G&H Are there any promising anti-integrin drugs in the pipeline?
WS Etrolizumab (Genentech) is an interesting drug in the same general class as vedolizumab that is currently being tested in phase 3 trials in patients with ulcerative colitis as well as in patients with Crohn’s disease. Like vedolizumab, etrolizumab blocks alpha-4 beta-7, but it also blocks alpha-E beta-7, which affects lymphocyte trafficking to the skin and to the gut. Blocking alpha-4 beta-1 can lead to progressive multifocal leukoencephalopathy (PML), but both etrolizumab and vedolizumab do not impact lymphocyte trafficking to the brain, which is mediated vs alpha-4 beta-1 integrins. Thus, these 2 drugs are seen as brain-sparing and are not associated with PML.
G&H Which sphingosine-1-phosphate receptor modulators are currently under clinical investigation?
WS Sphingosine-1-phosphate (S1P1) receptor modulators lead to internalization of the S1P1 receptor, which is located on surface C-C chemokine receptor type 7–positive lymphocytes, resulting in an inability for these lymphocytes to follow the S1P1 gradient on the lymphatic endothelium, thus functionally trapping the lymphocytes in lymph nodes until they die.
One promising S1P1 receptor modulator is RPC1063, or ozanimod (Celgene). This drug was shown to be effective in a phase 2 trial in ulcerative colitis and is currently being tested in a phase 3 trial in ulcerative colitis and a phase 2 trial in Crohn’s disease. There are 2 other S1P1 modulators in development for patients with inflammatory bowel disease: APD334 (Arena Pharmaceuticals) and MT-1303 (Biogen Idec).
G&H Are there any promising agents that block interleukin-12 and/or -23?
WS Anti-P40 and anti-P19 antibodies block signaling through the Th1 and Th17 pathways. Ustekinumab (Stelara, Janssen) is an anti-P40 antibody that blocks the P40 subunit of interleukin (IL)-12 and -23. This agent is currently approved by the FDA for psoriasis and psoriatic arthritis and has finished phase 3 testing in Crohn’s disease. Clinical trial data have recently been presented in abstract form showing that ustekinumab is effective for induction of remission in patients with inflammatory bowel disease who are failing conventional therapy (not anti-TNF drugs) and separately for induction of remission in patients who have failed anti-TNF drugs. A maintenance trial mixed these 2 populations and showed that the drug is effective for maintaining remission for over a year. Ustekinumab is currently under review for FDA approval, and a decision is expected in the third quarter of this year.
A number of other drugs are being developed that have anti–IL-23 antibodies directed toward P19. LY-2525623 (Lilly) is being evaluated in a phase 2 trial in ulcerative colitis. Boehringer Ingelheim just partnered with AbbVie to develop BI 655066, an anti–IL-12 antibody that has been tested in Crohn’s disease and has positive phase 2 data. AstraZeneca MedImmune, in partnership with Amgen, has an anti-P19 antibody drug called AMG 139/MEDI2070. A phase 2 study in Crohn’s disease showed that this drug was able to achieve clinical remission and improve blood and stool biomarkers. Janssen is developing a drug for psoriasis comprised of an anti-P19 antibody to IL-23 (guselkumab) that could be tested in Crohn’s disease in the future.
G&H Which Janus kinase inhibitors show promise?
WS Janus kinase (JAK) inhibitors block a variety of proinflammatory cytokines by blocking the JAK/Signal Transducer and Activator of Transcription signaling pathway. Tofacitinib (Xeljanz, Pfizer), which is currently approved by the FDA for rheumatoid arthritis, is a small molecule that blocks predominantly JAK1 and JAK3 receptors but also has some JAK2 effects at higher doses. A phase 2 study showed that the drug was highly effective in ulcerative colitis, and two phase 3 studies recently showed that the drug was effective for inducing response, remission, and mucosal healing, both in patients with moderate to severe ulcerative colitis who are failing anti-TNF drugs as well as in patients who are naive to anti-TNF therapy. A phase 3 maintenance trial will be completed in the third quarter of this year, which means that tofacitinib may be sent for FDA review sometime next year.
In addition, ABT-494 (AbbVie), a JAK inhibitor that is more JAK1-selective, is being evaluated for both ulcerative colitis and Crohn’s disease. The JAK inhibitor filgotinib (GLPG0634, Galapagos and Gilead) has positive phase 2 data in Crohn’s disease and will undergo phase 3 testing in ulcerative colitis and Crohn’s disease.
G&H Are there any other promising inflammatory bowel disease agents in the pipeline?
WS A metalloproteinase-9 antibody (GS-5745, Gilead) showed some evidence of efficacy in a phase 1A study in ulcerative colitis and will be undergoing phase 2/3 trials in ulcerative colitis and Crohn’s disease.
The oral SMAD7 antisense oligonucleotide drug called mongersen (GED-0301, Celgene) showed significant evidence of efficacy for inducing clinical remission in Crohn’s disease. It is now in another phase 2 trial and will soon be in a phase 3 trial for Crohn’s disease.
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