Horizon Scanning Research November 2015 & Intelligence Centre

Alicaforsen for active – second line

LAY SUMMARY

Ulcerative colitis is a type of chronic inflammatory bowel disease that causes ulcers on the lining of the large bowel. Patients suffer with pain and diarrhoea and the condition may deteriorate and lead to hospital This briefing is admissions. Ulcerative colitis can have a large impact on patients’ based on quality of life. information available at the time Alicaforsen is a new treatment option that may reduce in of research and a the large bowel. It is taken once a day or once every other day as an limited literature . search. It is not intended to be a Alicaforsen is currently being studied to see how well it works and definitive statement on the safety, whether it is safe to use in people with ulcerative colitis. If alicaforsen efficacy or is licensed for use in the UK, it will offer a new treatment option for effectiveness of the people with active ulcerative colitis. health technology covered and should NIHR HSRIC ID: 672 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

• Ulcerative colitis: distal colon; active – second line.

TECHNOLOGY

DESCRIPTION

Alicaforsen (AP-1450) is an anti-inflammatory, intercellular adhesion molecule (ICAM-1) inhibitor. It is a first-generation phosphorothioate-modified antisense oligodeoxynucleotide intended to downregulate ICAM-1 messenger RNA levels by RNase H-mediated degradation1. ICAMs are proteins that mediate inflammatory responses in bodily tissues, including those in the gastrointestinal tract. Induction of ICAM-1 expression occurs in many cell types, including colonic epithelial cells, in response to pro-inflammatory cytokines and mediators1. Alicaforsen switches off the production of ICAM-1 by binding to and degrading mRNA that encodes for it, thereby blocking the mechanism for local colonic inflammation in ulcerative colitis. Alicaforsen is currently being developed in a topical retention enema formulation for treatment of acute disease flares.

In phase II clinical trials, alicaforsen was delivered by enema once daily or once every other day over a six-week period2. The optimal dose for alicaforsen is reported to be 240mg/daya.

Alicaforsen does not currently have Marketing Authorisation in the EU for any indication. Alicaforsen is also in phase III clinical trials for .

INNOVATION and/or ADVANTAGES

If licenced, alicaforsen will provide an alternative topical treatment option for patients with active distal/left-sided ulcerative colitis where first line therapies have proven inappropriate or ineffective.

DEVELOPER

Atlantic Healthcare plc.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Ulcerative colitis is the most common type of chronic inflammatory bowel disease3. Ulcers develop on the lining of the colon and patients usually present with debilitating symptoms such as bloody diarrhoea, abdominal pain, urgency or tenesmus4. Consequently, ulcerative colitis can severely impact on a patient’s quality of life4. The severity of symptoms varies, depending on the extent of rectal and colonic inflammation. Patients may go for weeks or

a Company provided information.

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months with very mild or no symptoms (disease remission), interspersed by periods where the symptoms are particularly troublesome known as flare-ups or relapses3. Ulcerative colitis is thought to be an autoimmune condition, and while the causes are unknown, it is thought to result from a combination of genetic and environmental factors3.

Toxic megacolon is a rare and serious complication of ulcerative colitis3. Ulcerative colitis can also be associated with complications outside of the gut; some people develop painful and swollen joints (arthritis), liver disease, aphthous mouth ulcers, areas of painful, red and swollen skin, or irritated and red eyes3. In addition, osteoporosis affects 1 in 6 people with ulcerative colitis and develops as a side effect of prolonged use of steroids3. People with ulcerative colitis also have an increased risk of developing bowel cancer, especially if the condition is extensive or severe3.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Colorectal: Complex Inflammatory Bowel Disease (Adult) A08/S/c. • Improving quality of life for people with long term conditions (2013).

CLINICAL NEED and BURDEN OF DISEASE

The annual incidence of ulcerative colitis in the UK is estimated to be approximately 10 per 100,000 population and the prevalence is approximately 240 per 100,000 population5. This amounts to around 146,000 patients in the UK with the disease. Ulcerative colitis can present at any age, but the incidence has a bimodal age distribution, with peaks between the ages of 15 and 25 years and between 55 and 65 years5. About 55% of patients with ulcerative colitis have chronically active disease, which is subject to exacerbations every few weeks or months6. Typically, ulcerative colitis has a relapsing-remitting pattern5. Around 80% of the people affected have mild or moderate disease and 20% have severe disease7. Without treatment, the condition may deteriorate and may lead to hospital admission for intravenous corticosteroid treatment or even surgery. About 30% of people admitted to hospital with acute severe ulcerative colitis will require colectomy to avoid colonic perforation during the emergency admission5. An estimated 17% of children and young people, and 11.5% of adults diagnosed with ulcerative colitis are eligible for treatment with biological TNF-alpha inhibitors7.

