London Medicines Evaluation Network Review. Golimumab (Simponi ) for ulcerative colitis March 2014

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1 London Medicines Evaluation Network Review Summary Background and licensed indication [see section 1] Dosing [see section 2] Alternatives [see section 1] Clinical studies [see sections 3 & 4.1] Safety [see section 4.2] Convenience [see section 4.3.1] Risk assessment [see section 4.2.2] Budget impact [see section and Appendix 3] Funding Place in therapy [see section 7] Golimumab (Simponi ) for ulcerative colitis March 2014 Golimumab is a tumour necrosis factor alpha (TNF) inhibitor indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adult patients following an inadequate response to conventional therapy including corticosteroid and 6-mercaptopurine or azathioprine, or in patients who are intolerant to or have medical contraindications to such therapy. The initial dose is 200mg, followed by 100mg at week 2, then 50mg every 4 weeks (or 100mg every 4 weeks in patients 80kg), by subcutaneous injection. Other TNF-inhibitors licensed for the treatment of moderate to severely active UC are infliximab and adalimumab. PURSUIT-SC and PURSUIT-Maintenance trials were designed to assess the efficacy and safety of golimumab as an induction and maintenance regimen in UC, compared with placebo treatment in patients who were TNF- α antagonist naïve. In PURSUIT-SC, a clinical response after induction therapy was achieved by just over half of golimumab-treated patients (51%) in the 200/100mg group at week 6, compared with 30.3% with placebo (p<0.0001). Patients randomised in the PURSUIT-M study had already responded to golimumab induction therapy. Just under half of patients treated with golimumab maintained a clinical response through to week 54: 49.7% treated with 100mg and 47% treated with 50mg, compared with 31.2% receiving placebo maintenance p<0.001 and p=0.01 respectively. The numbers needed to treat (NNTs) for clinical responses through week 54 were 5 and 6 for the 100- and 50-mg golimumab groups, respectively. There are no direct data comparing golimumab with adalimumab or infliximab. All TNF-inhibitors can make patients more susceptible to infection. Prior to initiating golimumab therapy, patients must be evaluated for active and latent tuberculosis and hepatitis B virus infection. Golimumab can be given by self-administered subcutaneous (SC) injection Patients will require training in SC technique, and may self-inject if their clinician feels that this is appropriate. The list price for one golimumab 50 mg pre-filled pen or syringe is , and that for one golimumab 100 mg pre-filled pen is 1, However, under the Simply For Me Patient Support Programme, MSD will provide these doses with price parity, so the customer will pay only , even when a 100 mg dose is prescribed. Golimumab for UC is PbR excluded and funded by the CCG. A NICE guideline on infliximab, adalimumab and golimumab for the second-line treatment of moderately to severely ulcerative colitis is expected in January Background and introduction Golimumab is a tumour necrosis factor alpha (TNF) inhibitor, licensed for the treatment of moderately to severely active ulcerative colitis (UC) in adults. 1 Other TNF-inhibitors licensed for the treatment of moderately to severely active UC are infliximab and adalimumab. 2;3 Ulcerative colitis is the most common type of inflammatory disease of the bowel, with symptoms such as bloody diarrhoea, weight loss and anaemia. 4 Symptoms can flare up but then disappear for months to years, but around 50% of people with UC will relapse each year. 5 The annual incidence in the UK is ~10 per 100,000 people, with a prevalence of ~240 per 100, Most (80%) of incident cases are mild or moderate in severity. 5 The aim of treatment is symptom relief during a flare-up and maintenance of remission thereafter. 5 Management of mildly to moderately active colitis involves treatment with, oral or topical aminosalicylates or corticosteroids when aminosalicylates are contraindicated or not tolerated. Oral corticosteroids or immunosuppressants are also added on if the disease does not respond to treatment with aminosalicylates. Colectomy is a treatment option if symptoms are inadequately controlled or the patient has a poor quality of life on conventional treatment. 5 Infliximab is recommended by NICE (as an induction course of three doses) as an option for the treatment of acute exacerbations of severe UC when treatment with ciclosporin is contra-indicated or inappropriate. If patients do 1

