Gilead Sciences Inc. and partner Galapagos NV touched off a round of Wall Street chin-scratching as they disclosed phase IIb/III data showing that JAK1 inhibitor filgotinib in ulcerative colitis (UC) at the 200-mg dose achieved all primary endpoints in the study called Selection. The oral, once-daily candidate aced clinical remission (CR) at week 10 and maintained the positive result at week 58 in a significantly higher proportion of patients vs. placebo.
But there was a caveat. At the 100-mg dose in the trial, the hoped-for blockbuster fell short of statistically significant CR at week 10, while succeeding in the maintenance part of the experiment. As pundits mulled the candidate’s odds against marketed JAK therapies Xeljanz (tofacitinib) from New York-based Pfizer Inc. and Rinvoq (upadacitinib) from Abbvie Inc., of North Chicago, the findings were enough to nick shares of Galapagos (NASDAQ:GLPG) by $17.17, or 7.7%, for a closing price of $204.10. Gilead’s stock (NASDAQ:GILD) dipped only slightly, ending the day at $73.50, down 39 cents.
“The devil's in the details, none of which are currently available, so let the speculation begin,” as Wainwright analyst Debjit Chattopadhyay put it. J.P. Morgan’s Cory Kasimov quipped that the data, though headlined as positive, brought “not exactly the ‘filgood’ moment we were expecting.” Phil Nadeau, of Cowen, drily pointed out that the 10.8% placebo-adjusted increase in CR at week 10 is “comparable” to results generated by Xeljanz and below those turned up with Rinvoq, hence “likely on the lower end of investor expectations.”
The Selection study tested filgotinib in 1,348 biologic-naïve or biologic-experienced adult patients with moderately to severely active UC. CR was defined as an endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and ≥ 1-point decrease in stool frequency from baseline to tally a subscore of 0 or 1. Among the biologic-naïve cohort (cohort A induction trial; n=659), 52% of patients had a baseline Mayo Clinic Score (MCS) of nine or higher. In the biologically experienced cohort (cohort B induction trial; n=689), 74% of patients had a baseline MCS of nine or higher, and 51% were previously treated with two different classes of biologics (TNF-alpha antagonists and an integrin receptor antagonist).
Among the biologic-naïve patients, those achieving CR at week 10 when treated with filgotinib 200 mg was 26.1% (p=0.0157) compared with 15.3% on placebo. Among biologic-experienced patients, a statistically significant higher proportion of patients achieved CR at week 10 when treated with filgotinib 200 mg (11.5%, p=0.0103) compared with placebo (4.2%).
Patients who reached clinical response or remission after 10 weeks of treatment with filgotinib 100 mg or 200 mg were re-randomized to their induction dose of filgotinib or placebo in a 2-to-1 ratio and treated through week 58 (maintenance trial, n=558). Here, both doses of filgotinib achieved the primary endpoint. At week 58, 37.2% of biologic-naïve and biologic-experienced patients receiving filgotinib 200 mg hit CR, compared with 11.2% treated with placebo (p˂0.0001). Of patients receiving filgotinib 100 mg, 23.8% achieved CR at week 58, compared with 13.5% treated with placebo (p=0.0420).
In the induction trial of biologic-naïve patients, the incidence of serious adverse events (SAEs) was similar across treatment groups (200 mg: 1.2%; 100 mg: 4.7%; placebo: 2.9%). In the induction trial with biologic-experienced patients, the incidence of SAEs was also similar across treatment groups (200 mg: 7.3%; 100 mg: 5.3%; placebo: 6.3%). There were no deaths in either induction cohort.
In the maintenance trial, 4.5% of patients treated with filgotinib 200 mg experienced an SAE, compared with none for their corresponding placebo; 4.5% of patients treated with filgotinib 100 mg experienced an SAE, compared with 7.7% for their corresponding placebo.
