USTEKINUMAB. London New Drugs Group APC/DTC Briefing Document. May 2009

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1 Page 1 London New Drugs Group APC/DTC Briefing Document USTEKINUMAB Contents Summary 1 Background 4 Clinical efficacy 5 Cost implications 9 Reference list 10 Appendices 11 Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: Med.info@nwlh.nhs.uk Further copies of this document are available from URL: Summary The drug and the review was launched in the UK in January 2009 for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapies, including ciclosporin, methotrexate and PUVA. is a fully human monoclonal antibody that inhibits the activity of interleukin 12 and 23. Doses are given at weeks 0 and 4, then every 12 weeks thereafter. The purpose of this review is to evaluate the evidence to support use in this indication in adults with moderate to severe plaque psoriasis. Background Psoriasis is a chronic immune-mediated inflammatory skin disease, with an estimated prevalence of 2-3%. It is characterised by epidermal thickening and silvery scaling, commonly affecting extensor surfaces and scalp. Triggers include trauma, infection and certain drugs, including lithium, chloroquine, beta blockers and ACE inhibitors. Severe psoriasis is treated with immunosuppressants, biologics and acitretin. NICE Guidance for ustekinumab is due out in September Adalimumab, etanercept and infliximab are recommended by NICE for the treatment of adults with severe plaque psoriasis when other standard systemic therapies or PUVA have not worked or have caused an adverse effect or if there is a medical reason why they should not have these other treatments. Literature searched The following databases were searched: Medline (ustekinumab.af), Embase (USTEKINUMAB/), IDIS (ustekinumab.af). The results of these searches were supplemented with information from the EMEA, NICE and information supplied by Janssen-Cilag. Three phase III trials; two placebo-controlled (PHOENIX 1 and 2) and one comparator-controlled (ACCEPT, published as a conference poster), were identified. Efficacy studies PHOENIX 1 (n=766) and PHOENIX 2 (n=1230) were randomised, double-blind trials in which ustekinumab 45mg and 90mg were compared with placebo. Both studies were powered to detect whether ustekinumab was more effective than placebo. All efficacy data were analysed accord- PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 ing to the assigned treatment group (intention-to-treat population), whilst all the safety data were analysed according to the actual treatment received. Previous biological therapy had been given to approximately half the patients in PHOENIX 1 and approximately one third of patients in PHOENIX 2. The trial designs were complicated, with three phases. In the first phase (12 weeks) patients were randomly assigned to a treatment group: placebo, ustekinumab 45mg or ustekinumab 90mg. In both studies, treatment was given at weeks 0 and 4, then half the placebo-group patients were randomised to ustekinumab 45mg and the other half to 90mg at week 12. In the second phase (weeks in PHOENIX 1 and weeks in PHOENIX 2), patients initially randomised to placebo were then switched to ustekinumab. In the third phase, responders were re-randomised to either active or placebo treatment (PHOENIX 1) or partial responders were randomised to dose intensification (8- weekly treatment) or continued on 12-weekly treatment (PHOENIX 2). The EMEA recommend that two endpoints are used to assess the efficacy of a new treatment for psoriasis: the Psoriasis Area Severity Index (PASI) and a validated standardised global score, such as the Physicians Global Assessment (PGA). Both studies demonstrate the superiority of ustekinumab over placebo. Rapid, clinically significant improvements in patients with moderate to severe psoriasis, including those who had failed prior biological treatments, were seen in both trials. Over 80% of patients receiving ustekinumab had a PASI 50 response by week 12, and over 90% had a PASI 50 by week 28. The onset of response was seen as early as 2 weeks after the first dose, and the response was maintained in patients who continued treatment every 12 weeks for up to 76 weeks. PGA responses also indicated a sustained response, but the data for these were not shown. Symptoms gradually recurred in patients whose therapy was withdrawn and quality of life improvements were lost, indicating that the blockage of IL12 and 23 is temporary and does not reverse the underlying causal mechanisms of psoriasis. Patients who partially responded represent a distinct subgroup of patients who have higher bodyweight and a longer duration of psoriasis than those who responded to treatment. These individuals also tended to have a history of psoriatic arthritis and a greater resistance to biological agents, compared with responders. In the ACCEPT trial (n=903), ustekinumab 45mg or 90mg was compared with etanercept (50mg twice weekly). Patients were randomised to either ustekinumab at weeks 0 and 4, or etanercept twice weekly for 12 weeks. PASI 75 at week 12 was achieved by 68% and 74% of patients receiving ustekinumab 45mg and 90mg respectively, compared with 57% receiving etanercept. Patients treated with ustekinumab also achieved higher marked improvements in PASI 90 scores: 36% (45mg) and 45% (90mg) achieved PASI 90, compared with 23% receiving etanercept, p<0.001 for both comparisons vs. etanercept. A greater proportion of patients in the ustekinumab 45mg and 90mg groups achieved a PGA score of cleared or minimal (65% and 71% respectively), compared with 49% in the etanercept group, p<0.001 for both comparisons vs. etanercept. Safety Adverse events occurred in similar proportions of patients receiving ustekinumab or placebo; there is limited comparator data available to assess whether the adverse events were treatment-related. Injection site erythema occurred more frequently in the group of patients receiving etanercept in the 12 week study, which may be due to the greater number of etanercept injections required (up to 24), compared with two ustekinumab injections. The most commonly reported side effects were infections and nasopharyngitis. As with all monoclonal antibodies, patients with active tuberculosis should not be treated with ustekinumab and live vaccinations should not be given during ustekinumab therapy.

