Moving Forward in the Treatment of Crohn's Disease

RUSSELL D. COHEN, MD: Hello, and welcome to the program. Today, we will be focusing on new and promising treatment options for Crohn's disease.

I'm Dr. Russell Cohen, associate professor of medicine at the University of Chicago Medical Center. Joining me today is Dr. Edward Loftus, professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minnesota, and Dr. Scott Plevy, associate professor of medicine at the University of North Carolina School of Medicine.

Ed, you've been treating Crohn's disease for all, as we have all, and it's become apparent, in recent years, that there seem to be limitations to the therapies that are currently available to us. Can you perhaps expand upon the limitations and frustrations that you may be having with the current therapies?

EDWARD V. LOFTUS, MD: Sure, Russ. I think many of us think of treatment for Crohn's disease as a therapeutic pyramid. At the base of the pyramid are the patients with the mildly active disease and, historically, we've used either 5-aminosalicylate agents or 5-ASA agents or antibiotics for those mildly active patients. But it has become apparent, over the years, that there's actually very little evidence base for their effectiveness. They're safe medications, but, really, for Crohn's disease, they're just not that effective.

Moving up the pyramid, we typically employ corticosteroids and these are highly effective medications in the short term, but, over the long term, there's a problem of steroid dependence and all its attendant side effects, the short-term side effects, but also long-term side effects, such as osteoporosis, cataracts, hypertension, etc.

Immunosuppressives like azathioprine, mercaptopurine, methotrexate are fairly effective medications, but there's a substantial proportion of patients, probably half or more, in whom these medications either don't work or patients are intolerant to the various side effects.

In the early 1990s, we had the opportunity to use infliximab, an anti-TNF inhibitor, and we've had great success with that medication, but even infliximab has its own issues with regards to efficacy, but also in terms of safety issues. There are problems with infusion reactions and, over time, there are patients who have an attenuation of their response. They initially respond to the medication, but they gradually lose their response and that's thought to be, perhaps, related to the formation of anti-chimeric antibodies or antibodies to infliximab, if you will.

RUSSELL D. COHEN, MD: Scott, many of the new therapies we're going to be discussing today directly affect the immune system. It's very puzzling to many of us. Could you perhaps elucidate on some of the mechanisms of inflammation that we may be targeting?

SCOTT PLEVY, MD: Sure, Russ. Biologics that are currently being tested and being developed in Crohn's disease target an overactive immune system and immune pathways that specifically lead to the initiation of perpetuation of inflammation in the gut. Perhaps the concept that's familiar to most people is the idea of blocking pro-inflammatory proteins or cytokines that are made by activated cells of the immune system and we know are involved in tissue damage and inflammation. The paradigm for this is the development of infliximab which blocks the inflammatory cytokine, tumor necrosis factor or TNF. There's a host of other inflammatory cytokines that I think are going to be interesting targets over the next several years.

That's not the only way to inhibit inflammation. Some new biologic therapies that are currently being tested may look to target cell populations. In particular, immune cell populations that are involved in the inflammatory process.

One novel way of doing this is based on the concept that cells migrate through blood vessels to tissues where they exit the blood vessels and cause inflammation in these areas. If we have a biologic therapy that can block the migration of these cells from the blood vessels into the tissue, we may be able to prevent tissue damage that way.

So we can target the proteins made by inflammatory cells or we can directly target the cells and keep them out of sites of inflammation. I think these are some of the promising areas for the development of new biologics.

RUSSELL D. COHEN, MD: Terrific, thank you.

You know, Ed, you mentioned infliximab. As we all know, infliximab has been on the market now since late 1998. It's FDA-approved for the treatment of moderate to severe Crohn's disease and also to treat Crohn's fistulas. But, as you mentioned, for some patients, the medication stops working. How do you know when the medicine stops working? And what is your next option?

EDWARD V. LOFTUS, MD: There are a couple of ways to know when the medication stops working. I think most of us gauge this clinically, we ask the patient how they're doing? Do they feel the infliximab infusions are controlling their symptoms? What's their overall energy level? Are they having abdominal pain? Are they having diarrhea? How long is that effect lasting? Is it lasting the full eight weeks, the every-eight-week maintenance therapy or are they only seeing response for the first four weeks or five weeks? So, first of all, that's your hint that the infliximab is not effective.

And some people are beginning to use antibody levels or actually infliximab levels in patients in whom you suspect they're losing response. And some of us actually will check these levels four weeks after the last infusion and, if infliximab is absent from the serum and antibodies are present, then you know you have a problem.

RUSSELL D. COHEN, MD: So, Ed, your patient comes to you and you've checked these levels and, sure enough, it turns out that the infliximab is now being wiped out of the system before it can work. Are there other therapies currently available that you would put this patient on to target the anti-tumor necrosis factor?

EDWARD V. LOFTUS, MD: Well, first of all, one thing you can do is try to increase the dosage of the infliximab. So you can either increase the dosage or increase the frequency, but then you get into a point of diminishing returns at one point. And then I think you start talking about alternative methods of blocking tumor necrosis factor and that gets into some of these newer agents that will soon be available.

RUSSELL D. COHEN, MD: Scott, perhaps you could let us know a little history about the development of these other types of agents, what they are and the ones that seem to be either currently available for other indications or, hopefully, soon to be available.

SCOTT PLEVY, MD: Sure. So there are two anti-TNF agents other than infliximab that have been tested successfully in late-phase clinical trials in Crohn's disease. The first one, known as adalimumab, is actually an FDA-approved therapy for rheumatoid arthritis, so we actually have some open-label in addition to clinical trial experience with adalimumab in Crohn's disease.

