FDA Issues Complete Response Letter for Apomorphine Infusion Device SPN-830 in Parkinson Disease Treatment

Jack Khattar

Credit: Biohealth

According to a new announcement, the FDA has issued a complete response letter (CRL) to Supernus Pharmaceuticals’ for its new drug application (NDA) on SPN-830, an apomorphine infusion device treatment for OFF episodes in patients with Parkinson disease (PD).¹ The CRL indicated that the review cycle of the application is complete but it is not ready for approval in its current form.

In the CRL, the FDA cited 2 areas that require additional review or more information on SPN-830. The first area relates to product quality. Recently, the company submitted additional product quality data to the FDA but has not been reviewed yet. The other area relates to the master file for the infusion device, which is proprietary to the device manufacturer.

Supernus plans to discuss the provision of the requested information with the device manufacturer and the next steps required for resubmission of SPN-830's NDA. In February 2024, the agency completed a successful preapproval inspection of the device manufacturer’s facility, with no noted clinical safety or efficacy issues identified.

“We remain committed to bringing SPN-830 to the market as an important treatment option for PD patients who experience motor fluctuations associated with off episodes. We will work with the FDA to address the CRL and to successfully resubmit our SPN-830 NDA,” Jack Khattar, president and CEO of Supernus, said in a statement.¹

SPN-830, designed as an under-the-skin continuous infusion therapy used between doses of standard levodopa-based therapy, was submitted for the NDA using data from the phase 3 TOLEDO study (NCT02006121). The multicenter trial featured 106 patients with PD who received either 3-mg/hour to 8-mg/hour dose of apomorphine (n = 53) or placebo saline infusion (n = 53) during their waking hours for a 12-week period. All told, treatment with SPN-830 culminated in –1.89 hours per day of better OFF time than placebo, with reductions observed within 1 week of initiating therapy.²

Published in The Lancet Neurology in 2018, TOLEDO was the first randomized, double-blind, placebo-controlled study to investigate the efficacy, safety, and tolerability of apomorphine subcutaneous infusion in patients with PD whose motor fluctuations were uncontrolled despite optimized oral or transdermal therapy. At the conclusion of treatment period, those on SPN-830 experienced –2.47 h per day (SD, 3.70) of reduced OFF time compared with –0.58 (SD, 2.80) for those on placebo (P = .0025). Investigators concluded that this type of therapeutic approach might allow for a reduction in the required doses of concomitant oral antiparkinsonian medications.

SPN-830’s therapeutic pathway has been unique thus far. First, Supernus’ original NDA submission in September 2020 was met with a refusal to file letter months later, which cited an insufficiency in the application. Following a Type A meeting with the FDA, the company officially resubmitted the NDA in December 2021, with no additional safety and efficacy studies required. In October 2022, the company was once again met with pushback, this time in the form of a CRL.

In the CRL, the FDA required additional information and analyses related to the device, including labeling, product quality and manufacturing, device performance, and risk analysis. About a year later, Supernus resubmitted its NDA, and the agency accepted it a month later.³

Additional data from TOLEDO showed that 62% of patients on SPN-830 had at least a 2-hour reduction in OFF time vs 29% of those on placebo. Additionally, 71% of those in the active treated group perceived their general health state as improved vs 18% of those on placebo. This group also saw a 2.77 h/day increase in ON time without troublesome dyskinesia.²

In TOLEDO, investigators observed significantly improved Patient Global Impression of Change scores vs placebo (P <.001), as well as greater, nonsignificant reductions in oral levodopa dose (P = .0615). Those on SPN-830 also had a significantly greater reduction in oral levodopa-equivalent dose than placebo (P = .0014).

In terms of safety, SPN-830 was well tolerated and no unexpected safety signals were observed. Most events were mild or moderate in intensity, and no deaths occurred during the study. Treatment-emergent adverse events (TEAEs) were found in 93% (50 of 54) of patients on SPN-830 and 57% (30 of 53) of those on placebo, with the most common AEs being skin reactions, nausea, and somnolence. Of note, a greater proportion of patients in the apomorphine group experienced an AE that required dose modification.

Six patients, all in the apomorphine group, had an AE that led to study withdrawal. Three patients withdrew because of serious AEs, which includes 1 case of severe hypotension, 1 case of myocardial infarction, and 1 case of persistently abnormal hematology test results indicating mild leucopenia and moderate anemia, but was not found to be hemolytic. The 3 remaining patients withdrew because of experiencing visual hallucination (n = 1), moderate gait disturbance (n = 1), or mild infusion-site erythema (n = 1). All AEs leading to study withdrawal, except for myocardial infarction, were thought to be treatment-related, and all were resolved after cessation of study drug.

In the SPN-830 group, a few patients experienced neuropsychiatric AEs. These included 1 case of mild hypersexuality, 2 cases of mild punding, 3 episodes of confusion in a single patient, and 2 cases of hallucinations. In the placebo group, there were 3 reported episodes of mild confusion and 2 cases of mild hallucinations, which were both resolved.

REFERENCES
1. Supernus Provides Regulatory Update for SPN-830. News Release. Supernus Pharmaceuticals. Published April 8, 2024. Accessed April 8, 2024. https://ir.supernus.com/news-releases/news-release-details/supernus-provides-regulatory-update-spn-830-0
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 resubmits NDA for SPN-830 apomorphine infusion device. News release. Supernus Pharmaceuticals. October 9, 2023. Accessed April 3, 2024. https://ir.supernus.com/news-releases/news-release-details/supernus-resubmits-nda-spn-830-apomorphine-infusion-device-0