乌鸦传媒

As many as three fourths of patients with mild-to-moderate atopic dermatitis obtained statistically significant and clinically meaningful improvement in disease activity in a randomized, controlled trial of a novel topical therapy.

Patients treated with once- or twice-daily brepocitinib 1% had more than 70% improvement in the Eczema Area and Severity Index (EASI) after 6 weeks. Twice-daily application of the tyrosine kinase 2/Janus kinase 1 (TYK2/JAK1) inhibitor led to average improvement of 75%, and a single application of the 1% formulation achieved 70.1% improvement. The lowest dose evaluated (0.1% QD) led to a 58.3% reduction in EASI score from baseline to 6 weeks.

No treatment-emergent severe adverse events occurred in any of 182 patients treated with various concentrations of brepocitinib, Megan Landis, MD, of the University of Louisville in Kentucky, reported during the European Academy of Dermatology and Venereology (EADV) Virtual Conference.

"Topical brepocitinib is effective in patients with mild to moderate topical dermatitis and appears very safe, with only mild treatment-emergent adverse events," said Landis. "We saw significant reductions in the EASI score at 6 weeks with both 1% once-daily dosing and 1% twice-daily dosing. Improvement in the IGA [investigator global assessment] responder rate at week 6 was significant for all once-daily dosing and for the 0.3% twice-daily dosing."

"In addition, a significant proportion of patients experience at least a 4-point improvement in the Peak Pruritus Numerical Rating Scale (PP-NRS) in doses of 1% and 3%," she continued. "These results support the use of this novel and much-needed therapy for patients with mild-to-moderate atopic dermatitis."

Both TYK2 and JAK1 have key roles in the development of atopic dermatitis, as JAK1 blocks the T乌鸦传媒 axis and TYK2 blocks the Th17 axis, Landis noted in her introductory comments. That knowledge provided a strong scientific rationale for developing a therapy that targets the two factors.

Landis reported findings from a randomized phase II trial involving patients 12 to 75 years with mild or moderate atopic dermatitis (IGA score 2 or 3, EASI total score 3 to 21, body surface area 2-20%, PP-NRS ≥2). Investigators randomized a total of 292 patients to four different brepocitinib once-daily arms (0.1% to 3.0%), two twice-daily arms (0.3% and 1.0%), or two vehicle control arms (once daily or twice daily). The primary endpoint was change in EASI score at 6 weeks.

The primary analysis showed that once-daily brepocitinib led to EASI decreases of 58.3% to 70.1% versus 44.4% in the vehicle control arm. Only the brepocitinib 1% arm achieved statistical significance versus the control group (P<0.05). In the twice-daily arms, brepocitinib 1% significantly outperformed the control group, which had a mean improvement of 47.6% at 6 weeks (P<0.05). The brepocitinib 0.3% group led to mean EASI improvement of 58.6%.

The brepocitinib study was one of several EADV presentations reflecting the current interest in JAK inhibition for atopic dermatitis.

Upadacitinib

About three fourths of patients with moderate-to-severe atopic dermatitis had at least 75% improvement in disease status after 16 weeks of treatment with the higher of two doses of the selective JAK1 inhibitor upadacitinib (Rinvoq), data from two large randomized trials showed.

In the Measure Up 1 trial, 79.7% of patients who received 30 mg of upadacitinib daily met the coprimary endpoint of 75% improvement in EASI score (EASI 75), as did 72.9% of patients in the Measure Up 2 trial. Additionally, 69.6% and 60.1% of patients allocated with upadacitinib 15 mg achieved EASI 75 responses by week 16. In contrast, 16.3% and 13.3% of patients in the trials' placebo groups met the EASI 75 endpoint (P<0.001).

In both trials, the coprimary endpoint was IGA 0/1 (clear/almost clear). In Measure Up 1, 62% and 48.1% of patients treated with the higher or lower dose of upadacitinib met the endpoint, as compared with 8.4% of patients in the placebo group (P<0.001). IGA 0/1 rates in Measure Up 2 were 52.0% and 38.8% with the higher and lower doses of upadacitinib versus 4.7% with placebo (P<0.001).

Both trials, which involved a combined total of almost 1,700 patients, met all secondary endpoints: EASI 90, EASI 100, itch, symptom frequency, and quality of life, as reported by Emma Guttman-Yassky, MD, of Mount Sinai Medical Center in New York City.

"Improvements were seen in all aspects of atopic dermatitis, from skin disease activity to itch and patient-reported quality of life," said Guttman-Yassky. "Upadacitinib 30 mg showed numerically higher results than upadacitinib 15 mg for the coprimary and all secondary endpoints."

