The COMFORT trial: piclidenoson versus apremilast for plaque psoriasis

Piclidenoson is a highly selective small molecule targeting the A3 adenosine receptor (A3AR) that is overexpressed in keratinocytes in patients with psoriasis, inhibiting interleukin (IL)-17 and IL-23 production. A3AR has low or no expression in normal cells.¹ Piclidenoson has shown promising anti-psoriatic effects in early clinical proof-of-concept phase II/III trials in moderate to severe plaque psoriasis.¹

At the European Academy of Dermatology and Venereology Congress 2022, Papp reported safety and efficacy results at Week 32 from the proof-of-concept phase III, randomized COMFORT trial of piclidenoson in patients with plaque psoriasis.

Study design²

The double-blind, randomized, placebo-controlled COMFORT trial included patients with moderate to severe plaque psoriasis randomized 3:3:3:2 to twice-daily treatment with either piclidenoson 2 mg, piclidenoson 3 mg, apremilast 30 mg, or placebo, with the placebo cohort re-randomized (1:1:1) to treatment after Week 16. The study duration was 32 weeks with an optional extension of up to 48 weeks. The trial design is shown in Figure 1.

*Adapted from Papp et al.²

Results

Safety¹

Patients treated with piclidenoson exhibited fewer adverse events (AEs) than those treated with aprelimast, with a similar safety profile to the placebo group (Table 1). Of note was the difference in gastrointestinal (0.7% vs 6.3% for the piclidenoson 3 mg vs apremilast group, respectively) and nervous system disorder (0.7% vs 9.9% for the piclidenoson 3 mg vs apremilast group, respectively) AEs. In addition, the apremilast group had a higher discontinuation rate than the piclidenoson group.

Table 1. Occurrence of adverse events

*Data from Papp.1
Adverse event, %	Piclidenoson 3 mg (n = 142)	Apremilast (n = 142)	Placebo (n = 94)
Any	14.8	27.5	25.5
Gastrointentinal disorders	0.7	6.3	0
Infections/infestations	5.6	6.3	7.4
Metabolism/nutrition disorders	0.7	2.1	1.1
Nervous system disorders	0.7	9.9	3.2
Skin and subcutaneous tissue disorders	2.1	2.8	6.4

Efficacy

Efficacy data included a total of 426 patients (piclidenoson 2 mg, n = 127; piclidenoson 3 mg, n = 103; apremilast 30 mg, n = 118; placebo, n = 78).² Piclidenoson 3 mg was superior to placebo at Week 16 (Figure 2a) but inferior to apremilast at Week 32 (Figure 2b).² However, patients treated with piclidenoson had comparable improvement in Psoriasis Disability Index from baseline to Week 32 compared with those treated with apremilast.¹ Additionally, response to piclidenoson was seen to increase over time for both Psoriasis Area and Severity Index 75 and Physician Global Assessment scores up to Week 32.¹

PASI, Psoriasis Area and Severity Index.
*Adapted from Papp, et al.²

Conclusion

These findings demonstrate the superior efficacy of piclidenoson compared with placebo with statistically significant improvement in PASI 75 at week 16; however, it was shown to be comparable in efficacy to apremilast in patients with plaque psoriasis. The safety profile was acceptable, with fewer adverse events reported than those treated with apremilast and a significant reduction in gastrointestinal and nervous system disorder AEs.¹ The authors concluded that these results support the continued clinical development of piclidenoson, with a pivotal phase III trial is currently being planned.²