Naldemedine for Opioid-Induced Constipation in Adults

Horizon Scanning Research May 2016 & Intelligence Centre

Naldemedine for opioid-induced constipation in adults

LAY SUMMARY

Opioids are a class of drugs that are commonly prescribed for pain. Constipation is a side effect that affects nearly all patients taking opioid treatment. There has been an increase in the use of opioids to treat chronic pain in recent years. Current treatment for opioid-induced This briefing is based on constipation often involves laxatives. But, it has been estimated that information 50–80% of people taking laxatives for opioid-induced constipation get available at the time only a limited improvement in symptoms. of research and a limited literature Naldemedine is a new drug for the treatment of opioid-induced search. It is not constipation in adults that is taken as a tablet once a day. If it is intended to be a licensed for use in the UK, naldemedine may offer an additional definitive statement treatment option for adults with this debilitating condition. on the safety, efficacy or effectiveness of the NIHR HSRIC ID: 5267 health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Opioid-induced constipation: in adults.

TECHNOLOGY

DESCRIPTION

Naldemedine (S-297995) is an orally-active peripheral opioid receptor antagonist intended for the treatment of opioid-induced constipation. In preclinical models, naldemedine suppressed morphine-induced nausea and vomiting, and small intestinal hypomotility but did not affect the analgesic action of morphine.

In the phase III clinical trial, naldemedine was administered orally at 0.2mg once daily1.

Naldemedine is not currently licensed in the EU for any indication. It is also in phase II clinical trials for opiate-induced nausea and vomiting.

INNOVATION and/or ADVANTAGES

If licensed, naldemedine may offer an additional treatment option for adults with opioid- induced constipation.

DEVELOPER

Shionogi.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Opioids are a class of drugs that are commonly prescribed for their analgesic properties. They include substances such as morphine, codeine, oxycodone, and methadone2. Opioid- induced bowel dysfunction can occur very quickly and is a side effect that affects nearly all patients taking opioid treatment, not just chronic opioid usersa, of which opioid-induced constipation is the most common manifestation. Other symptoms of opioid-induced bowel dysfunction include nausea, vomiting, and dyspepsia3.

Opioid-induced constipation has been estimated to occur in 15 to 90% of chronic opioid users4. Opioid-induced constipation is characterised by any of the following: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency after initiating opioid therapy5. In recent years there has been a large increase in the use of opioids for the treatment of chronic non-cancer pain, and patients are commonly treated with opioids for

a Expert personal opinion.

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months or even years6. The effects of opioids on the gut are primarily mediated by mu- opioid receptors in the gastrointestinal tract. Opioid binding to these receptors decreases enteric nerve activity and gastrointestinal propulsive motor activity, inhibits ion and ﬂuid secretion, and increases resorption of water, leading to constipation7. The debilitating symptoms of opioid-induced constipation can seriously impair patients’ quality of life, comparable even to pain and up to a point where some prefer inadequate pain control to avoid these side effects8.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving quality of life for people with long term conditions (2013).

CLINICAL NEED and BURDEN OF DISEASE

Opioid-induced constipation is a side effect that affects nearly all patients taking opioid treatment and will persist unless treated9. Reported prevalence rates of constipation in the UK vary widely from 4 to 20%10. Estimates on the prevalence of opioid-induced constipation among people taking opioids may be around 45–57% for non-cancer pain patients and at least 90% for cancer-related pain11. The population prevalence of opioid-induced constipation is not known. It has been estimated that 50–80% of people taking laxatives for opioid-induced constipation report limited improvement in symptoms11. In England in 2015, there were 23,310,700 prescription opioid analgesic items dispensed with a total net cost of £313,531,60012.

The population likely to be eligible to receive naldemedine could not easily be estimated from available routine published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Lubiprostone for treating opioid induced constipation (ID646). Date of issue to be confirmed. • NICE technology appraisal in development. Constipation (opioid induced) – methylnaltrexone bromide (ID700). Expected February 2017. • NICE technology appraisal. Constipation (opioid-induced) – naloxegol (TA345). July 2015. • NICE technology appraisal. Lubiprostone for treating chronic idiopathic constipation (TA318). July 2014. • NICE technology appraisal. Prucalopride for the treatment of chronic constipation in women (TA211). December 2010. • NICE clinical guideline. Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults (CG140). May 2012

Other Guidance

• The British Pain Society. Opioids for persistent pain: good practice. 201013.

