番茄社区

The JAK-1 inhibitor upadacitinib (Rinvoq) was superior to placebo in inducing endoscopic remission in refractory Crohn's disease (CD) patients, the phase II randomized CELEST trial showed.

Julián Panés, MD, PhD, of Hospital Clinic Barcelona in Spain, and colleagues reported that while no placebo patients achieved endoscopic remission, patients across different treatment dose groups did so as follows:

• 10% (P<0.1 vs placebo)
• 8% (P<0.1 vs placebo)
• 8%, 22% (P<0.01 vs placebo)
• 14% (P<0.05 vs placebo)

The study, published online in , also found rates of clinical remission as follows among dosage groups:

• 13% of those receiving 3 mg of upadacitinib twice daily
• 27% of those receiving 6 mg of upadacitinib twice daily
• 11% of those receiving 12 mg twice daily
• 22% of those receiving 24 mg twice daily
• 14% of those receiving 24 mg once daily
• 11% of those patients receiving placebo

Furthermore, maintenance treatment over 36 weeks after an initial 16-week induction period was associated with continued clinical and endoscopic responses as well as decreases in markers of inflammation in patients who responded to the induction regimen.

Although efficacy persisted through week 52, during induction upadacitinib recipients had higher rates of infections and serious infections compared with the placebo group. Moreover, patients in the twice-daily 12-mg and 24-mg upadacitinib groups had significant increases in total, high-density, and low-density lipoprotein cholesterol compared with placebo recipients.

Over the 52 weeks of the study, the safety profile was consistent with that in rheumatoid arthritis (RA) patients, the researchers noted, adding that upadacitinib's benefit-risk profile supports further development for treatment of CD.

Last year, upadacitinib received FDA approval for refractory RA and showed improved patient-reported outcomes in RA.

Study Details

The current 52-week, double-blind, dose-ranging study, conducted from 2015 through 2017, analyzed CD patients ages 18 to 75 with an inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Across all dosage groups, about 57% of the participants were female, and mean age was 40 (range of 20-76).

At baseline, patients had had CD for at least 3 months (median 9.6 years) and had active disease, with an CD Activity Index of 220-450, average daily liquid/very soft stool frequency of at least 2.5, or a daily abdominal pain level of at least 2. Mucosa inflammation was gauged according to a Simplified Endoscopic Score for CD of 6 or higher (or at least 4 for those with isolated ileal disease).

The trial was conducted at 93 sites in 19 countries including the U.S., Israel, Australia, New Zealand, and Europe, and included a 16-week placebo-controlled induction period followed by a 36-week, double-blind maintenance period.

Participants were randomized in the 16-week induction phase to placebo (37 patients) or upadacitinib as follows: daily 3 mg (39 patients), 6 mg (37 patients), or 12 mg (36 patients); or to 24 mg twice daily (36 patients) or 24 mg once daily (35 patients).

After 4 months, 180 of the participants were re-randomized to have 36 weeks of double-blind maintenance with different doses of the drug.

"The results of the induction period showed that the 3-mg, 12-mg, and 24-mg BID and 24-mg QD upadacitinib doses were superior to placebo for endoscopic remission with significant dose-response relationships, and separately the 6-mg BID dose was superior to placebo for clinical remission 1.5/1.0 at the P<0.10 level," the investigators wrote.

In addition, they said, maintenance treatment over 36 weeks was associated with continued clinical and endoscopic responses as well as decreases in markers of inflammation in responders to the induction regimen.

Asked for his perspective, Siddharth I. Singh, MD, MS, of the University of California San Diego, who was not involved with the study, said: "This new mechanism of action surely has patients and providers excited. This trial provides exciting results about the potential of an oral JAK1 inhibitor in the treatment of refractory Crohn's disease."

In addition, Singh told 番茄社区, although most patients had not responded to conventional biologic therapy, a significant proportion achieved robust endoscopic and clinical remission endpoints with induction therapy. "This trial also used novel patient-reported outcome measures for primary assessment rather than conventional clinical disease activity indices, in line with the FDA's requirements for new therapies," he said.

Data from phase III trials of this drug are eagerly awaited, Singh said. "Optimal dosage remains to be seen, given some differences in efficacy for achieving clinical versus endoscopic endpoints. Additionally, the observation of intestinal perforation in two patients was somewhat higher than conventionally expected, and needs to be clarified in larger phase III trials."

Study limitations, Panés and co-authors said, included that although the sample size was sufficient to assess dose-response relationships for efficacy endpoints in the induction period, it was inadequate to fully evaluate some efficacy parameters between individual upadacitinib doses and placebo or to characterize the safety of upadacitinib. Another limitation was the lack of placebo control during the maintenance period and the small sample sizes, particularly for the 6-mg twice-daily dose group.

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