Background

In two phase 3 trials, oral povorcitinib significantly increased the lesion response rate at week 12 versus placebo in patients with moderate-to-severe hidradenitis suppurativa (HS). HS is a chronic inflammatory disease marked by severely painful nodules, abscesses, pus-draining tunnels, and scarring. Alongside pain, pus and odor place a substantial burden on patients’ social lives. Treatment options are expanding, but unmet needs remain substantial. The paper identifies subcutaneous biologics targeting tumor necrosis factor (TNF) or interleukin-17 (IL-17) as approved treatments for moderate-to-severe HS. Some patients do not respond to existing treatments, or their effects diminish over time. The route of administration can also be a barrier for patients reluctant to use injections.

Key findings

The study, published in Nature Medicine, evaluated povorcitinib, a selective Janus kinase 1 (JAK1) inhibitor. The identically designed randomized, double-blind, placebo-controlled STOP-HS1 and STOP-HS2 trials enrolled 608 and 619 adults, respectively. Participants had an inadequate response to, intolerance of, or a contraindication to existing systemic therapy.

Patients received once-daily povorcitinib at 45 mg or 75 mg, or placebo. The full treatment period was 54 weeks, but the placebo comparison was limited to the first 12 weeks. After that, participants in the placebo group switched to their preassigned povorcitinib dose and continued treatment for 42 weeks.

The primary endpoint was the rate of Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) at week 12. This requires at least a 50% reduction from baseline in the combined count of abscesses and inflammatory nodules, with no increase from baseline in either the abscess count or the draining tunnel count. The definition does not rule out the occurrence of new lesions. In STOP-HS1, HiSCR50 was achieved by 40.2% (82/204) of patients in the 45 mg group, 40.6% (82/202) in the 75 mg group, and 29.7% (60/202) in the placebo group. In STOP-HS2, the rates were 42.3% (88/208) in each of the two dose groups and 28.6% (58/203) with placebo. Both trials found statistically significant improvement versus placebo at both doses.

Reductions in draining tunnels and improvements in pain and quality of life were also observed. However, not all key secondary endpoints achieved statistical significance consistently across both trials. For example, HiSCR75 applies the same restrictions on increases in lesion counts as HiSCR50 but requires at least a 75% reduction in the combined count of abscesses and inflammatory nodules. It was significant at both doses in STOP-HS2 but did not meet the threshold accounting for multiple testing in STOP-HS1. Responses continued through week 54, and reductions in draining tunnels were generally greater in the 75 mg group. However, long-term efficacy was presented using descriptive statistics, and there was no formal statistical comparison between doses.

In the pooled 54-week safety analysis, which included patients who switched from placebo, serious treatment-emergent adverse events occurred in 5% of the 45 mg group and 6% of the 75 mg group. Acne, a common adverse event, was reported in 17% and 20%, respectively. One death of unknown cause was judged by the investigator to be unrelated to treatment, and no new or unexpected safety signals were reported.

Meaning and outlook

These results add clinical evidence for a once-daily oral treatment candidate for moderate-to-severe HS. Povorcitinib inhibits the intracellular enzyme JAK1, modulating inflammatory cytokine signaling. However, these were not head-to-head trials against existing injectable drugs, so the results cannot readily be interpreted as showing that povorcitinib is superior to or can replace them.

The long-term results also lack a placebo comparison after week 12 and are affected by patient discontinuation. The report of no new safety signals does not mean that risks of cardiovascular events, thrombosis, or infection are absent. The exclusion of patients with histories such as major cardiovascular disease or thrombosis is another limitation to consider. Further studies and regulatory review will need to clarify long-term benefits and risks, the appropriate dose, and suitable patient populations.

Sources: Nature Medicine paper, Europe PMC public full text.