Conference Coverage

Many drugs in the pipeline for IBD treatment


 

EXPERT ANALYSIS FROM THE CROHN’S & COLITIS CONGRESS

A wide variety of drugs are in the pipeline for both ulcerative colitis (UC) and Crohn’s disease patients who are failing currently available therapies.

“The challenge for all of us is to integrate the right drugs for the right patients,” William J. Sandborn, MD, said at the annual congress of the Crohn’s & Colitis Foundation, partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

Dr. William J. Sandborn of the University of California San Diego
Dr. William J. Sandborn
Dr. Sandborn, professor and chief of the division of gastroenterology at the University of California, San Diego, began his presentation by highlighting anti-integrin therapies for inflammatory bowel disease (IBD) treatment. These leukocyte membrane glycoproteins target beta1 and beta7 subunits. They interact with endothelial ligands VCAM-1, fibronectin, and MadCAM-1, and mediate leukocyte adhesion and trafficking. Approved anti-integrin therapies to date include natalizumab and vedolizumab, while investigational therapies include etrolizumab, PF-00547,659, abrilumab, and AJM 300.

In a phase 2 study of etrolizumab as induction therapy for moderate to severe UC, Séverine Vermeire, MD, Dr. Sandborn, and associates randomized 124 patients to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2 or a 420-mg loading dose at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo (The Lancet 2014 348;309-18). They found that etrolizumab was more likely to lead to clinical remission at week 10 than was placebo, especially at the 100-mg dose. Meanwhile, a more recent study of the anti-MAdCAM antibody PF-00547659 in patients with moderate to severe ulcerative colitis found that it was better than placebo for induction of remission (The Lancet 2017;390:135-144). Investigators for the trial, known as TURANDOT, found that the greatest clinical effects were observed with the 22.5-mg and 75-mg doses. “This is now being taken forward in phase 3 trials by Shire,” Dr. Sandborn said.

The anti-interleukin 12/23 antibody (p40) ustekinumab is being investigated for efficacy in UC, while anti-interleukin 23 (p19) antibodies being studied include brazikumab (MEDI2070), risankizumab (BI 6555066), geslekumab, mirikizumab (LY3074828), and tildrakizumab (MK 3222). In 2015, Janssen launched NCT02407236, with the aim of evaluating the effectiveness and safety of continuing ustekinumab as a subcutaneous (injection) maintenance therapy in patients with moderately to severely active UC who have demonstrated a clinical response to an induction treatment with intravenous ustekinumab. The estimated primary completion date is April 12, 2018. Meanwhile, a phase 2a trial of 119 patients with moderate to severe Crohn’s disease who had failed treatment with tumor necrosis factor (TNF) antagonists showed that treatment with MEDI2070 was associated with clinical improvement after 8 and 24 weeks of therapy (Gastroenterol 2017;153:77-86). The investigators also found that patients with baseline serum IL-22 concentrations above the median threshold concentration of 15.6 pg/mL treated with MEDI2070 had higher rates of clinical response and remission, compared with those with baseline concentrations below this threshold. According to Dr. Sandborn, who was not involved in the study, these results provide support for further research on the value of IL-22 serum concentrations to predict response to MEDI2070. “It’s a small study and is hypothesis generating,” he said. “This will need to be confirmed in subsequent trials.”


In a short-term study of 121 patients with active Crohn’s disease, Brian G. Feagan, MD, Dr. Sandborn, and associates found that risankizumab was more effective than placebo for inducing clinical remission, particularly at the 600-mg dose, compared with the 200-mg dose (Lancet 2017;389:1699-709). The researchers also observed significant differences in endoscopic remission among patients on the study drug, compared with those on placebo (17% vs. 3%; P = .0015) as well as endoscopic response (32% vs. 13%; P = .0104). The trial provides further evidence that selective blockade of interleukin 23 via inhibition of p19 might be a viable therapeutic approach in Crohn’s disease.

Janus kinase (JAK) inhibitors under investigation for Crohn’s disease include tofacitinib, filgotinib, upadacitinib, baricitinib, and TD-1473. In the OCTAVE Induction 1 trial led by Dr. Sandborn, 18.5% of the patients in the tofacitinib group achieved remission at 8 weeks, compared with 8.2% in the placebo group (P = .007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% vs. 3.6% (P less than .001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group vs. 11.1% in the placebo group (P less than 0.001 for both comparisons with placebo; N Engl J Med. 2017;376:1723-36). “In subgroup analyses, it looks like the 10-mg dose is more effective for maintenance in patients who previously received anti-TNF therapy,” said Dr. Sandborn, who also directs the UCSD IBD Center. “All secondary outcomes were positive. You don’t see that very often. It tells you that this is a really effective therapy. It’s currently being reviewed by the FDA.”

Meanwhile, a phase 2 trial found that a higher percentage of patients with mild to moderate Crohn’s disease who received a 200-mg dose of filgotinib over 10 weeks achieved clinical remission, compared with those who received placebo (47% vs. 23%, respectively; P = .0077; The Lancet 2017;389:266-75). Serious treatment-emergent adverse effects occurred in 9% of the 152 patients treated with filgotinib and 3 of the 67 patients treated with placebo. According to Dr. Sandborn, filgotinib is currently in phase 3 development trials for both Crohn’s Disease and UC. At the same time, results from an unpublished study presented at the annual Digestive Disease Week in 2017 found that 16 weeks of treatment with the investigational agent upadacitinib led to modified clinical remission in 37% of patients on the 24-mg bid dose, compared with 30% of patients in the 6-mg bid dose. There was also a dose response for endoscopic response. “Based on these data, this drug is now in a phase 3 trial, so lots of JAK inhibitors are coming along,” he said.

Sphingosine-1–phosphate receptor 1 (S1P1) modulators currently under investigation include fingolimod (not studied in IBD), ozanimod, and etrasimod. “These modulators cause the S1P1 receptors that are expressed on the surface of positive lymphocytes to be eluded back into the cell, which leads to a reversible reduction in circulating lymphocytes in the blood,” Dr. Sandborn explained. In a phase 2 trial, he and his associates found that UC patients who received ozanimod at a daily dose of 1 mg had a slightly higher rate of clinical remission, compared with those who received placebo, but the study was not sufficiently powered to establish clinical efficacy or assess safety (N Engl J. Med 2016;374:1754-62).

Dr. Sandborn reported having consulting relationships with Takeda, Genentech, Pfizer, Shire, Amgen, and many other pharmaceutical companies.

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