In 2013, there were 46,203 admissions for ulcerative colitis (ICD-10 K51) in England, resulting in 76,631 bed days and 55,502 finished consultant episodes8. 216 deaths from ulcerative colitis were registered in England and Wales in 20139.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Vendolizumab for treating moderately to severely active ulcerative colitis (TA342). June 2015.

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• NICE technology appraisal. Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including review of TA140 and TA262) [TA329]. February 2015. • NICE technology appraisal. Infliximab for acute exacerbations of ulcerative colitis (TA163). December 2008. • NICE technology appraisal. Infliximab for subacute manifestations of ulcerative colitis (TA140). April 2008. • NICE clinical guideline. Ulcerative colitis. Management in adults, children and young people (CG166). June 2013. • NICE clinical guideline. Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn's disease or adenomas (CG118). March 2011. • NICE clinical guideline. Faecal incontinence: The management of faecal incontinence in adults (CG49). June 2007.

Other Guidance

• European Crohn’s and Colitis Organisation consensus on ulcerative colitis. European evidence based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. 201210. • European Crohn’s and Colitis Organisation consensus on ulcerative colitis. European evidence based consensus on the diagnosis and management of ulcerative colitis: current management. 201211. • European Crohn’s and Colitis Organisation consensus on ulcerative colitis. European evidence based consensus on the diagnosis and management of ulcerative colitis: special situations. 201212. • British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. 201113.

CURRENT TREATMENT OPTIONS

Current medical approaches focus on treating active disease to address symptoms, improve quality of life, control flare-ups and thereafter to maintain remission5. Management of ulcerative colitis includes drug therapy, attention to nutrition, and surgery for severe or chronic active disease. Treatment will depend on the type and severity of the ulcerative colitis14. Depending on which part of the colon is affected, oral suppositories, or liquid or foam enema formulations are available.

Pharmacological treatment options include14,5: • Aminosalicylates – mild to moderate ulcerative colitis. These include mesalazine, balsalazide sodium and sulphasalazine. • Corticosteroids – moderate to severe relapsing ulcerative colitis. These include prednisolone, beclometasone dipropionate and hydrocortisone. • Immunosuppressants – if two or more courses of corticosteroids per year are needed. These include methotrexate, azathioprine and mecaptopurine and are increasingly being used to maintain remission in people with longstanding ulcerative colitis. • Ciclosporin – severe ulcerative colitis, not responding to first line intravenous corticosteroids. • TNF-alpha antagonists – moderate to severe ulcerative colitis refractory to corticosteroids and/or immunosuppressive agents. These include infliximab, which is recommended by NICE for treatment of acute exacerbations where ciclosporin is contraindicated or inappropriate.

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EFFICACY and SAFETY

Trial CS22, NCT00063414; alicaforsen vs CS27, NCT00063830; alicaforsen vs mesalazine; phase II. placebo enema; phase II. Sponsor Isis Pharmaceuticals. Isis Pharmaceuticals. Status Completed. Competed. Source of Trial registry2, manufacturer. Trial registry15, manufacturer. information Location USA. USA. Design Randomised, active-controlled. Randomised, placebo-controlled. Participants n=190; aged ≥18 years; diagnosis of n=112; aged ≥18 years; diagnosis of left- ulcerative colitis in the preceding 6 sided ulcerative colitis in the preceding 6 months; current left side flare; baseline months; current left side flare; baseline Disease Activity Index (DAI) score of 4-10 DAI score of 4-10 including abnormal including abnormal endoscopic score; ≥1 endoscopic score; ≥1 of the following of the following treatments for ulcerative treatments for ulcerative colitis prior to colitis prior to baseline visit: mesalazine baseline visit: mesalazine therapy for ≥30 therapy for ≥30 days, mercaptopurine for days, mercaptopurine for ≥60 days, ≥60 days, and/or azathioprine therapy for and/or azathioprine therapy for ≥60 days. ≥60 days. Schedule Randomised to alicaforsen 120mg or Randomised to alicaforsen 240mg rectal, 140mg rectal, once daily for a 6 week nightly for 6 weeks; 240mg rectal, nightly period; or mesalazine 4g rectal, daily for 6 for 10 days, then every other night for 32 weeks. days; 120mg rectal, nightly for 10 days, then every other night for 3 days; or placebo enema control nightly for 6 weeks. Follow-up Active treatment for 6 weeks, follow up at Active treatment for 6 weeks, follow up at 30 weeks. 30 weeks. Primary Percentage reduction in DAI at 6 weeks. Percentage reduction in DAI at 6 weeks. outcome/s Secondary Clinical improvement; clinical remission; Percentage change in DAI score; acute outcome/s relapse; safety and tolerability. response rate; clinical improvement; clinical remission; safety and intolerability. Expected Not reported. Not reported. reporting date

