While investors await an opt-in decision from partner Abbvie Inc. following 24-week data expected later this year, executives of Galapagos NV said they are prepared to move forward into phase III one way or another after disclosing what they called "really impressive data" from the first 12 weeks of the phase IIb DARWIN 1 trial testing JAK1 inhibitor filgotinib in rheumatoid arthritis (RA).

Results reported from the 594 patients with moderate to severe RA on a background therapy of methotrexate showed that treatment with filgotinib (formerly GLPG0634) achieved the primary endpoint of statistically significant improvement in ACR20 score vs. placebo after 12 weeks in the two highest dosing cohorts. Specifically, 69 percent of the once-daily 200-mg group achieved ACR20, while 80 percent of the twice-daily 100-mg group hit ACR20, both compared to 45 percent in the placebo group (p < 0.05 and p < 0.001, respectively).

While those data points ticked the box for the primary endpoint, the results from the more stringent ACR50 and ACR70 scores could help distinguish Galapagos' small molecule in the increasingly competitive oral RA therapy space and the already-well-entrenched intravenous RA anti-TNF-alpha drugs.

In RA patient surveys, fewer than 50 percent of patients reach ACR50 on current therapies, said Piet Wigerinck, Galapagos' chief scientific officer. "So we're really looking for treatment to bring a higher level of efficacy," while offering greater safety and convenient oral dosing.

"How high is the bar for a novel drug?" he asked during an investor call to disclose the data. "It's kind of a golden 60-40-20 rule." He explained that Galapagos aimed for efficacy of at least 60 percent for ACR20, at least 40 percent for ACR40 and at least 20 percent for ACR70. "You really need to be there to be in the game."

By those criteria, filgotinib so far stacks up well. The two highest dose groups hit above 40 percent for ACR50 in two dose groups (55 percent for the 100 mg twice daily group, p < 0.001; and 43 percent for the 200 mg once daily group, p < 0.001), while the 100 mg once daily group came close at 39 percent (p < 0.01).

Reaching 55 percent for ACR50 is "really impressive," Wigerinck said, calling it "one of the highest scores ever."

Three dose groups had at least 20 percent of patients achieve ACR70, the two highest reaching statistical significance: 31 percent for the 100 mg twice daily group (p < 0.01); 24 percent for the 200 mg once daily group (p < 0.05); and 20 percent for the 100 mg once daily group. The 50 mg twice daily group came close, with 19 percent of patients hitting ACR70.

Galapagos presented comparator 12-week data. Anti-TNF-alpha therapy Humira (adalimumab), for example, had more than 60 percent of patients achieve ACR20, but it fell slightly short of the 40 percent marker for ACR50 and well short – not even reaching 10 percent – of the ACR70 goal. Pfizer Inc.'s Xeljanz (tofacitinib), which was lauded as the first oral disease-modifying anti-rheumatic drug when it won early approval in late 2012, missed all three markers, showing only a 50 percent ACR20 rate. Xeljanz's efficacy – largely considered no better than the anti-TNF drugs – plus safety issues that led the EMA to reject Pfizer's application has kept the product from capturing the market share originally projected. (See BioWorld Today, Nov. 8, 2012.)

Likely the largest competitor to Galapagos' filgotinib will be baricitinib, a phase III-stage JAK inhibitor developed by Incyte Inc. and partnered with Eli Lilly and Co. That drug yielded positive data last year in the first of four late-stage III trials. According to 12-week comparator data from the KEYSTONE trial reported last year, more than 70 percent of baricitinib-treated RA patients reached ACR20 and more than 20 percent reached ACR70. The ACR50 rate fell just below 40 percent. (See BioWorld Today, Dec. 12, 2014.)

More data are coming, with the 24-week results expected in July, but so far "all the data we have are positive," Wigerinck said.

News sent shares of the Mechelen, Belgium-based firm (BRUSSELS:GPLG) up €4.21 (US$4.50), or 17 percent, to close Wednesday at €29.

ON THE TRACK OF JAK1

Galapagos began working on the product that would emerge as filgotinib about a decade ago. It was hardly the only firm interested in targeting JAK, or Janus kinase, but from early days the company had clear thoughts regarding selectivity, preferring to focus solely on inhibiting JAK1 rather than a pan-JAK approach as with Xeljanz.