3 Page 3 No drug-interaction studies have been carried out. In the trials, no effects on the pharmacokinetics of ustekinumab were seen in patients using paracetamol, ibuprofen, aspirin, metformin, atorvastatin and levothyroxine. Critical evaluation There is no gold standard for the systemic treatment of psoriasis and choice of an active comparator should be done in relation to the investigational product. The EMEA state that the clinical relevance of the demonstrated effect of a new drug for treating psoriasis can be evaluated only in relation to other available therapies and that the approvability of a new drug for the treatment of severe plaque psoriasis, supported only by efficacy results of placebocontrolled studies, can be seriously questioned. Ideally the study design should have threearms with both a placebo and active comparator arm to allow for a proper assessment of the benefit/risk ratio. This review is limited by the small amount of published comparative data currently available for evaluation. 12-week data from the ACCEPT study show that ustekinumab is significantly better than etanercept. The submission of data to the EMEA was before this study was completed; more comparative data is anticipated and should provide a fuller indication of how ustekinumab compares with etanercept. is significantly better than placebo in treating the symptoms of psoriasis, as would be expected. The design of the PHOENIX trials is complicated. The crossover design was used to investigate efficacy and safety of ustekinumab compared to placebo. The dosing intensification used in PHOENIX 2 was to investigate whether ustekinumab would improve skin response rates in partial responders. PHOENIX 1 and 2 also show that ustekinumab, when compared with placebo, is effective in patients who have failed prior biological therapies. Potential benefits over existing therapies There are currently three other biological therapies available for the treatment of psoriasis, all of which are TNF-inhibitors, which have been approved for use by NICE. is a different type of cytokine modulator for treating moderate to severe plaque psoriasis. Sequential use of ustekinumab appears to be effective. is given by subcutaneous (s.c.) injection at 12-week intervals. This dosing regimen offers advantages over the administration frequencies and/or routes of etanercept (weekly s.c. administration), adalimumab ( weekly or fortnightly s.c. administration) and infliximab (intravenous administration). Potential disadvantages There is a lack of active comparator controlled studies. As such, defining a place in therapy for ustekinumab in comparison with other biological therapies is not possible. Health economics No health economic studies of ustekinumab have been identified. Budgetary impact In the England the estimated incidence of psoriasis is 1.63%. Of these, 1.1% (1100 per 100,000) would be expected to have moderate to severe psoriasis and would be eligible for biological therapy. The estimated prevalence of patients with severe psoriasis who actually receive biological therapy (PASI 10 and DLQI 10) is 14/100,000. It is estimated that 60% of patients eligible for biologic therapy are currently receiving one. The estimated annual cost during the first 5 years of treatment with ustekinumab is 9876 per annum. Costs may vary in different settings because of negotiated procurement discounts. This compares with 4,290 for etanercept (treatment is limited to 24 weeks), 10,910 for infliximab (after loading doses, 6.5 infusions are given a year) and 9,295 for adalimumab (40mg on alternate weeks) (estimated costs).

