ESTEVE, a pharmaceutical company focused on developing novel therapeutics for pain (http://www.esteve.com/research-development) today announces positive top line results from its recently completed phase II trial, which was designed to evaluate the efficacy and safety of E-58425 in acute pain.
E-58425 is a patented new product co-crystal entity of two active pharmaceutical ingredients (APIs). Phase I clinical testing demonstrated that the new co-crystal entity exhibited distinct and optimized pharmacokinetic properties with respect to those of the simple co-administration of the two individual APIs, thus strongly differentiating E-58425.
The positive phase II data presented here confirm that E-58425 delivers synergistic efficacy accompanied by an excellent safety and tolerability profiles.
The study (420 patients) was randomized, double-blind, and controlled with Placebo and Tramadol (100 mg) in parallel groups in the post-operative management of moderate to severe pain following extraction of two or more impacted third molars requiring bone removal. The study was designed to evaluate the effective doses among four strengths of E-58425 (50 mg, 100 mg, 150 mg and 200 mg), and compared with Placebo and Tramadol. All of the dosage strengths of E-58425 tested contained amounts of the individual APIs that would be considered sub-therapeutic in the moderate to severe pain model used.
The results of the trial, in a complex pathophysiology pain model, show that:
The 100 mg, 150 mg and 200 mg doses of E-58425 were associated with a dose dependent, statistically significant and clinically relevant superior analgesic activity in the primary endpoint (sum of pain intensity differences at 8 h) versus Placebo (P < 0.002 for all three E-58425 doses).
The 100 mg, 150 mg and 200 mg doses of E-58425 were also associated with a dose dependent, statistically significant and clinically relevant superior analgesic activity in the primary endpoint versus Tramadol 100 mg (P < 0.02 for all three E-58425 doses). The 50 mg dose of E-58425 also exerted superior efficacy compared to the 100 mg Tramadol comparator; however this result was not statistically significant.
There was also a faster onset of action, longer duration of analgesia, and less need for rescue medication with E-58425.
Regarding safety and tolerability, 50 mg and 100 mg doses of E-58425 showed a frequency of treatment emergent adverse events (TEAEs) very similar to placebo, while the 150 mg dose of E-58425 was associated with 50% less TEAEs (in both % of patients with AEs as well as AE count) compared to Tramadol 100 mg.
The overall Phase II results support the Product Concept of E-58425: Clinically relevant and robust pain relief achieved at low doses of E-58425 (hence low dose of each active ingredient) associated with a better safety & tolerability profile and risk-benefit ratio. Therefore, E-58425 has demonstrated a strong improvement in efficacy and has significantly improved the risk-benefit ratio compared to that expected for the individual components.
The results also support that while both active ingredients act via different complementary central and peripheral mechanisms of action for synergy in efficacy, they have little or no overlap in safety, tolerability and metabolism, and therefore, neither unpredictable safety concerns nor clinically relevant drug-drug interactions between the active principles are expected.
ESTEVE is currently seeking partners to support the further development of E-58425 in both acute and chronic moderate to severe pain.