E-58425

Indication: Moderate to severe pain

Development Phase: II

Partnering Status: USA development by Esteve, exUSA development by Mundipharma

Development Objective:

Increased magnitude of efficacy without increasing side effects

Open to partnerships to optimize USA development and future commercialization

Overview:

E-58425 is a new orally administered therapeutic agent that integrates two well-known active molecules into a new co-crystal entity that provides clinically meaningful analgesic anti-inflammatory benefit over the concomitant use of both molecules or traditional dose combination

The rational for E-58425 is based on a multi-mechanistic approach targeting optimized multimodal analgesia. The key concept is to achieve a superior clinical analgesic effect due to synergism resulting from the complementary action of 4 different well-established and clinically validated mechanisms of actions for pain relief: µ-opioid receptor agonism, inhibition of the neuronal reuptake of norepinephrine and serotonin, and COX-2 inhibition

Human pharmacokinetic data indicate that, when compared to the concomitant administration of marketed single products, E-58425 exhibits significant differences which may result in improved efficacy (including onset of action) and safety and tolerability

Based on human data, neither unpredictable safety concerns nor pharmacokinetic clinically relevant drug-drug interactions between the two APIs are expected

E-58425 market exclusivity is robustly protected by multiple layers of intellectual property (patents granted), data protection, and technological advantage

EXECUTIVE SUMMARY

E-58425 is a novel first-in-class patented co-crystal product entity comprising Celecoxib and Tramadol.

E-58425 is a new therapeutic entity being developed for moderate to severe acute and chronic pain.

Since both APIs in the co-crystal are clinically well characterized, the overall development risk of E-58425 is moderate-low.

The advantage of E-58425 is derived from two key aspects: 1) the pharmacodynamic (efficacy) synergism between its components, and 2) the pharmacokinetic behavior (with clinical therapeutic implications), which is clearly distinct from that seen with a combination approach.

The therapeutic benefit of E-58425 will be achieved at lower –and hence more tolerable– doses of each component active ingredient resulting in a better safety profile and benefit-risk ratio.

A Phase II proof of concept study in acute postoperative pain has shown that E-58425 demonstrated superior efficacy and safety over both placebo and a standard of care.

The clinically relevant and robust pain relief achieved at low doses of E-58425 was associated with a better safety and tolerability profile and benefit-risk ratio.

E-58425 market exclusivity is robustly protected by multiple layers of intellectual property, data protection and technological advantage. E-58425 co-crystal entity new product patent granted in 2013.

PRODUCT CONCEPT

Co-crystal technology

A co-crystal is a crystalline structure formed by two or more different compounds where the intermolecular interactions are not ionic (as it is the case in salts), but weak non-covalent forces like hydrogen bonding and π-π stacking. Unlike polymorphs, which represent different crystalline forms of a compound, a co-crystal results from chemical synthesis and not random recrystallisation.

The co-crystal technology can modify the physiochemical properties of APIs including solubility, dissolution rate, and stability. Consequently, co-crystals may have properties quite distinct from simple combinations. These unique properties can result in improved clinically relevant characteristics such as better absorption and oral bioavailability, and faster onset of action.

ESTEVE has developed an extensive proprietary database and know-how in analgesia synergies between different mechanisms of action as well as compound molecules. This approach includes an analysis with pharmacological data of ratios of interacting mechanisms of action with the objective to identify synergistic efficacy in pain relief associated with the best benefit-risk ratio, that is, optimized efficacy with best safety & tolerability profiles. Through this analysis and assessment of physicochemical characteristics, pharmacological data, pharmacokinetics, metabolism and safety profiles as well as a Product Concept approach, ESTEVE identified Tramadol and Celecoxib as ideal candidates for the co-crystal approach.

Co-crystal proof of concept

E-58425 is designed as a new therapeutic entity and new product to provide a significantly differentiated and enhanced clinical behaviour.

E-58425 allows the optimal delivery of both APIs such that it enhances the overall therapeutic benefit with improved efficacy (superior pain relief) and a better safety profile, hence resulting in an optimized benefit-risk ratio.

The Phase I clinical data demonstrated proof-of-concept validating the co-crystal concept.

CLINICAL OVERVIEW

E-58425 exemplifies optimized multimodal analgesia

The objective of multimodal analgesia is to recruit different mechanisms of action that act at different sites in the central and peripheral nervous systems to produce superior pain relief.

E-58425 benefits from the complementary and synergistic activity across four clinically validated molecular mechanisms of pain relief.

Optimized multimodal analgesia is not equivalent to polymedication or the use of drug combinations per se since optimized multimodal analgesia needs to provide effective pain relief (in magnitude and onset) with minimal side effects, drug interactions, and safety risks.

E-58425 fulfills the criteria for optimized multimodal analgesia with a clinically differentiated and meaningful analgesic anti-inflammatory profile involving two active compounds at an optimal therapeutic ratio, and acting via complementary clinically validated modes of action (with little or no overlap in safety, tolerability and metabolism).

Completed Phase 1 studies in male and female subjects demonstrate that E-58425 presents an optimized differentiated profile when compared to the concomitant administration of the active principles.

Based on human data, neither unpredictable safety concerns nor pharmacokinetic clinically relevant drug-drug interactions between the APIs are expected.

A Phase 2 clinical study in moderate to severe acute pain involving 420 patients showed:

Superior efficacy and safety & tolerability over a standard of care

Clinically relevant and robust pain relief achieved at low doses of E-58425 associated with a better safety & tolerability profile and benefit-risk ratio

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