Systemic Therapies in Psoriasis: An Update on Newly Approved and Pipeline Biologics and Oral Treatments

Oral Medications

Only a few small-molecule, orally bioavailable therapies are on the market for the treatment of psoriasis, some of which are associated with unfavorable side-effect profiles that preclude long-term therapy.

BMS-986165
The intracellular signaling enzyme tyrosine kinase 2 is involved in functional responses of IL-12 and IL-23. BMS-986165, a potent oral inhibitor of tyrosine kinase 2 with greater selectivity than other tyrosine kinase inhibitors, demonstrated efficacy in a phase 2 trial of 267 participants with moderate to severe plaque psoriasis receiving any of 5 dosing regimens—3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, and 12 mg daily—compared to placebo.¹⁰ At week 12, the percentage of patients with a 75% or greater reduction in PASI was 7% with placebo, 9% with 3 mg every other day (P=.49 vs placebo), 39% with 3 mg daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). Adverse events occurred in 51% of patients in the placebo group and in 55% to 80% of BMS-986165–treated patients; the most common AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection.¹⁰

A phase 3 trial comparing BMS-986165 with placebo and apremilast is underway (ClinicalTrials.gov Identifier NCT03611751).

Piclidenoson (CF101)
A novel small molecule that binds the Gi protein–associated A₃ adenosine receptor piclidenoson induces an anti-inflammatory response via deregulation of the Wnt and nuclear factor κB signal transduction pathways, leading to downregulation of proinflammatory cytokines, including IL-17 and IL-23.¹¹

In a phase 2 dose-ranging study, 75 patients with moderate to severe plaque psoriasis received varying dosages—1, 2, or 4 mg—of oral piclidenoson or placebo twice daily for 12 weeks.¹² Progressive improvement in the mean change from baseline PASI score was observed in the 2-mg group, with statistically significant differences at weeks 8 and 12 compared to placebo (P=.047 and P=.031, respectively). At week 12, 35.3% of the 2-mg group achieved at least PASI 50. Improvements in PASI were less pronounced in the 4-mg group, and no therapeutic benefit was observed in the 1-mg group. Of the 20 AEs reported, 15 possibly were related to the study drug; 1 AE was severe.¹²

In a subsequent phase 2/3 trial, patients with moderate to severe plaque psoriasis received piclidenoson—1 or 2 mg—or placebo twice daily.¹³ At week 12, PASI 75 was achieved by 8.5% of patients in the 2-mg group and by 6.9% of patients receiving placebo (P=.621), thereby not meeting the primary study end point. Results at week 32 were more encouraging. In the 2-mg group, PASI mean percentage improvement was 57% (P<.002) compared to baseline, with linear improvements observed in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%), and PASI 100 (10.6%).¹³

A phase 3 trial comparing piclidenoson 2 and 3 mg to apremilast and placebo is in progress (ClinicalTrials.gov Identifier NCT03168256).

Future Directions

Despite abundant options for treating moderate to severe plaque psoriasis and psoriatic arthritis, the pipeline remains rich. Novel treatments might have improved efficacy, favorable safety profiles, and different modes of administration compared to current medications. In addition to the novel therapeutics covered here, several treatments are in development further down the pipeline, with only phase 1 or 2 data available. Remtolumab (ABT-122), a tumor necrosis factor α– and IL-17A–targeted immunoglobulin, is unique among biologics, given its dual inhibition of tumor necrosis factor α and IL-17A.¹⁴ M1095 (ALX-0761), a novel trivalent bispecific nanobody, is another intriguing candidate. This dual inhibitor of IL-17A/F might exhibit a number of advantages over conventional antibodies, including better tissue penetration, reduced immunogenicity, and a longer half-life (ClinicalTrials.gov Identifier NCT03384745).^15,16

As always with drug development, numerous medications that were under development failed to meet primary end points in phase 2 trials and have therefore been discontinued, including namilumab and prurisol. It is reassuring that the pace of drug discovery and development in psoriasis does not seem to be slowing; to our patients’ benefit, we will have an array of treatments available to tailor therapy to the individual.