Horizon Scanning Centre July 2013

Alicaforsen for – second line

SUMMARY NIHR HSC ID: 4202

Alicaforsen is intended to be used as second line therapy for the treatment of pouchitis refractory to, or contra-indicated for, antibiotic therapy. If licensed, it will offer a treatment option for patients with pouchitis, for whom there are currently no approved effective therapies. Alicaforsen is administered by retention , and may also achieve topical drug delivery to the affected area while minimising systemic bioavailability. Alicaforsen is a first- This briefing is generation phosphorothioate-modified antisense oligodeoxynucleotide for the based on down regulation of intercellular adhesion molecule 1 (ICAM-1) messenger information RNA levels by RNase H-mediated degradation. Several studies have available at the time reported increased ICAM-1 expression within inflamed gut mucosa as well as of research and a increased serum concentrations of soluble ICAM-1 in pouchitis and limited literature experimental colitis. search. It is not intended to be a The prevalence of (UC) in the UK is estimated to be 243 per definitive statement 100,000 (equating to 136,264 people in England and Wales), with an annual on the safety, incidence of 10 per 100,000. Approximately 30% of patients with UC efficacy or eventually require colectomy, usually restorative proctocolectomy with ileal effectiveness of the pouch-anal anastomosis. Pouchitis is the most common long-term health technology complication after restorative proctocolectomy for UC, affecting up to 60% of covered and should patients and accounts for 10% of pouch failures. The quality of life for not be used for patients with pouchitis is adversely affected by their symptoms (e.g. commercial diarrhoea, abdominal pain, and perianal or pelvic discomfort) and their poor purposes or functional status. commissioning without additional Second line treatment options for chronic pouchitis include mesalazine, anti- information. TNF therapies e.g. infliximab, probiotics, butyrate suppositories, bismuth carbomer , budesonide, corticosteroids, short-chain fatty acids or further surgery. Alicaforsen has completed a phase II single arm clinical trial to test its effect on change in Pouchitis Disease Activity Index.

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 Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

 Pouchitis: active flares in; after ileal pouch-anal anastomosis for ulcerative colitis (UC); refractory to, or contra-indicated for antibiotic therapy – second line.

TECHNOLOGY

DESCRIPTION

Alicaforsen (AP1007; AP 1431; AP-1451; ISIS-1570; ISIS-2302; ISIS-3082; ISIS-8005) is a first-generation phosphorothioate-modified antisense oligodeoxynucleotide for the down regulation of intercellular adhesion molecule 1 (ICAM-1) messenger RNA levels by RNase H-mediated degradation1. ICAM-1 is an inducible transmembrane glycoprotein which serves multiple functions in the inflammatory process1. Induction of ICAM-1 expression occurs in many cell types, including colonic epithelial cells, in response to pro-inflammatory cytokines and mediators1. Several studies have reported increased ICAM-1 expression within inflamed gut mucosa as well as increased serum concentrations of soluble ICAM-1 in pouchitis and experimental colitis2,3. Alicaforsen is intended for the treatment of active flares of pouchitis after restorative proctocolectomy with ileal pouch-anal anastomosis for UC. It is administered by 60ml retention enema as a hydroxypropyl-methylcellulose formulation at 4mg/ml daily for 6 weeks1,3.

Alicaforsen is also in phase II clinical trials for UC affecting the distal colon and rectum.

INNOVATION and/or ADVANTAGES

If licensed, alicaforsen will offer a treatment option for patients with pouchitis, for whom there are currently no approved therapies. Alicaforsen is administered by retention enema, so may also achieve topical drug delivery to the affected area while minimising systemic bioavailability.

DEVELOPER

Atlantic Pharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

Alicaforsen is a designated orphan drug in the EU and USA.

It is currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

Pouchitis is an idiopathic inflammatory condition that may occur in the ileal pouch formed after restorative proctocolectomy with ileal pouch-anal anastomosis4. This is well established as the procedure of choice for most patients requiring surgery for UC5 and involves the

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removal of the colon and rectum with construction of a pouch (made from a loop of ileum) to serve in place of the rectum4. Although the aetiology and pathogenesis of pouchitis are not known, it is speculated that alterations in the microbial environment of the ileal pouch and host immune response may play a role in its development6. Pouchitis occurs more frequently in patients with primary sclerosing cholangitis, preoperative extraintestinal manifestations, and in patients who have never smoked7. Clinical symptoms of pouchitis include increased stool frequency, rectal bleeding, abdominal cramping, faecal urgency and tenesmus, incontinence and fever4.

NHS or GOVERNMENT PRIORITY AREA

None identified.

