Date of Original Decision: 19th October 2010 Date Re-Reviewed: 21st July 2015

The sequential use of biologic agents in the treatment of Chronic or Plaque Psoriasis, for those patients, fulfilling NICE criteria for a biologic The Interface Prescribing & New Therapies Subgroup of the GMMMG discussed the above drug for the above indication. The recommendation of this subgroup is as follows*: The New Therapies Subgroup of the GMMMG considered the use of biological therapy (e.g. infliximab, adalimumab, etanercept and ustekinumab) after a first has failed in patients who fulfil the NICE criteria for a biologic agent. The group recommends that a second or third biological therapy may be tried after a first has failed. It is recommended that patients are treated according to the Salford Royal NHS Foundation Trust protocol for patients requiring biological therapy and should fulfil the NICE criteria for initiation and continuing therapy. (See accompanying pages) The group considered the evidence base for use of a second biologic after a first had failed and noted that the data was limited with varying response rates; however it was also noted that response to one biologic agent is not predictive of a patient’s response to a second agent. Costs of all agents are similar (annual cost: £9282£10228) and use of a second agent would be in place of the first so would be cost neutral. It was also noted that alternative treatments would be similarly priced with varying results. The group also noted that the NICE Clinical Guideline CG153 (2012) on the assessment and management of psoriasis now recommends switching people to a second biologic after the first has failed. This recommendation does not cover the use of a subsequent agent after a third has failed due to a lack of available data in this situation. If requested this would need to be reviewed by commissioners on a case by case basis to assess affordability. According to set criteria use of a biologic agent second or third line after a first has failed was deemed to be medium priority for funding.

Review date: July 2017 * Unless superseded by NICE guidance or substantial and significant new evidence becomes available. ▼ Newly marketed drugs and vaccines are intensively monitored for a minimum of two years, in order to confirm the risk / benefit profile of the product. Healthcare professionals are encouraged to report all suspected adverse drug reactions regardless of the severity of the reaction.

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Warren et al July 2015 Psoriasis Biologic Pathway GMMMG

GMMMG Psoriasis Biologics Pathway Background: Psoriasis is a common inflammatory skin condition which is frequently (30%) associated with an inflammatory arthropathy known as psoriatic arthritis (PsA) and if left untreated is often life ruining. Compelling data demonstrate that the impact on quality of life for patients living with psoriasis is comparable or worse than diabetes, heart disease and cancer1. Thus, it is imperative that for those with the most severe disease effective treatment strategies are utilised. The National Institute for Health and Care Excellence (NICE) have published individual HTAs for each of the 5 licensed systemic biological therapies for psoriasis; namely adalimumab, etanercept, infliximab (Anti-tumour necrosis factor alpha inhibitors -TNFi), ustekinumab (Interleukin 12/23 inhibitor) and most recently (anticipated July 22nd) secukinumab (Interleukin 17A inhibitor). Each of these individual biologics has approval for use following failure or unsuitability to methotrexate, ciclosporin and phototherapy when patients also have disease severity scores of psoriasis area and severity index (PASI) and Dermatology Life quality Index (DLQI) of >/= 10 and >10 respectively (Infliximab parameters are higher). Currently the psoriasis pathway in Greater Manchester allows 3 lines of biologic use before submitting an individual funding request (IFR). This allows sensible access to biologics without inundating the CSU / CCGs with IFRs. Given the publication of a new HTA for secukinumab it is necessary to update the GMMMG psoriasis biologic pathway and we would propose that 3 lines of biologic use is still acceptable as opposed to adding secukinumab as a 4th choice in the pathway. In line with NICE we propose that all 5 drugs can be used 1 st line with rarer scenarios being applicable to:  Or 

Infliximab (*or biosimilar for new patients) when patients have unstable disease and rapid control is required Etanercept - when infection risk is a significant concern.

Thus, the 3 core agents in the algorithm are adalimumab, ustekinumab and secukinumab.

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Warren et al July 2015 Psoriasis Biologic Pathway GMMMG

Logic for the 3 core drugs: Each of the 3 core drugs targets a different cytokine: adalimumab (TNF); ustekinumab (IL23) and; secukinumab (IL17A). It is likely that the key driver of any individual’s disease is one of these 3 cytokines so if one agent fails a 2nd or 3rd is likely to work. Each of the 3 drugs has clinical trial data demonstrating a 75% reduction in PASI, known as PASI 75, of at least 70% 2,3,4. Ustekinumab and secukinumab have demonstrated superiority to etanercept in large well designed clinical trials. 2,4 Secukinumab has demonstrated superiority to ustekinumab in a large well-designed clinical trial5. All 3 drugs have efficacy for psoriatic arthritis6,7,8 although the TNFi drugs (adalimumab from core set) are the gold standard drugs in this scenario7 Although all 3 drugs are highly efficacious in the short term, biologic drugs do have an attrition rate year on year of approximately 15% such that if switches are not allowed longer term disease control, for what is a life-long condition, will be lost. Ustekinumab has a lower attrition rate versus adalimumab9, no such “real world” data are available for secukinumab as yet. We have audited our use of ustekinumab and adalimumab locally and led on a national ustekinumab study showing that both these drugs work following failure of other biologics – all studies have been published in the British Journal of Dermatology 10,11,12 . As secukinumab has come to the market later many patients in the clinical trial programme had failed prior biologics and secukinumab was show to be efficacious in such scenarios 4.