4 Page 4 Background was launched in January 2009 for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapies, including ciclosporin, methotrexate and PUVA. 1 Psoriasis is a chronic immunemediated inflammatory skin disease, with an estimated prevalence of 2-3%. 2 It is characterised by epidermal thickening and silvery scaling, commonly affecting extensor surfaces and scalp. 3;4 Triggers include trauma, infection and certain drugs, including lithium, chloroquine, beta blockers and ACE inhibitors. Severe psoriasis is treated with immunosuppressants, biologics and acitretin. 3;4 Adalimumab, etanercept and infliximab are biological agents that have been recommended by NICE for the treatment of severe plaque psoriasis which has failed to respond to standard systemic treatments. 5-7 is a fully human monoclonal antibody that inhibits the activity of human interleukin (IL) 12 and IL-12 and IL-23 are secreted by cells such as macrophages, and contribute to natural killer cell activation and CD4 T cell differentiation and activation. Abnormal regulation of IL-12 and IL-23 has been associated with immune-mediated diseases, such as psoriasis. 1;8 prevents them from binding to the IL-12Rb1 receptor protein expressed on the surface of immune cells. cannot bind to IL-12 or IL-23 that is already bound to IL- 12Rb1 cell surface receptors. Dose The initial dose of 45mg is given subcutaneously at week 0, followed by another 45mg dose at week 4, then every 12 weeks thereafter. 1 A dose of 90mg should be used in patients who are over 100kg bodyweight Discontinuing therapy should be considered in patients who have not responded with up to 28 weeks of treatment. is not recommended for use in children under 18 years of age and in pregnant women. 1 Women of child-bearing potential should use effective contraception during and up to 15 weeks after treatment. It is not known whether ustekinumab is excreted into breast milk: a decision on whether to discontinue breast feeding during and up to 15 weeks after treatment or to discontinue ustekinumab should be made, taking into account the benefits of breast feeding to the child and ustekinumab to the mother. has not been studied in patients with renal or hepatic impairment; no dose recommendations can be made in these patient groups. 1 Precautions has the potential to increase the risk of infections and reactivate latent infections. 1 Patients should be evaluated for tuberculosis infection, and treatment should not be given if the patient has active TB. Immunosuppressants can increase the risk of malignancy. In trials, both cutaneous and noncutaneous malignancies developed in some patients receiving ustekinumab. Interactions Patients receiving ustekinumab should not be given live viral or bacterial vaccinations. 1 Before live vaccination, ustekinumab therapy should be withheld for 15 weeks, and resumed at least 2 weeks after vaccination. No drug-interaction studies have been performed. 1 In the trials, no effects on the pharmacokinetics of ustekinumab were seen in patients using paracetamol, ibuprofen, aspirin, metformin, atorvastatin and levothyroxine. Adverse events The safety data reflects exposure to ustekinumab in 2,266 patients for a minimum of 6 months. 1 Serious adverse events did not differ between the treatment groups. The most common adverse reactions that occurred in >10% of patients were nasopharyngitis and upper respiratory tract infection. Most were mild and did not require discontinuation of study treatment. The rates of malignancies reported in ustekinumab-treated patients were comparable to the rates expected in the general population. Approximately 5% of patients treated with ustekinumab developed antibodies, which were generally low-titer. Efficacy tended to be lower in patients with antibodies, but antibody positivity does not preclude a clinical response.

5 Page 5 Storage should be stored in a refrigerator and in the outer carton to protect it from light. 1 Before administration, the injection should be allowed to reach a comfortable temperature for administration (approximately half an hour). Clinical efficacy There are three main phase III trials: PHOE- NIX 1 and 2, and ACCEPT. Details of the PHOENIX trials are in table 1. The ACCEPT trial has not yet been fully published. The EMEA recommend that two endpoints are used to assess the efficacy of a new treatment for psoriasis: the Psoriasis Area Severity Index (PASI) and a validated standardised global score, such as the Physicians Global Assessment (PGA). 9 The PASI score incorporates the extent of psoriasis at four anatomical sites with the signs of erythema, scale and elevation. The scores range from 0 (no symptoms) to 72 (severe very marked plaque elevation, scaling and/or erythema). 9 The PGA of a patient s psoriasis status depends on whether the psoriasis is cleared (0), minimal (1), mild (2), moderate (3), marked (4) or severe (5). 2 There is no gold standard for the systemic treatment of severe psoriasis and the choice of an active comparator should be done in relation to the investigational product. 9 A new drug for the treatment of severe psoriasis should not be approved only on the efficacy results of placebo-controlled studies. 