Two different Janus kinase (JAK) inhibitors, one systemic and the other topical, showed activity in preliminary clinical trials of difficult-to-treat chronic hand eczema.
The oral multitargeted drug gusacitinib reduced the target lesion symptom score (TLSS) by as much as 70% at 16 weeks, and almost a third of patients treated with the higher of two doses achieved Physician Global Assessment (PGA) of 0-1 (clear/nearly clear) at the same time point. Adverse events across the range of doses evaluated were mostly sporadic and mild or moderate in severity, reported Howard Sofen, MD, of Dermatology Research Associates in Los Angeles, during the European Academy of Dermatology and Venereology Virtual Congress.
“Gusacitinib showed rapid efficacy in moderate to severe chronic hand eczema,” said Sofen. “The 80-mg dose met the primary endpoint of percent reduction in the modified TLSS at week 16. Rapid and significant improvement in PGA 0-1 was observed versus placebo with 80 mg. There was dose-dependent and rapid improvement in pruritus. Gusacitinib was well tolerated, and the safety has been consistent across studies involving more than 350 patients.”
In another study, as many as 37% of patients treated with topical delgocitinib met criteria for Investigator’s Global Assessment (IGA) of treatment success at 16 weeks. Patients treated with the two highest concentrations had statistically greater improvement at 4 to 6 weeks and maintained the difference to the end of the study, reported Margitta Worm, MD, of Charite Hospital in Berlin.
Multitargeted Oral Drug
Chronic hand eczema is a complex disease that affects about 7 million people in the U.S. The disease has a multifactorial etiology and pathogenesis that includes genetics, atopy, contact allergens, and irritating substances, said Sofen. Gusacitinib inhibits JAK1, JAK2, JAK3, TYK2, and SYK to target TH1 and TH2 pathways, TH17 and TH22 pathways, and SYK-mediated interleukin-17 signaling in keratinocytes.
Sofen reported findings from the first part of a phase IIb trial involving 105 patients with chronic hand eczema. The patients were randomized to placebo or one of two doses of gusacitinib. Randomized treatment continued for 16 weeks, at which point placebo-treated patients could switch to the higher dose of gusacitinib for continued treatment. The primary endpoint was percent change in the modified TLSS.
The study population had a mean baseline mTLSS of 13 and a mean baseline hand eczema severity index (HECSI) score of 63; 39% of the patients had a baseline PGA score of 3.
The 16-week results showed that patients allocated to the higher dose (80 mg) of gusacitinib had a 69.5% reduction in mTLSS, as compared with 49% of patients in the 40-mg group, and 33.5% of those assigned to placebo. Both gusacitinib groups had significantly greater improvement in mTLSS compared with placebo by week 2 (P<0.005), and patients in the higher-dose arm maintained that difference to 16 weeks.
The proportion of patients who achieved PGA 0-1 status by week 16 was 31.3% in the gusacitinib 80-mg arm, 21.25% in the 40-mg arm, and 6.3% in the placebo group. Significantly more patients in both gusacitinib groups had PGA 0-1 by week 2 as compared with the placebo arm (P<0.05), and the superiority persisted and increased to 16 weeks in the 80-mg arm (P<0.005).
The pruritus subscore of the mTLSS had improved significantly more in the gusacitinib groups by week 2 (P<0.05), and the superiority versus placebo was maintained in the 80-mg group out to 16 weeks when reduction in pruritus score averaged 65.7% in the 80-mg arm (P<0.05), 50.0% in the 40-mg arm, and 29.8% in the placebo group.
The only safety parameter that changed substantively with gusacitinib was mechanism-related asymptomatic elevation of CPK. Patients assigned to the JAK/SYK inhibitor did not have changes in cholesterol levels or hematology-associated laboratory values, and no patients treated with gusacitinib had opportunistic infections, thromboembolic events, major adverse cardiovascular events, or malignancies, said Sofen.
Few Options for Topical Therapy
Patients with chronic hand eczema have limited options for topical treatment, Worm noted in the introduction to her data. Delgocitinib cream is a pan-JAK inhibitor that blocks multiple cytokine-mediated signaling cascades associated with inflammation in chronic hand eczema.
The data came from a phase IIb trial involving 258 patients randomized to one of four doses of delgocitinib (1 to 20 mg/g twice daily) or to vehicle. The primary endpoint was the proportion of patients who achieved IGA 0-1 status with at least a two-step improvement from baseline to week 16.
All of the patients enrolled in the trial had longstanding hand eczema, ranging from 10 to 14 years across the five treatment groups. Overall, 20% of the patients had severe skin disease, 56.2% had moderate disease severity, and 23.6% had mild hand eczema. The baseline HECSI score averaged 44.5.
The 16-week results showed that 37.7% of patients in the 20-mg arm and 36.5% of those in the 8-mg arm met criteria for treatment success, as compared with 8% of the vehicle arm (P=0.0004). A statistically significant treatment effect was seen by week 4 in the 8-mg delgocitinib group and by week 6 in the 20-mg group. The mean HECSI score decreased by 26.4 points in the vehicle arm as compared with decreases of 36 to 47 points in the delgocitinib arms (P<0.05 for all active-treatment groups).
Most adverse events were mild or moderate in severity and not thought to be treatment related, said Worm. The most common adverse events were nasopharyngitis, worsening eczema, and headache.
The gusacitinib study was supported by Asana BioSciences.
Sofen disclosed relationships with AbbVie, Asana BioSciences, Lilly, Incyte, Galderma, Dermira, LEO, Menlo, and DS Biopharma.
The delgocitinib study was supported by LEO Pharma.
Worm disclosed a relationship with LEO Pharma. Multiple co-investigators disclosed relationships with LEO and with other pharmaceutical companies.