A3 adenosine receptor agonist showed modest efficacy but excellent tolerability

Although reaching statistical significance over placebo, piclidenoson did not surpass apremilast as an active comparator for treating psoriasis. However, a further increase in response after week 16 and a very good safety profile may speak in favour of further research.

Isoforms of adenosine receptors are almost universally present across all cell types, but the A3 isoform is almost exclusively present in inflammatory cells or immunocytes. As a consequence, a target such as piclidenoson, which is a selective activator of the A3 receptor, might provide a selective modulation of the inflammatory signals that are expressed or generated by these immunocytes. The phase 3 COMFORT trial (NCT03168256) explored the small molecule piclidenoson [1]. The agent has demonstrated the ability to inhibit IL-17 and IL-23 expression in keratinocytes [2].

The study randomised 529 patients into 4 different treatment arms with 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 piclidenoson 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). With regard to the trajectory of PASI-75 and Physician’s Global Assessment (PGA) response, Dr Kim A. Papp (Probity Medical Research, Canada) 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 incidence of >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 participants in the placebo group, with the highest incidence 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 his talk. When asked about a place for new drugs in the light of existing treatments with achievement of PASI-90 and PASI-100, Dr Papp conveyed that there will always be a segment of the population that does not respond and instead of surrendering them, one can continue to look for new therapies. “There are also other opportunities that may avail themselves because we have not fully explored the capabilities of activating the A3 receptor, so the future is still wide open,” Dr Papp stressed.

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.
2. Cohen S, et a. J Immunol Res. 2018:2310970.

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Posted on 5 November 202215 February 2024