9 PHOENIX 1 Baseline characteristics of the groups were similar, with approximately two-thirds of those enrolled men. A smaller percentage of patients treated with ustekinumab 45mg also had psoriatic arthritis, but this was not statistically significant. The average duration of psoriasis of 20 years and approximately a quarter of their body surface area was affected. Over half of the patients enrolled ( %) had received prior treatment with biologics, including etanercept, alefacept, efalizumab, infliximab or adalimumab. Results are tabulated in Appendix 1. Treatment phase 1: weeks 0 to 12. The primary endpoint of PASI 75 was achieved by significantly more patients in the ustekinumab 45mg (67.1%) and 90mg (66.4%) groups than in the placebo group (3.1%), (p< for each comparison vs. placebo). A higher proportion of ustekinumab-treated patients achieved at least a 50% improvement from baseline in PASI (PASI 50) by week 2, (p= for 45mg and p= for 90mg, both vs. placebo), and PASI 75 by week 4 (p< for each comparison vs. placebo). By week 12, PASI 50 was achieved by 83.5% of patients receiving 45mg ustekinumab, 85.9% receiving 90mg ustekinumab and 10.2% receiving placebo (p< for each comparison vs. placebo). Cleared or minimal disease, based on the physician s global assessment (PGA), was achieved in significantly more patients having active treatment: 60.4% (ustekinumab 45mg), 61.7% (90mg ustekinumab) and 3.9% (placebo), p< vs. placebo, both ustekinumab groups). Significantly more patients treated with ustekinumab 45mg or 90mg had a DLQI score of 0 or 1 (53.1% and 52.4% respectively), indicating that psoriasis was not affecting their quality of life, compared with 6% having placebo, (p< vs. placebo). Treatment phase 2: weeks The efficacy continued after the placebocontrolled part of the study, when patients on placebo were randomised to either 45mg or 90mg ustekinumab. Maximum efficacy was seen at week 24, with PASI 75 responses of 76.1% in the 45mg group and 85.0% in the 90mg group. At week 28, more than 90% of all patients had achieved PASI 50 and approximately half of the patients achieved PASI 90. Greatest responses were seen in patients who were originally allocated placebo and then randomised to ustekinumab 90mg. The responses were maintained through to week 40. Approximately 65% of patients were assessed to have cleared or minimal psoriasis and a similar amount had DLQI scores of 0-1, indicating that psoriasis was not affecting their quality of life. Treatment phase 3: weeks Among patients re-randomised at week 40 to either treatment or placebo, maintenance of PASI 75 (i.e. time to loss of PASI 75 response) was better in patients receiving maintenance therapy than in those withdrawn from therapy, as would be expected. In pa-

6 Page 6 Table 1: Design of the PHOENIX 1 and 2 trials. PHOENIX 1 10 PHOENIX 2 2 Study aim Design Endpoints To assess the safety and efficacy of ustekinumab compared with placebo for 12 weeks in 766 patients with moderate to severe plaque psoriasis, and long-term ustekinumab treatment for up to 76 weeks. Randomised, placebo-controlled, double-blind trial in adults with a baseline PASI score of 12 and at least 10% body surface area involvement. Patients were excluded if they had received prior biologic agents within the previous 3 months or conventional psoriasis treatment within 4 weeks. Three phases: 1. Weeks 0-12: placebo-controlled 45mg (n=255) or 90mg (n=256) or placebo (n=255) at weeks 0, 4 and then 12 weekly. Baseline randomised stratified according to site, weight ( or >90kg) and prior responses/treatments. 2. Weeks 12-40: placebo-crossover and active treatment 12-weekly. In the placebo group, 123 started 45mg and 120 started 90mg ustekinumab. 3. Weeks 40-76: randomised withdrawal phase Patients initially randomised to ustekinumab who achieved PASI 75, were re-randomised to ustekinumab or placebo (withdrawn from treatment). Patients on placebo were re-treated when they lost at least 50% of PASI improvement. Patients not achieving PASI 75 had their dosing modified or discontinued. Patients initially randomised to placebo were switched back to placebo. Primary: proportion of patients achieving PASI 75 at week 12. Those with missing data were deemed nonresponders. Secondary: proportion of patients with PGA score of cleared or minimal at week 12, change in DLQI from baseline to week 12, time to loss of PASI 75 at week 40. All parameters were assessed until week patients per group provided more than 99% power to detect at least one pairwise treatment effect in the primary endpoint. Efficacy data based on the intention-to-treat population (i.e. according to the treatment they were assigned to). To assess the efficacy and safety of ustekinumab in 1230 patients with moderate to severe psoriasis with up to 52 weeks of treatment, and if dosing intensification improves skin response rates in patients who partially responded to initial treatment. Randomised, placebo-controlled, double-blind trial in adults with a baseline PASI score of 12 and at least 10% body surface area involvement. Patients were excluded if they had received prior biologic agents within the previous 3 months or conventional psoriasis treatment within 4 weeks. Three phases: 1. Weeks 0-12: placebo-controlled 2. Weeks 12-28: placebo-crossover and active treatment. 45mg (n=409) or 90mg (n=411) at weeks 0, 4 and then every 12 weeks, or placebo (n=410) at weeks 0 and 4, then re-randomised to either 45mg or 90mg at weeks 12, 16 and then every 12 weeks thereafter. Baseline randomised was stratified according to site, weight ( 90kg or >90kg) and prior responses/ treatments. 