MICA: CB2 agonists as a novel treatment for women with endometriosis-associated pain

Endometriosis is a chronic incurable disease that affects an estimated 176 million women worldwide. This incidence in women of reproductive age is similar to that of diabetes mellitus or asthma (approximately 1.5 million women in the UK). Endometriosis can cause chronic, debilitating, pelvic pain including excessively painful periods and pain with sexual intercourse. Endometriosis costs the UK economy >£9 billion per year in health care and associated costs and has a devastating impact on the health and wellbeing of patients.

Up to 90% of women with endometriosis suffer from 'peritoneal disease' caused by the presence of small pieces of tissue ('endometrium' or womb lining) that have attached onto the wall of the pelvic cavity (peritoneum). Once embedded on the peritoneal wall these 'endometriosis lesions' attract nerves, and immune cells that interact with each other and relay pain messages to the brain. Thre is no cure for endometriosis. Surgical removal of lesions (with its inherent risks) can give temporary relief but symptoms recur in up to 75% of women. Current drugs used as an alternative to surgery include those that have an impact on hormones with unwanted side effects including those resembling a premature menopause (flushes, infertility). Many women also take non-steroidal anti-inflammatory drugs but there is no good evidence that they provide long-term relief and they can have an adverse effect on the gut.

The body is equipped with a sophisticated 'endocannabinoid' system that is part of our natural pain and immune defense network. These endocannabinoids are produced naturally from lipids in the body and they can alter the function of immune cells, such as macrophages and mast cells, dampening down of the body's pain responses. Phyto-cannabinoids, present in cannabis plants, have been widely used as a self-management strategy by patients suffering from chronic non-cancer pain. Cannabinoids are synthetic drugs that have been developed to mimic the beneficial effects of phytocannabinoids without triggering their intoxicating side effects. A new generation of 'smart' drugs targeting one of the cannabinoid receptors (CB2) has been developed as a front line therapy for treatment of chronic pain. To date these drugs have not been tested as a treatment for women with chronic pain due to endometriosis.

We will test a cannabinoid compound developed by Eli Lilly using our novel preclinical model of endometriosis. Using this model we will assess the impact of the cannabinoid on pain behaviours and also on the phenotype of cells within the lesions. The primary purpose of this study is to gather information in preparation for a clinical trial in women with endometriosis.

Endometriosis is a chronic, incurable, inflammatory disorder affecting ~10% of women of reproductive age half of whom suffer from debilitating pelvic pain. Current treatments include invasive surgeries and hormonal suppression with the latter having undesirable side effects. Peripheral neuro-inflammation plays a pivotal role in activation of both central and peripheral pain pathways in endometriosis. We have shown that nociceptive ion channels are overexpressed in the peritoneum and endometriosis lesions of women with pelvic pain and inflammatory cells are abundant in their lesions. The endocannabinoid system is known to modulate inflammatory/immune mechanisms and pain processing. Endocannabinoids act via CB1 or CB2 receptors; CB1 is responsible for the psychotomimetic side effects of cannabinoids. CB2 has emerged as a key therapeutic target for a range of painful conditions but has not been rigorously tested as a treatment for endometriosis.

We believe treatment with the CB2 receptor agonist LY2828360 offers a novel approach to treatment of women with endometriosis-associated pain. We will evaluate the impact of LY2828360 using a mouse model of endometriosis that replicates key features of the disease in women. A unique feature of our model is the introduction of 'menstrual' tissue into the peritoneum of immune competent mice. This menstrual tissue is cytokine-rich, with high concentrations of matrix remodeling proteins, mast cells and macrophages mimicking the endometrial tissue that is released into the peritoneal cavity leading to the establishment of endometriosis lesions that attract nerves and blood vessels. The lesions formed in recipient (ENDO) mice phenocopy those recovered from patients attending our pain clinic. Following establishment of lesions the ENDO mice exhibit altered pain behaviours (both spontaneous and induced) that can be quantified. The data from this study will be used to support a future clinical trial in women with endometriosis.

Impact on patients
Endometriosis is an incurable disorder that causes chronic pain. Current treatments include surgical excision or hormonal suppression. National patient organisations report that women want to avoid surgery and to have access to medical treatments with fewer side effects.
We will test the CB2 receptor agonist (LY2828360) as a novel therapeutic option for treatment of pelvic pain. This preclinical study is designed to provide evidence for a subsequent clinical trial which if successful will increase the treatment options for women allowing them to avoid surgery and the side-effects of current medical hormone suppressive therapies.

Impact on the biomedical research community
The results of our project will be communicated via primary publications, accessible review articles, conferences, our websites and presentations to Pharma. We will present at national and international meetings attended by clinicians and researchers involved in endometriosis research and care. At a national level, AWH and PTKS have initiated the formation of an Endometriosis Research Network providing a forum for exchange of ideas/experiences between researchers, health professionals and patients with biannual meetings. The results obtained will also be of particular interest to clinical researchers working on other chronic pain conditions and we will endeavor to disseminate the data to them as appropriate.

Impact on Policy makers
Endometriosis has received relatively little attention compared with other chronic disorders. In 2014, AWH organised an event (>100 attendees, including politicians, clinicians, patients) in the Scottish Parliament to campaign for better care and research across Scotland for women with endometriosis. AWH and colleagues have subsequently established a Scottish Government Endometriosis Short Life working group working closely with Scotland's Chief Medical Officer to take this forward. In addition, AWH and PTKS are members of the Steering Group for the Endometriosis Priority Setting Partnership being managed under the auspices of the James Lind Alliance run by NIHR [http://www.jla.nihr.ac.uk/]. The results of this Initiative will be published and widely disseminated to research organisations, organisations responsible for health care, and policy makers in the UK and Ireland.

Impact on the commercial sector
This project will test the efficacy of a product developed by Eli Lilly and Co. Lilly have already made a very significant investment in this compound including comprehensive toxicity testing in animals and humans. The CB2 agonist LY2828360 was well tolerated but its development as a treatment for osteoarthritic knee pain (the original clinical indication) was discontinued after Phase II clinical trials. Repurposing of this product for treatment of women with endometriosis-associated pain would open up a new market for LY2828360 and for other compounds targeting the endocannabinoid CB2 receptor.
Impact on training and capacity building
This project enables the postdoctoral fellow to gain experience in using a mouse model for preclinical testing using behavioural tests and a range of cell/molecular/protein analyses. The research technician will learn skills in animal handling, surgery, administration of substances and histological analysis. The postdoctoral fellow will gain experience in presenting and defending their research at national and international conferences.

Impact on the public and wider society
We engage with the public via print and a range of digital media including a dedicated webpage [www.exppectedinburgh.co.uk]. PTKS shares information about endometriosis on Facebook and we all participate in public events including the Edinburgh Science Festival.