Alicaforsen for Active Ulcerative Colitis – Second Line
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Horizon Scanning Research November 2015 & Intelligence Centre Alicaforsen for active ulcerative colitis – 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 inflammation in of research and a the large bowel. It is taken once a day or once every other day as an limited literature enema. 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 pouchitis. 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. Horizon Scanning Research & Intelligence Centre 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. Horizon Scanning Research & Intelligence Centre • 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