ESTIMATED COST and IMPACT

COST

The cost of alicaforsen is not yet known. The cost of other selected treatments for ulcerative colitis are7,16:

Drug Dose Drug cost per cycle Infliximab Initially 5mg/kg, then 5mg/kg after Induction cycle of 8 weeks: £5,035 2 weeks, then 5mg/kg after Maintenance cycle of 26 weeks: £5,455b 4 weeks, if condition has responded, then maintenance 5 mg/kg every 8 weeks.

b Assumes wastage, and based on average adult bodyweight of 77.9kg.

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Mesalazine 1g/metered application £26.72 per 14-application canister. foam enema Budenofalk 2mg/metered application £57.11 per 14-application canister. corticosteroid enema

IMPACT – SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 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:

 Other: uncertain unit cost compared to current  None identified alternative therapies.

Other Issues

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

REFERENCES

1 Miner PB, Wedel MK, Xia S et al. Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial. Alimentary Pharmacology and Therapeutics 2006:23;1403-1413. 2 ClinicalTrials.gov. ISIS 2302-CS22, Phase II, double blinded, active-controlled study of alicaforsen (ISIS 2302) enema, an antisense inhibitor of ICAM-1, for the treatment of patients with mild to moderate active ulcerative colitis (Left-Sided Colitis or Pancolitis with Left Sided Disease Flare). https://clinicaltrials.gov/ct2/show/NCT00063414?term=NCT00063414&rank=1 Accessed 3 November 2015. 3 NHS Choices. Ulcerative Colitis. http://www.nhs.uk/conditions/ulcerative- colitis/pages/introduction.aspx Accessed 3 November 2015. 4 Naidoo K, Gordon M, Fagbemi AO et al. Probiotics for the maintenance of remission in ulcerative colitis (review). . Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group. 2011; doi: 10.1002/14651858.CD007443.pub2. 5 National Institute for Health and Care Excellence. Ulcerative colitis; management. Clinical guideline CG166. London: NICE; June 2013. 6 Tsai HH, Punekar YS, Morris J et al. A model of the long-term cost effectiveness of scheduled maintenance treatment with infliximab for moderate-to-severe ulcerative colitis. Alimentary Pharmacology and Therapeutics 2008:28;1230-1239.

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7 National Institute for Health and Care Excellence. Infliximab, adalimumab and golimumab for treating moderately to severe active ulcerative colitis after the failure of conventional therapy (Including a review of TA140 and TA262). Technology appraisal TA329. London: NICE; February 2015. 8 Health and Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2013-2014. www.hscic.gov.uk/hes 9 Office for National Statistics. Mortality Statistics: Deaths Registered in England and Wales (series DR), 2013. www.ons.gov.uk 10 Dignass A, Eliakim R, Magro F et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. https://www.ecco- ibd.eu/images/6_Publication/6_3_ECCO%20Guidelines/2012_UC_Cosensus_Update_1_Definitio nand_Diagnosis.pdf Accessed 16 November 2015. 11 Dignass A, Lindsay JO, Sturm A et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: current management. https://www.ecco- ibd.eu/images/6_Publication/6_3_ECCO%20Guidelines/2012_UC_Cosensus_Update_2_Current _Management.pdf Accessed 16 November 2015. 12 Van AG, Dignass A, Bokemeyer B et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: special situations. https://www.ecco- ibd.eu/images/6_Publication/6_3_ECCO%20Guidelines/2012_UC_Cosensus_Update_3_SPECIA L_SITUATIONS.pdf Accessed 6 November 2013. 13 Mowat C, Cole A, Windsor A et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607. 14 Crohn’s and Colitis UK. Ulcerative Colitis. http://www.crohnsandcolitis.org.uk/Resources/CrohnsAndColitisUK/Documents/Publications/Book lets/Ulcerative-Colitis.pdf Accessed 3 November 2015. 15 ClinicalTrials.gov. ISIS 2302-CS27, A 6-Week, placebo-controlled clinical study to evaluate the effectiveness of alicaforsen (ISIS 2302) in patients with mild to moderate active ulcerative colitis. https://clinicaltrials.gov/ct2/show/NCT00063830?term=NCT00063830&rank=1 Accessed 3 November 2015. 16 Joint Formulary Committee. British National Formulary. BNF November 2015. BMJ Group and Pharmaceutical Press. www.medicinecomplete.com