Regulatory Decision Summary for Radicava

Radicava (injection) was previously approved for intravenous (IV) infusion, and is supported by a randomized placebo-controlled Phase 3 clinical trial. The safety of Radicava (oral suspension) was supported by an open-label Phase 3 clinical trial in ALS patients. The efficacy of Radicava (oral suspension) was supported by a comparative bioavailability study in healthy volunteers. Additional clinical studies evaluating food effect, drug interactions, and administration by feeding tube were also evaluated to support the oral route of administration. Non-clinical studies supporting the oral route of administration included absorption, metabolism, repeated-dose toxicity, and carcinogenicity studies. The effects of hepatic and renal impairment and potential QT effects were evaluated using the IV route of administration to complement the safety package submitted in the original New Drug Submission (NDS) for Radicava (injection).

The efficacy of Radicava (oral suspension) was based on a comparative bioavailability study of Radicava (injection) and Radicava (oral suspension) in healthy subjects, which demonstrated comparable exposure with both formulations. Additional exploratory efficacy data were collected from a Phase 3 open-label clinical study in 185 ALS patients treated with 105 milligram (mg) edaravone oral suspension for 24 weeks. The study population was slightly different (i.e., less stringent) compared to the pivotal edaravone IV study, and a placebo group was not included. No efficacy conclusions could be drawn from this study, but the results contributed to the overall profile of the treatment, including the safety assessments discussed below.

Radicava (oral suspension) 105 mg administered orally to healthy subjects under fasting conditions was shown to demonstrate an equivalent area under the concentration-time curve (AUC) with Radicava (injection), 60 mg/60 minute (min) IV infusion, and a maximum plasma concentration (C_max) not less than that of Radicava (injection).

Following fasted oral dosing in healthy subjects, edaravone was rapidly absorbed, with median peak concentrations occurring at approximately 0.5 hour. The mean absolute bioavailability of the oral suspension was 57.3%. The mean terminal elimination half-life of orally administered edaravone was approximately 9 hours. Edaravone was mainly metabolized to sulfate and glucuronide conjugates, which are not pharmacologically active. In human plasma, edaravone was mainly detected as the sulfate conjugate. Edaravone was excreted mainly in the urine as its glucuronide conjugate form.

Edaravone has no identified or expected drug-drug interactions. In vivo and in vitro studies suggested that edaravone is unlikely to have inhibitory effects on CYP3A4 enzymes or P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1 and MATE2-K transporters.

The absorption of oral edaravone in healthy subjects was significantly reduced when it was taken with food. The timing of meals relative to the administration of Radicava is important. Radicava (oral suspension) should be taken in the morning after fasting overnight for at least 8 hours. For patients who are unable to fast overnight, the required fasting interval can be shortened to 4 hours if Radicava (oral suspension) is taken after a low-fat meal (400 - 500 calories, 25% fat), or 2 hours if Radicava (oral suspension) is taken after caloric supplement (250 calories, e.g., a protein drink). Patients should wait at least 1 hour after the dose before eating or drinking anything except water.

Following a single IV infusion of 30 mg Radicava over 60 minutes, the exposure of unchanged edaravone was increased by less than 30% in non-ALS subjects with renal impairment (mild or moderate) or hepatic impairment (mild, moderate, or severe). The studies were conducted using only half of the recommended IV dose. The effects of severe renal impairment on the pharmacokinetics of edaravone have not been studied. Despite some level of uncertainty with the full recommended dose in patients with hepatic or mild to moderate renal impairment, these changes in exposures were not considered to be clinically significant. As a result, no dosage adjustments are necessary in patients with hepatic impairment or mild to moderate renal impairment.

Most of the Phase 1 clinical pharmacology studies for edaravone were conducted in Japanese subjects. However, based on the limited available data, there were no significant racial differences in the exposure of edaravone between Japanese and Caucasian subjects.

In a single-arm study with 9 ALS subjects, the pharmacokinetics of oral edaravone (105 mg) were generally similar to healthy subjects. The data in ALS patients suggested that the pharmacokinetic conclusions drawn from clinical pharmacology studies conducted in healthy subjects can be extrapolated to patients with ALS.

