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Background: None of the currently approved treatments for rheumatoid arthritis (RA) can achieve ACR50 in >50% of the patients, and ~20% of the RA patients are considered “difficult to treat”, failing ≥2 targeted therapies. TLL-018 is a highly selective dual JAK1/TYK2 inhibitor. Its TYK2 activity might contribute to efficacy in RA patients.
Objectives: Compare efficacy of TLL-018 with tofacitinib in RA patients.
Methods: 101 patients with moderate-to-severe active RA who had inadequate response or were intolerant to methotrexate were randomized (1:1:1:1 ratio) to receive twice-daily oral TLL-018 10mg, 20mg, 30mg or tofacitinib 5mg. After 12-weeks of treatment, patients who achieved ACR50 continue the same treatment, and those who didn’t change treatment as follows: patients on tofacitinib and TLL-018 10mg change to TLL-018 20mg; patients on 20mg and 30mg change to or continue 30mg TLL-018. The Primary endpoint is the proportion of patients achieving ACR50 at Week 12. Secondary endpoints include the proportion of patients achieving DAS28-CRP <2.6, ACR20, ACR70 at all scheduled time points, ACR50 at scheduled time points exclude week 12, CDAI and other parameters at 12 week. Safety was assessed via adverse event (AE) and laboratory examinations.
Results: 101 patients were randomized, ~50% of them also had prior bDMARDs and ~30% had prior JAK inhibitors. Demographics and baseline disease characteristics were balanced across treatment arms. At week 12, ACR50 response rates in TLL-018 treated groups [10mg, 20mg and 30mg, 48.0% (95% CI, 28.42 - 67.58), 65.4% (95% CI, 47.10 - 83.67), 72.0% (95% CI, 54.40 - 89.60), respectively] were higher than that for tofacitinib [41.7% (21.94 - 61.39)]. TLL-018 20 and 30mg were statistically superior to tofacitinib (p<0.05). Proportions of patients achieving clinical remission (DAS28-CRP<2.6) at week 12 were 39.1%, 34.8%, 54.5% and 17.4% at week 12 for the 10, 20, 30mg TLL-018 and tofacitinib, respectively. TLL-018 20 and 30mg demonstrated high efficacy in patients who had prior bDMARDs, achieving ACR50 rates of >66%. TLL-018 20mg dramatically improved responses in patients who didn’t achieve ACR50 on tofacitinib at week 12. The most frequently reported treatment-emergent AEs were hyperlipidemia and respiratory infection in TLL-018 or tofacitinib-treated patients. There was one case of malignancy in tofacitinib treatment group. No death, venous thromboembolism or major adverse cardiovascular event was observed in the study. (The data cut-off time was December 19th).
Conclusion: TLL-018 20 and 30mg demonstrated superior efficacy over tofacitinib in RA patients, suggesting that inhibition of TYK2, in addition to JAK1, enhances efficacy. TLL-018 was well tolerated with most AEs being Grade 1 or 2 as expected from this class of compounds. No unexpected safety concerns were observed in the study. TLL-018 20 and/or 30mg BID warrants further studies in “difficult to treat” RA patients.
REFERENCES: NIL .
Acknowledgements: NIL .
Disclosure of Interests: Xiaofeng Zeng: None declared, Chanyuan Wu: None declared, Jiankang Hu: None declared, Shengyun Liu: None declared, Zhenyu Jiang: None declared, Jingyang Li: None declared, Xiaoxia Wang: None declared, Ju Liu: None declared, Chirs Liang Employee of: highlightll pharma, Guang Yang Employee of: HIghlightll Pharma.