Activation of the A3 adenosine receptor: a new mode of action to treat psoriasis?

Piclidenoson reached its primary endpoint with a statistical difference over placebo while showing a very good safety profile but did not outperform apremilast.

Piclidenoson can inhibit IL-17 and IL-23 expression in keratinocytes

“I think we can all agree that despite the fact that we may have very effective treatments for any disease it’s always important to explore new targets and develop new therapies,” Dr Kim A. Papp (Probity Medical Research, Canada) said, referring to his point that no medication is universally effective for every patient1. The phase 3 COMFORT trial (NCT03168256) explored the small molecule piclidenoson, a selective A3 adenosine receptor agonist that only binds to inflammatory cells. The agent has the ability to inhibit IL-17 and IL-23 expression in keratinocytes.

The study randomised 529 patients into 4 different treatment arms with a twice-daily medication: piclidenoson 2 mg, piclidenoson 3 mg, placebo, or the active comparator apremilast 30 mg. At week 16 of the 32-week trial, the placebo group was re-randomised to 1 of the 3 active arms. After week 32, an extension up to week 48 was optional. 

The study’s primary endpoint was met at week 16, as the 3 mg dosing group statistically exceeded the placebo group in the accomplishment of Psoriasis Area and Severity Index (PASI) 75 with 9.7% versus 2.6% (P=0.037).

An excellent safety profile, and better tolerability than apremilast

With regard to the trajectory of PASI 75 and PGA response, Dr Papp pointed out that there appears to be evidence of progressive improvement over time. “While week 16 is the primary endpoint, it is clearly not the endpoint which achieves maximal success and maximal response,” Dr Papp underlined.

Any treatment-emergent adverse events >2% were seen in 14.8% of participants in the piclidenoson group (3 mg), in 27.5% of participants in the apremilast group, and in 25.5% of patients in the placebo group, with the greatest difference in gastrointestinal disorders (0.7%, 6.3%, and 0%). 

“Overall we have superiority of piclidenoson over placebo, we see this interesting progressive improvement in response up to week 32, we see an excellent safety profile, with placebo-like characteristics, and certainly a better tolerability of piclidenoson compared with apremilast,” Dr Papp concluded.

  1. Papp KA. Treatment of plaque psoriasis with piclidenoson: Efficacy and safety results from a phase 3 clinical trial (COMFORT). D3T01.1K, EADV Congress 2022, Milan, Italy, 7–10 September.