In a single-arm study with 6 ALS patients with percutaneous endoscopic gastrostomy (PEG), the pharmacokinetics of edaravone (105 mg) were similar to ALS patients administered edaravone orally. In a cross-over comparative bioavailability study with 36 healthy subjects, edaravone administered orally or via nasogastric tube (NGT) had comparable bioavailability. Therefore, Radicava (oral suspension) can be administered via a feeding tube in ALS patients without the need for dose adjustment.

At exposures approximately 5 times higher than that of the recommended dose of Radicava (injection) and Radicava (oral suspension), edaravone did not prolong the QT interval to any clinically relevant extent in healthy Japanese male subjects. The effects of edaravone on QT prolongation have not been studied in females or in other races. However, clinical studies did not suggest a race or gender effect on the pharmacokinetics of edaravone.

The primary safety analysis for Radicava (oral suspension) was based on an integrated safety analysis cross-comparing treatment-emergent adverse events (TEAEs) pooled across the Phase 3 edaravone IV studies and the ongoing 24-week interim analysis from the open-label oral suspension study (MT-1186-A01) in 185 ALS subjects. TEAEs due to ALS progression were excluded from this analysis (they were not coded as TEAEs in the IV dataset and they were difficult to distinguish from ALS progression in the open-label study). Secondary analyses for study MT-1186-A01 included events due to ALS progression.

At the 24-week interim analysis of the edaravone oral suspension study, 160 (87%) subjects remained, with a mean exposure of 61 days; 24 (13%) subjects discontinued mostly due to withdrawal (8 patients), TEAEs (7 patients), and death (6 patients).

In the IV formulation studies, 92% of edaravone-treated and 88% of placebo-treated patients remained at 24 weeks; discontinuations (edaravone; placebo) were mostly due to adverse events (AEs) (4 versus 8 patients), or other reasons (11 versus 13 patients).

In the oral edaravone study, the most common TEAEs were muscular weakness (16%), fall (16%), fatigue (8%), constipation (7%), headache (6%), and dyspnea (5%). A total of 60 treatment-related TEAEs were reported in 36 (20%) patients (including those due to ALS), the most common being fatigue, dizziness, headache, constipation, nausea, muscular weakness, and musculoskeletal stiffness. A total of 24 treatment emergent serious adverse events (TESAEs) were reported in 21 (11%) patients, the most common being ALS in 3 patients, dyspnea and respiratory failure in 2 patients each. A total of 17 events in 11 (6%) patients led to discontinuation including respiratory failure (3 patients) and muscular weakness (2 patients). TEAEs leading to death were reported in 6 (3%) patients, including respiratory failure (3 patients); pneumonia, suicide, and ALS (1 patient each). 

In the integrated safety analysis comparing both Radicava formulations and placebo, the oral suspension had a lower incidence of TEAEs, severe and serious TEAEs, primarily driven by a lower incidence of infections. However, there was a higher incidence of treatment-related TEAEs, and TEAEs leading to death excluding AEs related to ALS progression. Common TEAEs that occurred in 2% or more of patients with greater than or equal to 2% difference between groups included fatigue, dizziness, depression, nausea, and decreased appetite. Treatment-related TEAEs included: dizziness, headache, hepatic function abnormal, and fatigue.

Most common adverse drug reactions identified for the IV formulation included contusion, gait disturbance, headache, dermatitis, eczema, respiratory failure, respiratory disorder, glycosuria, and tinea infection. The only additional potential adverse drug reaction reported with oral edaravone was fatigue. An imbalance had been noted for contusion, with no laboratory evidence of effect on coagulation, and was not observed with oral edaravone.

A higher incidence of skin-related TEAEs was identified in edaravone-treated compared to placebo-treated subjects: eczema, dermatitis, rash, erythema, pruritus, urticaria, photosensitivity and toxic skin eruption. Increased incidence across multiple dermatologic AEs suggests a drug–related etiology. Hypersensitivity AEs, including anaphylactic reactions, have been reported post-marketing, and identified as an important potential risk.

Considering the limitations of a single arm open-label study and cross-comparison of oral edaravone safety with pooled studies of IV edaravone, no signal of concern was identified in association with the oral suspension and no significant differences were identified between formulations. The safety profile for the oral edaravone was included in the Product Monograph. Overall, the benefit-harm-uncertainty profile is favorable for Radicava (oral suspension) for the recommended indication.

For further details about Radicava, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.