CLINICAL NEED and BURDEN OF DISEASE

The prevalence of UC in the UK is estimated to be 243 per 100,000 (equating to 136,264 people in England and Wales), with an annual incidence of 10 per 100,0008. Acute severe colitis has a mortality rate of up to 2%8; 166 deaths from UC were registered in England and Wales during 2011 (ICD-10 K51)9. UC 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 years8.

Approximately 30% of patients with UC eventually require colectomy10, usually restorative proctocolectomy with ileal pouch-anal anastomosis5,10. Some degree of in the newly formed ileal pouch develops in about 50% of casesb. Pouchitis is diagnosed when histologically proven acute inflammation is associated with symptoms of frequency, urgency and liquid stool in the presence of endoscopic evidence of inflammationb. Pouchitis is the most common long-term complication after restorative proctocolectomy for UC, and accounts for 10% of pouch failures11. The incidence of a first episode of pouchitis at 1, 5 and 10 years post operatively is approximately 15%, 33% and 45%, respectively3. Two-thirds of pouchitis cases recur and manifest either as acute relapsing pouchitis (three quarters of the recurrent population) or chronic, unremitting pouchitis (one quarter of the recurrent population)3. Expert opinion state that the prevalence of chronic persisting pouchitis is around 5%a. Half of the chronic, unremitting population will eventually require further surgical treatment3. Resection of the pouch can be associated with long term morbidity e.g. small bowel obstructionb. The use of recurrent antibiotic therapy for chronic recurrent pouchitis is also associated with significant side effectsb. The quality of life for patients with pouchitis is adversely affected by their symptoms (e.g. diarrhoea, abdominal pain, and perianal or pelvic discomfort) and their poor functional status6.

In 2011-12, there were 289 hospital admissions in total for panproctocolectomy and anastomosis of ileum to anus and creation of pouch however further qualified (HFQ) (OPCS4 H04.2) and anastomosis of ileum to anus and creation of pouch HFQ (OPCS4 G72.5) in England and Wales, resulting in 2,843 bed days and 290 finished consultant episodes12.

a Expert personal communications.

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PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

 NICE clinical guideline in development. Management of ulcerative colitis. Expected June 20139.

Other Guidance

 Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. 201313.  Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. 201214.  Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. 201215.  The Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults. 20128,16.  British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. 201117.  Clinical guidelines for the management of pouchitis. 200918.

EXISTING COMPARATORS and TREATMENTS

Antibiotics are the mainstay treatment for pouchitis19 and the use of metronidazole or ciprofloxacin are recommended by current guidelines for first line treatment17. However patients with chronic unremitting pouchitis may not respond to antibioticsb. Other first line treatments include aminosalicylates and corticosteroids (to control or reduce the inflammation)3.

Second line treatment options for chronic pouchitis (not licensed for this indication) include19:  mesalazine-containing preparations (oral or enema formulation)19  further antibiotics i.e. low dose metronidazole or ciprofloxacin17,19  anti-TNF therapies e.g. infliximab17,19,20,c  probiotics19 e.g. VSL#3 probiotic food supplement17 (as maintenance treatment)c  butyrate suppositories19  bismuth carbomer enemas19  budesonide17,21  corticosteroids19  short-chain fatty acids17

Some people with pouchitis will require surgical treatment of the pouch3.

b Expert personal communication.

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EFFICACY and SAFETY

Trial ISIS 2302-CS23; alicaforsen; pouchitis; chronic; unremitting; phase II. Sponsor Isis Pharmaceuticals. Status Published. Source of Publication3, manufacturer. information Location USA. Design Non-randomised, single arm. Participants n=12; aged ≥18 years; unremitting pouchitisc; chronic; failed alternative therapies; Pouchitis Disease Activity Index (PDAI) score ≥7; ≥2 weeks since last antibiotic therapy. Schedule Received alicaforsen 60ml retention enema at 4mg/ml nightly for 6 weeks. Follow-up Active treatment for 6 weeks, follow-up at weeks 10 and 18. Subjects had the option of 9-month extended follow-up period after the week 18 visit. During this time, a 3- week re-treatment of alicaforsen enema was permitted if the subject relapsed (defined as a PDAI score = 7), but only if 3 months had elapsed since last alicaforsen enema. A maximum of 2 re-treatment courses were allowed during the extended follow-up period. Primary Change in PDAI at week 6. outcome Secondary Change in PDAI at week 10; safety. outcomes Key results Mean reduction in PDAI score, -4.59 (p=0.001) at week 6; mean reduction in PDAI endoscopy sub-score, -2.17 at week 3 (p=0.0039) and -2.67 at week 6 (p=0.0005); mean reduction in PDAI clinical symptom sub-score, -1.42 at week 3 (p=0.0156) and -1.5 at week 6 (p=0.0117); mean reduction in PDAI histology sub-score, -0.4 at week 6 (p>0.05); 83% achieved a PDAI mucosal appearance score of 0 or 1 at endoscopy at week 6; 42% had a decrease in PDAI histology sub-score of -1 at week 6 (p>0.05); 58% were in remission (PDAI <7), with a mean reduction in PDAI score of -6 at week 6.

