榴莲视频

MILAN -- A novel oral agent that blocks two different kinase enzymes was possibly more effective against rheumatoid arthritis (RA) than the currently approved drug tofacitinib (Xeljanz) in a head-to-head study, a researcher reported here.

Patients receiving different doses of the dual-acting agent, called TLL-018, achieved 50% reductions in symptoms by American College of Rheumatology criteria (ACR50) after 12 weeks at higher rates than those assigned to tofacitinib in the randomized, phase II trial, according to Chris Liang, PhD, of HighlightII Pharma in Hangzhou, China.

Speaking during a late-breaking abstract session at the European Alliance of Associations for Rheumatology (EULAR) annual meeting, Liang said the ACR50 response rates of 65.4% and 72.0% for the two highest doses of TLL-018 were significantly greater than the 41.7% seen for tofacitinib.

Tofacitinib targets the Janus-activated kinase (JAK) family of immune-related signaling molecules, mainly inhibiting the JAK-1 and JAK-3 species. TLL-018, on the other hand, was designed to inhibit both JAK and another kinase called TYK2, which Liang said is involved in immune pathways distinct from those in which JAK1 plays a role.

In particular, he said, TYK helps mediate activation of interleukin (IL) proteins 17 and 23. Biologic drugs targeting IL-17 and IL-23, such as secukinumab (Cosentyx) and risankizumab (Skyrizi) are established therapies for RA-adjacent diseases including psoriatic arthritis and axial spondyloarthritis. Thus, TLL-018 offers the possibility of improved efficacy compared with a single-acting drug such as tofacitinib.

The concern about blocking multiple immune pathways, however, has been the potential to suppress immune function too broadly and thus increase susceptibility to infection. Layering targeted drugs with different mechanisms on top of one another is therefore generally avoided in autoimmune disease for this reason. The TLL-018 trial didn't reveal notably higher rates of infections in comparison with tofacitinib, but it was a small study (101 patients distributed among four arms) and such questions are likely to linger.

Patients in the new trial, conducted in China, were an average age of 52 and roughly 80% were women. About half had previously received a biologic agent and around one-quarter had already tried a JAK inhibitor. To be eligible, patients had to have had inadequate responses to methotrexate, although failing a targeted drug was not a requirement. Neither methotrexate nor steroid drugs were allowed during the study. The three TLL-doses were 10, 20, and 30 mg twice daily, while tofacitinib was given at 5 mg twice daily.

The primary endpoint was ACR50 response at 12 weeks. However, the trial continued beyond this point: patients in the tofacitinib and low-dose TLL-018 groups not achieving ACR50 at week 12 were then switched to the middle dose of TLL-018. Participants in the middle-dose TLL-018 groups not reaching ACR50 went on the high dose, and those already receiving 30 mg twice daily continued on it for the 12-week extension. All patients stopped treatment at week 24 and were followed for a final 4 weeks.

At week 12, other efficacy endpoints such as the 28-joint Disease Activity Score mirrored the ACR50 findings. So did ACR50 rates when patients were stratified by their previous therapies, with the exception of those who had received JAK inhibitors. In this latter group, at least 60% of all four study arms reached ACR50 by week 12.

Liang also reported results for the nine patients in the tofacitinib arm who switched to TLL-018 at 20 mg for the extension. At week 20 and again at week 24, eight had achieved either ACR50 or ACR70 (70% symptom reduction) responses.

Rates of treatment-emergent adverse events of grade 3 or higher at week 12 were similar at 64%- 81% across the four arms, and there were no differences in the number needing medical intervention. Treatment was stopped temporarily for six patients in the TLL-018 arms, but all were able to recommence the drug.

No patients assigned to tofacitinib had serious infections, while two receiving the middle TLL-018 dose experienced grade ≥3 herpes zoster attacks. None were seen with the other TLL-018 doses. Overall infection rates were similar at 15%-20% in the four study arms.

One patient in the low-dose group had a serious elevation in gamma-glutamyl acetyltransferase, but no other lab abnormalities were seen.

Liang said a phase III trial in patients for whom biologic RA drugs had failed was expected to start this summer. He didn't say whether it would be conducted in the U.S.; the FDA has traditionally been skeptical of drugs tested exclusively in China. HighlightII did run a phase I study of TLL-018 in the U.S.

One issue in the study to which an audience member alluded was participants' previous use of JAK inhibitors. Could the deck have been stacked by including patients who had already had inadequate responses to tofacitinib, and who would then want to try something else? Such patients assigned to tofacitinib would probably continue to respond poorly.

After his presentation, Liang was asked directly about this. Was previous use of tofacitinib allowed and, if so, why would such individuals want to join the new trial? He said it was allowed and, when pressed about participants' rationale for enrolling, he suggested, "Maybe they wanted a free drug." The questioner then chuckled and said, "Maybe."

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