Psoriasis biomarkers modulated with TAK-279 treatment
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Key takeaways:
- TAK-279 is an oral TYK2 inhibitor designed to bind the Janus homology 2 domain of TYK2.
- Significant correlations were found between PASI improvement and histological response.
SAN DIEGO — Modulation of psoriasis biomarkers and pathways were observed in patients who experienced clinical success with TAK-279, according to phase 2b trial results.
“At this point it is well understood that psoriasis is a disease mediated by a central IL-23/Type 17 T-cell axis of inflammation,” James G. Krueger, MD, PhD, head of the Laboratory for Investigative Dermatology at The Rockefeller University, told Healio. “[Interleukin-23] signaling requires [tyrosine kinase 2 (TYK-2)] and the results of this provide proof that TAK-279 strongly inhibited this central pathway and reverses pathological and molecular measures of disease.”
A phase 2b trial randomly assigned patients with moderate to severe disease to receive once-daily oral TAK-279 at 2 mg, 5 mg, 15 mg or 30 mg or placebo for 12 weeks.
Of those in the 30 mg group, PASI 75, 90 and 100 was achieved by 67%, 46% and 33%, respectively, compared with 6%, 0% and 0% in the placebo cohort.
“Both 15 mg and 30 mg doses produce high-level improvements in psoriasis and might be reasonable doses to pursue in clinical management of psoriasis, provided future, larger studies confirm the safety and efficacy of TAK-279 that have been seen in phase 2,” Krueger said.
This analysis evaluated the association between TAK-279’s use and PASI response to histological response.
Optional skin biopsies of both lesioned and non-lesioned skin were taken on day 1 and weeks 4 and 12. Immunochemistry, quantitative reverse transcription polymerase chain reaction, proteomics and RNA sequencing were then used to evaluate changes in the lesions and biomarkers of psoriasis.
Lesional epidermal thickness and infiltrating T cells were both reduced in all PASI 90 responders in the treatment groups. In patients treated with the 30 mg dose who achieved PASI 90, the number of infiltrating T cells decreased and there was a reduction of lesion epidermal thickness, CD3+ T cells counts and CD11c+ myeloid dendritic cell counts compared with baseline.
All patients in the treatment groups had dose and time-dependent reductions in serum IL-17A, IL-17C and IL-17F, whereas all serum levels increased in the placebo group.
PASI improvement was also significantly associated with reduced KRT16 expression at week 12 (P < .0001).
Those in the 15 mg and 30 mg dose cohorts showed decreases in key psoriasis and TYK2 biomarkers to non-lesion levels.
“The size of this study and the range of drug doses used provide us with the best estimates of the ‘IL-17 burden’ that causes psoriasis. Data suggest that increases in IL-17A and IL-17F (cytokines produced by activated T-cells) need to be inhibited by about 80% in skin lesions in order to reverse cellular and molecular disease features that are reflected in clinical scores of disease improvement, eg, the PGA score or the PASI score,” Krueger said. “The data strongly re-affirm our understanding of psoriasis pathogenesis and show strong activity for a new, selective TYK2 inhibitor for this disease.”