Race to the top: how high will treatment response rates in RA reach? Save

We have become accustomed to the 60/40/20% rule for the outcome of ACR 20/50/70 respectively for biologics and targeted synthetic DMARDs. When a new agent is launched, we look out for the treatment response with much anticipation if it will be higher or lower than the benchmark we expect. 

The late breaking abstract L09 presented at #ACR23 by Wu C et al, is one such paper where the outcome scores have exceeded the benchmark. The agent studied was LNK01001, a selective oral JAK1 inhibitor for treating rheumatoid arthritis (RA). This was a 24-week efficacy and safety study of LNK01001 in patients with moderate to severe active RA who had an inadequate response to csDMARDs.

Patients aged 18 to 75 with a diagnosis of moderate to severe active RA with an inadequate response to csDMARDs, were randomised (1: 1: 1) to receive LNK01001 12 mg or 24 mg twice daily (BID), or placebo for 12 weeks, followed by a 12-week extension treatment with LNK01001 12mg or 24mg. The primary endpoint was the proportion of patients achieving an ACR20 response at Week 12. Baseline characteristics were similar across treatment groups.

At week 12 for LNK01001 at 12mg the ACR 20/50/70 was 60/40/12% and at 24mg 73.1/  42.3/23.1% compared to placebo 31.5/9.3/1.9% respectively. There was a statistically significant difference between both doses and placebo.  This difference was seen as early as Week 1 with the ACR20 in the 12 mg/24 mg/placebo groups being 18/23.1/0 % respectively. There was also improvement in the DAS28-CRP score in the 12mg/24mg/placebo with -2.52/-2.64/-1.26 and HAQ-DI (-0.64/-0.73/-0.34). During extension treatment, the proportion of patients achieving ACR20/50/70 continued to increase. At week 24, the ACR 20 for LNK01001 for the 12 mg and 24 mg doses were 91.1 and 90.7%. There were no severe adverse events and no new safety signals.

The achievement of the ACR 20 at 90% at week 24 shows great promise of LNK01001 in the treatment of moderate to severe RA. This achievement is higher than the benchmark. This may be due to a host of factors including patient selection, study design and disease duration. Longer term follow up and further details of the study will be very important to analyse the reasons for a high ACR20 seen.

This paper reminds me of the late breaking abstract LB0001 (LB0001) by Zeng X et al at EULAR 2023, where the agent TLL-018 was studied in RA against tofacitinib. TLL-018 is a highly selective dual JAK1/TYK2 inhibitor. Its TYK2 activity might contribute to efficacy in RA patients. In this study the ACR50 at week 12 for the doses 10mg, 20mg and 30mg was 48.0%, 65.4%, 72.0% respectively and were higher than that for tofacitinib 41.7%. There was a dose response curve with the higher doses achieving a higher ACR 50 response. 

Both these two agents LNK01001 and TLL-018 achieved higher than expected ACR 20/50/70 responses. Further details of these studies will be needed to understand the mechanisms and reasons behind this. The longer-term follow up will also be needed to see if this response is sustained in the longer term. For now, from the existing information available, there is a race to the top with new agents challenging the status quo and achieving higher levels of ACR 20/50/70.