番茄社区

On April 10, 2020, 番茄社区 published a story on the success seen with guselkumab (Tremfya) for psoriatic arthritis in two large pivotal phase III trials, DISCOVER-1 and DISCOVER-2. Guselkumab is a monoclonal antibody that binds the interleukin-23 p19 subunit, and was approved for use in psoriasis in July 2017.

On July 14, 2020 the FDA approved guselkumab for psoriatic arthritis, based on the results of the DISCOVER trials.

In DISCOVER-1, which included 381 patients with active psoriatic arthritis who were either biologic-naive or had previously been treated with a tumor necrosis factor inhibitor, a 20% improvement on the response criteria of the American College of Rheumatology (ACR20) was observed at week 24 in 59% of patients given 100 mg of guselkumab subcutaneously every 4 weeks and by 52% of those receiving the medication every 8 weeks compared with 22% of those randomized to receive placebo.

DISCOVER-2 randomized 741 patients who were biologic-naive to one of the two guselkumab regimens or placebo, with ACR20 responses being seen at week 24 in 64% of both guselkumab groups compared with 31% of the placebo group. The differences between guselkumab and placebo were statistically significant in both studies.

Since the publication of the original studies in April in the Lancet, further analyses of the data have emerged, with longer follow-up and more patient-reported outcomes. An additional study focusing on the disease manifestations of enthesitis and dactylitis also was published.

DISCOVER Week-52 Results

At the 2020 ACR virtual meeting, the 1-year results of the two DISCOVER trials were presented. After week 24 in both studies, patients who had originally received placebo were switched to guselkumab, 100 mg every 4 weeks, while the every 8 week group maintained that dosage schedule. In , ACR20 responses at week 52 were 73.4% for the every 4-week group and 59.8% for the every 8-week group. ACR50 responses were observed in 53.9% and 38.6%, respectively, while ACR70 responses were seen in 28.9% and 26%.

Through week 60, serious adverse events were reported in 4% of guselkumab-treated patients and serious infections in 1%. There were no deaths, cases of inflammatory bowel disease (IBD), or opportunistic infections among guselkumab-treated patients.

By week 52 in , ACR20 responses were observed in 70.6% of the every 4-week group and in 74.6% of the every 8-week group. ACR50 responses were seen in 48.4% and 45.7%, respectively, while ACR70 responses were observed in 27.8% and 26.1%.

Resolution of dactylitis occurred in 81.1% and clearance of enthesitis was seen in 60%. A 75% improvement in the Psoriasis Area and Severity Index was observed in 91.9%, and mean change on the Health Assessment Questionnaire was -0.5.

Serious adverse events were reported in 4.2% of guselkumab-treated patients and serious infections in 1.2%. As in DISCOVER-1, there were no deaths, cases of IBD, or opportunistic infections among guselkumab-treated patients.

of data from a subset of patients in DISCOVER-2 examined the effects of guselkumab on collagen turnover markers, which are dysregulated in patients with psoriatic arthritis. Levels of the marker C1M, which indicates breakdown of collagen type 1 in the bone and tracks with joint responses, was significantly decreased after weeks 24 and 52, and to a greater extent in patients classified as ACR responders compared with nonresponders, "providing insight into how guselkumab may be working to protect against degradation of bone in psoriatic arthritis," the investigators noted.

Patient-Reported Outcomes

A of the DISCOVER trials also found that guselkumab improved fatigue, which is a common complaint among patients with psoriatic arthritis. Fatigue was measured according to the FACIT-Fatigue score, which is a 13-item measure of fatigue and its impact on function, with scores ranging from 0 to 52 and higher scores indicating less fatigue.

At week 24 in DISCOVER-1, scores on the FACIT-Fatigue had declined by 5.9 points in the every 8-week group, by 5.6 points in the every 4-week group, and by 2.6% in the placebo group. By week 52, the changes were 7.5 and 6.9 in the every 8-week and every 4-week groups and 6.6 in the group that initially was on placebo but was switched to every 4 weeks at week 24.

In DISCOVER-2, changes from baseline on the FACIT-Fatigue by week 52 in the three groups were 8.9, 7.7, and 7.5 points, respectively. Moreover, "substantial proportions of those effects were independent of the effects on ACR20," the authors wrote.

Work productivity and daily activity also benefited from guselkumab treatment, as was shown by an . At week 24, the least squares mean difference from baseline in overall work productivity impairment was -8.8 (95% CI -14 to -3.7, P<0.001) in the every 8-week group and -9.2 (95% CI -14.3 to -4, P<0.001) in the every 4-week group.

Mean differences from baseline in daily activity impairment at week 24 were -11.1 (95% CI -15 to -7.4, P<0.001) in the every 8-week group and -10.2 (95% CI -14 to -6.4, P<0.001) in the every 4-week group.

In addition, potential yearly indirect savings from improved work productivity was $10,242 for the every 8-week regimen and $10,404 for the every 4-week regimen compared with $5,648 for placebo.

Enthesitis and Dactylitis

A that enrolled 149 patients focused specifically on the effects of guselkumab on enthesitis and dactylitis, which are thought to affect more than half of patients with psoriatic arthritis and may reflect greater disease activity and worse functional impairment.

At baseline, 107 patients had enthesitis, with a mean score of 2.7, which represented moderate-to-severe involvement. Dactylitis was present in 81, with a mean score of 5.7 on a scale of 0 to 6.

Patients were randomized to 100 mg guselkumab or placebo at weeks 0 and 4 and then every 8 weeks. Those initially receiving placebo were switched to the active treatment at week 24 and followed through week 56.

At week 24, changes from baseline in the enthesitis score were -0.7 in the placebo group and -1.5 in the guselkumab group (P<0.05), and the proportions with resolution of the enthesitis were 56.6% compared with 29% (P<0.05). By week 56, when all patients were receiving guselkumab, the proportions with resolution were 70.8% and 62.5%.

For dactylitis, the changes in score from baseline at week 24 were -0.4 in the placebo group and -3.8 in the guselkumab group (P<0.01) and the proportions with resolution of dactylitis were 17.4% and 55.2% (P<0.01).

Correlations were seen at week 24 between enthesitis and various measures of disease activity, including swollen and tender joint counts, patient's global assessment, and the Short Form 36 Health Survey physical and mental components. Correlations with dactylitis were observed from swollen and tender joint counts and the Health Assessment Questionnaire-Disability Index. "These results suggest that guselkumab is able to improve multiple domains of disease in patients with psoriatic arthritis and add to the evidence that enthesitis and dactylitis resolution are important treatment goals," the investigators concluded.

Comment