Developments in understanding the immunological pathways involved in psoriasis pathogenesis have provided insights into potential new targets and have led to the development of novel biological treatments.
While the first IL-23 antagonist, guselkumab, was approved for use in moderate-to-severe plaque psoriasis in 2017, additional IL-23 antagonists remain under development (Tremfya® SPC, 2017).
The IL-23 antagonist mirikizumab is currently in Phase III trials assessing its efficacy in psoriasis and Crohn’s disease (Gisondi et al., 2019).
A Phase II trial has been completed demonstrating that mirikizumab improves patient-reported signs and symptoms of psoriasis by Week 16. (Reich et al., 2018b). Phase III trials for ulcerative colitis and psoriasis are ongoing (ClinicalTrials.gov, mirikizumab).
Table 13. Efficacy and safety of mirikizumab in a Phase II trial.
Bimekizumab is a potent and selective biologic in Phase III of clinical development. Bimekizumab neutralises both the IL-17A and IL-17F pro-inflammatory cytokines. In preclinical experiments the simultaneous neutralization of both IL-17A and IL-17F resulted in a higher suppression of cytokine responses and neutrophils chemotaxis than the neutralization of either cytokines (Gisondi et al., 2019).
In the BE ABLE 1 Phase IIb trial, PASI 90 and PASI 100 were achieved with bimekizumab at Week 12 by 75% and 60% of those treated with 160 mg with loading dose and by 79.1% and 55.8% of those treated with 320 mg (Papp et al., 2018b).
Humanised monoclonal antibody against IL-17A, netakimab has completed a multicentre, randomised, double-blind, placebo-controlled Phase II trial (Gisondi et al., 2019). In this trial 92.68% of patients with plaque psoriasis who received the 120 mg dose achieved PASI 75 by Week 12 (Samtsov et al., 2017). The drug is now in phase III of development (NCT03390101).
Novel molecule M1095 is a nanobody targeting IL-17A and IL-17F. Nanobodies are small antibody fragments derived through recombinant gene technology. Nanobodies are more stable than conventional antibodies. They also have an excellent tissue penetration and exhibit a low immunogenicity (Steeland et al., 2016). M1095 completed a phase I trial and a phase II trial is ongoing (NCT03384745).
Other biologics have also been developed, with novel mechanisms of action.
Humanized monoclonal antibody neihulizumab (AbGn- 168H) targets CD162, which is expressed on activated T-cells, which then causes apoptosis of activated T lymphocytes. No results for Neihulizumab were published, despite the fact it has has undergone phase II trials for psoriasis and psoriatic arthritis, Two trials on ulcerative colitis and graft versus host disease (GVHD) are currently active (Gisondi et al., 2019).
Namilumab is an inhibitor of granulocyte-macrophage colony stimulating factor (GM-CSF). In a recent phase II multicentre, randomised, double-blind, placebo-controlled clinical trial in plaque psoriasis, there was no significant difference between percentage of patients reaching PASI 75 at 12 weeks with placebo versus namilumab (Papp et al., 2019).
Transduction of many of the receptors involved in cytokine signalling pathways in psoriasis requires association with kinases from the Janus kinase (JAK) family, which consists of four members: JAK1, JAK2, JAK3 and TYK2. JAK inhibitors can, therefore, interfere with cytokine signalling and suppress cellular activation and the inflammatory pathways involved in psoriasis (Thomas et al., 2010; Ghoreschi et al., 2011b; Sohn et al., 2013; Belge et al., 2014).
Tofacitinib is a JAK inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis in the USA and is one of the most advanced and well-studied JAK inhibitors in clinical development for psoriasis (Belge et al., 2014; Xeljanz® PI, 2018).
