麻豆传媒

In a 24-week Eli Lilly-sponsored study, selective inhibition of Janus kinase (JAK) 1 and 2 with once-daily oral baricitinib demonstrated superior clinical and structural efficacy compared with placebo in patients with active rheumatoid arthritis (RA) for whom conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) had failed.

The 22-country randomized controlled , published in Annals of the Rheumatic Diseases, reported that at week 12, more patients on baricitinib achieved an American College of Rheumatology 20% (ACR20) response with baricitinib at 4 mg than with placebo: 62% versus 39% (P≤0.001). The findings also suggested that a 4 mg dose was more effective than a 2 mg dose.

"Additional studies in different populations and long-term exposure are needed to provide further insight into the safety and sustainability of response," wrote the researchers, headed by , of Paris-Descartes University in France.

The patients, drawn from 182 centers, had shown inadequate response to at least one csDMARD (with most trying at least two) but had not received biologic (b) DMARDs. The JAK inhibitor produced significant short-term improvements versus placebo as early as 12 weeks: "Importantly, a beneficial treatment effect was observed in all baricitinib-treated, analyzed subgroups, irrespective of concomitant csDMARD use," Dougados and colleagues wrote.

The study randomized 684 patients 1:1 to placebo or baricitinib (2 or 4 mg) once daily. The mean age of patients was about 52, more than 80% were female, and the mean duration of disease was about 8 years. In addition to the 62% ACR20 response at 12 weeks, the study also found statistically significant improvements in the following: the Disease Activity Score in 28 Joints, Simple Disease Activity Index, Health Assessment Questionnaire-Disability, morning joint stiffness, worst joint pain, and worst fatigue.

In addition, radiographic progression of structural joint damage at week 24 was reduced in both doses of the baricitinib groups versus placebo. Significantly lower degrees of progression in the total score and components (erosion and joint space narrowing) and a significantly reduced proportion of patients with disease progression (changes exceeding 0.5 Sharp units or the smallest detectable change) emerged in the 4 mg group only.

"The data suggest that both doses may effectively treat signs and symptoms of RA, but that baricitinib 4 mg has a more rapid and pronounced effect in improving measures including [patient-reported outcomes], composite disease activity scores, and a more robust structural preservation effect," the authors wrote.

In the 24-week also funded by Lilly, once-daily baricitinib showed clinical efficacy in patients with active RA refractory to aggressive standard-of-care treatment with both csDMARDs and bDMARDs.

"Baricitinib is a superb addition to our armamentarium in the management of rheumatoid arthritis and should be considered during the course of treatment," said , of Nova Southeastern University in Boca Raton, Fla. "Although many insurers require that other biologics be tried first, I think baricitinib should be considered for treatment at earlier stages."

Greer, who was not involved with the study but who has done some consulting for Lilly, said that unlike biologics that block inflammatory cytokines, "baricitinib goes a step further downstream, so to speak, to prevent activation of JAK. Baricitinib will also block the action of several cytokines, including interleukin 6, tumor necrosis factor, and a host of others, so it has a more comprehensive inhibitory action."

The caveat is that no test exists to determine the most appropriate therapy at the outset, he added. "We don't have the Holy Grail of a test we can do now to tell us which is the best drug for an individual patient."

Greer noted that one 52-week and three 24-week Lilly trials have now been rolled into one open-label extended study called , which may help clarify the safety and sustainability of response with JAK inhibition.

The rates of adverse events during the treatment period and serious adverse events (SAEs), including infections, were comparable, with SAEs occurring in 5% of patients on baricitinib 4 mg as well as those on placebo. One patient developed tuberculosis with baricitinib 4 mg and one had non-melanoma skin cancer at that dose. Two deaths and three major adverse cardiovascular events occurred with placebo. Baricitinib was associated with a mean decrease in neutrophils and increases in low-density and high-density lipoprotein cholesterol, as well as a small increase in platelets and serum creatinine.

Among the study limitations noted by the authors were its short length, precluding definite conclusions about the durability of response with this inhibitor and a design that did not allow comparison of the two active doses for statistically significant differences. There was also a relatively high, "inexplicable" placebo response for the primary endpoint, with almost 40% of placebo recipients achieving ACR20 at week 12, the team said. Placebo ACR20 responses appeared consistent across regions: the United States and Canada 34%, Asia 38%, Eastern Europe 42%, Central/South America and Mexico 43%, Western Europe 44%, and the rest of the world 45%.

The drug's co-developers, Incyte and Eli Lilly, submitted baricitinib for FDA approval in January 2016.

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