Last updated on April 19, 2014 at 9:20 EDT

ESTEVE Announces Publication of Key Preclinical Data for a Novel Oral, First-in-class New Chemical Entity (NCE) Sigma-1 Receptor Antagonist (E-52862), that has Completed Phase I and Initiated its Phase II Clinical Trial Program

July 16, 2012

BARCELONA, July 17, 2012 /PRNewswire/ –

        - The sigma-1 receptor (S1R) is an important development target for
          innovative medications to treat neuropathic pain, for which new medications are much
        - Developed by ESTEVE, E-52862 is a potent, highly selective NCE with a novel
          mechanism of action (S1R antagonism) currently being evaluated for the treatment of
        - In studies conducted to date in preclinical models, a direct relationship
          between dose of E-52862, levels of E-52862 interacting with the S1R in the brain, and
          analgesic activity (pain-relieving effect) was demonstrated.
        - Importantly, in these models, the pain-relieving effect of E-52862 is
          maintained with repeated treatment.
        - E-52862 has completed a rigorous Phase I programme that included more than 300
          subjects. Results show good safety, tolerability, pharmacodynamic and pharmacokinetic
        - Phase II clinical trials evaluating E-52862 are ongoing.

ESTEVE announces the recent publication in the British Journal of Pharmacology[1] of
important preclinical data that furthers understanding of its highly potent and selective,
once-daily, S1R antagonist E-52862, developed by the ESTEVE Research and Development (R&D)

Jose Miguel Vela, PhD, responsible for ESTEVE Drug Discovery and Preclinical
Development, stated, “These data demonstrate the role of ESTEVE’s E-52862, a NCE from our
programme of sigma-1 receptor antagonists, as a novel modulator of pain sensitisation and
relief. It also highlights that the target of this new compound, the sigma-1 receptor, is
correlated mechanistically with the compound’s ability to relieve pain.”

Key data reported in the publication highlight the pharmacological activity of the
selective S1R antagonist E-52862, which acts on the central nervous system (CNS) in
various preclinical models of pain. Importantly, the data show E-52862′s highly targeted
mode of action (MOA) acts specifically on the S1R in relation to pain models evaluated,
meaning normal perception and sensations remain unaffected. In addition, not only was pain
relief sustained with repeated administration of E-52862, but in specific models, some
improvement was observed over time; likely due to the MOA of E-52862 and not to changes in
concentrations of E-52862 in plasma and brain, which were similar after single and
repeated E-52862 administration.

A close correlation was observed between the extent that E-52862 was able to enter the
brain and bind with the S1R in the CNS and the level of pain relief exerted by E-52862. In
studies of CNS excitability, E-52862 significantly reduced the amplification of the
message (hyperexcitability) coming from pain sensors, without affecting non-pain fibers
that transmit other types of sensory stimuli.

The S1R also modulates another receptor – mu-opioid – and affects its activity. As a
result, E-52862 may enhance the pain relief effects of opioids (potentiation of opioid
analgesia) without increasing opioid-related side effects.

The Phase I programme with E-52862 is complete and included more than 300 subjects
(more than 250 received E-52862). Results from the programme show good safety,
tolerability, pharmacodynamic and pharmacokinetic profiles at all doses of E-52862 tested.

Today, ESTEVE’s E-52862 clinical programme focuses on pain management – highlighting
both neuropathic pain and the potentiation of opioid analgesia. The Phase II clinical
trial programme for E-52862 started in early 2012.

E-52862, whose MOA is both novel and complementary to that of other pain medications,
could provide a much-needed addition to future pain management choices with, perhaps, the
option to be used as monotherapy, as well as in combination with other pain relief
compounds, depending on the type of patient and clinical indication.


ESTEVE is a leading pharmaceutical chemical group based on Barcelona (Spain) with
significant international presence. Since it was founded in 1929, ESTEVE has been firmly
committed to excellence in healthcare, dedicating its efforts to innovative R&D of new
medicines for unmet medical needs and focusing on high science and credible,
evidence-based research. ESTEVE has a strong partnership approach to drug discovery,
development and commercialisation. The company works both independently and in
collaboration to bring new, differentiated best-in-class treatments to patients who need
them. ESTEVE currently has a team of about 2800 professionals, and has subsidiaries and
production facilities in several European countries, USA, China and Mexico.

About E-52862 and Pain R&D at ESTEVE

ESTEVE’s dedicated in-house R&D team is focused on the development of novel pain
medications, an area of high unmet medical need. Considerable progress in the knowledge of
the biology and pharmacology of the S1R (a unique protein) during the last few years has
re-energised research into the potential benefits of S1R ligands in a range of
neurological and psychiatric conditions.

New data has addressed key questions on modulation, MOA and pathophysiology of the
S1R. The proprietary ESTEVE S1R knockout mouse demonstrated a direct role of the S1R in
sensitisation phenomena associated with neuropathic pain mechanisms and behaviours.
E-52862 induces robust, dose-dependent analgesic activity in multiple preclinical
neuropathic pain models. E-52862 could have potential applications for other neurological
and psychiatric indications. Besides information reported here, an extensive preclinical
regulatory safety package is available for E-52862 (including 13-week repeat dose toxicity
studies in rats, dogs and monkeys). E-52862 also has robust intellectual property

ESTEVE’s portfolio in pain also includes a technology platform-derived new co-crystal
entity (E-58425) developed by the in-house R&D team at ESTEVE. E-58425 has completed Phase
I, with Phase II currently ongoing. E-58425 is being developed for moderate to severe
acute and chronic pain.


[1] Romero L et al. Pharmacological properties of S1RA, a new sigma-1 receptor
antagonist that inhibits neuropathic pain and activity-induced spinal sensitisation. Br J
Pharmacol 2012 Mar 9 [Epub ahead of print]. doi: 10.1111/j.1476-5381.2012.01942.x.

For more information and enquiries into partnership opportunities, please contact:

Mark Mayhew, PhD, Head of ESTEVE R&D Strategic Partnering, Tel. +34-93-446-6000,

For corporate communications/media enquiries, please contact:

Ma. Angels Valls, Head of ESTEVE Corporate Communications, Tel. +34-93-446-6000,

Visit our new R&D website: http://www.esteve.com/research-development

Follow us on Twitter: @ESTEVE_news


Source: PR Newswire