Ixekizumab for axSpA patients in remission: To continue or not?

For individuals with axial spondyloarthritis (axSpA) who have achieved remission following treatment with ixekizumab, continuing the drug led to better outcomes than withdrawal, suggests findings from the randomized withdrawal-retreatment period (RWRP) of the ongoing phase III COAST-Y trial.

Inactive disease, remission, or low disease activity (LDA) has been proposed as a therapeutic target for axSpA, a condition that carries a high disease burden and warrants long-term treatment to maintain disease control. [Ann Rheum Dis 2018;77:3-17; RMD Open 2019;5:e001108; Ann Rheum Dis 2017;76:978-991]

“[Our findings show that] patients with axSpA who continued ixekizumab were significantly less likely to flare* and had significantly delayed time-to-flare (TTF) vs patients who withdrew to placebo,” said the researchers. This aligns with results of other RW studies of TNFis** in patients with axSpA showing that TNFi discontinuation leads to flare in most individuals.

The RWRP comprised 155 (mean age 37.9 years, 63 percent with radiographic axSpA) of the 741 participants*** who completed the 24-week lead-in phase and achieved remission^#. They were rerandomized 1:1:1 to continue ixekizumab 80 mg Q4W or Q2W or withdraw to placebo (WTP). [Ann Rheum Dis 2021;80:1022-1030]

Eighty-three percent of ixekizumab recipients (p<0.001, p=0.003, and p=0.001 for the respective combined, Q4W, and Q2W arms) remained flare-free as opposed to only 55 percent in the WTP arm. Though more than half of WTP patients remained flare-free for up to 40 weeks without treatment, they seemed to have greater disease activity at the time of flare vs those who continued treatment.

Of those who flared and were retreated for at least 16 weeks with ixekizumab, half of ixekizumab recipients and 93 percent of those in the WTP arm recaptured ASDAS LDA. These findings align with evidence showing that disease control may be recaptured with retreatment despite flares. [Ann Rheum Dis 2020;79:920-928; Lancet 2018;392:134-144]

“However, the number of patients who flared and received retreatment during the first 40 weeks of the RWRP was limited. Longer-term data from this ongoing study … will likely provide additional information regarding response to retreatment with ixekizumab, as well as predictors of flare,” the researchers noted.

Predictors of flare

Post hoc analyses identified ASDAS AUC^## as one of several factors associated with flares. “[This implies] that patients with less well-controlled disease over time may have been more likely to flare than those who had stable disease control,” the researchers explained.

Other identified predictors were ixekizumab withdrawal, higher baseline C-reactive protein, non-normal BMI (ie, <18.5 or ≥25 kg/m²), and higher BASDAI^### pain score at week 24. However, the BASDAI score was only seen among those on continued ixekizumab treatment. “[Nonetheless,] identifying predictors of flare is important to help clinicians better understand the risk of flare for patients following treatment interruption,” they continued.

TTF, safety

Compared with the WTP arm, continuing ixekizumab significantly delayed TTF (p<0.001, p=0.004, and p<0.001 for the combined, Q4W, and Q2W arms, respectively). “Separation between the continuous ixekizumab and WTP arms first occurred 20 weeks after withdrawal from ixekizumab treatment,” said the researchers.

Nearly half (44 percent) of ixekizumab recipients reported treatment-emergent adverse events (AEs), but these were generally mild or moderate. Two patients in each ixekizumab arm reported serious AEs. Only two ixekizumab recipients discontinued owing to AEs.

Long-term treatment, less flares

One of the study’s strengths is the inclusion of individuals across the axSpA spectrum with symptom duration ranging between 2 and 45 years, with and without prior TNFi failure. Moreover, the long active treatment phase before RW signals long-term sustained treatment in clinical practice before treatment withdrawal for those with stable disease control, the researchers noted.

“[T]he long durability of treatment response following ixekizumab withdrawal suggests that temporary treatment interruption, such as during infection or prior to surgical procedures, is unlikely to result in flare for most patients,” they added.

Overall, the findings underscore the importance of continuous ixekizumab treatment to maintain optimal long-term disease control in this setting. “These results are important for clinicians when making treatment decisions regarding treatment interruption and optimizing long-term management of axSpA,” they concluded.