2 not meet this criteria, then infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in clinical trials. 6 NICE does not recommend infliximab for treating subacute manifestations of moderately to severely active ulcerative colitis; these are usually managed in an outpatient setting and do not require hospitalisation or urgent surgical intervention. 7 No evidence submission to NICE was made for adalimumab because the randomised, controlled trials of adalimumab in UC included people with moderate to severe disease who were treated as outpatients and excluded people who were in hospital. The manufacturer would not be able to address the clinical and cost effectiveness of adalimumab in people with an acute exacerbation of ulcerative colitis who need hospitalisation Proposed place in therapy Golimumab is indicated for the treatment of moderately to severely active UC in adult patients following an inadequate response to conventional therapy including corticosteroid and 6-mercaptopurine or azathioprine, or in patients who are intolerant to or have medical contraindications to such therapy. The initial dose is 200mg, followed by 100mg at week 2, then 50mg every 4 weeks (or 100mg every 4 weeks in patients 80kg), by subcutaneous (SC) injection. 1 A NICE guideline on infliximab, adalimumab and golimumab for the second-line treatment of moderately to severely ulcerative colitis is expected in January Evidence selected for inclusion There are two main studies evaluating the efficacy and safety of golimumab for the treatment of moderate to severe ulcerative colitis: PURSUIT-Maintenance (NCT ), a phase 3 randomised, double-blind study and PURSUIT-SC (NCT ), an integrated analysis of a phase 2 dose-finding study and a phase 3 randomised, double-blind study. Assessments used: Disease activity was assessed using the Mayo score, which is the sum of 4 sub-scores (stool frequency relative to normal, rectal bleeding, endoscopic findings and physician s global assessment sub scores), with 0 = no disease activity and 3 = severe disease activity (total score 0 12). 10;11 Partial scores omit the endoscopy sub-score and range from 0 to 9. Clinical response: a decrease from baseline in Mayo score of 30% and 3 points, plus rectal bleeding sub-score of 0 or 1 or a decrease from baseline of 1 point. Clinical remission: a Mayo score 2 points, with no individual sub-score >1. Mucosal healing: a Mayo endoscopy score of 0 (normal / inactive disease) or 1 (erythema, lack of vascular pattern, mild friability). The Inflammatory Bowel Disease Questionnaire (IBDQ) was used to assess health-related quality of life in PURSUIT- SC. IBDQ is a 32-item questionnaire where a score of 7 = not a problem at all and 1 = a very severe problem ; (total score , with higher scores indicating greater quality of life). 10 Serum samples were collected for determination of golimumab serum concentrations. 10;11 PURSUIT studies: Inclusion/exclusion criteria 10;11 Inclusion - TNF-inhibitor naïve. - Moderate to severe UC (Mayo score 6-12 and endoscopic subscore 2). - Inadequate response to or failed to tolerate 1 conventional therapy or were corticosteroid dependent. Exclusion - History of or imminent risk for colectomy. - GI surgery within 2 months of screening. - Colitis limited to 20cm of colon (indicating ulcerative proctitis). - Use of natalizumab, rituximab or alemtuzumab within 12 months of, or ciclosporin, tacrolimus, sirolimus or mycophenolate mofetil within 8 weeks of first study drug injection. - Oral corticosteroids at a dose of >40mg prednisolone or equivalent per day. PURSUIT-SC (NCT ): Induction of clinical response / remission PURSUIT-SC combined a phase 2 dose-finding and phase 3 dose-confirmation study (total n=1065); only the phase 3 results evaluating the safety and efficacy of SC golimumab induction regimens are described here. 10 Just over half (56%) of patients were male and most (82%) were Caucasian. Mean