The potential of colokinetics to assist in bowel management in people with spinal cord injury Translation from Laboratory to Clinic

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1 The potential of colokinetics to assist in bowel management in people with spinal cord injury Translation from Laboratory to Clinic Principal Investigators: John Furness, Albert Frauman, Andrew Ellis, Doug Brown, Dorota Ferens, Melinda Millard, Brid Callaghan, Ruslan Pustovit, Leni Rivera, James Brock, Mark Habgood Connections 2014

2 Living with SCI: The impact of bowel problems Widerström-Noga,1999: reported that 86% of people with SCI had problems with bowel control Snoek 2004: 75% of paraplegics nominated bowel problems as important to solve this was their highest rated problem The daily problem has two parts: The bowel cannot be emptied at will And The individual is fecally incontinent, which means that if there are feces in the bowel they can and will be released spontaneously If the bowel could be emptied in the morning the patient could go about daily life without there being a reservoir of feces threatening to be released Other complications: The bowel cannot be cleared for colonoscopy Bowel function continues to deteriorate. The damaged bowel may have to be removed and the person then has to live with an ileostomy

3 The discovery pathway 2004 A Side effect of a ghrelin receptor agonist developed for disorders of growth and appetite noticed in human trials 2005 Animal investigation of mechanism studies commenced in Melbourne 2006 First evidence that ghrelin receptor agonists stimulate defecation centres in the lumbo-sacral spinal cord published by Melbourne group 2008 Obtained first financial support to study autonomic effects of ghrelin receptor agonists (NHMRC), began local medicinal chemistry collaboration 2009 Data on actions in unanaesthetised animals published by Melbourne group 2009 Obtained TAC support for work in SCI and begin animal proof of principle studies 2010 Pfizer agrees to release Phase 1 and 2 trial data under confidentiality agreement. Proof of Principle experiments underway 2010 Obtain ethics for Human Trial 2011 Animal Proof of Principle data for SCI treatment published, patient recruitment commenced Pfizer and RaQualia agree to transfer of clinical grade compound to us in Melbourne Investigations of second generation compounds 2012 September - trial begins 2014 March - trial complete

4 Average number of pellets, cumulative Effect of the ghrelin receptor agonist, CP464709, on fecal pellet output in the conscious rat ** ** ** CP ** Saline PBS SB Shimizu, Furness et al., Collection times after injection (hr) n=6, mean±sem

5 Defecation control circuits: Intact and SCI Cortical control Medullary relay centres Facilitating & Inhibiting pathways Spinal lesion Enteric reflex pathways Visceral afferents Defecation centres (site of action of ghrelin receptor agonists) Defecation centres at L5- S2 almost always intact Lack of cortical control after SCI Furness 2012

6 Effects of ghrelin and ghrelin agonists on colonic propulsive activity Intrathecal at S1-2 Intrathecal at S1-2 Intravenous Shimizu, Furness et al., 2006

7 Hunne, Furness 2011 Ghrelin receptor in the spinal cord

8 Second generation compound, Ulimorelin, effect on colorectal motility Pustovit et al 2014

9 Animal Proof of Principle: Defecation centre stimulant, Capromorelin, was effective in causing defecation after SCI Ferens et al 2011

10 Capromorelin, effect on colorectal motility 6 weeks after SCI no supersensitivity Ferens et al 2011

11 The Human Trial Open label, ascending dose trial to determine safety and drug handling/ availability in people living with SCI, compared to uninjured controls. Limited dose range and confined to paraplegics to assure safety 5 people with SCI, 10 uninjured controls Pharmacokinetic profile 30 min to 12 h. Follow up at 4 weeks Monitoring blood pressure, heart rate, temperature, fecal output 12 lead ECG Full blood and urine analysis

12 Pharmacokinetics of Capromorelin Peak plasma concentrations were similar, but clearance was slower in those with SCI Andrew Ellis, Albert Frauman 2014

13 Blood Pressures after Capromorelin (SCI) Continuously monitored There was no evidence of any cardiovascular response to capromorelin, even at the highest dose All SCI subjects had a bowel movement within the period of continuous monitoring. There was no instance of associated dysreflexia (5 subjects x 3 doses) Andrew Ellis, Albert Frauman 2014

14 Other parameters after Capromorelin (SCI) Body Temperature and pulse rate No changes Electrocardiogram: No events Blood: No evidence of any changes in blood cells, blood chemistry or liver function Urea, Haematocrit, Bilirubin, Total CO2, Red Cell Count, White Cell Count, Creatinine, Sodium, Potassium, Chloride, Monocytes, Platelets, Lymphocytes, Neutrophils, Basophils, Alkaline Phosphatase, Albumin, Total Protein, Mean Corpuscular Volume, Eosinophils, Gamma Glutamyl Transpeptidase, Alanine Transaminase, Mean Corpuscular Haemoglobin, Globulin, Haemoglobin Urine: No changes ph, Glucose, Bilbruin, Ketone, Specific Gravity, Blood, Protein, Urobilinogen, Nitrite, Leukocytes Physical examination: No change Defecation Time to defecation after capromorelin: 89 +/- 32 min (mean, standard deviation)

15 Conclusions, ongoing and future studies Animal proof of principle studies showed that capromorelin is similarly effective in stimulating defecation in animals with spinal cord injury and in controls In human, capromorelin reached similar levels in blood in SCI and healthy controls, but was metabolised more slowly. There were no adverse effects/ no adverse events in spinal cord injured patients (paraplegics) treated with capromorelin. An animal study of a second generation ghrelin agonist, ulimorelin, showed a stronger effect on defecation and less desensitisation. A planned placebo controlled, randomised multiple repeated dose, double blinded study of capromorelin in quadriplegics has been submitted for ethics approval. This will be supported by TAC, through ISCRR

16 Preclinical Studies Dorota Ferens Mark Habgood James Brock Leni Rivera Ruslan Pustovit Brid Callaghan Medicinal Chemistry Jonathan Baell Pharma Industry Collaboration RaQualia, Pfizer Funding Transport Accident Commission NHMRC In-kind support University of Melbourne Spinal Research Institute Acknowledgements Clinical trials design, ethics Albert Frauman Doug Brown Andrew Ellis Melinda Millard Patient liaison, recruitment, logistics Melinda Millard Doug Brown Albert Frauman Nucleus Network Joanna Gajewski Conduct of Trial, analysis Albert Frauman Andrew Ellis Melinda Millard Nucleus Network