Dual-target oral drug outperforms tofacitinib in RA treatment

The novel, highly selective dual JAK1/TYK2 inhibitor TLL-018 appears to have better efficacy than the currently approved JAK inhibitor tofacitinib in the treatment of patients with rheumatoid arthritis (RA), according to the results of a head-to-head trial presented at EULAR 2023.

After 12 weeks of treatment, more patients who received the 10-, 20-, or 30-mg dose of TLL-018 achieved the primary endpoint of a 50-percent reduction in symptoms by American College of Rheumatology criteria (ACR50) compared with those on tofacitinib. [EULAR 2023, abstract LB0001]

The ACR50 response rates of 65.4 percent and 72.0 percent with TLL-018 20 mg and 30 mg, respectively, were both significantly greater than the 41.7 percent obtained with tofacitinib (p<0.05), reported one of the study authors Dr Chris Liang of Peking Union Medical College Hospital, Beijing, China.

Such finding, Liang added, suggests that inhibition of TYK2, in addition to JAK1, enhances efficacy.

Clinical remission

For the study, Liang and colleagues enrolled 101 patients with moderate-to-severe active RA who had inadequate response or were intolerant to methotrexate. These patients were randomly assigned to receive twice-daily oral TLL-018 at 10 mg (n=25, mean age 50.2 years, 12.0 percent men), 20 mg (n=26, mean age 50.0 years, 15.4 percent men), or 30 mg (n=25, mean age 52.5 years, 30.8 percent men), or tofacitinib 5 mg (n=24, mean age 55.0 years, 16.7 percent men).

At week 12, patients who achieved ACR50 continued the same treatment, whereas those who didn’t respond switched treatment as follows: patients on tofacitinib and TLL-018 10 mg switched to TLL-018 20 mg; patients on 20 mg and 30 mg switched to or continued 30 mg.

Results for clinical remission (measured using the 28-joint Disease Activity Score–C-reactive protein <2.6) at week 12 were consistent with the primary endpoint data. Clinical remission occurred for 39.1 percent, 34.8 percent, and 54.5 percent of patients who received 10 mg, 20 mg, and 30 mg TLL-018, respectively, and for 17.4 percent of patients who received tofacitinib.

Other endpoints

Of note, TLL-018 20 and 30 mg demonstrated greater efficacy across the subgroup of patients who had prior exposure to methotrexate, biologic disease-modifying antirheumatic drugs (bDMARDs), or tyrosine kinase inhibitors, with ACR50 response rates of >66 percent, according to Liang.

“Among the patients who didn’t reach ACR50 on tofacitinib at week 12, switching to TLL-018 20 mg … dramatically improved responses,” indicating that the 20-mg dose was able to overcome resistance to tofacitinib and meet the “difficult to treat” unmet clinical need, Liang said.

TLL-018 was well tolerated, with most adverse events being mild or moderate in severity as expected from this class of compounds. Liang noted no unexpected safety concerns with TLL-018 and no significant dose-safety relationship among the various dose groups.

In light of the present data, TLL-018 20 and 30 mg twice daily warrants further examination in “difficult to treat” RA patients, Liang said. He shared that a phase III trial in RA patients with inadequate response to bDMARDs will begin in the third quarter of this year.