duration of UC was 6.3 years, with 57.8% having disease limited to the left side of the colon and 42% having extensive disease. The mean Mayo score at baseline was 8.5. All patients from PURSUIT-SC (n=1064) were eligible for enrolment in PURSUIT-Maintenance. The primary analysis of the phase 3 dose-confirming stage was based on 761 patients. The primary endpoint, clinical response at week 6 was achieved by 51% of the 200/100mg group and 54.9% of the 400/200mg group, compared with 30.3% of the placebo group, p< for both comparisons, number needed to treat (NNT) approximately = Serum golimumab concentrations were dose-proportional and clinical efficacy was associated with increasing serum 2

3 concentrations. Patients with the highest concentrations had greater improvements in Mayo score and greater rates of clinical response and remission, compared with those with lower concentrations [See Appendix 1 for further details]. PURSUIT-MAINTENANCE (NCT ): Maintenance of clinical response / remission In PURSUIT-M, SC golimumab maintenance therapy was administered every 4 weeks to week 52 (n=1,228). 11 UC was moderate (91.1% of enrolled patients) or severe (8.9%) and the mean Mayo score was 8.4. Almost half (45.8%) of patients were taking corticosteroids. There were two patient populations: randomised (primary analysis population, analysed according to the assigned treatment group) and non-randomised (demographic, pharmacokinetic and safety analyses). Mayo scores were calculated at weeks 0, 30 and 54, and partial Mayo scores at each clinic visit (every 4 weeks). Patients who maintained clinical response at each clinic visit were said to be in a state of continuous response through week 54. Randomised treatment: Patients who responded to golimumab induction therapy (SC or intravenous*, n=464) were randomised to treatment with placebo or golimumab 50mg or 100mg by SC injection every 4 weeks, to week 52. Of these, 75.6% (351/464) completed the study to week 54. Dose adjustments were required in 37.1% of patients: 75 patients treated with placebo had their therapy switched to golimumab 100mg every 4 weeks; 43 patients randomised to golimumab 100mg continued to receive 100mg every 4 weeks and 51 patients randomised to 50mg were re-randomised to 50mg or 100mg every 4 weeks. Assuming a 35% response rate for placebo and 55% for golimumab 100mg, approximately 128 patients per group were required to provide an overall power of 90% for the primary endpoint. A post-hoc analysis was carried out to identify predictors of clinical remission at weeks 30 and 54. *Intravenous therapy not discussed in this review; the licensed administration route is subcutaneous. Primary endpoint, maintenance of clinical response through week 54 was achieved by 49.7% in the golimumab 100mg group, 47% in the golimumab 50mg group and 31.2% in the placebo group (p<0.001 and p=0.01 respectively, NNTs 5 and 6 respectively). Although dose escalation was allowed for patients who lost response in the maintenance phase, there was inadequate power to assess dose adjustments. The major secondary endpoints were clinical remission and mucosal healing at weeks 30 and 54, achieved in significantly more patients treated with golimumab 100mg than placebo. Further details are in Appendix 2. Time to loss of clinical response was 27 weeks with placebo but >54 weeks with both doses of golimumab. At week 54, more patients treated with golimumab 100mg (21.9%) or 50mg (25.8%) had normal or inactive mucosal disease compared with placebo (13%, nominal p=0.033 and respectively). Health-related quality of life was not assessed. Steady-state golimumab concentrations were reached at week In general, from week 8 to week 54, serum levels were twice as high in the golimumab 100mg group than in the 50mg group: median serum golimumab levels were 3.81mcg/L vs. 1.73mcg/L at week 30, and 3.52mcg/L vs. 1.81mcg/L at week 54 in the 100mg and 50mg groups respectively. 11 Higher concentrations were associated with more patients achieving clinical response [see Appendices]. Patients who did not respond to golimumab in the induction phase, or who were treated with placebo in the induction phase, comprised the non-randomised patient group. 