Vertex Pharmaceuticals Incorporated announced positive results from its Phase 3 program for the selective NaV1.8 inhibitor, VX-548, in the treatment of moderate-to-severe acute pain. The Phase 3 program included two randomized, double-blind, placebo-controlled, pivotal trials, one following abdominoplasty surgery and one following bunionectomy surgery, as well as a single arm safety and effectiveness study which enrolled patients with a broad range of surgical and non-surgical pain conditions. Treatment with VX-548 following abdominoplasty or bunionectomy surgery resulted in a statistically significant improvement on the primary endpoint of the time-weighted sum of the pain intensity difference from 0 to 48 hours (SPID48) compared to placebo as well as a clinically meaningful reduction in pain from baseline at 48 hours on the Numeric Pain Rating Scale (NPRS) in both studies (abdominoplasty: LS mean difference in SPID48 between VX-548 and placebo = 48.4 (95% CI: 33.6, 63.1; P<0.0001); bunionectomy: LS mean difference in SPID48 between VX-548 and placebo = 29.3 (95% CI: 14.0, 44.6; P=0.0002)).

For the first key secondary endpoint, Vertex tested the hypothesis that VX-548 was superior to hydrocodone bitartrate/acetaminophen (HB/APAP) on SPID48 following abdominoplasty surgery or bunionectomy surgery. Neither trial met this key secondary endpoint (abdominoplasty: LS mean difference between VX-548 and HB/APAP = 6.6 (95% CI: -5.4, 18.7; P=0.2781); bunionectomy: LS mean difference between VX-548 and HB/APAP = -20.2 (95% CI: -32.7, -7.7; P=0.0016)). The second key secondary endpoint in both trials was time to meaningful pain relief defined as =2-point reduction in NPRS from baseline compared to placebo.

VX-548 had a more rapid onset to meaningful pain relief than placebo in both the abdominoplasty and bunionectomy trials. (The median time to meaningful pain relief was 8 hours for placebo in both studies compared to 2 hours in abdominoplasty and 4 hours in bunionectomy for VX-548, with nominal P<0.0001 and 0.0016, respectively.) Other secondary endpoints in both trials were generally consistent with the primary endpoint. The Phase 3 single arm safety and effectiveness study evaluated treatment with VX-548 for up to 14 days across a broad range of other surgical and non-surgical acute pain conditions and demonstrated favorable safety and tolerability, as well as effectiveness as measured by a Patient Global Assessment (PGA) at the end of treatment (83.2% of patients rated VX-548 as good, very good, or excellent in treating pain).

VX-548 was safe and well tolerated in all three Phase 3 studies. The majority of adverse events (AEs) were mild to moderate, and there were no serious adverse events (SAEs) related to VX-548. In general, AEs in the two randomized controlled trials were consistent with the post-surgical setting.

In the VX-548 arm, the incidence of AEs was lower than placebo (patients with any AEs in VX-548 and placebo arms: 50.0% and 56.3%, respectively, following abdominoplasty, and 31.0% and 35.2%, respectively, following bunionectomy). Efficacy Results: Patients aged 18 to 80 years with moderate or severe pain after abdominoplasty surgery were eligible to participate in the trial. 1,118 patients were randomized and dosed with either VX-548 administered orally with an initial dose of 100 mg followed by 50 mg every 12 hours (at 12, 24 and 36 hours after the first dose), hydrocodone bitartrate/acetaminophen (5 mg/325 mg administered orally every 6 hours over 42 hours), or placebo.

Safety Results: VX-548 was generally well tolerated in this study. The majority of adverse events (AEs) were mild to moderate, and there were no serious adverse events (SAEs) related to VX-548. In general, AEs were consistent with the post-surgical setting.

In the VX-548 arm, the incidence of AEs was lower than placebo (patients with any AEs in VX-548 and placebo arms: 50.0% and 56.3%, respectively). AEs with an incidence =5% in any treatment groups (VX-548, placebo, or HB/APAP, respectively) were nausea (19.0%, 25.2%, 32.8%), constipation (10.5%, 10.8%, 8.7%), headache (4.2%, 5.0%, 7.1%), dizziness (4.0%, 7.7%, 5.4%), and hypotension (2.5%, 6.8%, 3.6%). VX-548 Phase 3 Results in Patients Undergoing Bunionectomy: Efficacy Results: Patients aged 18 to 80 years with moderate or severe pain after bunionectomy surgery were eligible to participate in the trial.

1,073 patients were randomized and dosed with either VX-548 administered orally with an initial dose of 100 mg followed by 50 mg every 12 hours (at 12, 24 and 36 hours after the first dose), hydrocodone bitartrate/acetaminophen (5 mg/325 mg administered orally every 6 hours over 42 hours) or placebo. NPRS Reductions From Baseline at 48 Hours in Phase 3 Study of Acute Pain Following Bunionectomy: Safety Results: VX-548 was generally well tolerated in this study. The majority of AEs were mild to moderate, and there were no SAEs.

In general, AEs were consistent with the post-surgical setting. In the VX-548 arm, the incidence of AEs was lower than placebo (patients with any AEs in VX-548 and placebo arms: 31.0% and 35.2%, respectively). AEs with an incidence =5% in any treatment groups (VX-548, placebo, or HB/APAP, respectively) were nausea (8.2%, 10.6%, 14.4%), headache (4.9%, 9.3%, 10.4%), constipation (3.5%, 4.2%, 5.1%), and dizziness (3.5%, 5.1%, 5.3%).

VX-548 Phase 3 Safety and Effectiveness Study Results: Vertex conducted an additional Phase 3 study in 256 patients to evaluate safety and effectiveness in a broad range of surgical and non-surgical moderate-to-severe acute pain conditions. Treatment with VX-548 administered orally with an initial dose of 100 mg followed by 50 mg every 12 hours for up to 14 days demonstrated safety, tolerability and effectiveness across these populations. VX-548 was generally safe and well tolerated in this study.

AEs were mostly mild or moderate, and there were no SAEs related to VX-548. The safety profile in this study was generally consistent with randomized, controlled Phase 3 studies with VX-548. Patient perception of VX-548 effectiveness in treating pain as measured by a patient global assessment (PGA) at the end of treatment showed 83.2% of patients reporting VX-548 as good, very good, or excellent.