Decrease in PDAI scores, 39% at week 6 and 42% at week 10; proportion of subjects with clinical remission, 16.7% at week 6 and 41.7% at week 10; proportion of subjects with clinical improvement, 33.3% at week 6 and 25.0% at week 10. Adverse No serious AEs reported. effects 105 AEs: mild or moderate AEs, 89/105; severe non-serious AEs, 14/105 related to (AEs) the disease.

ESTIMATED COST and IMPACT

COST

The reported costs (including consultation and administration) of selected second line treatments for recurrent pouchitis are as follows20:

Drug 6-month cost Annual cost Alicaforsen £7,884 £15,242 Infliximab (not licensed £9,968 £15,764 for indication) Surgery £14,291 £15,833 c Chronic unremitting pouchitis defined as intolerance of or no response to treatment with antibiotics, mesalazine, or steroid enemas for at least 4 weeks.

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IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on 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

 Increased drug treatment costs.  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs: alicaforsen will be self-administered.

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified: the patient group eligible for treatment (i.e. chronic refractory pouchitis) and their previous medical approach needs to be defined carefully. Cost analysis will be paramount. Efficacy needs to be assessed clinically (PDAI score), endoscopically and histologically to allow objective measures of response. Long term follow-up data for the completed trial is required to assess medium and long term outcomes.

REFERENCES

1 Miner PB, Wedel M K, 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 van Deventer SJH, Tami JA and Wedel MK. A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis. Gut 2004:53(11);1646-1651. 3 Miner P, Wedel M, Bane B et al. An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis. Alimentary Pharmacology and Therapeutics 2004;19(3):281-286. 4 Holubar SD, Cima RR, Sandborn WJ et al. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD001176. DOI:10.1002/14651858.CD001176.pub2. 5 Wasserman M, Hyman N, Iyer A et al. The natural history of anal transition zone inflammation and possible relationship to pouchitis: A long term longitudinal study. Colorectal Disease 2013; DOI: 10.1111/codi.12322. 6 Shen B, Fazio VW, Remzi FH et al. Comprehensive evaluation of inflammatory and noninflammatory sequelae of ileal pouch-anal anastomoses. The American Journal of Gastroenterology 2005;100(1):93-101.

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7 Kornblut A and Sachar DB. The Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults. American Journal of Gastroenterology 2010;105:501-523. 8 National Institute for Health and Care Excellence. Management of ulcerative colitis. Clinical guideline in development. Expected June 2013. 9 Office for National Statistics. Deaths registered in England and Wales, series DR 2011. http://www.ons.gov.uk 10 Shen B and Lashner BA. Diagnosis and Treatment of Pouchitis. Gastroenterology and Hepatology 2008;4(5):355-361. 11 Landy J, Al-Hassi HO, McLaughlin SD et al. Etiology of pouchitis. Inflammatory Bowel Disease 2012;18(6):1146-55. 12 NHS Hospital episode statistics. NHS England 2011-12 HES data. 2012. http://www.hesonline.nhs.uk. 13 Van Assche G, Dignass A, Bokemeyer B et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. Journal of Crohns and Colitis. 2013;7(1):1-33. 14 Dignass A, Lindsay JO, Sturm A et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. Journal of Crohns and Colitis. 2012;6(10):991-1030. 15 Dignass A, Eliakim R, Magro F et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. Journal of Crohns and Colitis. 2012;6(10):965-990. 16 Eugène C. Ulcerative colitis practice guidelines in adults. Clinics and Research in Hepatology and Gastroenterology 2012;36(2):103-106. 17 Mowat C, Cole A, Windsor A et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607. 18 Pardi DS, D'Haens G, Shen B et al. Clinical guidelines for the management of pouchitis. Inflammatory Bowel Diseases 2009;15(9):1424-1431. 19 Steinhart A H and Ben-Bassat O. Pouchitis: a practical guide. Frontline Gastroenterology 2012;00:1–7. doi:10.1136/flgastro-2012-100171. 20 Vegter S, Tolley K, Jones H et al. P424 A cost analysis of alicaforsen compared with infliximab or surgery for chronic, unremitting pouchitis in the UK. Journal of Crohn's and Colitis 2012: 7th Congress of the European Crohn's and Colitis Organisation February 2012. Barcelona, Spain. Abstract P424. Poster. http://dx.doi.org/10.1016/S1873-9946(12)60443-7, 21 McLaughlin SD, Clark SK, Tekkis PP et al. The bacterial pathogenesis and treatment of pouchitis. Therapeutic Advances in Gastroenterology 2010;3(6):335-348.

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