3. Weeks 28-52: randomised dose intensification phase At week 28 patients with PASI 50 but not PASI 75 (partial responders) were re-randomised to either study drug every 12 weeks or intensified dosing every 8 weeks. Patients not achieving PASI 50 at week 28 discontinued treatment and those achieving PASI 75 continued with study drug every 12 weeks. Primary: proportion of patients achieving PASI 75 at week 12. Those with missing data were deemed nonresponders. Secondary: proportion of patients with PGA score of cleared or minimal at week 12, change in DLQI from baseline at week 12, and in the re-randomised partial responders, the number of visits with PASI 75 response between weeks in patients receiving study drug every 8 weeks compared with those receiving it every 12 weeks patients would give the study more than 99% power to determine whether at least one ustekinumab group was more effective compared with placebo for the primary endpoint. Efficacy data based on the intention-to-treat population (i.e. according to the treatment they were assigned to). Psoriasis Area Severity Index (PASI): 0 = no psoriasis, 72 = severe psoriasis 2, PASI 50/75 = 50% /75% improvement in symptoms from baseline. PGA: Physicians global assessment of psoriasis: 0 = cleared, 1 = minimal, 2 = mild, 3 = moderate, 4 = marked, 5 = severe 2 DLQI: Dermatology life quality index: 10 items determining extent of the effect of psoriasis on quality of life: 0 = not at all, 30 = very much. 2

7 Page 7 tients who were receiving maintenance therapy, the median percentage improvement in PASI remained stable to at least week 76. PASI 50, 75 and 90, and the PGA responses were also generally sustained. In the withdrawal group, PASI improvements began to decline by week 44. The improvements decreased from 96% at week 40 to about 40% at week 64. The median time to loss of PASI 75 in patients withdrawn from treatment was about 15 weeks; rebound psoriasis was not reported. treatment was restarted in 195 patients, of whom 85.6% achieved PASI 75 within 12 weeks. DLQI responses worsened in patients withdrawn from therapy. In general, adverse events that occurred were mild, non-serious and did not require treatment adjustment. The most commonly reported were upper respiratory tract infections, nasopharyngitis, headache and arthralgia. The rates of adverse events, serious adverse events or adverse events leading to study discontinuation did not appear to be dose-related. The size and duration of the trial do not rule out a potential effect of ustekinumab on uncommon events or ones that may occur after a longer duration of exposure or in larger patient populations.. PHOENIX 2 2 The PHOENIX 2 trial identified a small proportion of partial responders in both the 45mg and 90mg treatment groups at week Dose escalation from 90mg every 12 weeks to 90mg every 8 weeks led to significant improvement by weeks 52, nearly doubling the PASI 75 response rate. An improvement in response rate was not observed in partial responders who were escalated from 45mg every 12 weeks to 45mg every 8 weeks. Baseline characteristics of the treatment groups were well balanced, with the mean duration of psoriasis of 20 years and the extent of the body surface area affected of about 25%. Approximately two-thirds of the patients were male. Approximately 40% of patients had received a prior biological agent (slightly lower numbers than in PHOENIX 1). Most patients had used topical agents and two-thirds had received phototherapy. Results are tabulated in Appendix 2. Treatment phase 1: week Significantly more patients receiving ustekinumab achieved the primary endpoint of PASI 75: 66.7% (ustekinumab 45mg) and 75.7% (ustekinumab 90mg), vs. 3.7% (placebo), p< for each comparisons vs. placebo. PASI 50 was achieved by 83.6% (ustekinumab 45mg), 89.3% (ustekinumab 90mg) and 10.0% (placebo). The PGA of cleared or minimal psoriasis was seen in 68% (ustekinumab 45mg) and 73.5% (ustekinumab 90mg) compared with 4.9% (placebo), indicating a significantly greater response in the ustekinumab groups. At other thresholds, such as PASI 90 and PASI 100, a greater proportion of ustekinumabtreated patients had responded at week 12 than those receiving placebo. The median percentage improvement in PASI was 86.36% (45mg), 90.20% (90mg) and 3.28% (placebo), p< for both vs. placebo. Significant improvements in patient-reported outcomes, based on greater decreases in dermatology life quality index (DLQI) scores, were seen in each ustekinumab group. DLQI scores of 0 or 1 were seen in 55.3% (45mg) and 56.4% (90mg), p< for each comparison vs. placebo indicating that psoriasis was not affecting the quality of life of patients receiving ustekinumab, compared with 3.2% having placebo. Onset of efficacy was apparent by week 2, as measured by PASI 50 and by week 4, as measured by PASI 75 response rates. Treatment phase 2: weeks PASI 75 response rates continued to increase after the placebo-controlled phase, with maximum response achieved at week 20: 74.9% (ustekinumab 45mg) and 83.5% (ustekinumab 90mg). After crossover to active treatment, the response rates in the placebo to ustekinumab groups were similar to those seen in individuals originally randomised to ustekinumab. By week 28, PASI 75 response rates were 69.5% to 78.5%, whilst PASI 50 response rates were over 92%. Median percentage improvements in PASI ranged from 86.9% to 92.29%. Psoriasis was considered to be cleared or minimal in 61-70% of patients. The greatest response rates were seen in those patients switched from placebo to ustekinumab 90mg, as in PHOENIX 1.

