Exciting developments and new approaches in psoriasis

Exciting developments and new approaches in psoriasis

The psoriasis market

Psoriasis is a chronic inflammatory disease of the skin and joints, affecting about 1–3% of the population in most regions. There are a variety of topical treatments, such as corticosteroids, vitamin D and phototherapy for the milder cases, plus systemic treatments for more severe ones, including monoclonal antibodies (biologics). Studies have demonstrated annual treatment discontinuation rates of up to 25%, so there is a need for new therapies with more convenient dosing regimes and reduced side effects. Expense is also an issue: in the US, for example, the cost of treating severe psoriasis increased by 30% between 2000 and 2008, reaching an annual total of $30,000–$60,000 per patient in 2010. Worldwide, the market for psoriasis drugs is expected to reach $7.4 billion by 2020. The disease also creates additional challenges: up to a third of people with chronic psoriasis go on to develop psoriatic arthritis, and studies show that patients with psoriasis also have increased prevalence of cardiovascular risk factors which require extra treatment.

Effective therapy for moderate to severe psoriasis

The most effective treatments are provided by a group of injectable systemic agents which target the immune response that causes the symptoms of the disease. Currently tumour necrosis factor-α (TNFα) inhibitors dominate, including adalimumab (Humira) from AbbVie, Amgen’s etanercept (Enbrel) and Johnson and Johnson’s infliximab (Remicade), but these will come under increasing pressure from biosimilars and newer monoclonal antibodies.

A second generation of drugs for psoriasis is making its mark and this includes certolizumab pegol (Cimzia), a TNFα antagonist from UCB, and golimumab (Simponi), a follow-up to Remicade from Johnson & Johnson and shared with Merck Inc. Ustekinumab (Stelara), an infusion drug and human interleukin-12 and -23 antagonist, again from Johnson & Johnson, has shown superiority to etanercept in the ACCEPT trial, has rising sales and is demonstrating long-term safety. Secukinumab (Cosentyx), an antibody to interleukin-17A (IL-17A) from Novartis, showed better efficacy than etanercept in the FIXTURE trial and better efficacy than ustekinumab in the CLEAR study. Secukinumab was approved for psoriasis in the EU and USA early in 2015. In clinical studies 70% or more patients taking secukinumab 300mg achieved clear skin (PASI 100) or almost clear skin in the first 16 weeks of treatment, and the effect was maintained in the majority of patients up to week 52.

New delivery approaches

Most of the top sellers in moderate to severe psoriasis are delivered by injection or infusion. Apremilast (Otezla) from Celgene is delivered orally and offers greater convenience and a good safety record, along with the ability to simplify patient management as routine lab monitoring is not needed – although these features have to be balanced against the lower efficacy in clearing patients’ skin compared to most biologic treatments. Now approved for psoriasis in the EU and USA, Celgene predicts apremilast sales of $2 billion by 2017. It will be priced below Humira, Enbrel and Stelara. Safety and acceptable side effects will be strong points for apremilast, which is also FDA-approved for psoriatic arthritis.

Biosimilars

Approved by the FDA in 2007, adalimumab (the current top seller) earned $1.4 billion in 2011 from psoriasis alone, and though the drug is set to go off-patent in 2016, as a complex biologic it will not be easy to replicate with biosimilars, so analysts expect it to remain the top global seller until 2018. New infliximab biosimilars Remsima (from Hospira/Celtrion) and Inflectra (from Napp) are already challenging Remicade, an older psoriasis drug which is due to go off-patent in 2015 in the EU and 2018 in the USA. Once the market leader, Enbrel (etanercept) made $1.3 billion from psoriasis in 2010, and at its peak accounted for a third of total sales. Though it claims patent protection to 2028, new treatments and biosimilars are expected to erode this dominance, suggesting it will account for a fifth of the market by 2020. Cipla, Sandoz, Amgen and Hospira/Celltrion have biosimilars to compete when the Enbrel patent expires and could offer a potential 30% discount on prices.