4. Critical evaluation 4.1. Clinical application The PURSUIT studies were designed to gain regulatory approval for the marketing of golimumab for the treatment of ulcerative colitis in patients with moderate-to-severe disease; they were not designed to compare the efficacy and safety of golimumab in treating UC in patients who had received prior treatment with another TNF-inhibitor, identify patient subgroups or compare golimumab with adalimumab or infliximab. 12 Patients enrolled in both studies were TNF-α antagonist -naïve and active treatment was compared with placebo. The primary endpoint in PURSUIT-M was only assessed in patients who had already responded to golimumab therapy in PURSUIT-SC or IV. PURSUIT-SC showed that SC golimumab, administered as an induction regimen, led to statistically significant and clinically meaningful improvements in the signs and symptoms of UC, induced clinical remission and mucosal healing and improved health-related quality of life, at 6 weeks. 10 The primary endpoint of PURSUIT-M was maintenance of clinical response at week 54, which was seen in significantly more patients treated with golimumab than placebo. 11 The investigators state that this study design was more rigorous than for other UC trials because partial Mayo scores were assessed every 4 weeks and only those with a clinical response at each visit were considered to have a continuous clinical response. In both PURSUIT studies, patients with the highest serum levels of golimumab had the best clinical responses. 10;11 3

4 How does golimumab compare with adalimumab and infliximab? Golimumab has not been directly compared with adalimumab or infliximab in clinical trials. The main studies supporting the use of adalimumab and infliximab for treating moderate to severe UC (defined as per PURSUIT) are ULTRA 2 and ACT 1&2 respectively. 13;14 Direct comparisons across different studies should be done with caution due to differences in trial design and patient populations. For example, the infliximab trials were carried out when no approved medication was available for patients who failed conventional therapy. In ULTRA-2, the Mayo score was calculated on the worst score from the last 3 days for stool frequency and rectal bleeding, while in ACT 1 & 2, the average score was used. 14 In ULTRA-2, 40% of those enrolled had prior treatment with a TNF-α antagonist. 14 The primary endpoints of the studies differed: clinical response at week 8 (ACT 1 & 2), clinical remission at week 8 and week 52 (ULTRA 2) and maintenance of continuous clinical response through week 54 (PURSUIT). In ACT 1 & 2, 364 patients per study were randomised to treatment at weeks 0, 2, 6 then every 8 weeks with infliximab 5mg/kg or 10mg/kg, or placebo, through to week 46 (ACT 1) or 22 (ACT 2). 13 Mayo scores were determined at weeks 0, 8 and 30 in both studies, then week 54 in ACT 1; mean baseline scores were 8.4. Partial Mayo scores were determined at weeks 0, 2, 6, 8 then every 8 weeks until endpoint. The primary endpoint was clinical response at week 8 see table 1. Table 1: ACT 1 and 2 results 13 ACT 1 ACT 2 Endpoint Placebo (n=121) Infliximab 5mg/kg (n=121) Infliximab 10mg/kg (n=122) Placebo (n=123) Infliximab 5mg/kg (n=121) Infliximab 10mg/kg (n=120) Clinical RESPONSE (1 ) Week % 69.4%, p< % 29.3% 64.5%, p< %, p<0.001 Week % 52.1%, p< %, p= % 47.1%, p< %, p<0.001 Week % 45.5%, p< %, p< Clinical REMISSION (2 ) Week % 38.8%, p< %, p= % 33.9%, p< %, p<0.001 Week % 33.9%, p= %, p< % 25.6%, p= %, p<0.001 Week % 34.7%, p= %, p= In ULTRA 2, 494 patients were treated with SC adalimumab 160mg at week 0, 80mg at week 2 and then 40mg EOW from week 4, or matching placebo, to week Full Mayo scores were determined at weeks 0, 8, 32 and 52; mean baseline score was 8.9. Partial Mayo scores were assessed every 4 weeks to week 20 then every 6 weeks to week 52. The primary endpoints were the proportions of patients in clinical remission at week 8 and at week 52 (defined as per PURSUIT) see table 2 below. A sustained clinical response was a CR at both weeks 8 and 52. Analysis was carried out on the overall patient population (ITT population) and subgroup according to prior anti-tnf drug exposure. At both time points, a greater proportion of patients treated with adalimumab than with placebo were in