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• The Journal of Pain. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. 200914. • Scottish Intercollegiate Guidelines Network. Management of chronic pain. SIGN 136 201315.

CURRENT TREATMENT OPTIONS

Current opioid-induced constipation management consists of nonpharmacological and/or pharmacological approaches. These may include:16,3,6

• Lifestyle modification, such as increasing dietary fibre, fluid intake and physical activity. This should commence at the start of opioid therapy and continue for the duration of treatment. However, increasing dietary fibre and physical activity is very often not possible in patients with cancer pain taking opioidsb. • Laxatives: combine a stimulant and stool softener, also recommended at the start of opioid therapy. o Senna or bisacodyl — a gastrointestinal stimulant. Docusate — a surfactant emulsifier that facilitates the mixture of fat and water in o c faeces. It is a stool softener . o Mineral oil — a lubricant that delays the absorption of water from stools in the colon. o Lactulose or polyethylene glycol (PEG) — an osmotic that pulls water into the colon, thereby hydrating the stool. o Prostaglandins or prokinetic drugs—change the way the intestines absorb water and electrolytes, and increasing the weight and frequency of stools while reducing transit time. • Enemas. • Opioid-antagonists bind to opioid receptors without activating them, effectively blocking the receptors. These include: o Peripherally selective opioid antagonist: . Methylnaltrexone bromide — a selective antagonist at the mu receptor, which crosses the blood-brain barrier only poorly. . Naloxegol o Targinact — an oral combination of oxycodone and naloxone. o Lubiprostone — a selective chloride channel-2 activator that acts in the small intestine causing an increased fluid secretion and gut mobility.

Currently, there is a consensus that laxative treatment should commence with the opioid therapy and continue throughout treatment. However, lifestyle modification and laxatives can be insufficient in some patients and most patients receiving long-term opioid therapy will 16,17 ultimately require more aggressive pharmacological treatment .

EFFICACY and SAFETY

Trial COMPOSE IV, JapicCTI- COMPOSE V, JapicCTI- COMPOSE I, 132340; naldemedine vs 132342; naldemedine vs NCT01965158, placebo; phase III. placebo; phase III EudraCT2013-002241-11, extension. 1314V9231; naldemedine vs placebo; phase III. Sponsor Shionogi. Shionogi. Shionogi. Status Complete but Complete but unpublished. Completed and published

b Expert personal communication.

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unpublished. in abstract. 19 Source of Trials registry18. Trial registry . Trial registry20, poster21. information Location Japan. Japan. EU (incl UK), USA, and other countries. Design Randomised, placebo- Randomised, placebo- Randomised, placebo- controlled. controlled. controlled. Participants n=193; chronic opioid n=100; age >20yrs old; n=547; age 18 to 80 years therapy for cancer pain; cancer patients with old; non-malignant opioid-induced constipation associated chronic pain treated with constipation; spontaneous with administration of opioid opioids; opioid-induced bowel movement (SBM) analgesics; SBM frequency constipation; treated with frequency <3 per week; at per week is <3 per week; at a stable opioid regimen at least one of the following least one of the following a total daily average dose symptoms: staining during symptoms: straining during of ≥ 30mg equivalent of bowel movement, feeling bowel movement, feeling of oral morphine sulfate; not of incomplete evacuation, incomplete evacuation, or currently using laxatives or passage of hard stools passage of hard stools or or willing to discontinue or pellets; no hepatic or pellets; no constipation laxative use, and willing to renal disorders; no potentially attributable to use only the rescue constipation attributable to causes other than opioid laxatives provided causes other than opioid analgesics; no hepatic or throughout the study; analgesics. renal disorders. meet opioid-induced constipation criteria based on the BMCA diary; no significant structural abnormalities of the gastrointestinal tract; no active medical diseases affecting bowel transit; presence of pelvic disorders that may be a cause of constipation; no surgery (except for minor procedures) within 60 days of screening; no chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation; no current use of opioid antagonists, partial agonists or mixed agonists/antagonists. Schedule Randomised to 0.2mg Randomised to 0.2mg Randomised to naldemedine once daily or naldemedine once daily or naldemedine 0.2mg oral placebo, both oral. placebo once daily, both once daily or placebo oral oral. once daily. Follow-up Not reported. Not reported. Active treatment for 12 weeks; follow-up not reported. Primary Primary proportion of Safety (AEs). Proportion of responders outcome/s SBM responders; mean (defined as having ≥ 9 change in the frequency positive response weeks of SBM, AEs, out of the 12 weeks, and pharmacokinetics. 3 positive response

