Pooled analysis boosts guselkumab safety for psoriatic arthritis

A pooled safety analysis of two phase III DISCOVER trials demonstrated the favourable safety profile of the novel interleukin(IL)-23p19-specific monoclonal antibody guselkumab through 1 year for psoriatic arthritis (PsA).

Despite the established safety of biologics for rheumatologic disorders, [Immunopharmacol Immunotoxicol 2012;34:548-560; Drug Saf 2019;42:751-768] long-term adverse events (AEs) are of significant concern. [Clin Ther 2019;41:1376-1396; Int J Mol Sci 2020;21:1690] “As most PsA patients who receive biologics will require continual therapy to maintain control of their disease, under­standing the safety of long-term treatment with cumulative exposure, particularly for a new mechanism of action for the disease, is critical,” said the researchers.

The pooled cohort comprised 1,120 individuals (n=381 [DISCOVER-1] and 739 [DISCOVER-2]; mean age 47 years, 53 percent male) with active PsA due to inadequate response to standard therapies* who were biologic-naïve (except for 118 DISCOVER-1 patients who received TNF inhibitors). Participants were randomized 1:1:1 to receive SC guselkumab 100 mg Q4W or Q8W, or placebo. At week 24, placebo recipients transitioned to guselkumab Q4W. Treatment continued through 1 and 2 years for DISCOVER-1 and DISCOVER-2, respectively. [J Rheumatol 2021;doi: 10.3899/jrheum.201532]

The rate of the most common infections (ie, nasopharyngitis, upper respiratory infections, and bron­chitis) seen at 1 year mirrored those observed at week 24 (8.4, 7.1, and 3.4 percent, respectively).

Through 1 year, active** tuberculosis (TB), opportunistic infections, or inflammatory bowel disease (IBD) were not reported with guselkumab. While TB is less common with biologics compared with anti-TNF*** agents, [Mediators Inflamm 2017;2017:8909834; J Eur Acad Dermatol Venereol 2020;34:1449-1456] TB screening and latent TB infection (LTBI) treatment are imperative prior to initiating any biologic therapy for PsA. “[Also,] while further long-term safety data are awaited, the choice of biologic treatment for PsA, particularly in TB endemic regions, should include consideration of the current data on TB reactivation.”

The absence of opportunistic infections and IBD also places guselkumab at an advantage over anti-IL-17 antibodies, which are tied to increased incidences of mucocutaneous infections and IBD. [Lancet 2015;386:1137-1146; Arthritis Care Res 2019;71:367-378; Drugs Context 2020;9:2020-2-1]

The rates of malignancy (n=3) and major adverse cardiovascular events (n=1) with guselkumab were low. Injection-site reactions with guselkumab remained low (1.7 percent) and were mostly mild.

Overall incidence of antibodies to guselkumab also remained low (4.5 percent) and most were non-neutralizing. “[Hence,] no definitive conclusions about the influence of antibodies on pharmacokinetics or phar­macodynamics of guselkumab can be drawn,” said the researchers.

Decreased neutrophil counts with either guselkumab regimen were generally mild (grade 1 or 2), transient/reversible, and did not require treatment discontinuation, with minimal change from week 24 (7 percent) to 1 year (10 percent). A similar trend was observed with increased grade 1 or 2 ALT/AST^# (34 percent/22 percent [week 24] and 36 percent/27 percent [1 year]).

Taken together, the current findings show that AEs with guselkumab remained stable from the initial 24-week analysis, thus reinforcing the initial efficacy findings. [Lancet 2020;395:1115-1125; Lancet 2020;395:1126-1136; Arthritis Rheumatol 2021;73:604-616; RMD Open 2021;7;e001457] These also correlate with the VOYAGE findings evaluating guselkumab for moderate-to-severe psoriasis. [J Dermatolog Treat 2020;13:1-9; J Am Acad Dermatol 2020;82:936-945] The DISCOVER-2 2-year results shall shed light on the longer-term safety of guselkumab.