The Future of Interleukin-based Therapy

Representing the next phase in the systemic treatment of psoriasis, interleukin (IL) inhibitors have carved out their own identity among other biologic therapies. The phase began six years ago, with the approval of ustekinumab (Stelara, Janssen). Subsequent years have seen a flurry of new developments, including approvals (such as secukinumab (Cosentyx, Novartis)) and a growing pipeline of investigational IL therapies. Moreover, as clinicians have gained greater familiarity with IL inhibitors, we’ve seen continued benefit both practically and clinically with the use of these agents. Ahead, I will take stock of the IL phase as part of the overall trajectory of biologic agents and attempt to look forward to the role they will play in the future.

The Science of IL

Ustekinumab is a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds to the p40 component shared by both IL-12 and IL-23, thus preventing binding to the IL-12RB1 cell surface receptor. This facilitates the proliferation of Th-1 cells (which produce TNF alpha and interferon gamma) and Th-17 cells (which produce IL-17 and IL-22). To put it another way, both IL-12 and IL-23 are heterodimers, each containing a p40 subunit. While IL-12 is composed of p40 and p35, IL-23 is composed of p19 and p40. Notably, IL-23 mRNA is elevated in human psoriatic plaques and is mainly produced by dendritic cells.

The IL-23 inhibitors work by binding only to the p19 component of IL-23, inhibiting the proliferation of Th-17 cells while having little to no effect on Th-1 proliferation. Thus, it is a more selective inhibitor while also still inhibiting the synthesis of molecules such as IL-17 and IL-22, (yet not through extracellular inhibition). By binding to p19, IL-23 is prevented from binding the IL-23 receptor (IL-23R) complex, which thereby prevents the activation of Janus Kinase2 and decreases the synthesis of IL-17 and IL-22.

Another interleukin-based agent is the recently approved secukinumab, a monoclonal antibody binding to IL-17. Produced by Th-17 cells as well as neutrophils, IL-17 tends to be elevated in psoriatic skin. It is likely that IL-17 indirectly induces keratinocytes into a hyperproliferative state. The loading dose of secukinumab is high: Two 150mg subcutaneous injections (for a total of 300mg) once per week for five weeks, followed by 300mg dosing every four weeks. Fortunately, the efficacy data is encouraging, with roughly 80 percent of patients achieving PASI 75 and roughly 60 percent achieving PASI 90 in clinical trials.

IL Inhibitors in Practice

Beyond their clinical attributes, real-world use of IL agents has articulated new benefits. For example, one of the beautiful attributes of using ustekinumab is the infrequent number of subcutaneous injections (four per year) that results in high efficacy (with 80 percent of patients achieving PASI 75 by week 28). This is particularly significant in view of the fact that at present there is no cure for psoriasis and therefore the approximation to a cure would be safe clearance with the least number of treatments possible.

The reality is that most psoriasis sufferers want to be clear and do nothing about it. In other words, many patients would prefer not to undergo invasive therapy. Not only does four injections per year help in diminishing the noticeable aspects, but also one could even possibly forget about having the disease between shots. In my own practice, some of my happiest patients on ustekinumab are clear or almost clear after receiving only four shots in a year.

Emerging Therapies

Currently three IL-23 inhibitors are in development for psoriasis:

• Guselkumab (CNTO 1959, Janssen): a human monoclonal antibody to p19 component of IL-23
• BI 655066 (Boehringer Ingelheim): a selective IL-23 inhibitor
• Tildrakizumab (MK-3222, Sun Pharma): a humanized, anti-IL-23p19 monoclonal antibody that binds specifically to IL-23p19

 Clinical trials have yielded encouraging results for all three agents.1-5 Of note, 75 to 80 percent of patients receiving guselkumab achieved PASI 75 by 16 weeks. Notably, 29 percent of patients achieved PASI 100 after 12 more weeks. Tildrakizumab has also shown positive results, with roughly 80 percent of patients on both the 100mg dose and 200mg dose achieving PASI 75 at week 16. Finally, BI 655066 was examined in a head to head comparison with ustekinumab. Results showed that nearly double the percentage of patients with moderate-to-severe plaque psoriasis achieved PASI 90 after 12 weeks of treatment with BI 655066 as compared to ustekinumab (77.1 percent versus 40 percent).

Conclusion

It’s clear based on the data that the IL class of biologic agents is developing based on a deeper understanding of the pathogenesis of psoriasis. With more patients wanting complete clearance, these agents (both current and in the pipeline) can offer a glimpse of a better future in which full clearance is no longer a pipedream but an achievable result. n

1. Callis-Duffin K. et al. Poster presentation. 2014 AAD Meeting. P8353

2. Papp, K. et al. 2015 AAD Meeting. Poster presentation. Late breaker.

3. Reich, K. et al. 2013 EADV. Poster presentation: P1540.

4. Sofen, H. et al. J Allergy and Clin Immun. 2014 Apr;133(4):1032-40.

5. Hu, C. et al. J Pharmocokinetics Pharmacodynamics. 2014 Jun;41(3):239-50