Supernus Pharmaceuticals, Inc. (NASDAQ:SUPN), a pharmaceutical company focused on developing and commercializing products for the treatment of central nervous system diseases, today announced positive topline results from each of two pivotal Phase III studies of SPN-812 in children for the treatment of attention deficit hyperactivity disorder (ADHD).
Both trials were successful in achieving the primary endpoint, with SPN-812, at daily doses of 100 mg and 200 mg in study P301 and 200 mg and 400 mg in study P303. Robust statistical significance in improvement in the symptoms of ADHD from baseline to end of study as measured by the ADHD Rating Scale-5 was achieved. Both active doses in each study were well tolerated.
The Company expects to announce topline data from study P302, the first adolescent Phase III trial of SPN-812, by the end of December 2018. Topline data from the second adolescent Phase III trial, P304, are expected by the end of the first quarter of 2019. The Company expects to submit a New Drug Application (NDA) for SPN-812 in the second half of 2019, and to launch it, pending U.S. Food and Drug Administration (FDA) approval, in the second half of 2020.
“These are very exciting data demonstrating the important role we believe SPN-812 can play in treating patients with ADHD,” stated Jack Khattar, President and Chief Executive Officer of Supernus Pharmaceuticals. “We believe these data from the two pivotal Phase III studies, which are consistent with the Phase IIb data, demonstrate that SPN-812 is a well-differentiated novel non-stimulant treatment option for many children with ADHD.”
About the P301 and P303 Studies
Both studies are randomized, double-blind, placebo controlled, multicenter, parallel group clinical trials in children 6 to 11 years of age diagnosed with ADHD. Each treatment was administered orally once a day over five weeks in study P301 and seven weeks in study P302, after the titration phase.
A total of 477 patients were randomized in the P301 study across placebo and two doses of SPN-812 (100mg/200mg). A total of 313 patients were randomized in the P303 study across placebo and two doses of SPN-812 (200mg/400mg). The primary objective of both studies was to assess the effect of SPN-812 in reducing the symptoms of ADHD in children. The primary outcome measure was the change from baseline to the end of the study in the ADHD-RS-5 total score. Safety and tolerability of SPN-812 were assessed by the monitoring of adverse events, clinical laboratory tests, vital signs, ECGs, suicidality and physical examinations. Patients who completed the study were offered the opportunity to continue into an open-label phase that is currently on-going.
At the end of the study, SPN-812 100 mg and 200 mg doses reached statistical significance compared to placebo in the primary endpoint. Patients receiving SPN-812 100 mg and 200 mg had a -16.6 point change (p=0.0004) and a –17.7 point change (p<0.0001) from baseline, respectively, in the primary endpoint vs. -10.9 for placebo at week 6.
This primary result based on Mixed Model Repeated Measures (MMRM) analysis in the Intent-To-Treat (ITT) population was confirmed by sensitivity analyses using Analysis of Covariance (ANCOVA) (100 mg, p=0.0008; 200 mg, p<0.0001). With respect to the effect size, patients receiving SPN-812 100 mg and 200 mg had an effect size of 0.54 and 0.57, respectively, within the range of 0.46 to 0.63 in the Phase IIb study results.
The study demonstrated fast onset of action, reaching statistical significance for 100 mg and 200 mg doses as early as week 1 with p- values of 0.0004 and 0.0244, respectively. Statistical significance was maintained on a weekly basis through the end of the trial at week 6.
In addition, at the end of the study, SPN-812 100 mg and 200 mg reached statistical significance compared to placebo on the hyperactivity/impulsivity and inattention subscales of the ADHD-RS-5 scale with p- values ranging from <0.0001 to 0.0026.
Finally, SPN-812 100 mg and 200 mg met all secondary endpoints, including the important analysis of the Clinical Global Impression Improvement (CGI-I) secondary endpoint, with p- values of 0.002 and <0.0001, respectively, compared to placebo.
At the end of the study, SPN-812 200 mg and 400 mg doses reached statistical significance compared to placebo in the primary endpoint. Patients receiving SPN-812 200 mg and 400 mg had a -17.6 point change (p=0.0038) and a –17.5 point change (p=0.0063) from baseline, respectively, in the primary endpoint vs. -11.7 for placebo at week 8.
This primary result based on Mixed Model Repeated Measures (MMRM) analysis in the ITT population was confirmed by sensitivity analyses using Analysis of Covariance (ANCOVA) (200 mg, p=0.0058; 400 mg, p<0.0121). With respect to the effect size, patients receiving 200 mg and 400 mg had an effect size of 0.46 and 0.49, respectively, within the range of 0.46 to 0.63 in the Phase IIb study results.
Onset of action for SPN-812 showed clear differences compared to placebo starting by week 1, reaching statistical significance at week 5, which was sustained through the rest of the trial.
Similar to the P301 study, at the end of the P303 study, SPN-812 200 mg and 400 mg reached statistical significance compared to placebo on the hyperactivity/impulsivity and inattention subscales of the ADHD-RS-5 scale with p- values ranging from 0.0020 to 0.0248.
In addition, SPN-812 200 mg and 400 mg met the CGI-I secondary endpoint with p- values of 0.0028 and 0.0099, respectively, compared to placebo.
Safety and tolerability
Overall, both trials exhibited favorable tolerability and safety profiles with low incidence of adverse events (AEs) across all doses. AEs were mild leading to low discontinuation rates due to AEs of 2.2% to 4.8%. Treatment related AEs that reported at more than or equal to 5% for SPN-812 were somnolence, headache, decreased appetite, fatigue, and upper abdominal pain.
“Considering the strong efficacy and robust statistical significance on the primary endpoint, and several other key measures, coupled with a fast onset of action and a favorable tolerability and safety profile, we believe the data from these two pediatric Phase III trials for SPN-812 point to a well-differentiated ADHD product,” stated Dr. Stefan Schwabe, Executive Vice President R&D, Chief Medical Officer of Supernus Pharmaceuticals.
SPN-812 is a norepinephrine reuptake inhibitor with selective serotonin modulation activity that Supernus is developing as a novel non-stimulant for the treatment of ADHD. Based on data generated to date, the Company believes SPN-812 could be a well-differentiated ADHD treatment compared to other non-stimulant treatments for ADHD due to its different pharmacological and pharmacokinetic profile. The active ingredient in SPN-812, viloxazine hydrochloride, has an extensive safety record in Europe, where it was previously marketed for many years as an antidepressant.
About Supernus Pharmaceuticals, Inc.
Supernus Pharmaceuticals, Inc. is a pharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases. The Company currently markets Trokendi XR® (extended-release topiramate) for the prophylaxis of migraine and the treatment of epilepsy, and Oxtellar XR® (extended-release oxcarbazepine) for the treatment of epilepsy. The Company is also developing several product candidates to address large market opportunities in the CNS market, including SPN-810 for the treatment of Impulsive Aggression in ADHD patients, SPN-812 for the treatment of ADHD and SPN-604 for the treatment of bipolar disorder.