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16 December 2020

Peripheral NOP agonist addressing chronic peripheral neuropathic pain enters clinical development

Light microscopy of a nerve ganglion
Grünenthal announced today that the first participants have been enrolled in a Phase I trial of a peripherally restricted Nociceptin/orphanin peptide receptor (NOP) agonist, an oral investigational medicine with a unique mechanism of action for the treatment of chronic peripheral neuropathic pain.

In Phase I studies, investigational medicines are initially tested on humans, after they succeeded in rigorous pre-clinical tests. The Phase I trial at hand will include 76 healthy participants. The trial aims to demonstrate a favourable safety and tolerability profile and to confirm the pharmacokinetic characteristics of the compound following single and multiple-ascending doses. The results of the study are expected to be available in 2021.

Pain remains a high unmet medical need that Grünenthal strives to address with innovative medicines. Progressing this peripheral NOP agonist into clinical development is a major success in the company’s efforts to build an industry-leading pipeline of investigational medicines. By driving the development of these compounds, Grünenthal strives to change the life of patients for the better and make progress towards its vision of a world free of pain.

Grünenthal is committed to research and development in the therapeutic area of pain. Recently, the company announced that it has agreed to acquire the European rights of Crestor®, the latest milestone in a series of deals and acquisitions worth a total of more than $1.7 billion since 2016. By adding strong brands to its portfolio, Grünenthal significantly strengthens its financial performance and thus ensures sufficient financial headroom to be able to invest in innovative research-projects in the long term.

The investigational medicine at hand is a Grünenthal proprietary development based on extensive research in the field of the NOP receptor and currently the most advanced compound of the company’s peripheral, selective Nociceptin/orphanin FQ (N/OFQ) peptide receptor agonist programme. Pre-clinical data has shown an analgesic effect in a wide range of models1. In addition, the investigational medicine’s selectivity for the NOP receptor, combined with its peripherally restricted mode of action, may lead to an improved safety profile compared to the currently available standards of care.

About chronic neuropathic pain

Neuropathic pain is defined as pain that arises as a direct consequence of a lesion or diseases affecting the somatosensory system, i.e. a complex system of sensory neurons and pathways that responds to changes at the surface or inside the body. Neuropathic pain can result from nerve injury or disease affecting the peripheral or central nervous system. It is characterised by symptoms such as shooting or burning pain, numbness, altered sensation, and sensations that are very difficult to describe. General population studies, using validated screening instruments, have found that 7-10% of adults currently have chronic pain with neuropathic characteristics2. According to the International Association for the Study of Pain (IASP), this pain is generally more severe, and is associated with worse health, in every measured dimension compared to non-neuropathic pain3. 17% percent of those who had pain with neuropathic characteristics had health-related quality of life scores equivalent to “worse than death” in a U.K study, compared to only 3% of those without neuropathic characteristics4. Patients with neuropathic pain generally do not respond to analgesics such as acetaminophen, NSAIDs or weak opioids such as codeine5. Despite the availability of various treatment options as well as guidelines, treatment remains a challenge6.

About Pharmacokinetic characteristics

Pharmacokinetics examines how a substance is processed through the mechanisms of absorption, distribution and excretion. It also examines the metabolic changes of the substance from the moment that it is administered into the living organism up until the point at which it is completely eliminated from the body.

About NOP Receptor

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) is a G protein-coupled receptor whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ).7 NOP agonists have been shown to act as powerful, non-addictive painkillers in pre-clinical models. Although NOP shares high sequence identity (~60%) with classical opioid receptors μ-OP (MOP), κ-OP (KOP), and δ-OP (DOP), it possesses little or no affinity for opioid peptides or morphine-like compounds. Likewise, classical opioid receptors possess little affinity towards NOP's endogenous ligand nociceptin.8

1 Grünenthal Data on file
2 Colloca L et al. Nat Rev Dis Primers. 2017 Feb 16
3 IASP, Factsheet “Epidemiology of Neuropathic Pain”, 2014,
4 Torrance N et al 2014 Oct; 155 (10): 1996
5 Torrance N et al 2014 Oct; 155 (10): 1996
6 Colloca L et al. Nat Rev Dis Primers. 2017 Feb 16
7 Henderson G, McKnight AT (August 1997). "The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ". Trends in Pharmacological Sciences. 18 (8): 293–300. doi:10.1016/S0165-6147(97)90645-3. PMID 9277133.
8 Butour JL, Moisand C, Mazarguil H, Mollereau C, Meunier JC (February 1997). "Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids". European Journal of Pharmacology. 321 (1): 97–103. doi:10.1016/S0014-2999(96)00919-3. PMID 9083791.