Scratching the surface

Psoriasis is an autoimmune disorder affecting approximately 100m people worldwide. It results from the body's immune system sending incorrect signals, leading to a loss of control of skin cell production. Consequently there is an overproduction of skin cells, which leads to thickening of the skin, inflammation and scaling.

This puzzling skin disease is estimated to cost patients $11.25bn annually in direct and indirect healthcare costs, with work loss accounting for approximately 40 per cent of the total cost burden.

There is no cure for psoriasis, and treatment is only suppressive while it is being administered. Current therapies include sunlight and topical treatments (for mild psoriasis), and phototherapy with or without concomitant chemotherapy or systemic drugs (for moderate-to-severe psoriasis). However, over the past decade, a wave of biotech drugs for the treatment of psoriasis has hit the market: since 2003, the number of treatments for moderate-to-severe psoriasis approved by the US Food and Drug Administration (FDA) has burgeoned.

This growth looks set to continue, with more than 20 potential treatments currently in clinical trials or under review by the FDA. Notably, the driver for developing these new treatments is the serious adverse events associated with standard treatment (systemic drugs, such the immunosuppressant ciclosporin, the chemotherapeutic agent methotrexate or retinoids). This evolution of the marketplace is surely a step in the right direction for improving the quality of life of psoriasis patients.

Biotechs battle it out
Biogen's Amevive (alefacept) was the first biotech drug to be approved by the FDA for moderate-to-severe psoriasis, and was launched in US and European markets in February 2003. Amevive was followed by Immunex's Enbrel (etanercept), Abbott's Humira (adalimumab), Johnson & Johnson's Remicade (infliximab) and Genentech and XOMA's Raptiva (efalizumab).

The predominance of immunotherapy for psoriasis reflects the belief that the pathology of the disease is primarily T-cell mediated. In general, these biologics appear not only to offer an improved safety profile, largely because they produce no organ toxicity, but are also highly effective in reducing symptoms. This makes biologics ideal for the long-term management of psoriasis. However, there are exceptions, and in April of last year, Raptiva was withdrawn from the US market because of the potential risk of patients developing progressive multifocal leukoencephalopathy.

The new generation
Hot on the heels of these already established drugs is a series of up-and-coming therapies that are set to challenge the effective treatment of psoriasis. The most recent addition is Centocor's Stelara (ustekinumab), which was approved in the EU and the US in January and September 2009, respectively.

The authorisation of Stelara was based on positive results from the pivotal PHOENIX 1 and PHOENIX 2 trials, collectively involving nearly 2,000 patients. Just over two-thirds of patients achieved a reduction in psoriasis severity of at least 75 per cent (measured using 'PASI', the Psoriasis Area and Severity Index) by week 12. A long-term extension of PHOENIX 2 is ongoing and is expected to reach completion in October 2011.

One healthcare advisory prediction report suggests that infliximab, the current clinical 'gold standard' treatment for moderate-to-severe psoriasis, is likely to be supplanted by ustekinumab by 2015. This is due to its comparable efficacy in plaque clearance and superior efficacy with respect to remission time, the two factors that are strongly regarded by surveyed dermatologists to be the most important drivers of prescribing decisions in this indication.

Abbott Laboratories' briakinumab and Stiefel Laboratories' calcipotriol, both in pre-registrational phases of development, look set to follow in the footsteps of Stelara.

Briakinumab is a fully human monoclonal antibody that targets interleukin-12 and interleukin-23. It surpassed methotrexate in the M10-255 trial, with a greater proportion of patients achieving 75 per cent or better skin clearance. An application for regulatory approval was submitted in the US and Europe in the third quarter of this year based on these positive results. Briakinumab is expected to reach the market by 2011 and sales are expected to exceed $550m in 2018. Similarly, a New Drug Application (NDA) has been submitted in the US for Steifel's calcipotriol, a vitamin D analogue and calcitriol receptor agonist.

According to inThought analysts, based on analyses of clinical data, trial design and historical approval rates of similar drugs, the likelihood of briakinumab and calcipotriol gaining regulatory approval is 79 per cent and 62 per cent, respectively.

What else is in the pipeline?
A number of other potential therapies are currently in phase III trials and will be gearing up for regulatory submissions in the foreseeable future.

Pfizer's tasocitinib, a janus kinase 3 inhibitor (JAK3 inhibitor) and oral immunosuppressant, entered a phase III efficacy trial in September 2010. Pfizer also initiated a long-term safety trial in October this year. Results from phase II analyses indicated significant reductions in PASI from baseline with tasocitinib in patients with moderate-to-severe psoriasis.

Furthermore, patient-reported health-related quality-of-life outcomes were significantly improved. According to inThought analysts, the likelihood of tasocitinib gaining approval is 62 per cent. In addition, the revenue forecast is set to increase from $7m in 2012 to $600m in 2016, indicating that tasocitinib could become a major player in the psoriasis market.

The ESSENCE and SPIRIT trials have been completed for Isotechnika's voclosporin, a calcineurin inhibitor and oral immunosuppressant. The likelihood of voclosporin gaining approval is 58 per cent, according to inThought analysts. A submission for marketing approval of voclosporin in Canada was planned for the end of 2009; however, no news of the submission has yet been received.

Trials are ongoing for Celgene Corporation's apremilast, Biocon's T1h, and Taro Pharmaceuticals' desoximetasone topical spray.

Celgene is currently recruiting for its phase III ESTEEM 1 trial of apremilast, a small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase. The expected end date of this trial is June 2016. Positive top-line results were achieved in phase IIb trials (including the PSOR-005 trial) and a long-term extension study began in March 2010 in the US and Canada.

In June 2010, Biocon initiated the TREAT-PLAQ study in India. TREAT-PLAQ studies Biocon's T1h, a humanised monoclonal antibody that suppresses T-cell proliferation by blocking CD-6.

Phase III trials of Taro's desoximetasone topical spray were initiated in August 2010.

inThought analysts predict the likelihood of approval of both apremilast and T1h as 29 per cent and the likelihood of approval of desoximetasone topical spray as 78 per cent.

Phase II possibilities
A number of therapies currently in phase II trials have the potential to flood the psoriasis market further. These include CanFite's CF 101 (an adenosine A3 receptor agonist) and Incyte Corporation's INCB 18424 (a janus kinase 2 inhibitor). Novartis's AIN 457 (an interleukin 17 receptor antagonist) is also in phase II and a regulatory submission of the compound is expected from the company in 2013.

As treatment options for patients continue to grow as more therapies enter development, so the cost to health authorities follows suit. By 2015, the market value for psoriasis therapies is projected to exceed $4.1bn, which represents a significant increase from the $2.4bn estimated worth in 2008. This growth is driven by the increase in emerging therapies and higher prescription rates. However, whether these new products fulfil the unmet need of high efficacy and favourable tolerability is yet to come to light. Watch this space!

The Author
Pipeline was written by Ashley Hallsmith of Adis International - Wolters Kluwer Pharma Solutions - using data derived from Adis R&D Insight, Clinical Trials Insight and inThought

For information on Adis services, contact Kuljeet Sohanpal on + (0)207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

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