Contextualizing JAK Safety With Povorcitinib in HS, With Martina Porter, MD

The 54-week STOP-HS data for povorcitinib showed deepening inflammatory response, broad and sustained improvements across patient-reported outcomes in people with moderate-to-severe hidradenitis suppurativa (HS), and a manageable safety profile.1,2

Povorcitinib is an investigational oral JAK1-selective inhibitor - the JAK inhibitor class carries FDA black box warnings for major adverse cardiovascular events (MACE) and thromboembolic events, and these labels that loom over any new agent in the class.

Martina L. Porter, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, presented the 54-week STOP-HS data at the 2026 American Academy of Dermatology (AAD) Annual Meeting, and sat down with HCPLive to discuss povorcitnib’s safety and efficacy data in the context of JAK safety signals.

The STOP-HS1 (NCT05620823) and STOP-HS2 (NCT05620836) phase 3 trials enrolled a combined 1,227 adults with moderate-to-severe HS, randomized 1:1:1 to povorcitinib 75 mg once daily, 45 mg once daily, or placebo for 12 weeks, followed by a 42-week blinded extension through week 54. The HS population enrolled in these trials shares several features with patients historically associated with elevated cardiovascular and thromboembolic risk in other JAK inhibitor programs: high rates of obesity, significant smoking history, and elevated systemic inflammatory burden. These are the same comorbidity factors implicated in the cardiovascular safety signals that emerged from JAK inhibitor trials in older rheumatoid arthritis populations and contributed to the class-wide black box labeling. Porter acknowledged this concern directly, noting it was among the most frequent questions she fielded at the meeting.

The STOP-HS safety data through 54 weeks did not reveal a pattern consistent with amplified risk in this higher-comorbidity population. Across both studies, thromboembolic events were infrequent, and MACE occurred in 1 patient (0.3%) in STOP-HS2. Porter noted that this MACE event — an ischemic cerebrovascular event — was also counted within the thromboembolic event category per the study's classification scheme, meaning that the total cardiovascular and thromboembolic event count is partially overlapping rather than additive. Serious treatment-emergent adverse events (AEs) occurred in 3.7% to 6.4% of patients across arms, and laboratory abnormalities were relatively uncommon — a finding Porter suggested may reflect the relative JAK1 selectivity of povorcitinib compared with less selective agents in the class, since hematologic abnormalities in particular tend to be mediated through JAK2 rather than JAK1 signaling.

She also noted that the absence of a dose-dependent safety signal across the 45 mg and 75 mg arms was specifically reassuring. JAK inhibitor AEs typically track with degree of JAK pathway inhibition, and a flat safety profile across doses is consistent with a compound that achieves meaningful JAK1 engagement without proportional off-target JAK2 or JAK3 effects. The most common treatment-emergent AE was acne, occurring in 16.4% to 21.1% of patients — a rate Porter contextualized as likely reflecting 2 overlapping factors: the known acne association with JAK inhibitor use as a class, and the demographic profile of the STOP-HS population, which skews toward younger women who may be on oral contraceptives as a trial requirement, some formulations of which have known acne-promoting effects independent of JAK inhibition. The acne observed was predominantly mild in severity and did not drive meaningful discontinuation.

At the primary efficacy endpoint of HiSCR50 at week 12, both doses achieved statistical significance versus placebo in both studies — 40.2% (45 mg) and 40.6% (75 mg) versus 29.7% for placebo in STOP-HS1 (P <.025), and 42.3% for both doses versus 28.6% for placebo in STOP-HS2 (P <.01) — with responses deepening through week 54 to HiSCR50 rates of 60.2% to 67.5% across studies and doses on continuous povorcitinib. Up to 29.0% of patients achieved HiSCR100 at week 54. Porter's overall assessment of the safety profile was that it is consistent with the established JAK class picture but without the amplification in cardiovascular or thromboembolic events that the comorbidity burden of the HS population might have been expected to produce — a finding she characterized as meaningful precisely because it was not the obvious outcome given the patient profile.

“[I thought the safety data] looked quite good for a HS clinical population. And I say this because HS clinical trials and Hs patients tend to have a lot more adverse events that occur. And we see this even in the beginning of the trial, when it's placebo controlled, that the patients on placebo have very high rates of adverse events, and it's probably related to their comorbidity burden,” Porter said.

Relevant disclosures for Porter include Abbvie, Bristol Myers Squibb, Janssen, Eli Lilly, Novartis, Pfizer, UCB, Trifecta Clinical, Incyte, and Anaptys Bio.

References

1. Porter ML, et al. Povorcitinib in moderate-to-severe hidradenitis suppurativa: 54-week results from the phase 3 STOP-HS1 and STOP-HS2 trials. Presented at: AAD Annual Meeting; Denver, Colorado; March 27-31, 2026.

2. Porter ML, et al. Povorcitinib efficacy in biologic-experienced patients with moderate-to-severe hidradenitis suppurativa: subgroup analysis from STOP-HS1 and STOP-HS2. Presented at: AAD Annual Meeting; Denver, Colorado; March 27-31, 2026.