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weeks out of last 4 weeks of the 12 weeks, a positive response week will be defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week). Secondary Not reported. Assessments of Not reported. outcome/s constipation symptoms and Quality of Life (QOL). Key results A statistically significant Not reported. A statistically significant increase in the SBM improved frequency of responder rate compared SBM compared with to placebo was reported placebo was reported over 2 weeks. over 12 weeks; Naldemedine was naldemedine was generally well-tolerated generally well-tolerated and no attenuation of with the most commonly opioid analgesic effects reported side effects was observed. being gastrointestinal disorders. Adverse Mild diarrhoea was the Not reported. Abdominal pain and effects (AEs) only AE reported in more diarrhoea were the only than 5 % of subjects. treatment related adverse events reported. Expected Not reported. Not reported. December 2014 (final reporting data collection date for date primary outcome measure).

Trial COMPOSE II, NCT01993940, COMPOSE III, NCT01965652, EudraCT2013-002948-91; naldemedine EudraCT2013-002949-11; naldemedine vs placebo; phase III. vs placebo; phase III. Sponsor Shionogi. Shionogi. Status Ongoing. Ongoing. Source of Trial registry22. Trial registry23. information Location EU (not UK), USA and other countries. EU (incl UK), USA, Canada and other countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=553 (planned); aged 18 to 80 years; n=1,200(planned); aged 18 to 80 years non-malignant chronic pain treated with old; non-malignant chronic pain; opioid- opioids; opioid-induced constipation; induced constipation; treated with a treated with a stable opioid regimen at a stable opioid regimen at a total daily total average daily dose of ≥ 30 mg dose on average of ≥ 30 mg equivalent equivalent of oral morphine sulfate; not of oral morphine sulfate; may or may not currently using laxatives or willing to be on routine laxative regimen at the discontinue laxative use, and willing to time of screening; no significant use only the rescue laxatives provided structural abnormalities of the throughout the study; meet opioid- gastrointestinal tract; no active medical induced constipation criteria based on diseases affecting bowel transit; no the Bowel Movement and Constipation pelvic disorders that may be a cause of Assessment (BMCA) diary; no significant constipation; no surgery (except for structural abnormalities of the minor procedures) within 60 days of gastrointestinal tract; no active medical screening; no chronic constipation prior diseases affecting bowel transit; no to starting analgesic medication or any

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presence of pelvic disorders that may be potential non-opioid cause of bowel a cause of constipation; no surgery dysfunction that may be a major (except for minor procedures) within 60 contributor to the constipation; no days of screening; no chronic subjects who have never taken laxatives constipation prior to starting analgesic for the treatment of opioid induced medication or any potential non-opioid constipation. cause of bowel dysfunction that may be a major contributor to the constipation; no current use of opioid antagonists, partial agonists, or mixed agonists/antagonists. Schedule Randomised to naldemedine 0.2mg oral Randomised to 0.2mg naldemedine once once daily or placebo oral once daily. daily or placebo once daily, both oral. Follow-up Active treatment for 12-weeks; follow-up Active treatment for 52 weeks; follow-up not reported. not reported.

Primary Proportion of responders (defined as Safety (AEs and serious adverse outcome/s having ≥9 positive response weeks out of events). the 12 weeks, and 3 positive response weeks out of last 4 weeks of the 12 weeks, a positive response week defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week).

Secondary Not reported. Not reported. outcome/s Key results A statistically significant improved _ frequency of SBM compared with placebo was reported over 12 weeks; naldemedine was generally well- tolerated with the most commonly reported side effects being gastrointestinal disorders. Adverse As above. No further details reported. _ effects (AEs) Expected May 2015 (Final data collection date for January 2016 (final data collection reporting primary outcome measure). date for primary outcome measure). date

ESTIMATED COST and IMPACT

COST

The cost of naldemedine is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: wider societal benefits - earlier return to  No impact identified normal activities, including employment.

