in MDS-UPDRS Part III scores was observed for SD 2 DLs vs 1 DL higher group. The ER model (13,171 MDS-UPDRS measurements from 631 subjects) predicted greater decreases in MDS-UPDRS Part III scores with higher doses, supporting the current analysis. Increasing the APL dose from 10 to 35 mg resulted in a faster time to FULL “ON” (18 to 12 minutes) and a greater MDS-UPDRS response with a longer duration of effect (2.4 to 3.9 hours).

Conclusion: Apomorphine sublingual film given at doses above those initially observed to produce a FULL “ON” may provide greater improvement in motor function. Dose optimization may offer greater clinical benefit and should be attempted as tolerated.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dose-optimization-of-apomorphine-sublingual-film-for-on-demand-treatment-of-off-episodes-in-patients-with-parkinsons-disease-clinical-and-exposure-response-findings/