Lilly/Incyte's JAK inhibitor needs RA Phase III to compare with Pfizer's tofacitinib
This article was originally published in Scrip
Lilly and Incyte have reported positive 12-week data from a Phase IIb study of baricitinib, formerly LY3009104 (INCB28050), an orally available Janus kinase (JAK) inhibitor, in patients with active rheumatoid arthritis (RA).
However, Incyte said it was not clear from this set of trial data what advantages baricitinib might have, if any, over its own marketed JAK inhibitor, Jakafi (ruxolitinib, for myelofibrosis) or Pfizer's tofacitinib (which is under review for RA in the US, Europe and Japan).
Incyte said, "It is not possible to compare the results because the patient populations studied and the design of the clinical trials were different. Based on this relatively small data set and preliminary efficacy data, we believe baricitinib could provide an additional treatment option for RA patients."
It continued, "Baricitinib differs from other molecules in development, including tofacitinib (a twice-daily JAK1/JAK2/JAK3 inhibitor). Large scale trials will be needed to better understand baricitinib's efficacy and safety profile."
Those trials look set to begin in RA in late 2012 or early 2013, Incyte told Scrip. Timings for potential regulatory submissions or approvals have not yet been disclosed.
The Phase IIb trial consists of three parts: Part A, Part B and an open-label extension. The announced data come from Part A, a double-blind and placebo-controlled section of the study in which patients randomised to baricitinib received one of four doses administered once daily for 12 weeks.
In Part B, patients initially randomised to placebo or the 1mg baricitinib dose were re-randomised to receive either 4mg once daily or 2mg twice daily for 12 weeks. Patients initially randomised to the 2mg, 4mg and 8mg doses continued therapy for an additional 12 weeks. Patients completing Part B were eligible to continue in an open-label extension arm on either the 4mg or 8mg once daily doses of baricitinib for 52 additional weeks.
Lilly and Incyte said that Part B of the study has completed and data analysis is underway. Patients are continuing to participate in the open-label long-term extension of the trial.
Incyte said, "We hope to present the results from part B (the 24-week data) later this year at a medical meeting – possibly ACR [The American College of Rheumatology meeting in November in Washington DC]."
The latest data, which were presented at a late-breaking session at the European League Against Rheumatism's (EULAR) annual European Congress of Rheumatology in Berlin, Germany, showed that the trial achieved its primary endpoint by demonstrating a significant difference in the American College of Rheumatology 20 (ACR20) response between the combined 4mg and 8mg baricitinib groups (76%) compared with placebo (41%) after 12 weeks of treatment (p <>
The companies said that a significant improvement was observed at the first assessment point after two weeks of treatment and was sustained through week 12.
The product is an oral JAK1 and JAK2 Inhibitor that is JAK3-sparing. Currently, a Phase IIa trial is also underway investigating baricitinib in patients with moderate to severe psoriasis.
JAK inhibition
Late last year, Incyte's Jakafi (ruxolitinib) became the first in the new class of JAK inhibitors to be approved in the US with the drug being cleared for use in myelofibrosis (scripintelligence.com, 17 November 2011). Looking to the RA indication and the next likely market entrant, Pfizer's tofacitinib, recently received the backing of the US FDA's arthritis advisory committee and is also under review in Europe and Japan (scripintelligence.com, 10 May 2012). Its launch is anticipated for early next year in certain markets.
Lilly and Incyte entered into this exclusive worldwide licence and collaboration agreement for the development and commercialisation of Incyte's baricitinib and certain follow-on compounds for inflammatory and autoimmune diseases in December 2009.
Under the agreement, Lilly received worldwide rights to develop and commercialise the oral treatment for all inflammatory conditions. In exchange, Incyte received an initial payment of $90 million and was eligible for up to $665 million in additional potential development, regulatory, and commercialisation milestones, as well as tiered, double-digit royalty payments on future global sales with rates ranging up to 20% if a product is successfully commercialised.
Incyte said that since it has opted in to co-develop baricitinib for RA. As part of the deal, the company is now responsible for funding 30% of the associated future global development costs (beginning with this Phase IIb trial). "As a result, Incyte will receive an incremental royalty rate increase across all tiers resulting in effective royalty rates ranging up to the high twenties on potential future global sales for compounds and/or indications that Incyte elects to co-develop," it added.
baricitinib trial details
The Phase IIb randomised double-blind, placebo-controlled, dose-ranging study, known as JADA, involved a total of 301 patients with active RA on stable doses of methotrexate. Patients were randomised to receive either placebo or one of four once-daily doses of baricitinib (1mg, 2mg, 4mg or 8mg) for 12 weeks.
In addition to the primary endpoint, the companies reported that a statistically significant difference in response for the secondary endpoints, ACR20, ACR50 and ACR70, were observed with the 1 mg, 4 mg and 8 mg dose groups compared with placebo.
The 8, 4, 2 and 1mg doses gave a 78% (p < 0.001),="" 75%="" (p="">< 0.001),="" 54%="" (not="" significant)="" and="" 57%="" (p="">< 0.05)="" improvement="" in="" acr20="" respectively,="" compared="" with="" 41%="" with="" placebo.="">
On ACR50, the 8, 4, 2, and 1mg doses led to a 40% (p < 0.001),="" 35%="" (p="">< 0.001),="" 17%="" (not="" significant)="" and="" 31%="" (p="">< 0.05)="" improvement="" respectively="" versus="" 10%="" with="">
For the ACR70 the 8, 4, 2, and 1mg doses produced a 20%, (p < 0.001),="" 23%="" (p="">< 0.001),="" 8%="" (not="" significant)="" and="" 12%="" (p="">< 0.05)="" improvement="" respectively,="" compared="" with2%="" with="">
The most common treatment-emergent adverse event class was infections, with a similar rate observed among patients in the placebo group (12%) and patients receiving baricitinib (14%). No deaths or opportunistic infections occurred in the active treatment groups.
There were seven serious adverse events reported in six patients (two events in the placebo group, four in the 2mg group and one in the 8mg group). Dose-dependent changes in laboratory tests (haemoglobin, neutrophil, serum creatinine, LDL and HDL) were observed, with greater changes being observed in the 8mg baricitinib group.