Biosimilar competition in psoriasis for adalimumab will come from ABP 501 from Amgen/AET Biotech (in Phase III), GP 2017 from Sandoz (in Phase III) and PF 0641093 from Pfizer (in early studies). Biosimilar competition for etanercept will come from GP 2015 from Sandoz, CHS 0214 from Baxter/Coherus Biotech/Daiichi Sankyo and HD 203 from Sandoz (all in Phase III). Biosimilar competition for infliximab comes from Remsima from Hospira/Celltrion and Inflectra from Napp Pharma, now launching worldwide. Biosimilars cannot be launched until expiry of the patent of the originating drug. Note: this list of biosimilar competitors is not comprehensive.

Next generation treatments

The first in a new class of immunosuppressant treatments, the oral Janus kinase (JAK) inhibitor tofacitinib (Xeljanz), from Pfizer, is in Phase III trials for psoriasis in the EU and was filed in the US in early 2015. It shows ‘similar efficacy’ to etanercept, though its use in rheumatoid arthritis has been dogged by side-effects including elevated risk of serious infections, liver damage and cancer. Sales for tofacitinib in rheumatoid arthritis have been slow. At the 5 mg dose, tofacitinib proved less effective than etanercept in psoriasis, and even then, the drug produced serious side effects in mid-stage trials, according to one analyst.

Monoclonal antibody treatments that target interleukin-17 (IL-17) seem to be offering a better prospect, and a few pipeline drugs aim to follow in the footsteps of secukinumab. Ixekizumab, an anti-IL-17 monoclonal antibody from Eli Lilly, has shown itself in the Phase III UNCOVER studies superior to etanercept. In the UNCOVER-2 and -3 studies, 78–90% of patients achieved at least a 75% reduction in PASI scores at 12 weeks, and 38–41% achieved PASI 100 (clearance) at week 12 compared to just 5–7% of patients taking etanercept. The company intends to submit ixekizumab to regulatory authorities in 2015. These antibodies are all delivered subcutaneously, but if side-effects do not prove serious, their impressive clear-up rates could make them hugely successful treatments. Brodalumab, an interleukin-17 (IL-17) receptor agonist, from Amgen/AstraZeneca has run into difficulties: Amgen has withdrawn from the collaboration with AstraZeneca, after suicidal ideation and behaviour events were observed in the programme. The future of this drug is now uncertain.

Over the horizon

With a number of studies indicating the role played by IL-23 in psoriasis, the industry is turning its attention to drugs that block its action. To date, ustekinumab is the only IL-23 antagonist on the market. Just entering Phase III studies, Merck’s tildrakizumab is also an antibody treatment that targets IL-23. Guselkumab, from Johnson and Johnson, is in Phase III trials and showing positive results, namely 86% of moderate to severe psoriasis patients with clearance after 16 weeks in the X-PLORE trial, and superiority over adalimumab was demonstrated. Other targets for next generation psoriasis treatments include T-regulatory cells – as seen with Biotest’s tregalizumab, in Phase II trials in collaboration with AbbVie. As a first-in-class true human antibody, XBiotech hopes its MABp1, also in Phase II trials, will have a smaller immunogenic footprint than other antibody treatments, thus reducing side-effects.

References

Research gaps in psoriasis: opportunities for future studies. Ryan C, Korman NJ, Gelfand JM, Lim HW, Elmets CA, Feldman SR, Gottlieb AB, Koo JY, Lebwohl M, Leonardi CL, Van Voorhees AS, Bhushan R, Menter A. J Am Acad Dermatol. 2014;70(1):146-67. doi: 10.1016/j.jaad.2013.08.042.

Psoriasis and metabolic syndrome: a systematic review and meta-analysis of observational studies. Armstrong AW, Harskamp CT, Armstrong EJ. J Am Acad Dermatol. 2013;68(4):654-62. doi: 10.1016/j.jaad.2012.08.015.