The JAK inhibitor had a rapid onset of activity, as some patients reported improvement in itch as soon as the day after receiving the first dose, she added.

Upadacitinib was well tolerated, as the most common adverse event in the upadacitinib groups was acne.

The trials had an identical design. Investigators enrolled patients ages 12 to 75 who had atopic dermatitis symptoms for at least 3 years associated with EASI score ≥16, vIGA-AD score ≥3, worst pruritis NRS score ≥4, and ≥10% body surface area affected. Patients were randomized to 15 or 30 mg of upadacitinib once daily or to matching placebo.

The primary analysis occurred after 16 weeks of randomized treatment, at which point patients could enter a blinded extension phase that continued to week 136. After 16 weeks, patients in the placebo arm were randomized to extension treatment with 15 or 30 mg of upadacitinib.

Baricitinib

Response to the JAK1/JAK2 inhibitor baricitinib (Olumiant) proved durable for up to 68 weeks for patients with moderate-t0-severe atopic dermatitis enrolled in a long-term extension study that followed two randomized trials.

The best results occurred in patients who received baricitinib 2 mg QD. By last observation carried forward (LOCF) methodology, the proportion of patients who attained EASI 75 responses at week 16 increased from 74.1% to 81.5% at 68 weeks. Similarly, 46.3% of patients met the endpoint of vIGA-AD 0/1 after 16 weeks, and that increased to 59.3% at 68 weeks. By nonresponder imputation (NRI) analysis, EASI 75 rates were 74.1% after 16 weeks and 64.8% after 68 weeks, whereas vIGA-AD 0/1 rates increased slightly from 46.3% to 50.0%, reported Jonathan Silverberg, MD, PhD, of George Washington University in Washington.

Among patients randomized to baricitinib 4 mg, 70.0% met EASI 75 response criteria at 16 weeks and 55.7% at 68 weeks by LOCF. The vIGA-AD 0/1 rates remained stable at 45.7% and 47.1%. By NRI the EASI 75 rates declined from 70.0% to 51.4% and the vIGA-AD 0/1 rates from 45.7% to 40.0%.

Patient-reported outcomes were analyzed after 32 weeks of treatment but showed similar durability, Silverberg reported. By LOCF or NRI, response rates for sleep quality, skin pain, and itch generally remained stable from the end of randomized therapy through the extension period.

The findings involved patients who participated in two 16-week randomized, placebo-controlled trials of baricitinib. Patients who met criteria for complete or partial response were eligible to continue randomized therapy for a maximum of 68 weeks. The trials had coprimary endpoints of EASI 75 response and vIGA-AD 0/1 rates. The long-term extension involved a total of 124 patients treated with baricitinib 2 or 4 mg.

Abrocitinib

Patients with moderate-to-severe atopic dermatitis continued to improve with longer treatment in an extension of two phase III randomized trials of the JAK1-selective inhibitor abrocitinib.

Among 361 patients who entered the extension study, the EASI 75 rate abrocitinib 200 mg increased from 61.9% after 12 weeks to 82.5% at 16 weeks, 86.2% at 24 weeks, 90.1% at 36 weeks, and 87.2% at 48 weeks. For patients randomized to abrocitinib 100 mg, the EASI 75 rate increased from 42.1% at 12 weeks to 64.4% at 16 weeks, 75.5% at 24 weeks, 74.5% at 36 weeks, and 68.0% at 48 weeks, reported Kristian Reich, MD, of the University of Hamburg in Germany.

A similar pattern was observed for EASI 90 and EASI 100 response rates. For patients assigned to abrocitinib 200 mg, the EASI 90 rate was 38.1% at 12 weeks, peaked at 65.5% after 36 weeks, and was 61.8% at 48 weeks. The 100-mg group had an EASI 90 response rate of 21.1% after 12 weeks, peaked at 50.4% at 36 weeks, and remained at 45.3% at 48 weeks. For EASI 100, the rate in the 200-mg group was 10.1% at 12 weeks, reached a peak of 31.6% at 24 weeks, and stood at 24.0% at 48 weeks. Among patients randomized to 100 mg, EASI 100 rates were 5.8% at 12 weeks and 19.5% at 48 weeks.

Improvement in pruritus also continued to increase with longer treatment, said Reich. The proportion of responding patients increased from 56.3% at 12 weeks to 72.5% at 48 weeks in the 200-mg group and from 41.6% to 52.0% in the 100-mg group.