Integrin inhibitors go with the gutTakeda has filed for European approval of vedolizumab in inflammatory bowel disease, potentially providing new hope for spurned integrin inhibitors.

David Holmes

Patients have waited years for a new inflammatory bowel disease (IBD) drug, and now three integrin inhibitors are coming along at once. In March, Takeda filed vedolizumab for approval in the European Union to treat patients with ulcerative colitis and Crohn’s disease, and AstraZeneca and Amgen’s AMG181 and Roche’s etrolizumab are in pursuit in Phase II trials. Success for these monoclonal antibodies (mAbs) could at last realize some of the latent potential of a family of drugs that has been blighted by safety issues.

For years, millions of patients worldwide with the IBD subtypes Crohn’s disease and ulcerative colitis have been treated in the same way, despite a growing appreciation that there is wide variation in how individuals respond to treatment. Patients with mild disease are usually advised to alter their diet, and flare-ups are treated with antidiarrhoeal drugs and short courses of corticosteroids. More severe symptoms are treated with immunosuppressants such as cyclosporine, and tumour necrosis factor (TNF)-specific mAbs such as infliximab are held in reserve for patients who become refractory to treatment. TNF-specific mAbs are effective in around two-thirds of patients with Crohn’s disease and/or ulcerative colitis but are associated with onerous side effects, and many patients become refractory to treatment over time.

To address the need for more effective IBD drugs, several companies have turned their attention to integrins — transmembrane receptors, composed of α and β subunits, that mediate the attachment of cells to the extracellular matrix and are involved in a wide range of processes including immune surveillance and cell migration. Integrins containing the α4 subunit seemed particularly promising for the treatment of IBD because of their role in the migration of memory T lymphocytes to areas of inflammation. But early optimism proved to be short-lived.

“The discovery of integrins led to the belief that we were going to have a new generation of drugs with significant potential in many different diseases. However, over 20 years later, we are still waiting,” says Dermot Cox, a specialist in molecular and cellular therapeutics at the Royal College of Surgeons in Ireland, based in Dublin. The fundamental problem, says Cox, is that individual integrins are involved in so many physiological processes. Consequently, their inhibition can give rise to unpredictable and severe adverse events, as in the case of the first α4 integrin-specific mAb to gain approval: Biogen Idec’s natalizumab.

Natalizumab, which has found success as a multiple sclerosis drug, is also approved in the United States for Crohn’s disease in patients who are refractory to standard therapy. The agent prevents memory T lymphocytes from migrating to the bowel and thus reduces inflammation. But because it also prevents T lymphocytes from entering the brain (providing activity in the multiple sclerosis indication), it increases the risk of a rare and potentially fatal viral brain infection — progressive multifocal leukoencephalopathy (PML). As a result, it is rarely prescribed to patients with Crohn’s disease, and the European Medicines Agency rejected the drug for use in Europe in this IBD patient population.

Beyond α4β1The lesson learned from the natalizumab experience was that anti-integrin IBD treatments need to preferentially reduce the migration of T lymphocytes to the gut rather

than to the brain. The discovery that there are two types of α4 integrin gave rise to the hope that this might be possible. α4β1 integrin mediates the migration of T lymphocytes into the central nervous system, bone marrow and skin via adhesion to its ligand vascular cell adhesion molecule 1 (VCAM1), whereas α4β7 integrin preferentially mediates the migration of T lymphocytes into the gastrointestinal tract via adhesion to the ligand mucosal addressin cell adhesion molecule 1 (MADCAM1; the target of Pfizer’s Phase II IBD candidate PF-00547659).

AMG181, etrolizumab and vedolizumab all specifically target α4β7 integrin, and so far the results they have generated have been encouraging. Takeda filed vedolizumab in Europe on the basis of four Phase III trials in 3,000 patients. GEMINI I, in patients with moderate to severe ulcerative colitis who had failed at least one prior therapy, hit its primary end point: 47% of vedolizumab-treated patients had a clinical response at 6 weeks, compared with 25% of placebo-treated patients. The GEMINI II trial in patients with Crohn’s disease who had prior treatment with corticosteroids, purine antimetabolites and/or TNF antagonists, also hit its primary end points. Patients were significantly more likely to be in remission at 52 weeks when treated with vedolizumab than those who were treated with placebo, although there was no statistically significant difference in durable remission. Data from the other ongoing trials were not yet available as Nature Reviews Drug Discovery went to press.

As yet, there have been no signs of PML in patients treated with α4β7 integrin-specific mAbs. Joseph Berger, of the Department of Neurology at the University of Kentucky Medical Center in Lexington, USA, has been involved in the PML surveillance programmes of both AMG181 and vedolizumab, and predicts that “we will not see PML with α4β7 integrin inhibitors”. This is an exciting time for the gastrointestinal world, says Berger. “There are so many refractory patients who have been on virtually everything, and some of these currently available drugs have fairly significant side effects. I can’t tell you whether these [α4β7 integrins] will be blockbusters, but I think they’ll be a useful addition.”

Others, including Cox, remain to be convinced. “The assumption here is that PML is due to inhibition of α4β1 integrin, or at least that the lack of inhibition of α4β1 integrin provides some protection.

I can’t tell you whether these [α4β7 integrins] will be blockbusters, but I think they’ll be a useful addition.

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We don’t know whether this is true,” says Cox. Genentech withdrew its psoriasis drug efalizumab, which targets αL integrin, after the mAb was linked to PML, he points out. And even though PML has not yet been identified in the trials of α4β7 integrin antagonists, it is a rare adverse event that occurs in only about 1 in 1,000 patients in a time-dependent manner (that is, the longer a patient is on the drug, the more likely he or she is to develop PML). “We will only know if PML is associated with vedolizumab after a large Phase IV study has been carried out,” argues Cox.

Whether or not success for vedolizumab will result in renewed interest in integrins in general remains to be seen. The more fundamental problem of integrin involvement in so many disparate biological processes means the spectre of adverse events is ever present. This has been further complicated by companies rushing drugs such as αIIbβ3 antagonists, including xemilofiban and orbofiban, into Phase III trials without understanding their basic pharmacology, says Cox. “Companies were badly stung by that, and it has made them very reluctant to proceed further.” A positive outcome for the α4β7 class might help them conquer their reticence.

Although consensus worldwide sales forecasts for Takeda’s vedolizumab suggest

that the drug could bring in US$1 billion per year by 2018, the α4β7 integrin inhibitors — if approved — will have market hurdles to overcome. They will need to show better efficacy than current anti-TNF agents, and need to be priced competitively, to avoid being reserved as a last-line option. They may also have to contend with a suite of non-integrin-based IBD therapies that are also in late-stage development. Johnson & Johnson’s interleukin-12 (IL-12)- and IL-23-targeted mAb ustekinumab and GlaxoSmithKline’s CC-chemokine receptor 9 inhibitor vercirnon are in pivotal trials for Crohn’s disease, and Pfizer’s Janus kinase inhibitor tofacitinib is in pivotal trials for ulcerative colitis. Until these factors are ironed out, speculation on the ultimate success or failure of α4β7 inhibitors will remain largely the province of gut feeling.

We will only know if PML is associated with vedolizumab after a large Phase IV study has been carried out.

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