Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced positive results from its Phase 2 dose-ranging study of the selective NaV1.8 inhibitor VX-548 in people with painful diabetic peripheral neuropathy (DPN). Treatment with all doses of VX-548 resulted in a statistically significant and clinically meaningful reduction in the primary endpoint of change from baseline in the weekly average of daily pain intensity on a Numeric Pain Rating Scale (NPRS) at Week 12. The study also included an active reference arm of pregabalin to support the evaluation of the VX-548 treatment effect.
VX-548 was generally well tolerated at all doses tested in the study. Most adverse events (AEs) were mild to moderate and there were no serious adverse events (SAEs) related to VX-548.
“We are very pleased with these results which add to the body of safety and efficacy data for VX-548 and provide further validation of the analgesic effects of NaV1.8 inhibitors,” said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex. “Given the favorable benefit/risk profile of VX-548 seen in this study, we are working with urgency to advance this investigational non-opioid pain medicine into Phase 3 in painful diabetic neuropathy with the goal of changing the standard of care for neuropathic pain, where treatment options are limited. In addition, our Phase 3 studies of VX-548 in acute pain are on track to read out in the first quarter of 2024.”
“I am excited by the results from the VX-548 Phase 2 DPN study, which demonstrate a promising safety and efficacy profile and represent a significant milestone in pain management,” said Roy Freeman, M.D., Professor of Neurology, Director of the Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center and a member of Vertex’s Pain Steering Committee. “Based on these Phase 2 results, VX-548 could offer the potential for a new class of medicine for the millions of patients suffering from neuropathic pain who are desperate for new options.”
Efficacy Results
The study’s primary endpoint was change from baseline in the weekly average of daily pain intensity at Week 12 in patients with painful DPN dosed with VX-548 using the standard pain assessment Numeric Pain Rating Scale, or NPRS. This 11-point scale ranges from 0 (no pain) to 10 (worst pain imaginable). Patients were randomized to four treatment arms: VX-548 once daily at 69 mg (high dose), 46 mg (mid dose), or 23 mg (low dose), or the reference arm of pregabalin 100 mg three times per day (TID) for 12 weeks.
All VX-548 treatment groups showed statistically significant and clinically meaningful reductions from baseline in pain with mean change in NPRS at Week 12 of -2.26, -2.11 and -2.18 at the high, mid and low doses, respectively. The pregabalin reference arm mean change from baseline in NPRS at Week 12 was -2.09 and is provided for context. All VX-548 dose groups had sustained mean reductions in pain from baseline starting at Week 1, with pain continuing to decrease until Week 5, which was then maintained throughout the treatment period.
Secondary and other endpoints were supportive of the study’s primary endpoint. Importantly, in the responder analysis, more than 30% of patients treated with VX-548 achieved ≥50% reduction in all dose groups, and more than 20% of patients in the mid- and high-dose groups achieved ≥70% reduction in weekly average of NPRS at Week 12 compared to baseline. In the pregabalin reference arm, 22% of patients achieved ≥50% reduction and 10% achieved ≥70% reduction in weekly average of NPRS at Week 12 compared to baseline.
Primary Efficacy Outcomes
| Pregabalin100 mg tidN=47(Reference Arm) | VX-548Low Dose23 mg qdN=24 | VX-548Mid Dose46 mg qdN=48 | VX-548High Dose69 mg qdN=48 | ||
| Baseline | |||||
| Mean (SD) | 5.98(1.28) | 5.70(1.32) | 5.88(0.97) | 5.79(1.22) | |
| Change from baseline at Week 12 | |||||
| LS mean (SE) | -2.09(0.29) | -2.18(0.39) | -2.11(0.28) | -2.26(0.28) | |
| 95% CI | (-2.65, -1.52) | (-2.94, -1.41) | (-2.67, -1.55) | (-2.82, -1.70) | |
| P-value | <0.0001 | <0.0001 | <0.0001 | <0.0001 |
The three VX-548 doses achieved overlapping exposures at the high end of the expected therapeutic range.
Safety Results
VX-548 was generally well tolerated at all doses studied for up to 12 weeks of treatment. The majority of the AEs were mild or moderate in severity. There were no SAEs related to VX-548 or pregabalin in the study. There was one death in the mid-dose VX-548 group due to atherosclerotic cardiovascular disease, which was not related to study drug.
The most common AEs (incidence >5% in either VX-548 combined or pregabalin group, respectively) were creatinine clearance decrease (5.1%, 1.9%), dizziness (0.7%, 9.3%), peripheral edema (0.7%, 5.6%) and weight increased (0%, 7.4%). Related AEs were 14.5% in patients treated with VX-548 and 27.8% in patients treated with pregabalin.
Next Steps for the Pain Portfolio
Vertex plans to advance VX-548 into pivotal development following discussions with regulators.
Vertex has also initiated a second Phase 2 study of VX-548 in peripheral neuropathic pain. This trial will evaluate VX-548 in patients with painful lumbosacral radiculopathy, or LSR, which is pain caused by impairment or injury to nerve roots in the area of the lumbar spine.
Additionally, the three Phase 3 studies of VX-548 in acute pain are on track to read out in the first quarter of 2024.
In line with its portfolio strategy, Vertex continues to advance preclinical and clinical development of additional NaV1.8 and NaV1.7 inhibitors, for use alone or in combination, in acute and neuropathic pain.