clinical remission, for all three patient populations. Greater responses may have been seen with weekly dosing. Table 2: ULTRA-2 results 14 Endpoint Placebo (n=246) Clinical REMISSION (1 ) Overall Anti-TNF naïve Anti-TNF experienced Adalimumab (n=248) Placebo (n=145) Adalimumab (n=150) Placebo (n=101) Adalimumab (n=98) Week 8 9.3% 16.5%, p= % 21.3%, p= % 9.2, p=0.559 Week % 17.3%, p= % 22%, p= % 10.2%, p=0.039 Weeks 8 & % 8.5%, p= % 10.7%, p= % 5.1%, p=0.115 Clinical RESPONSE (2 ) Week % 50.4%, p< % 59.3%, p< % 36.7%, p=0.228 Week % 30.2%, p= % 36.7%, p= % 20.4%, p=0.038 Weeks 8 & % 23.8%, p< % 29.3%, p= % 15.3%, p=0.032 The proportions achieving clinical response are lower than those seen in PURSUIT-M, but the proportions achieving clinical remission are comparable. It is worth noting that the primary endpoint in PURSUIT-M was 4

5 assessed in patients who had already responded to a golimumab induction regimen in PURSUIT-SC / IV, rather than golimumab-naïve patients. Limitations to PURSUIT-M There were no data on rates of hospitalisation or colectomy; ACT 1 & 2 and ULTRA 2 also did not report these. It was not powered to show a statistical difference between golimumab and placebo with respect to maintenance of clinical remission. Post-hoc analyses were used to assess maintenance of clinical remission over time, and to assess several secondary endpoints related to corticosteroid use in the study. Fixed rather than flexible dosing was used; assessment of dosing flexibility was limited to dose adjustments to a higher dose with the same dosing interval if there was disease worsening, rather than adjustment of dosing interval. The patient population was too small to draw definitive conclusions regarding this dosing strategy to regain clinical response Safety Key adverse events In PURSUIT-SC, 1030 (96.7%) of 1065 randomised patients completed study participation to week 6. The mean duration of follow-up was 6 weeks and similar proportions of patients treated with placebo (38.2%) and golimumab (39.1%) reported adverse events. 10 The most commonly reported AEs were headache (5.2% with placebo and 4.1% golimumab) and nasopharyngitis (3.3% and 2.9% respectively). Seven patients discontinued due to an adverse event; three (0.9%) in the placebo group and four (0.5%) treated with golimumab group. Injection site reactions occurred in 3.4% and 1.5% of golimumab- and placebo-treated patients. In PURSUIT-M, safety was evaluated in both randomised and non-randomised patients through to week Overall, 63.9%, 72.7% and 73.9% of patients treated with placebo, golimumab 50mg and golimumab 100mg experienced one or more adverse event. Four cases of TB developed in patients from endemic areas; three were active TB. The fourth patient had tested positive for latent TB on study entry and, as per study protocol, was being treated but unfortunately died of disseminated TB despite isoniazid therapy. All TNF-inhibitors can make patients more susceptible to infection. Prior to initiating golimumab therapy, patients must be evaluated for active and latent tuberculosis and hepatitis B virus infection. 1 Further details of adverse events, precautions, contra-indications and drug interactions can be found on the Summary of Product Characteristics Risk assessment. Golimumab is given by subcutaneous injection. Patients will require training in subcutaneous injection technique, any may self-inject if their clinician feels that this is appropriate. If multiple injections are required, they must be administered at different sites on the body. 1 Golimumab is available as 100mg and 50mg single-use, pre-filled pens or pre-filled syringes. These must be stored in a refrigerator and removed 30 minutes prior to administration Potential advantages and disadvantages over existing technologies Convenience Golimumab can be given by self-administered subcutaneous (SC) injection. After the initial induction at week 0 and 2, doses are given every 4 weeks. 1 Infliximab is given by intravenous infusion, usually as an outpatient/day-case setting. The induction regimen is on weeks 0, 2 and 6, following by maintenance doses every 8 weeks. 15 Adalimumab is given by self-administered SC injection on weeks 0 and 2, then either on alternate weeks or weekly. 