Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and “OFF” episodes

Abstract

The efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of "OFF" episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. Methods: Adult patients with levodopa-responsive PD and "OFF" episodes were enrolled. In practically defined "OFF," patients were observed for a FULL "ON" after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10-35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. Results: Among 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL "ON" (66.1% at 10-20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). Conclusion: Among eligible patients with PD and "OFF" episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of "OFF" episodes.

Pharmacokinetics and Comparative Bioavailability of Apomorphine Sublingual Film and Subcutaneous Apomorphine Formulations in Patients with Parkinson’s Disease and “OFF” Episodes: Results of a Randomized, Three-Way Crossover, Open-Label Study

“…Although not specifically measured in this subgroup of patients, clinical and patient-reported findings from studies of apomorphine sublingual film help contextualize the PK findings of this report. In a post hoc analysis of the pivotal phase 3 trial, patients receiving apomorphine sublingual film experienced a ~ two-fold higher magnitude of motor response at 15 min postdose versus patients treated with CD/LD, the gold standard of therapy for PD [ 24 ]. In the pivotal trial, 37% of patients receiving apomorphine sublingual film noted improvement in their condition compared with 20% receiving placebo, as measured by the Patient Global Impression of Improvement scale; patients also reported improvement in their quality of life compared with placebo as measured by European Quality of Life–5 Dimensions instrument [ 17 ].…”

“…Exposure-response modeling based on data from > 600 patients with PD enrolled across several apomorphine sublingual film studies demonstrated substantial interpatient variability in both plasma levels of apomorphine and changes in the MDS-UPDRS Part III scores, suggesting that a plasma concentration to achieve FULL “ON” will vary by patient [ 26 ]. In other clinical trials and in real-world use, at initiation of treatment, apomorphine sublingual film is titrated to the maximum efficacious and tolerated dose to provide a clinical benefit for the individual patient, thus overcoming some of the interpatient variability concerns observed in this small, single-dose study [ 17 , 18 , 24 ].…”

Off-time Treatment Options for Parkinson’s Disease

“…This formulation is conceived to systemically deliver the drug via absorption from the oral cavity mucosa, thus bypassing the extensive first-pass liver metabolism. Titration can be started at a 5–10 mg dose, which could be increased on subsequent days in 5–10 mg increments to a maximum of 40 mg until a full On-response is achieved [ 77 ]. The optimal dose is determined based on individual response, with a titration that can be performed at home without medical supervision, while anti-nausea therapy is not necessary.…”

Should “on-demand” treatments for Parkinson’s disease OFF episodes be used earlier?

“…In addition, patient-assessed onset of ON within 60 min postdose was achieved on more days treated with apomorphine hydrochloride injection versus levodopa (93 % vs 54 %, respectively) [21] . In a post hoc analysis of the pivotal study of apomorphine sublingual film, the magnitude of motor response during open-label dose titration was ∼ 2-fold higher for sublingual film versus the first morning levodopa dose at 15 min postdose, and the peak response occurred earlier (45 vs 90 min) [60] . Further, patient-reported FULL ON was achieved by 72 % of patients treated with apomorphine sublingual film within 30 min postdose [60] .…”