OPT Pivotal-1, -2 and open-label extension
Long-term data from OPT Pivotal-1 and -2 demonstrated sustained efficacy over two years. Psoriasis patients who received tofacitinib (5 mg or 10 mg, both bd), achieved PASI 75 at Week 16 in higher percentages: 5 mg 39.9%; 10 mg 59.2% (OPT Pivotal-1) and 5 mg 46.0%; 10 mg 59.6% (-2), compared with those who received placebo; 6.2% (OPT Pivotal-1) and 11.4% (-2) (Papp et al., 2015c). Results from OPT Pivotal-1 and -2 further suggested that efficacy is reduced in patients with higher BMI and those with prior biologic experience, and, achieving a PASI 50 response after 8 weeks of treatment is a reliable predictor of achieving a PASI 75 response at Week 16 (Menter et al., 2016c; Tan et al., 2017).
The results showed that tofacitinib 10 mg bd (but not 5 mg bd), was superior to placebo and not inferior to etanercept at Week 12, as assessed by PASI 75 response rates (39.5% for 5 mg, 63.6% for 10 mg, 58.8% for etanercept and 5.6% for placebo) and Physician Global Assessment scores (Bachelez et al., 2015).
In addition, a recent meta-analysis, which included seven randomised controlled trials involving 3,743 patients, showed that tofacitinib 10 mg twice daily was effective in treating chronic plaque psoriasis as measured by PGA responses, PASI 75, and PASI 90 (Tian et al., 2019).
Tofacitinib treatment results in significant improvements across multiple patient-related outcomes and these improvements were maintained over 52 weeks (Valenzuela et al., 2016; Feldman et al., 2016).
Improvements with tofacitinib were significantly greater than placebo and comparable to etanercept (by Week 12, 47.3% tofacitinib and 43.6% etanercept had a DLQI score of 0/1 vs. 7.8% for placebo [p<0.0001 both comparisons]). Improvements in itch were greater and more rapid with tofacitinib than placebo and etanercept (p<0.0001 and p<0.005) with effects observed after just one day of treatment (Valenzuela et al., 2016).
Baricitinib is an oral JAK1/JAK2 inhibitor that has been approved for the treatment of rheumatoid arthritis and is currently in development for other immune-mediated disorders including psoriasis (Papp et al., 2016d; Olumiant® PI, 2018; Olumiant® SPC, 2018).
Efficacy and safety
Efficacy and safety of baricitinib were investigated in a Phase II trial (Papp et al., 2016d).
Ruxolitinib is a topical JAK1/JAK2 inhibitor that has been approved for the treatment of myeloproliferative disease and is currently being tested in Phase II trials for psoriasis (Fragoulis et al., 2019).
PF-04965842, itacitinib and solcitinib
These are selective JAK-1 inhibitors which have also been found to be more effective than placebo in Phase II psoriasis trials (Fragoulis et al., 2019).
Mechanism of action
Tyrosine kinase 2 (TYK2) associates with the receptors for several cytokines including IL-12, IL-23, IL-6, IL-10 and type 1 interferon (Sohn et al., 2013). Blocking TYK2 is believed to inhibit the signal transducer and activator of transcription (STAT) dependent pathway resulting in decreased production of IL-12 and IL-23.
Results from a Phase II, double-blind trial of the TYK2 inhibitor BMS-986165 revealed treatment with the TYK2 inhibitor was more effective than placebo at reducing PASI score in patients with moderate to severe psoriasis. The study randomised 267 patients to receive one of five doses of BMS-986165 (3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, 12 mg daily), or a matching oral placebo.
The percentage of patients achieving the primary endpoint, a PASI score reduction of 75% or greater from baseline, increased as the dose of BMS-986165 increased:
Percentage of patients achieving a ≥75% reduction in PASI score at Week 12:
Adverse events were reported in 51% of the placebo group and 55–80% of patients in the active treatment groups, with 5 serious adverse events reported across all 3 mg active treatment groups and the placebo group.
The results of the Phase II study have shown promise for the future of TYK2 inhibitors, but larger studies are required to determine the durability of the effects and safety of BMS-986165 (Papp et al., 2018c).