15 The advantage of golimumab is self-administration at a longer dosing interval Drug cost MSD have provided the following information regarding the cost of golimumab. 16 The list price for one golimumab 50 mg pre-filled pen or syringe is , and that for one golimumab 100 mg pre-filled pen is 1, However, under the Simply For Me Patient Support Programme, MSD will provide these doses with price parity, so the customer will pay only , even when a 100 mg dose is prescribed. 16 The list price for adalimumab is per 40mg pen or syringe. Further details are in Appendix Healthcare resource utilisation MSD support the home delivery of golimumab through a comprehensive patient support service ( Simply for Me ) which is provided by a third party homecare provider. 16. It provides a number of unique features including multiple support visits from a qualified nurse, injection SMS reminders, educational resources and a delivery schedule tailored to meet the critical review and decision points within the patient treatment pathway. The patient s 5

6 disease activity and clinical response will be scored by the homecare provider using a partial Mayo score and IBDQ questionnaire. This will be reported to the hospital clinical team to support patient management. MSD anticipate this may support a reduction in outpatient attendances. 16 As with other biologic agents, before commencing treatment with golimumab all patients must be evaluated for both active and inactive ( latent ) tuberculosis and tested for HBV infection. Patients who are confirmed carriers of HBV who require treatment with golimumab should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy Suitability for shared care The Inflammatory Bowel Disease (IBD) Standards, 2013 Update, state that care for patients with IBD should be delivered as locally as possible, with rapid access to more specialised services when needed. 17 Some aspects of the management of adults with IBD can be provided outside secondary care where this will help to take services closer to the patient or offer choice, subject to demonstration that the standards of IBD care provision will be met. Currently, a shared care agreement with general practice has not been considered for golimumab, it is proposed that the Simply for Me patient support programme will provide locally delivered care with a clear interface with secondary care clinicians and access to specialised services when needed Likely budgetary impact It is estimated that the number of patients with moderate to severe UC who would be treated with a biologic agent is 7 per 100, The cost of providing golimumab for one patient per year is 16 : Induction Drug Acquisition Year 1 Subsequent Yearly Drug Acquisition Costs 2, , , The full budget impact is in Appendix Health Economics Health economic analyses are not currently available. A NICE Multiple Technology Appraisal of infliximab, adalimumab and golimumab is in development with final guidance anticipated January Likely commissioning and funding pathway Golimumab for UC is PbR excluded and funded by the CCG. 7. Suggested place in therapy Golimumab is indicated for treatment of moderately to severely active UC in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies. 1 The data from the PURSUIT studies are insufficient to determine the place of golimumab in the treatment of moderate to severe UC in comparison with adalimumab and infliximab. Available data suggest that clinical response is usually achieved within weeks of treatment (after 4 doses). Continued therapy should be reconsidered in patients who show no evidence of therapeutic benefit within this time period. 1 Infliximab and adalimumab are also licensed to treat moderate to severe UC; NICE recommendations are stated in Section 3. A NICE guideline on infliximab, adalimumab and golimumab for the second-line treatment of moderately to severely ulcerative colitis is expected in January

