FDA Approves Apomorphine Infusion Device SPN-830 as New Parkinson Treatment

Nearly 4 and a half years since its original submission, the FDA has approved Supernus Pharmaceuticals’ investigational agent SPN-830 (Onapgo) as the first and only subcutaneous apomorphine infusion device for the treatment of motor fluctuations in adults with advanced Parkinson disease (PD). The company also noted that it will make SPN-830 available in the second quarter of 2025 with a support team of experts, including a robust nurse education program, and access support at launch.¹

The therapy’s approval was based on data from the TOLEDO study (NCT02006121), a randomized, double-blind study in which treatment with the device was associated with a difference of –1.89 hours per day of OFF time for patients with PD in comparison with placebo. Published in the Lancet Neurology in 2018, the study randomly assigned 106 patients living with the disease to either 3-mg/hour to 8-mg/hour dose of apomorphine (n = 53) or placebo saline infusion (n = 53) during their wake hours for a 12-week period.²

“Continuous subcutaneous apomorphine infusion already has a proven and established 30-year history in Europe, where it has helped deliver more consistent control of motor fluctuations for thousands of patients,” clinical trial investigator Rajesh Pahwa, MD, Laverne and Joyce Rider Professor of Neurology at the University of Kansas School of Medicine, Director of the Movement Disorder Program at The University of Kansas Health System, said in a statement.¹ “In a clinical trial in Europe, patients treated with ONAPGO experienced a significant reduction in daily OFF time and a similar significant increase in GOOD ON time. Today’s approval of ONAPGO means patients in the U.S. who are not responding well to their current treatment regimen, including levodopa, will now have the option of using a small and lightweight wearable device to deliver a continuous infusion without the need for an invasive surgical procedure.”

In TOLEDO, the intervention group, with a mean final drug dose of 4.68 mg/hour, showed significant improvements, including a reduction in OFF time of –2.47 hours/day compared with –0.58 hours/day for placebo (P = .0025), and an increase in ON time without troublesome dyskinesia of 2.77 hours/day versus 0.80 hours/day for placebo (P = .0008). Additionally, 62% of the apomorphine group were responders compared with 29% in the placebo group (P = .0008).

The timeline for SPN-830 dates back to September 2020, when Supernus sent its original new drug application (NDA) to the FDA.³ Shortly after, the FDA issued a refusal to file letter indicating that the NDA was not sufficiently complete to permit a substantive review. Nearly a year later, in December 2021, the company resubmitted its NDA; however, it was once again met with resistance, as the FDA issued a complete response letter (CRL) months after in October 2022.^4,5

In the CRL, the agency noted that it required additional information and analyses related to the device, including labeling, product quality and manufacturing, device performance, and risk analysis. At the time, no additional efficacy or safety clinical studies were required. Notably, the FDA mentioned in the letter that the application's approval would require inspections that could not be completed in a timely manner, primarily because of travel restrictions amid the COVID-19 pandemic.

“As the motor symptoms of Parkinson’s disease worsen over time, patients report alternating states between ON when their medication is working, and OFF when it’s not working optimally,” Andrea Merriam, CEO of the Parkinson & Movement Disorder Alliance, said in a statement.¹ “These on-again, off-again changes are disruptive and can happen at any time, which is why consistent daily control of OFF time is key to improving how patients feel and move. For many, continuous treatment options like ONAPGO can help to make days with Parkinson’s more predictable.”

Supernus submitted a second NDA for SPN-830 in October 2023 which was subsequently accepted by the FDA less than a month later.⁶ In April 2024, the FDA issued another CRL for the device, citing 2 areas that required additional review or more information.⁷ The first was related to product quality while the second related to the master file for the infusion device, which is proprietary to the device manufacturer. Supernus went back to make adjustments and thus, towards the latter half of 2024, the company announced that the FDA accepted its resubmission of the NDA for SPN-830, giving it a PDUFA date of February 1, 2025.⁸

READ MORE: Updates in Therapeutic Development: Clinical Trial Readouts to Watch in the First Half of 2025

At the end of the treatment period in TOLEO, patients on SPN-830 experienced a mean reduction in OFF time of –2.47 hours per day (SD, 3.70) compared with –0.58 hours per day (SD, 2.80) for those on placebo (P = .0025). Investigators suggested that this therapy could potentially reduce the need for higher doses of concomitant oral antiparkinsonian medications.

Additional data from the study showed that 62% of patients on SPN-830 achieved at least a 2-hour reduction in OFF time compared with 29% of those on placebo. Overall, 71% of the SPN-830 group reported improvements in their general health compared with 18% in the placebo group. Patients on the active treatment also experienced a 2.77-hour/day increase in ON time without troublesome dyskinesia and significantly improved Patient Global Impression of Change scores (P < .001). While reductions in oral levodopa dose were not significant (P = .0615), SPN-830 led to a significantly greater reduction in levodopa-equivalent dose than placebo (P = .0014).