8 Page 8 Treatment phase 3: weeks Patients who were PASI 75 responders at week 28 continued to receive the study drug every 12 weeks until week 52. All clinical responses were sustained until week 52 (PGA data not given in the study write-up). The median percentage improvement in PASI from baseline was 95.3% (45mg) and 95.6% (90mg). Partial responders at week 28, 22.7% in the 45mg group and 15.8% in the 90mg group, were more likely to have a higher body weight, more marked or severe disease, as measured by the PGA, and a higher incidence of psoriatic arthritis. More of these partial responders had used conventional systemic agents and were more likely to have failed treatment with at least one conventional systemic or biological agent, than responders. A higher percentage of partial responders (12.7%, 20/158) had antibodies against ustekinumab than PASI 75 responders (2.0%, 12/589) and they were also more likely to have lower ustekinumab serum levels than responders, e.g mcg/ml in PASI 75 responders treated with 90mg, vs mcg/ ml in partial responders, at week 28. Dosing intensification in the partial responders receiving ustekinumab 45mg did not result in greater efficacy, in terms of number of visits at which PASI 75 was achieved (1.13 visits in patients treated every 8 weeks compared with 1.54 visits in those treated every 12 weeks), or PASI 75 response. In contrast, dosing intensification in the partial responders receiving 90mg resulted in a greater number of visits at which PASI 75 was reached (2.63 vs visits, p=0.014) and higher PASI 75 response rates (68.8% vs. 33.3%, p=0.004), than those treated every 12 weeks. Dosing intensification resulted in a 4-5 times increase in mean trough serum drug levels, e.g 1.45 microg/ml in the 90mg group at week 52. In general, adverse events were mild and did not required treatment adjustment. During the placebo-controlled phase, the number of infections was similar between the groups. Serious adverse events did not occur to a greater extent in the ustekinumab groups, but in the dose intensification phase were reported more in patients receiving ustekinumab every 12 weeks than in those receiving it every 8 weeks. Cutaneous malignancies were reported in two patients, one in the placebo group (squamous cell carcinoma) and one in the 90mg group (basal cell cancer). No differences in liver function tests were seen between the groups. In the dose intensification phase, when all patients were treated with ustekinumab, adverse events were similar to those reported in the placebocontrolled phase. What both PHOENIX 1 and 2 demonstrate is that ustekinumab gives rapid, clinically significant improvements in patients with moderate to severe psoriasis, including those who had failed prior biological treatments, when measured by PASI, PGA and quality of life scores. The PGA data has not been published. The data also support the idea that IL 12 and 23 have a key role in the immunopathophysiology of psoriasis. Results were consistent across both trials. Clinically meaningful improvements that were seen in patients treated with ustekinumab were paralleled by improvements in patientreported outcomes. Over 80% of patients receiving ustekinumab had a PASI 50 response at week 12, and over 90% of all patients had a PASI 50 response at week 28, indicating that ustekinumab is effective in patients who had inadequate response to prior biologic therapy. The onset of response was seen within 2 weeks of the first ustekinumab dose and the response was maintained in patients who continued treatment every 12 weeks for up to 76 weeks. Symptoms gradually recurred in patients whose therapy was withdrawn and quality of life improvements were lost, indicating that the blockage of IL12 and 23 is temporary and does not reverse the underlying causal mechanisms of psoriasis. In patients withdrawn from ustekinumab, response was generally restored. Patients who partially responded represent a distinct subgroup of patients who have higher bodyweight and a longer duration of psoriasis than those who responded to treatment. These individuals also tended to have a history of psoriatic arthritis and a greater resistance to biological agents, compared with responders. These patients are more likely to respond to higher doses (90mg) given more frequently (every 8 weeks).