7 Reference List (1) Summary of Product Characteristics. Simponi 50mg solution for injection. Date of revision of the text: 07/10/2013. Merck Sharp & Dohme Limited. (2) Summary of Product Characteristics. Humira Pre-filled Pen, Pre-filled Syringe and Vial. Date of revision of the text: 20 September AbbVie Limited. (3) Summary of Product Characteristics. Remicade 100mg powder for concentrate for solution for infusion. Date of revision of the text: 27 June Merck Sharp & Dohme Limited. (4) NICE Clinical Guideline 166. Ulcerative colitis. Management in adults, children and young people. Issued: June National Institute for Health and Care Excellence. (5) Final scope for the multiple technology appraisal of infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262). November National Institute for Health and Care Excellence. (6) NICE technology appraisal guidance 163. Infliximab for acute exacerbations of ulcerative colitis. December National Institute for Health and Care Excellence. (7) NICE technology appraisal guidance 140. Infliximab for subacute manifestations of ulcerative colitis. April National Institutes of Health (8) NICE technology appraisal guidance 262. Adalimumab for the treatment of moderate to severe ulcerative colitis (terminated appraisal). July National Institute for Health and Care Excellence. (9) Ulcerative colitis (moderate, severe) - infliximab (review TA140), adalimumab (review TA262) & golimumab (2nd line) [ID695]. National Institute for Health and Care Excellence. (10) Sandborn WJ, Feagan BG, Marano C et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146: (11) Sandborn WJ, Feagan BG, Marano C et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146: (12) Hanauer SB. Still in Pursuit. Gastroenterology 2014; 149: (13) Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353(23): (14) Sandborn WJ, Van Assche G, Reinisch W et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142: (15) British National Formulary 66th edition. September Khanderia S, editor. British Medical Association and Royal Pharmaceutical Society of Great Britain. (16) Personal communication: Healthcare Access, Merck Sharp Dohme, February (17) Standards for the Healthcare of People who have Inflammatory Bowel Disease (IBD). IBD Standards Update. The IBD Standards Group. Medline: GOLIMUMAB.af AND *COLITIS, ULCERATIVE/ Embase: *GOLIMUMAB/ AND *ULCERATIVE COLITIS/ Written by Alexandra Denby, London Medicines Information Service, Northwick Park Hospital, Harrow, HA1 3UJ. alexandra.denby@nhs.net. Merck Sharp Dohme has commented on this review. LMEN would like to thank Jackie Eastwood, Pharmacy Manager, St Mark s Hospital, Harrow, for her comments on this review. 7

8 Appendix 1 Main results from the Phase 3 stage of PURSUIT-SC 10 Endpoint Placebo (n=251) Golimumab 200/100mg Golimumab 400/200mg (n=253) (n=257) Primary endpoint: 51%, p< %, p< % Clinical response at week 6 NNT approximately = 5 NNT approximately = 5 Secondary endpoints Clinical remission 16 (6.4%) 45 (17.8%), p< (17.9%), p< NNT approximately = 9 NNT approximately = 9 Mucosal healing 72 (28.7%) 107 (42.3%), p= (45.1%), p< NNT approximately = 8 NNT approximately = 7 IBQD mean change from baseline (range 32 to 224) 14.8 ± (n=250) 27 ± 33.72, p< (n=252) 26.9 ± 34.28, p< (n=255) Mayo score mean change from baseline -1.6 ± ± 2.90, p< ± 2.95, p< Normal or inactive mucosal disease (endoscopy score =0) (n) 10 (4%) 21 (8.3%), p= NNT approximately = (12.1%), p= NNT approximately = 13 Figure 1: Serum golimumab concentrations and proportions of patients with clinical response and remission. 10 A and C show the median improvements from baseline in Mayo score at week 6 by serum golimumab concentration. A represents phase 2 patients and C represents all randomised patients. B and D show the proportion of patients with a clinical response or remission at week 6 by serum golimumab concentration. B represents phase 2 patients and D represents all randomised patients. 8

9 Appendix 2 Main results from the Phase 3 stage of PURSUIT-M 11 Endpoint Primary endpoint: Maintenance of clinical response through week 54 Golimumab 100mg (n=151) Golimumab 50mg (n=151) Placebo (n=154) 49.7%, p< %, p= % Numbers needed to treat Major secondary endpoints Clinical remission at both weeks 30 and %, P= %, P=NS* 15.6% Mucosal healing at both weeks 30 and %, P= % 26.6% Clinical remission at baseline and at both weeks 30 and %, P=NS* 36.5% 24.1% Corticosteroids at baseline; corticosteroidfree at both weeks 30 and % 28.2% 18.4% *P = NS: P = not significant, subsequent endpoints could not be claimed as significant Figure 2: Proportion of patients with clinical response through week 54 and the proportion in clinical remission at both weeks 30 and 54 by serum golimumab concentration quartiles at week