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Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services: reduced complications of opioid therapy.

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs: reduced complications of opioid therapy

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Clinical.Trials.gov. A randomized double-blind, placebo-controlled, parallel-group, multicenter, phase 3 study to evaluate the long-term safety of naldemedine for the treatment of opioid- induced constipation in subjects with non-malignant chronic pain receiving opioid therapy. https://www.clinicaltrials.gov/ct2/show/NCT01965652 Accessed 11 May 2016. 2 Peppin JF. Opioid-induced constipation: causes and treatments. May 2012. //www.practicalpainmanagement.com/opioid-induced-constipation-causes-treatments Accessed 11 May 2016. 3 Ketwaroo G, Cheng V, and Lembo A. Opioid-induced bowel dysfunction. Current Gastroenterology Reports 2013;15(9):344-350 DOI 10.1007/s 1189-013-0344-2. 4 Boswell K, Kwong WJ, Kavanagh S. Burden of opioid-associated gastrointestinal side effects from clinical and economic perspectives: a systematic literature review. Journal of Opioid Management. 2010;6(4):269-89. 5 Camilleri. M, Drossman DA, Becker G et al. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterology Motility 2014;26(10):1386-1395. 6 Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. The American Journal of Gastroenterology 2011;106:835-842. 7 Michna E, Weil A, Duerden M et al. Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: a responder post hoc analysis. Pain Medicine 2011;12(8):1223- 1230. 8 Bader S, Jaroslawski K, Blum H et al. Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide. Clinical Medicine Insights. Oncology 2011;(5):201-211. 9 National Institute for Health and Care Excellence. Constipation (opioid induced) - Lubiprostone for treating opioid-induced constipation in people with chronic, non-cancer pain final scope. London: NICE; November 2013. 10 National Institute for Health and Care Excellence. Lubiprostone for treating chronic idiopathic constipation final scope. London: NICE; November 2013. 11 NICE Costing statement Naloxegol for treating opioid-induced constipation(TA345). 12 Health and Social Care Information Centre. Prescription Cost Analysis England 2015. http://www.hscic.gov.uk 13 The British Pain Society. Opioids for persistent pain: good practice. London: January 2010. 14 Chou R, Fanciullo G, Fine P et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. The Journal of Pain 2009;10(2):113-130. 15 Scottish Intercollegiate Guidelines Network . Management of chronic pain. Edinburgh: SIGN; 2013. (SIGN publication no. 136). December 2013.

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16 Kumar L, Barker C and Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterology Research and Practice. 2014; article ID 141737. 17 Peppin JF. Opioid-induced Constipation: Causes and Treatments. May 2012. www.practicalpainmanagement.com/opioid-induced-constipation-causes-treatments Accessed 11 May 2016. 18 JAPIC Clinical Trials Information. A phase III, multicentre, randomised, double-blind, placebo- controlled, parallel-group study of naldemedine in cancer patients with opioid-induced constipation. (JapicCTI-132340) http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132340 Accessed 11 May 2016. 19 JAPIC Clinical Trials Information. A phase III, multicenter, open-label study of naldemedine in cancer patients with opioid-induced constipation - extension study -(JapicCTI-132342). http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132342. Accessed 19 April 2016. 20 Clinical.Trial.gov. COMPOSE I for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain receiving opioid therapy. https://www.clinicaltrials.gov/ct2/show/NCT01965158 Accessed 11 May 2016. 21 Shionogi Inc. Naldemedine phase 3 study shows significant improvement for patients with opioid- induced constipation. http://www.shionogi.com/newsroom/index.html# Accessed 11 May 2016. 22 ClinicalTrials.gov. A randomized, double-blind, placebo-controlled, parallel-group study of naldemedine in the treatment of opioid-induced constipation in subjects with non-malignant chronic pain receiving opioid therapy. https://www.clinicaltrials.gov/ct2/show/NCT01993940 Accessed 11 May 2016. 23 Clinical.Trials.gov. A randomized double-blind, placebo-controlled, parallel-group, multicenter, phase 3 study to evaluate the long-term safety of naldemedine for the treatment of opioid- induced constipation in subjects with non-malignant chronic pain receiving opioid therapy. https://www.clinicaltrials.gov/ct2/show/NCT01965652 Accessed 11 May 2016.