Novel URAT1 Inhibitor Successful in Proof-of-Concept Trial & More Late-Breaking Abstracts

A proof-of-concept trial of AR882, a novel and selective uric acid transporter 1 (URAT1) inhibitor, showed safe and efficacious resolution of tophi and dissolution of urate crystal volume in patients with gout compared to allopurinol. Tophi were measured with calipers and urate crystal volume was measured using dual-energy computed tomography (DECT).

Robert Keenan, MD, MPH, MBA, Chief Medical Officer for Arthrosi Therapeutics, presented the first of five Late-Breaking Abstracts in a dedicated session at ACR Convergence 2023. The session is available on demand for registered ACR Convergence participants through October 31, 2024, on the meeting website.

A phase 2B global trial randomized 42 gout patients with subcutaneous tophi to once-daily AR882 75 mg, once-daily AR882 50 mg plus allopurinol, or once-daily allopurinol at up to 300 mg, Dr. Keenan explained. The primary endpoint was change in serum urate (sUA) over three months. Secondary endpoints included resolution of target tophi and change in crystal volume at six months.

At three months, patients in both of the AR882 groups showed 50% reduction in sUA compared to a 35% reduction for allopurinol monotherapy. Four patients in the AR882 75 mg group had complete resolution of ≥1 tophi versus one each in the allopurinol groups. AR882 monotherapy showed a 30.7% decrease in urate crystal volume versus 31.5% for AR882 plus allopurinol, and 16.8% for allopurinol monotherapy.

“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Dr. Keenan said.

Immunosuppressants beat steroid withdrawal in long-term IgG4-RD

A multicenter investigator-initiated trial, WinS IgG4-RD, found that immunosuppressants (IM), with or without low-dose glucocorticoids (GC), are more effective at preventing relapse in patients with stable IgG4-RD than withdrawing steroids. GC treatment is usually effective in treating fibroinflammatory IgG4-RD, but relapse is common following GC withdrawal for patients with stable disease.

The open-label trial randomized patients with stable IgG4-RD on GC plus IM to withdrawal of both agents (Group 1, 48), withdrawal of GC plus maintenance of IM (Group 2, 49), or maintenance of both agents (Group 3, 49). The primary endpoint was relapse within 18 months.

Relapse occurred in 52.1% of Group 1 versus 14.2% in Group 2 and 12.2% in Group 3, reported Linyi Peng, MD, PhD, Associate Professor of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, China. Patients in Group 1 also had worse scores on the responder index and Physician Global Assessment versus Group 2 or Group 3 (p<0.001 for all).

“This is the first randomized controlled trial investigating maintenance treatment in long-term stable IgG4-RD,” Dr. Peng said. “Our findings highlight the efficacy of immune suppression in preventing relapse with or without glucocorticoids.”

Positive phase 1 results for TLR7/8 inhibition in CLE

Afimetoran, a first-in-class inhibitor of toll-like receptor (TLR) 7 and 8, showed positive results against cutaneous lupus erythematosus (CLE) in a phase 1B randomized controlled trial. CLE is a heterogeneous group of inflammatory skin conditions sharing common histopathologic features that can occur in isolation or as a manifestation of systemic lupus erythematosus (SLE).

Overproduction of TLR 7/8 is central to the pathogenesis of CLE, noted Fareeda Hosein, MD, MBA, Senior Director, Early Clinical Development, Immunology, Cardiovascular & Fibrosis, Bristol Myers Squibb. Afimetoran is the first oral, small molecule agent designed specifically to inhibit these two TLRs to improve the cutaneous manifestations of lupus.

This phase 1B trial randomized 13 patients with CLE to afimetoran (8) or placebo (5) to assess safety and tolerability with exploratory assessment of efficacy over 16 weeks. The study was conducted at a single center during the COVID-19 pandemic.

Twelve of the patients completed the trial and one interrupted treatment due to moderate COVID-19, Dr. Hosein reported. There were no serious adverse events or safety signals.

By week 15, half of the afimetoran patients showed a clinically significant reduction in CLE Disease Area and Severity Index-Activity (CLASI-A) scores (>4 points from baseline) versus none for placebo. The CLASI-A improvement persisted through a four-week follow-up.

“These results represent the first clinical evidence of therapeutic benefit from afimetoran,” Dr. Hosein said. “The totality of the evidence supports continued investigation, including the ongoing phase 2B SLE study.”

Repeat injections of novel long-acting steroid beneficial for knee OA

Intra-articular injections of corticosteroids can relieve the pain of osteoarthritis (OA), reduce inflammation, and increase mobility, but the effects are neither predictable nor long acting. Two intra-articular injections of a novel, controlled-release liposomal formulation of dexamethasone sodium phosphate (DSP) can provide better pain relief versus placebo for up to 52 weeks.

A phase 3 randomized, double-blinded trial randomized 506 patients in a 2:1:1 ratio to an injection of TLC599 12 mg (252), DSP 4 mg (126), or saline placebo (126). At week 24, eligible patients in the TLC599 and placebo arms received a second blinded injection of the same treatment, while patients in the DSP arm received a blinded injection of TLC599 with safety and efficacy assessment through week 52. The primary outcomes were changes in average daily pain (ADP) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores.

There was a clear separation of ADP and WOMAC scores at 12 weeks, with TLC599 providing significantly greater relief than the other two injections (p<0.05 for both), which continued to week 24. Following the repeat injection at week 24, TLC599 remained superior to placebo through week 52.

There were numerically more reports of injection site pain in the TLC599 group, and other adverse event types and severities were similar across the three arms.

“TLC599 may provide prolonged benefits and an alternative treatment to corticosteroids for the management of pain for people who have osteoarthritis of the knee,” said David Hunter, PhD, MBBS, FRACP, Professor and the Florance and Cope Chair of Rheumatology and Co-Director of the Sydney Musculoskeletal Health Flagship, The University of Sydney, Australia.

Telitacicept shows good results in RA patients with poor response to methotrexate

Initial phase 3 results showed the human recombinant telitacicept is both safe and effective in patients with moderate-severe rheumatoid arthritis (RA) who have an inadequate response to methotrexate. The agent is currently approved for SLE in China.

The blinded 24-week trial randomized 479 patients to weekly subcutaneous injections of telitacicept 160 mg (360) or placebo (119), followed by open-label treatment with telitacicept for an additional 24 weeks. The primary endpoint was the proportion of patients achieving an ACR20 response at week 24.

At week 24, 60% of telitacicept patients had achieved ACR20 versus 26.9% of the placebo group (p<0.001). Telitacicept also showed superiority for patients achieving ACR50, 21.4% versus 5.9% (p<0.001), as well as improvements in the individual ACR components and DAS28-ESR. There were significantly more patients in the telitacicept arm with no radiographic progression at week 24, 90.2% versus 66.4% for placebo (p<0.001).

There were no deaths in the trial and the two arms showed similar safety, tolerability, and discontinuation.

Results of the 24-week, open-label follow-up were not reported.

“The study demonstrates the efficacy telitacicept and gives us a very favorable safety profile in patients with RA,” said Qing Zuraw, MD, MPH, MBA, Head Senior Vice President, Autoimmune Disease Clinical Development, RemeGen Biosciences.