10 Appendix 3: Budget Impact Model 16 In order to draw a comparison between golimumab and adalimumab, consideration should be given on how each is licensed for use in clinical practice. GOLIMUMAB dosing is dependent upon patient s bodyweight: Body weight <80kg: An initial dose of 200mg followed by 100mg at week 2, then 50mg every 4 weeks, thereafter. Body weight 80kg: An initial dose of 200mg followed by 100mg at week 2, then 100mg every 4 weeks, thereafter. ADALIMUMAB The recommended adalimumab induction dose regimen for adult patients with moderate to severe UC is 160mg at Week 0 and 80mg at Week 2. After induction treatment, the recommended dose is 40mg every other week. Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg adalimumab every week. A per-patient cost comparison between golimumab and adalimumab is provided in the tables below. Table 3 compares the net budgetary impact of providing golimumab with the 50mg and 100mg doses at price parity versus treatment with adalimumab with a 40mg every other week dosing regimen. Table 4 draws a similar comparison, but demonstrates the change in budgetary impact when the maintenance dose of adalimumab is increased to 40mg once weekly. 16 Table 3. Net budgetary impact of golimumab (200/100mg induction, 50mg or 100mg every 4 weeks) versus adalimumab (160/80mg induction, 40mg every other week) Treatment Duration Induction Year 1 Year 2 Year 3 Year 4 Year 5 Net budgetary impact* Table 4. Net budgetary impact of golimumab (200/100mg induction, 50mg or 100mg every 4 weeks) versus adalimumab (160/80mg induction, 40mg once weekly) Treatment Duration Induction Year 1 Year 2 Year 3 Year 4 Year 5 Net budgetary impact* , , , , , *Please note, a negative value for net budget impact indicates a cost saving when golimumab is provided. The cost of providing golimumab for one patient per year is shown in Table 5 below. 16 Table 5. Drug acquisition costs for golimumab per year Induction Drug Acquisition Year 1 Subsequent Yearly Drug Acquisition Costs GOL Price Parity 2, , , The number of UC patients expected to receive with a biologic, per 100,000 population, were calculated as outlined below: The future population was calculated from the base year of 2012 using the formula: 2012) where r = 0.8% (UK population growth rate, Approximate Base Year Population (2013) Rate 100, % Year 1 Year 2 Year 3 Year 4 Year 5 Estimated Population 101, , , , ,897 10

11 From this the prevalent population was calculated by applying a prevalence rate for Ulcerative Colitis of 240 per 100,000 to the population in each year. 4 Year 1 Year 2 Year 3 Year 4 Year 5 Estimated Population 101, , , , ,897 Prevalence (%) 0.24% 0.24% 0.24% 0.24% 0.24% Prevalent Population The incident population was calculated using a rate of incidence of 10 per 100,000 or 0.01%. 4 Year 1 Year 2 Year 3 Year 4 Year 5 Estimated Population 101, , , , ,897 Incidence (%) % % % % % Incident population The net number of patients in each of the first five years was estimated as follows: ( ) NB: Mortality rate = 0% Based on the literature it was assumed that the mortality associated with moderate-severe UC was comparable with the general population in England so no adjustment is made to the risk of mortality. Year 1 Year 2 Year 3 Year 4 Year 5 Prevalent Population Incident Population Net Number of Patients It is estimated that a total of around 49% adults will have moderate-severe UC. Of those, it is estimated that 15% are eligible for treatment with biologics. Further, it is estimated that 38% of these biologiceligible patients will receive treatment with a biologic. (Ref: MSD data on file) Year 1 Year 2 Year 3 Year 4 Year 5 Net number of patients Percentage of patients with moderatesevere UC Number of patients with moderate to severe UC Percentage of patients eligible for biologic Total number of patients eligible for biologic Percentage of eligible patients expected to receive treatment with a biologic Number of eligible patients expected to receive treatment with a biologic 49% 49% 49% 49% 49% % 15% 15% 15% 15% % 38% 38% 38% 38%