Introduction
Neuropathic pain is caused by a lesion or disease of the somatosensory system that results in altered and disordered transmission of sensory signals into the spinal cord and brain. There are numerous causes of neuropathic pain including spinal cord injury or other trauma to the nervous system, peripheral diabetic neuropathy, HIV and herpes virus infections, autoimmune disorders and chemotherapy-induced peripheral neuropathy (CIPN). (Colloca et al., 2017) CIPN has a complex and multifactorial aetiology and can present as either acute or chronic neuropathy. For example, acute neuropathy associated with oxaliplatin is characterised by painful cold hyperalgesia or laryngeal dysaesthesia and cramps, while chronic oxaliplatin-induced neuropathy is characterised by numbness in hands and feet which can be functionally disabling. (Saif & Reardon, 2005; Zajaczkowska, Kocot-Kepska, Leppert, Wrzosek, Mika & Wordliczek, 2019) The prevalence of chronic oxaliplatin-induced polyneuropathy is approximately 26–46% at 12 month follow-up. (Zajaczkowska, Kocot-Kepska, Leppert, Wrzosek, Mika & Wordliczek, 2019) Depending on the duration and severity of neurosensory toxicity, the chemotherapy dose may need to be reduced, delayed or the treatment terminated. (Accord Healthcare Limited, October 2019) Current treatments for acute, painful neuropathy provide modest benefit at best and treatment of established chronic neuropathy is largely ineffective. Thus, effective new treatment approaches for CIPN are needed. (Hou, Huh, Kim, Kim & Abdi, 2018)
The sigma1 receptor (σ1R) is a ligand-operated chaperone at the endoplasmic reticulum which regulates multiple processes, including modulation of intracellular signalling cascades related to noxious stimuli, and sensitization and trafficking of proteins involved in nociception. (Ortiz-Renteria et al., 2018; Pabba et al., 2014; Vela, Merlos & Almansa, 2015) The σ1R is expressed at high levels in areas of the central and peripheral nervous system involved in pain transmission and transduction and neuropathic pain-like behaviours are attenuated in σ1R -knockout mice. (Bravo-Caparros et al., 2019; Davis, 2015; Sanchez-Fernandez, Entrena, Baeyens & Cobos, 2017) MR309 (previously E-52862) is a selective σ1R antagonist with a high affinity for human σ1R (Ki=17 nM). (Romero et al., 2012) Data from animal studies indicate MR309 crosses the blood–brain barrier and binds to σ1R in the central nervous system (CNS) and support a potential role in the treatment of neuropathic pain. (Romero et al., 2012) For example, MR309 inhibited formalin-induced nociception, capsaicin-induced mechanical hypersensitivity and sciatic nerve injury-induced mechanical and thermal hypersensitivity in a dose-dependent manner. (Bravo-Caparros et al., 2019; Romero et al., 2012) Knockout animal studies have also implicated σ1R activation in sensory nerve mitochondrial damage and the development of neuropathic pain induced by paclitaxel treatment, indicating a potential role for σ1R antagonists for preventing CIPN. (Nieto et al., 2014) Indeed, in a model of oxaliplatin-induced neuropathy, MR309 prevented hypersensitivity to cold stimuli, and twice daily (BID) administration for 1 week increased the antinociceptive effect. (Gris et al., 2016) Based on preclinical pharmacological studies and animal neuropathic pain models, σ1R occupancy >75% is needed to obtain maximal antinociceptive effect. (Romero et al., 2012)
In early clinical trials MR309 was well tolerated by healthy volunteers, with no serious adverse events (AEs) reported with single doses up to 800 mg, or 400 mg once daily (QD) for 8 days, and some mild-to-moderate transient CNS effects observed with the highest dose. (Abadias, Escriche, Vaque, Sust & Encina, 2013) MR309 400 mg QD was also well tolerated by patients with colorectal cancer receiving oxaliplatin within a FOLFOX regimen, with preliminary signs of efficacy for oxaliplatin-induced peripheral neuropathy and hyperexcitability motor symptoms. (Bruna et al., 2018) A four-week study with MR309 400 mg QD in patients with chronic post-surgical neuropathic pain (PSNP) for > 6 months reduced the primary end point (average pain intensity between baseline and last week of dosing) significantly better than placebo (EU Clinical Trials Register (EudraCT 2012-000402-30)). Pharmacokinetic (PK) data in healthy volunteers indicate that MR309 is absorbed rapidly, and systemic exposure (AUC\(\tau\)) increased proportionally with ascending dose up to 100 mg QD. At higher doses extent of exposure increased in a greater than dose proportional manner. (Abadias, Escriche, Vaque, Sust & Encina, 2013) Based on Cmax, the estimated therapeutic dose range of MR309 was 100–400 mg. (Abadias, Escriche, Vaque, Sust & Encina, 2013) Although not investigated to date, BID dosing might be expected to result in less fluctuation of MR309 plasma concentrations compared with QD administration, thereby potentially improving tolerability and efficacy.
While clinical data are needed to provide insight into the efficacy of MR309, (Bruna et al., 2018) pharmacodynamic (PD) markers to guide dose selection for agents targeting the σ1R pathway are currently lacking. [11C]SA-4503 is a selective σ1R positron emission tomography (PET) radioligand suitable for quantifying σ1R density in the human brain, and has been used to estimate brain σ1R occupancy in healthy volunteers administered haloperidol and fluvoxamine. (Ishikawa et al., 2007; Ishiwata et al., 2006; Mansur et al., 2019) Assessment of the relationship between σ1R occupancy and the plasma concentration of MR309 will confirm the drug target interaction in the human brain, and help establish a suitable dose range for future clinical studies.
Here, we report two exploratory studies which assessed the relationship between MR309 given BID and QD and plasma concentration at steady-state (PK study), and the relationship between plasma exposure of MR309 and occupancy of σ1R in the brain, using PET with the selective σ1R radioligand, [11C]SA-4503 (PET study).