The Choice of Drug. 1st Line There are numerous factors which would influence the choice of which drug should be used at which point in the pathway. In those with psoriasis (minus PsA) ustekinumab is 1st line on the basis of better drug survival and a now well established safety record9. In those with both psoriasis and PsA (or signs of early PsA / risk of PsA) adalimumab is the 1st line choice drug. Whist safety data are being accrued in the real world secukinumab would be 1st choice in settings where there are concerns or possible problems with the other 2 drugs e.g. demyelination risk / tuberculosis risk / rapid efficacy required. Given the access costs to secukinumab are slightly cheaper than existing drugs and the high clinical efficacy, including superiority to ustekinumab, this agent may in a short period of time (1-2 years) be

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Warren et al July 2015 Psoriasis Biologic Pathway GMMMG

considered 1st line in an increasing range of scenarios as experience is gained in the real world setting.

2nd Line After failing either adalimumab or ustekinumab, secukinumab would be used based on the high efficacy levels in psoriasis, the clinical trial data showing that the agent will work in patients who have failed other biologics and the FUTURE studies showing promising efficacy in the setting of PsA. If secukinumab has been used 1st line we would recommend either ustekinumab or adalimumab depending on the presence of PsA (adalimumab) or not (ustekinumab). In the rare scenarios when etanercept or infliximab (or biosimilar) have been used 1st line we would recommend secukinumab based on the same logic given above. 3rd Line Acknowledging that PsA often develops after the development of psoriasis those patients who have failed ustekinumab or secukinumab, or who go on to develop PsA whilst on these agents, would be best treated with adalimumab based on its efficacy for both psoriasis and PsA. In those patients who have failed adalimumab and secukinumab we would suggest ustekinumab based on the completely differing mechanism of action for this agent vs the 1st two agents and the excellent tolerability and persistence data that support the use of ustekinumab in people who develop adverse events on other biologic drugs. There are other clinical factors which will also inform into the decision around choice of drug which may have current or future relevance and also add significant support to the need for 3 therapeutic options:    



Risk of candida infection with secukinumab that may make this a poor choice in those prone to such infections. Presence of inflammatory bowel disease would be a contraindication for the use of secukinumab Body weight – ustekinumab has 2 dosing regimens with those > 100KG getting access to the higher dose of drug, for heavier patients this may be of relevance. Immunogenicity risk –emerging data show that certain drugs such as adalimumab may be neutralised by anti-drug antibodies. It is not immediately clear which populations are at risk of this but work that our unit is leading on nationally will help inform this. Genetic factors - Certain HLA subtypes may make patients more or less likely to respond to ustekinumab.

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Warren et al July 2015 Psoriasis Biologic Pathway GMMMG

References: 1 Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999 Sep;41(3 Pt 1):401-7. 2 Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, Guzzo C, Xia Y, Zhou B, Li S, Dooley LT, Goldstein NH, Menter A; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010 Jan 14;362(2):118-28 3 Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, Strober BE, Kaul M, Gu Y, Okun M, Papp K. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial.J Am Acad Dermatol. 2008 Jan;58(1):106-15 4 Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C; ERASURE Study Group; FIXTURE Study Group. Secukinumab in plaque psoriasis--results of two phase 3 trials.N Engl J Med. 2014 Jul 24;371(4):326-38 5 Thaci D – Oral Communication at the Annual Academy of American Dermatology. San Francisco, March 2015. 6 McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, Brodmerkel C, Li S, Wang Y, Mendelsohn AM, Doyle MK; PSUMMIT 1 Study Group. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013 Aug 31;382(9894):780-9 7 Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, Sharp JT, Ory PA, Perdok RJ, Weinberg MA; Adalimumab Effectiveness in Psoriatic Arthritis Trial Study Group. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial.Arthritis Rheum. 2005 Oct;52(10):3279-89. 8 Mease P Oral Communication Annual College of Rheumatology Meeting November 2014 Boston 9 Warren RB, Smith CH, Yiu ZZ, Ashcroft DM, Barker JN, Burden AD, Lunt M, McElhone K, Ormerod AD, Owen CM, Reynolds NJ, Griffiths CE. Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2015 Jun 8. doi: 10.1038/jid.2015.208. [Epub ahead of print] 10 Warren RB, Brown BC, Lavery D, Ashcroft DM, Griffiths CE. Biologic therapies for psoriasis: practical experience in a U.K. tertiary referral centre. Br J Dermatol. 2009 Jan;160(1):162-9 11 Warren RB, Brown BC, Lavery D, Griffiths CE. Adalimumab for psoriasis: practical experience in a U.K. tertiary referral centre. Br J Dermatol. 2010 Oct;163(4):859-62

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Warren et al July 2015 Psoriasis Biologic Pathway GMMMG

12 Laws PM, Downs AM, Parslew R, Dever B, Smith CH, Barker JN, Moriarty B, Murphy R, Kirby B, Burden AD, McBride S, Anstey AV, O'Shea S, Ralph N, Buckley C, Griffiths CE, Warren RB. Practical experience of ustekinumab in the treatment of psoriasis: experience from a multicentre, retrospective case cohort study across the U.K. and Ireland.Br J Dermatol. 2012 Jan;166(1):189-95.

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Warren et al July 2015 Psoriasis Biologic Pathway GMMMG

Further information / commissioning implications for CCGs Recommendation From the NICE Costing Template for secukinumab which accompanied TA350, annual savings were projected through use of this drug compared to other biologics. Similarly savings are associated with the use of infliximab biosimilars. Thus moderate savings on PbRe drugs may be anticipated. Formulary and Interface considerations All these drugs are in the Formulary by virtue of their positive NICE TAs. With the exception of infliximab, all have modest criteria in terms of PASI and DLQI scores to be considered as treatment options. The pathway provides criteria for choosing between them. Summary of impact The pathway will reduce the requirement for IFRs while providing a consistency of treatments which strike a balance between cost and experience while backed up by sound clinical rationale. Major area of risk / implications: primary care [through re-charge of PbRe drugs]

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