Praying Manta’s men are OK
Rates of serious infections, herpes zoster (HZ), venous thrombosis (VT), pulmonary embolism (PE) and gastrointestinal perforation were low in Selection and comparable across treatment groups in both the induction and maintenance phases of the study. Two deaths were observed in the filgotinib 200-mg treatment group in the maintenance trial. One with pre-existing asthma died due to asthma exacerbation; the second with pre-existing atherosclerosis died due to left ventricular heart failure according to the autopsy report. Neither death was deemed related to filgotinib by the investigator.
In his report, Chattopadhyay complained that no exact data were available on HZ infection rates, which bedeviled Xeljanz trials. “While the statistically significant benefit with the 200-mg dose is a welcome positive, comparisons with other JAK inhibitors remains hard, as the enrollment into the Selection trial was probably skewed to more advanced patients in the 200-mg dose,” he wrote. “We think an absolute comparison may be premature, with no clarity currently provided on percent of patients on corticosteroids, and baseline [C-reactive protein], which could swing interpretations of efficacy.”
Kasimov called the findings “mixed at best,” adding that while “the positive result at the 200-mg dose is encouraging, a miss during the induction phase for the 100-mg [dose] is a disappointment, and we don’t quite know what to make of the high placebo rate (which was also observed in rheumatoid arthritis [RA], relative to competitors). The safety profile (at least what was disclosed) appears fine overall, but we did not get a lot of details around PE and VT rates,” he said in his report. The latter two problems, which constitute a general concern for the class, matter more in the context of the imperfect efficacy results that just rolled out. “Ultimately, we find this hard to compare to other JAK inhibitors and will look to full data to better understand how/if filgotinib’s clinical profile is differentiated,” Kasimov said.
Foster City, Calif.-based Gilead and Galapagos, of Mechelen, Belgium, joined forces in the summer of 2019, the latter banking $3.95 billion up front in cash plus another $1.1 billion in equity, in return for which Gilead gained an option to ex-European rights on everything emanating from the Belgium firm's clinical and preclinical pipeline.
The Selection trial is one of multiple clinical studies of filgotinib in a range of inflammatory conditions, including the Finch phase III program in RA, the Diversity phase III study in Crohn’s disease (CD), the phase III Penguin trials in psoriatic arthritis (PA), and the phase II studies in uveitis and in small bowel and fistulizing Crohn’s disease. During the May 8 conference call on earnings, Galapagos’ chief medical officer, Walid Abi-Saab, said that, based on efforts in CD, RA, PA and ankylosing spondylitis, he was optimistic about UC. “You would expect that filgotinib is going to be performing at the top line in all of these, from an efficacy perspective compared to the other JAKs, particularly [Rinvoq] and perhaps a bit better than [Xeljanz],” he said. Xeljanz gained its first approval, in RA, in late 2012; UC was added to the label almost exactly two years ago. Rinvoq was cleared by U.S. regulators for RA in August 2019. It’s undergoing late-stage research in UC and other indications.
Investors are watching next for data from the phase II study called Manta, a randomized, double-blind, placebo-controlled experiment to evaluate the testicular safety of filgotinib in adults with moderately to severely active inflammatory bowel disease. The trial is designed to dispel frets about preclinical findings that suggest a negative effect on semen parameters in younger males. If the side effect is real in humans, the drug could end up with a black-box warning or contraindication for young men – a segment of the UC population that Wainwright’s Chattopadhyay characterized as “non-trivial.” Manta’s outcomes would only affect the 200-mg dose, since 100 mg was not expected to cause reproductive effects. Given the latest miss with 100 mg, the stakes for filgotinib in Manta stand even higher. The 250-patient trial started in July 2017 and is still recruiting.
Gilead is expected to file the Selection data with the FDA in the second half of 2020. The prospect of a black box – whether for semen side effects, thromboembolic risk or concerns about infection – remains the big worry for investors, since that could hamstring filgotinib in the race with more potent JAKs such as Rinvoq. On the other hand, if Gilead/Galapagos can dodge that bullet, the drug might be used in earlier lines of disease, conferring an important advantage. SVB Leerink analyst Geoffrey Porges in his report called filgotinib the potential “Goldilocks of JAKs.” He predicted approval in 2021 and said the drug could generate about $315 million in global UC sales.