9 Page 9 ACCEPT trial In the phase III ACCEPT trial, ustekinumab was compared with etanercept in the treatment of 903 patients with moderate to severe plaque psoriasis. 11 Patients were randomised to either subcutaneous injections of ustekinumab 45mg or 90mg at weeks 0 and 4 (n=209 and 347), or etanercept 50mg twice weekly for 12 weeks (n=347). The primary endpoint was the percentage of patients achieving a PASI 75 response at week 12. PASI 75 at week 12 was achieved by 68% and 74% of patients receiving ustekinumab 45mg and 90mg respectively, compared with 57% receiving etanercept (p=0.012 for 45mg, p<0.001 for 90mg). Patients having ustekinumab also achieved higher marked improvements in PASI 90 scores: 36% (45mg) and 45% (90mg) achieved PASI 90, compared with 23% having etanercept, p<0.001 for both comparisons vs. etanercept. A greater proportion of patients in the ustekinumab 45mg and 90mg groups achieved a PGA score of cleared or minimal (65% and 71% respectively), compared with 49% in the etanercept group, p<0.001 for both comparisons vs. etanercept. Adverse events (AE) occurred in similar proportions of patients in each group, with approximately 68% of patients experiencing at least one AE. One AE occurred more frequently in the etanercept group (injection site erythema), which was reported by 14.7% of patients in this group compared with 0.7% having ustekinumab. This may be due to the greater number of etanercept injections required (up to 24 in the 12 week study), compared with two ustekinumab injections. What this short study shows is that ustekinumab demonstrated superior response, as measured by PASI and PGA, when compared with etanercept, for the treatment of plaque psoriasis. Economic / Cost implications In the England the estimated incidence of psoriasis is 1.63%, affecting approximately 644,198 adults. 12 Of these, 1.1% (1100 per 100,000) would be expected to have severe psoriasis and would be eligible for biological therapy. The estimated prevalence of patients with severe psoriasis who do actually receive biological therapy (PASI 10 and DLQI 10) is 14/100,000. It is estimated that 60% of patients eligible for biologic therapy are currently receiving one. 12 The table below shows the cost per treatment period /year for etancercept, infliximab and adalimumab. Costs may vary in different settings because of negotiated procurement discounts. Etanercept Infliximab Adalimumab Dose Discontinue if no response after: 25mg twice weekly for 24 weeks 5 mg/kg, repeated 2 weeks and 6 weeks after initial infusion, then every 8 weeks 12 weeks 14 weeks 12 weeks 40 mg on alternate weeks Price for 25mg-prefilled syringe per 100mg vial, ~4 vials/pt 1, per 40mg-prefilled pen or syringe. Annual usage 48 doses per 24 week treatment period: 4, infusions per year: 10, doses per year: 9,295.00

10 Page 10 Dosing schedule and associated annual costs of ustekinumab are in the table below. 13 In year 1, 5 doses are required which equates to a cost of 10,735. In subsequent years of maintenance treatment the average number of vials per year is 4.33 ( 9300). When these are combined over the first 5 years of treatment it equates to a cost of per annum. Number of vials Annual cost Average annual cost over 5 years Year ,735 Year ,735 Year 3 4 8,588 Year 4 4 8,588 9,876 Year ,735 Reference List (1) Summary of Product Characteristics. Stelara 45mg solution for injection. Date of first authorisation/renewal of the authorisation: 16th January Janssen-Cilag Ltd. (2) Papp KA, Langley RG, Lebwohl M et al. Efficacy and safety of ustekinumab, a human interleukin- 12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: (3) British National Formulary, 57th edition. March Ed. Martin J. British Medical Association and Royal Pharmaceutical Society of Great Britain. Accessed via on 24/04/09. (4) Anon. Psoriasis. Merck Manual Professional Acessed via: print/sec10/ch116/ch116b.html. (5) TA146 Psoriasis - Adalimumab for the treatment of adults with psoriasis, June 2008: quick reference guide. NICE Accessed via on 10/03/09. (6) TA103 Psoriasis - Efalizumab and etanercept for the treatment of adults with psoriasis, July 2006: quick reference guide. NICE Accessed via pdf/english on 10/03/09. (7) TA 134 Psoriasis - Infliximab for the treatment of adults with psoriasis, Jan 2008: Quick reference guide. NICE Accessed via on 10/03/09. (8) Bartlett BL, Tyring SK. for chronic plaque psoriasis. Lancet 2008; 371: (9) Guideline on Clinical Investigation of Medicinal Products indicated for the Treatment of Psoriasis. Nov Committee for Medicinal Products for Human Use (CHMP) Accessed via on 24/04/09. Ref: CHMP/EWP/2454/02 corr. (10) Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of ustekinumab, a human interleukin- 12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: (11) Griffiths CEM, Strober B, van der Kerkhof PCM et al. A phase 3, multicenter, randomized study comparing ustekinumab and etanercept for the treatment of moderate to severe plaque psoriasis. Poster FP1336. European Academy of Dermatology and Venereology, Paris, France. September 17-20, 2008 (12) Costing template for adalimumab for the treatment of adults with psoriasis. NICE Accessed via on 27/04/09. (13) Personal communication. Estimated costs of ustekinumab. Janssen-Cilag. April L Harper, Health Economy Liaison Manager. Janssen-Cilag have commented on this review.

