PracticeUpdate Conference Series World Congress of Dermatology 2019

Experimental Topical Tropomyosin Receptor Kinase A Inhibitor Improved Psoriasis Severity Phase III trials are in the works, pending regulatory approval.

S NA-120 (pegcantratinib), a topical, non- steroidal inhibitor of tropomyosin receptor kinase A (TrkA) significantly improved measures of psoriasis disease severity, although patient-reported itch severity was not significantly improved, according to the results of a phase IIb study. “It was important to conduct the study to reaffirm data from earlier … work regarding the impor- tant role than the [nerve growth factor] NGF/ TrkA pathway plays in psoriasis pathogenesis,” presenter Paul F. Lizzul, MD, PhD, of Sienna Biopharmaceuticals, manufacturer or SNA-120, told Elsevier’s PracticeUpdate . “… NGF and TrkA are overexpressed in psoriasis patients. In those psoriasis patients who are more itchy, … TrkA is even further upregulated.” Thus, scientists “could think of itch as a clinical biomarker of elevated NGF and/or TrkA.” Lizzul highlighted the fact that SNA-120 “works at the intersection between the skin, the nervous, and the immune systems. And it does so with a very good safety profile, with no to very low systemic exposure.” For this double-blind study, investigators enrolled 208 adult aged ≥18 years with mild-to-moderate psoriasis and at least moderate itch, defined as ≥5 on the Itch Numeric Rating Scale (I-NRS). Patients were randomized to receive one of three condi- tions: twice daily SNA-120 at 0.05% concentration, twice daily SNA-120 at 0.5% concentration, or vehicle control, each for 12 weeks.

The prespecified primary endpoint for the study was change in itch, as measured by the I-NRS score from baseline to week 8. Prespecified secondary endpoints included the composite of a ≥2-point decrease in Investigator Grade Assessment (IGA) and ‘clear’ or ‘almost clear’ as well as a 75% reduc- tion in Psoriasis Area and Severity Index (PASI 75) at week 12. The study failed to meet the primary endpoint, in that mean reduction in I-NRS score was not signif- icantly better at week 8 among patients receiving 0.05% SNA-120 (4.2) or 0.5% SNA-120 (3.6) than among patients receiving vehicle control (3.9). “While itch did not statistically separate from vehicle in this study,” Dr. Lizzul noted, “this was likely attrib- uted to a high vehicle response on the subjective measure of itch, related to expectations and bias [deriving from] heavy emphasis and interrogation on this symptom.” He predicted that less “intensive and focused interrogation on this subjective symp- tom in future studies should recapture the clear separation observed in earlier studies, which did not overemphasize the benefit to patients”. SNA-120 did produce clinically meaningful, statisti- cally significant improvements in psoriasis severity at week 12, however. Relative to vehicle control, subjects who received 0.05% SNA-120 were sig- nificantly more likely to achieve the composite of ≥2-point improvement on IGA and ‘clear’ or ‘almost clear’ (29% vs 13%; P = .036) or PASI75 (27% vs 13%; P = .045) at week 12. However, 0.5% SNA- 120 did not repeat the same statistically significant response in IGA and PASI75 scores.

" …the results of this trial confirm what astute clinicians have noted for many years, that peripheral nerves play an important role in psoriasis. The data highlight the link between these clinical observations and the basic mechanisms and pathology underlying them. " PRACTICEUPDATE CONFERENCE SERIES • WCD 2019 14