"According to us, quite honestly, there is no role for JAK2 inhibition in the management of RA," Wigerinck explained, "because JAK2 is essential for the normal functioning of EPO and other growth factors which are important for maintaining and restoring the health of patients under treatment. That's why we've been pushing so hard on the JAK1 vs. JAK2 selectivity."

Galapagos, which has "stayed on the track of JAK1," is convinced that "selectivity is key for long-term safety," he added.

The 12-week data from DARWIN 1 showed a very low rate of serious adverse events – about 1.3 percent overall, which Jefferies analysts called "negligible" – and the trial had a discontinuation rate of 1.7 percent for safety reasons and a 6.4 percent discontinuation rate overall. Typical discontinuation rates in RA trials at 12 weeks are between 10 percent and 20 percent, Wigerinck said.

In addition, there were no discontinuations due to anemia or neutropenia, and patients' hemoglobin levels actually increased during the trial (up to 0.4 g/dL, or 3.7 percent increase from baseline). More than 90 percent of patients remained within normal serum alanine transaminase levels, while lipids, including HDL and LDL, "increased in a well-balanced way," with the largest increase in HDL leading to a an improved cholesterol over HDL ratio, based on the atherogenic index, when filgotinib was given at 200 mg per day, Wigerinck said.

The company reported no statistically relevant differences between the once-daily and twice-daily dosing regimens. And all treatment cohorts separated from placebo within one or two weeks of treatment, suggesting a rapid onset of activity.

All those results indicate a far superior safety profile vs. Xeljanz. More detailed data will be needed on Incyte's baricitinib, which, though an inhibitor of both JAK1 and JAK2, showed a promising safety profile based on phase III data that have been disclosed. (See BioWorld Today, Jan. 13, 2015.)

Galapagos is also studying filgotinib as a monotherapy in RA patients in the ongoing DARWIN 2 study, with 12-week data expected from that trial in a couple of weeks and 24-week data expected in August.

WITH OR WITHOUT ABBVIE

Once the final data from those studies read out, it will be up to Abbvie to decide whether it wants to take the drug further. Under the companies' 2012 alliance, Galapagos earned a company-transforming $150 million up-front payment and could pick up $200 million more if Abbvie elects to license the drug in RA – another $50 million could come if a phase II study testing filgotinib in Crohn's disease also yields positive data. (See BioWorld Today, March 1, 2012.)

The DARWIN 1 data so far "make a compelling case for Abbvie's opt-in decision," wrote Jefferies analyst Peter Welford, expecting that decision around late September.

That move would put North Chicago-based Abbvie in charge of running phase III studies and responsible for commercialization, offering another potential advantage to filgotinib given the big pharma's experience selling Humira, which became the first-ever biologic to hit top-selling drug status. Under the companies' deal, Galapagos has retained co-promotion rights in Belgium, the Netherlands and Luxembourg.

It also would give Abbvie a product to replace Humira, for which a patent expiration is looming, starting in 2016.

Still, Abbvie is in midstage testing with its own JAK1 inhibitor, ABT-494, which, as Jefferies' Welford acknowledged, "offers the pharma potentially better economics, with its albeit phase II dose-finding trials likely to read out" by the fourth quarter of this year in RA and in mid-2018 in Crohn's disease.

When asked on the call, Galapagos CEO Onno van de Stolpe said development of filgotinib will continue either way.

"If the data are good, personally, I'm confident that Abbvie will license the molecule," he said. "If they decide for whatever reason not to license the molecule, I think it would be very beneficial for Galapagos.

"We believe we have a potential drug here, and we will move this forward, Abbvie licensing this or not," he added. "It's not a crucial aspect of the filgotinib story."

And, while analysts view filgotinib as the chief value driver for Galapagos, van de Stolpe maintained that his firm has many other programs in development, including a cystic fibrosis collaboration, also with Abbvie, involving potentiator and combination therapies that will yield "a lot of data points" by the end of this year. (See BioWorld Today, Sept. 25, 2013.)

The company also has two fully owned phase II-stage programs in inflammatory bowel disease and idiopathic pulmonary fibrosis and has a "pipeline of 20 programs in discovery, all backed by a strong financial position [and] important partnerships," van de Stolpe said.

Galapagos ended 2014 with about €198 million, including €11 million in restricted cash. It added another €5.8 million through warrant exercises earlier this year.