Selective Sigma-1 Receptor Antagonist (S1RA), E-52862

Indicator: Neuropathic pain / acute and chronic pain in patients receiving opioids

Development Phase: II

Partnering Status: Worldwide Development Rights Mundipharma-Purdue

Development Objectives:

Improved efficacy higher response rate and increased magnitude of effect

Increased magnitude of effect

Improved safety and tolerability

Improved benefit-risk ratio


Pharmacological activity in multiple preclinical pain models at doses devoid of adverse effects. Extensive preclinical regulatory safety package available.

Low potential for drug-drug interactions

Fast absorption and good oral bioavailability

Human PK compatible with once-a-day administration and fast onset of action

Comprehensive Phase I program completed (>250 male and female subjects exposed to S1RA) showing good safety and tolerability profile in healthy human volunteers

Robust IP protection through 2025 + extensions


Compound: Sigma 1 receptor antagonist (S1RA): New Chemical Entity.

Mechanism of Action: Sigma 1 receptor antagonism; new mechanism of action for pain.

Stage of Development: Phase 2

Clinical Indications: Neuropathic pain caused by various conditions, and treatment of pain in patients receiving opioids (add-on therapy to analgesic opioids for the enhancement of the analgesic effect: better or similar efficacy, better tolerability with fewer and less severe opioid-related adverse events and a reduction in opioid consumption). S1RA also has potential applications for other neurological and psychiatric indications.

Intellectual Property: Composition of matter protection through 2025 plus extensions; multiple patents on methods of use, formulation and manufacturing process, metabolites, amongst others.


ESTEVE has been working in the field of sigma-1 receptors and has accumulated significant know-how and expertise.

S1RA is a potent and highly selective sigma-1 receptor antagonist that represents a novel approach and a new mechanism of action for pain in a field with a significant need for new therapies.

Robust activity has been demonstrated in vitro and in vivo in multiple animal models of neuropathic pain (including nerve injury, diabetic neuropathy, chemotherapy-induced neuropathy), bone cancer pain, and potentiation of opioid analgesia.

CM&C data show a highly developable profile.

The PK profile in human indicates that S1RA can be conveniently administered once daily, potentially with no requirement for titration and with a low risk of drug-drug interactions.

S1RA penetrates into the brain and binds to the sigma-1 receptors. There is a direct relationship between dose, receptor occupancy of S1RA in brain and pharmacological activity.

Comprehensive preclinical regulatory safety package available. Regulatory toxicology package includes 13-week repeated dose oral toxicity studies in rats, dogs and rhesus monkeys.

Not teratogenic in rat and rabbit studies.

No findings that preclude further development.

As many currently available treatments for pain are associated with troublesome side effects, and/or limited efficacy, and/or require frequent dosing and/or titration, S1RA offers the potential for improvement over current therapeutic options.

S1RA provides a novel approach with a mechanism of action which is complementary to those of other drugs used in pain management, and also supports potential combination usage with other analgesic compounds.


In the Phase 1 program, 255 human subjects (male and female) were administered S1RA. Good safety, tolerability, pharmacodynamic and pharmacokinetic profiles were observed at all doses of S1RA tested (5-800 mg). The maximum tolerated single dose of S1RA is at least 800 mg/day.

Clinical chemistry, hematology, and urinalysis were normal.

Electrocardiography: No clinically relevant changes in QTc interval or in any parameter of the 12-lead ECG, or in the 24-hour Holter monitoring were observed.

CNS safety pharmacodynamic assessments: No clinically relevant CNS effects were observed in psychometric tests (VASs), Evaluation of Sleep and Awakening Quality (SSA), Addiction Research Center Inventory (ARCI), End-of-Session (EOS) questionnaire about drug-liking and drug-identification, or in computerized cognitive evaluations.

The majority of AEs were CNS related as would be expected from a centrally active molecule.

S1RA exhibits a fast absorption (Tmax = 0.75 - 2.0 h), rapid distribution and slow terminal elimination (T½ = 14.8 - 19.7 h for the estimated therapeutic dose range). Cmax and AUC increase with dose. In the human multiple dose study, steady-state was reached. There were no gender differences in the pharmacokinetics (PK) of S1RA. Hence, human PK is compatible with once-a-day administration and fast onset of action.

Phase 2 clinical studies with S1RA in neuropathic pain of different etiologies (including from diabetic, post-surgical and chemotherapy origins) as well as in moderate to severe acute post-operative pain are ongoing.


The project S1RA has mostly been funded with Esteve's own resources, as well as being aided by the Ministry of Economy and Competitiveness, through the Center of Industrial Technological Development (CDTI) for clinical validation in neuropathic pain.

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