GLP-1 Drugs Pick Up Another Win, This Time in Psoriatic Arthritis

DENVER — Adding a GLP-1 agonist to psoriasis medication significantly improved outcomes in patients with psoriatic arthritis (PsA) and overweight or obesity, a phase III randomized trial showed.

After 36 weeks, almost a third of patients randomized to ixekizumab (Taltz) and tirzepatide (Zepbound) had at least 50% improvement in psoriatic arthritis status (ACR50) and 10% weight loss. In contrast, fewer than 1% of patients treated with ixekizumab alone met the composite endpoint. Significantly more patients treated with both drugs attained ACR50 status, at least 10% weight loss, or ACR20 plus at least 5% weight loss.

Other arthritis-related endpoints all favored the combination as did patient-reported outcomes (PROs), reported Joseph F. Merola, MD, of the UT Southwestern Medical Center in Dallas, at the American Academy of Dermatology meeting.

“I think the early separation and statistical separation of ACR50 were really key,” said Merola. “For me, this represents a paradigm shift as we think about how other combination therapies have not made a major dent in our ability to move ACR50 and other endpoints. We’re now seeing clear improvement, and I truly believe that helping our patients deal with this key comorbidity of the disease will dramatically improve quality of life over time and frankly, survival, among these patients.”

During a discussion that followed the presentation, Merola was asked whether the patients who lost weight had more ixekizumab available.

“We know that when people lose weight there probably is a better effect of drug on these patients,” said Merola. “I would argue that in the short term, for whatever reason, they’re seeing a benefit, and I’m excited about it. I think the other piece I’m quite excited about, which we don’t have here but will be coming, are some of the medical benefits, which I have no doubt you will be excited to see, too.”

A mechanistic study is ongoing in an attempt to understand better the factors involved in the superior results observed with the combination, he added.

The therapeutic potential of GLP-1 agonists increasingly has attracted the interest of clinicians and researchers in psoriatic disease. At the 2024 meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis, a key address focused on the therapeutic potential of GLP-1 agonists, acknowledging the lack of direct evidence linking the drug class to psoriatic disease and calling for more studies.

A recent review article provided an update on GLP-1 agonists for rheumatology specialists. The National Psoriasis Foundation recently added information about GLP-1 agonists for clinicians and patients to its website. The International Psoriasis Council website also has information on the therapeutic potential of GLP-1 agonists in psoriasis.

Despite the paucity of hard evidence, interest in GLP-1 agonists in psoriatic disease has a strong rationale based on the drugs’ proven effects on obesity and metabolic syndrome, two common comorbidities of patients with psoriasis and psoriatic arthritis. A recent retrospective chart review of 1,500 patients with psoriasis or hidradenitis suppurativa showed that 60% qualified for use of GLP-1 agonists.

Overweight and obesity combined affect 70-80% of patients with PsA, Merola noted. Obesity is associated with worse outcomes in PsA, and patients with PsA have a higher incidence of cardiovascular comorbidities.

The rationale for combined therapy led to the TOGETHER studies, two phase III trials evaluating ixekizumab with or without tirzepatide, one for PsA and the other for psoriasis (PsO). Results of the psoriasis study will be reported at a later date, said Merola.

Investigators in TOGETHER-PsA enrolled patients with active PsA and who had obesity (body mass index [BMI] ≥30) or overweight (BMI ≥27 to <30) plus at least one weight-related comorbidity. They were randomized to ixekizumab with or without tirzepatide, and the primary endpoint was the composite of ACR50 and ≥10% weight reduction at 36 weeks.

Data analysis included 271 patients who had a mean age of 55 and mean BMI of 37.6. Women accounted for 70% of the study population, and 63% of the patients had received advanced therapy.

The 36-week results showed that 31.7% of the combination arm met the composite endpoint as compared with 0.8% of the ixekizumab group (P<0.001). The combination offered a significant advantage for the key secondary endpoints:

• ACR50: 33.5% vs 20.4%, P<0.05
• ACR 20 and ≥5% weight loss: 69.7% vs 10.3%, P<0.001
• ≥10 weight loss: 84.5% vs 4.5%, P<0.001

Patients in the combination arm had an average weight loss of 18.0% of baseline body weight as compared with 1.1% for the patients randomized to ixekizumab alone. PROs were significantly improved with the combination (P<0.05 to P<0.001).

The combination therapy was generally well tolerated, said Merola. No severe or unexpected events occurred and the most common events were gastrointestinal in nature, as expected.

Preliminary (36-week) data for the TOGETHER-PsO trial, involving patients with moderate/severe PsO, showed that more patients treated with the combination achieved Psoriasis Activity and Severity Index (PASI) goals, including PASI 75, PASI 90, and PASI 100.