“ONAPGO represents a novel approach for adults with Parkinson’s disease who are experiencing motor fluctuations,” Jack Khattar, president and CEO of Supernus Pharmaceuticals, said in a statement.¹ “Supernus’ significant experience in CNS has fueled the success of more than eight widely recognized products in CNS and other therapeutic categories. The addition of ONAPGO demonstrates our continued commitment to developing novel alternatives to manage Parkinson’s disease and other neurological conditions.”

Apomorphine was first approved in 2004 under the brand name Apokyn for the acute, intermittent treatment of OFF episodes in PD. Apokyn is different from SPN-830, as it is administered by subcutaneous injection with a multiple-dose pen injector that can be used up to 5 times a day, with doses no less than 2 hours apart. Apomorphine works as a dopamine agonist that binds with high affinity to the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C receptors.

In TOLEDO, SPN-830 was generally well tolerated, with no unexpected safety concerns. Most adverse events (AEs) were mild or moderate, and no deaths occurred. TEAEs were reported in 93% of patients on SPN-830 compared with 57% on placebo, with common AEs including skin reactions, nausea, and somnolence. A higher proportion of patients in the apomorphine group experienced AEs requiring dose modification.

Six patients in the SPN-830 group withdrew from the study due to AEs. Three of these withdrawals were due to serious events: severe hypotension, myocardial infarction, and abnormal hematology results indicating mild leucopenia and moderate anemia (non-hemolytic). The remaining three withdrawals were attributed to visual hallucinations, moderate gait disturbance, and mild infusion-site erythema. Except for myocardial infarction, all AEs leading to withdrawal were considered treatment-related and resolved after discontinuation of SPN-830.

"As Parkinson’s disease progresses, levodopa treatment often becomes less effective at delivering consistent motor control in part due to GI dysmotility, variable absorption of oral medication, and the resulting pulsatile stimulation of dopamine pathways in the brain," clinical trial investigator Stuart Isaacson, MD, director of Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida, said in a statement.¹ "With ONAPGO, the continuous infusion of apomorphine directly stimulates postsynaptic dopamine receptors with no metabolic conversion needed. In addition, the subcutaneous delivery of apomorphine bypasses the GI tract and enters the brain, which can allow for more predictable symptom improvement."

REFERENCES
1. Supernus Announces FDA Approval of ONAPGO™ (apomorphine hydrochloride) for Parkinson’s Disease. News Release. Supernus. Published Febrauary 4, 2025. Accessed February 4, 2025. https://ir.supernus.com/news-releases/news-release-details/supernus-announces-fda-approval-onapgotm-apomorphine
2. Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomized, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759. doi:10.1016/S1474-4422(18)30239-4
3. Supernus Submits NDA for SPN-830 for Continuous Treatment of ON-OFF Episodes in Adults with Parkinson’s Disease Who Have Failed Two Treatments. News release. Supernus Pharmaceuticals. September 14, 2020. Accessed February 1, 2025. https://ir.supernus.com/news-releases/news-release-details/supernus-submits-nda-spn-830-continuous-treatment-episodes
4. Supernus Resubmits NDA for SPN-830 Apomorphine Infusion Device. News release. December 8, 2021. Accessed February 1, 2025. https://ir.supernus.com/news-releases/news-release-details/supernus-resubmits-nda-spn-830-apomorphine-infusion-device
5. Supernus Provides Regulatory Update on SPN-830. News release. Supernus Pharmaceuticals. October 2022. Accessed February 1, 2025. https://ir.supernus.com/news-releases/news-release-details/supernus-provides-regulatory-update-spn-830
6. Supernus resubmits NDA for SPN-830 apomorphine infusion device. News release. Supernus Pharmaceuticals. October 9, 2023. Accessed February 1, 2025. https://ir.supernus.com/news-releases/news-release-details/supernus-resubmits-nda-spn-830-apomorphine-infusion-device-0
7. Supernus Provides Regulatory Update for SPN-830. News Release. Supernus Pharmaceuticals. Published April 8, 2024. Accessed February 1, 2025. https://ir.supernus.com/news-releases/news-release-details/supernus-provides-regulatory-update-spn-830-0
8. Supernus Announces SPN-830 Apomorphine Infusion Device NDA Accepted for Review by FDA. News release. Supernus Pharmaceuticals. August 19, 2024. Accessed February 1, 2025. https://ir.supernus.com/news-releases/news-release-details/supernus-announces-spn-830-apomorphine-infusion-device-nda-0