11 Page 11 Appendix 1: PHOENIX 1 trial results 10 Week 12 Week 28 45mg (n=255) 90mg (n=256) Placebo (n=255) 45mg (n=250) 90mg (n=243) Placebo to ustekinumab 45mg (n=123) Placebo to ustekinumab 90mg (n=119) PASI (85.9%)* 220 (85.9%)* 26 (10.2%) 228 (91.2%) 234 (96.3%) 118 (95.9%) 117 (98.3%) PASI (67.1%)* 170 (66.4%)* 8 (3.1%) 178 (71.2%) 191 (78.6%) 81 (65.9%) 101 (84.9%) PASI (41.6%)* 94 (36.7%)* 5 (2.0%) 123 (49.2%) 135 (55.6%) 55 (44.7%) 74 (62.2%) PASI (12.5%)* 28 (10.9%)* 0 52 (20.8%) 71 (29.2%) 24 (19.5%) 40 (33.6%) % improvement in PASI score N mean 75.6 (27.04) 77.2 (23.67) 7.0 (30.77) 80.3 (23.65) 85.2 (19.40) 80.4 (20.60) 88.2 (15.73) Median (65.8 to 94.7)* (66.2 to 93.8)* 2.82 (-7.5 to 21.7) (69.7 to 97.9) (77.8 to 100.0) (67.8 to 97.6) (81.8 to 100.0) PGA Cleared 47 (18.4%)* 45 (17.6%)* 1 (0.4%) 66 (26.4%) 86 (35.4% 28 (22.8%) 48 (40.3%) Cleared or minimal 154 (60.4%)* 158 (61.7%)* 10 (3.9%) 147 (58.8%) 161 (66.3%) 75 (61.0%) 87 (73.1%) Marked or severe 5 (2.0%)* 14 (5.5%)* 105 (41.2%) 15 (6.0%) 5 (2.1%) 1 (0.8%) 2 (1.7%) DLQI change from baseline N Mean -8.0 (6.87) -8.7 (6.47) -0.6 (5.97) -8.1 (7.23) -9.6 (7.17) -8.7 (7.56) -9.6 (6.75) median (-12.0 to -3.0)* (-12.0 to -4.0)* 0.00 (-3.0 to 3.0) (-12.o to -3.0) (-13.0 to -4.0) (-13.0 to -4.0) (-14.0 to -4.0) DLQI score 0 or (53.1%) 131 (52.4%) 15 (6.0%) 146 (58.6%) 167 (69.0%) 74 (60.2%) 90 (76.3%) * p< vs. placebo

12 Page 12 Appendix 2: PHOENIX 2 trial results 2 Week 12 Week 28 45mg (n=409) 90mg (n=411) Placebo (n=410) 45mg (n=397) 90mg (n=400) Placebo to ustekinumab 45mg (n=193) Placebo to ustekinumab 90mg (n=194) PASI (83.6%)* 367 (89.3%)* 41 (10%) 369 (92.9%) 380 (95.0%) 180 (93.3%) 185 (95.4%) PASI (66.7%)* 311 (75.7%)* 15 (3.7%) 276 (69.5%) 314 (78.5%) 135 (69.9%) 153 (78.9%) PASI (42.3%)* 209 (50.9%)* 3 (0.7%) 178 (44.8%) 217 (54.3%) 82 (42.5%) 100 (51.5%) PASI (18.1%)* 75 (18.2%)* 0 74 (18.6%) 118 (29.5%) 30 (15.5%) 42 (21.6%) % improvement in PASI score N mean 77.0 (25.78) 82.1 (22.57) 4.9 (34.78) 79.8 (23.70) 84.8 (20.46) 79.7 (21.40) 84.0 (19.44) Median (67.7 to 95.7)* (76.7 to 96.8)* 3.28 (-10.1 to 20.1) (71.5 to 96.7) (78.7 to 100.0) (69.2 to 95.2) (76.1 to 95.7) PGA Cleared 93 (22.7%)* 115 (28.0%)* 0 88 (22.2%) 137 (34.3%) 46 (23.8%) 49 (25.3%) Cleared or minimal 278 (68.0%)* 302 (73.5%)* 20 (4.9%) 243 (61.2%) 280 (70.0%) 125 (64.8%) 136 (70.1%) Marked or severe 15 (3.7%)* 10 (2.4%)* 148 (36.1%) 8 (2%) 8 (2%) 3 (1.6%) 4 (2.1%) DLQI change from baseline N Mean -9.3 (7.12) (6.67) -0.5 (5.66) -9.5 (7.26) (6.96) -9.2 (6.06) -8.9 (6.19) median DLQI score 0 or (-14.0 to -4.0)* (-14.0 to -5.0)* (-4.0 to 3.0) (-14.0 to -4.0) (-16.0 to -5.0) (-13.0 to 5.0) (-12.0 to -4.0) 223 (55.3%)* 228 (56.4%)* 13 (3.2%) 251 (63.4%) 258 (63.4%) 88 (46.6%) 108 (56.0%) * p< vs. placebo