Adalimumab is given somewhat differently than infliximab, which is given intravenously. It's given by subcutaneous injections. In the clinical trials, looking at indication of remission, it was given most efficaciously at a dose of 160 mg followed by 80 mg subcutaneously three weeks later. Then, in a large maintenance trial, it was shown to be effective at a dose of 40 subcutaneously every other week.

The second anti-TNF agent, which also hit the primary endpoints in late-phase clinical trials, is an agent known as certolizumab pegol. This is a protein somewhat different from adalimumab and infliximab which are both monoclonal antibodies is that this is a fragment of a monoclonal antibody which has then been linked to a polyethylene glycol moiety. The idea behind this is the polyethylene glycol or PEG will prolong the half-life of this antibody fragment.

This is also given by subcutaneous injection and it's been shown, in phase III clinical trials to be effective in inducing response when given at week zero, 2 and 4 at 400 mg subcutaneously and to then maintain remission when given by 400 mg every four weeks. So these are the two agents that are certainly the furthest-advanced in terms of clinical data in Crohn's disease and would be welcome additions to our armamentarium to treat Crohn's patients, based on the problems that Ed had outlined with patients losing response to infliximab.

RUSSELL D. COHEN, MD: Terrific. Well, thanks, that's a very nice summary of the generic adalimumab and certolizumab therapies. Now, Ed, Scott had earlier explained that there's another major area of inflammation, that of cellular trafficking. And natalizumab has been an agent that's been under study. Perhaps you could give us some information about natalizumab.

EDWARD V. LOFTUS, MD: So natalizumab is an antibody that's directed against alpha-4,beta-7 integrin. And this is an adhesion molecule that it's blocking, basically. This is a drug that is administered intravenously. It's already approved by the FDA for the use in patients with multiple sclerosis who have failed standard therapies. This has been studied in several phase III trials in Crohn's disease and the drug appears to be effective, both in inducing and in maintaining remission in patients with Crohn's disease. The data for this drug for induction was little bit softer than it was for maintenance, but, clearly, the trials do show efficacy with these medications.

RUSSELL D. COHEN, MD: Terrific. So not only anti-TNF therapies. We have anti-adhesion molecule therapies, one of which if natalizumab; there are some others under development. Scott, there's also some other targets that we have discussed in the past, some other types of interleukins that may be helpful to block or promote. Could you just give us a very quick rundown of what you think is kind of in the near future or the not-so-far future?

SCOTT PLEVY, MD: Absolutely. So, based on a recent description of a new Crohn's disease susceptibility gene, in the receptor for a cytokine known as interleukin-23, I think one of the hottest areas of research and of drug development is the development of monoclonal antibodies that block the related cytokines, interleukin-12 and interleukin-23. These are cytokines that may be very proximal in the immune pathways and they may lead to the development of inflammatory T-cell subsets which ultimately mediate the tissue damage that we see.

And there is one study looking at an anti-IL-12, IL-23 antibody that has been published, a phase II study that suggested a signal of efficacy, and another one using a different antibody with the same target that's recently been completed.

RUSSELL D. COHEN, MD: Well, we've discussed efficacy of the various new biologic therapies, but we haven't touched on safety. Ed, there's a lot of concern about whether these agents will make patients more prone to certain infections or even neoplasms. Perhaps you could provide us with some of the information we already know about these agents.

EDWARD V. LOFTUS, MD: Sure, Russ. Well, I think we should preface any remarks by starting it's very difficult to study safety with these agents. Most of our clinical trials are powered for efficacy and not safety and some of these events that we're trying to study are very low-frequency events, so we often rely on uncontrolled data. We don't have control groups to compare these events to and the issue always arises, "Is the particular event we're studying related to the drug? Is it related to another drug that they might be on or is it related to the underlying condition, Crohn's disease, itself?" And it's often very difficult to sort out those three things. So a lot of what we say about safety is just not as well-characterized as about efficacy.

I think, with the TNF inhibitors, the concerns center around, number one, infection risk; number two, malignancy; number three, demyelination; and then there's sort of a grab bag of miscellaneous side effects that may or may not be truly associated with the drug.

Infection risk. There's particular increased risk in getting granulomatous infections, such as tuberculosis, listeria, Pneumocystis, coccidioidomycosis, etc, so certain invasive fungal infections and then tuberculosis. We try to mitigate those risks by checking a chest X-ray, checking a PPD. There's no evidence that checking serologies of any type are predictive of later development of reactivation of some of these infections.

And then I think there's just a general overall sense that there is an overall increased risk of bacterial infections, but that isn't as well characterized as the risk with tuberculosis and some of these other granulomatous infections.

In terms of neoplasms, again, you get into the issue. Is it concomitant medications? Is it the underlying Crohn's disease itself? Although most population-based studies suggest that lymphoma risk is not increased in Crohn's disease, the data is conflicting and there are hints that there might be just a very smidgen increased risk, maybe a 20% elevation in the relative risk of lymphoma in Crohn's.

Then you've got concomitant medications like azathioprine, mercaptopurine, methotrexate, all of which are known to cause lymphoma and then you throw infliximab into the mix. So, yes, there have been case reports of lymphoma and, when you compare lymphoma incidents in the clinical trials to what you would have expected in the general population, it is elevated, but you just can't tease out those other underlying effects.

I think, overall, most of our sense is that the benefit-risk ratio is still very favorable and you have to counsel patients about these theoretical risks, but, overall, if you're at the point that you're talking about TNF agents, you're probably at the point where the benefit is going to outweigh that risk.

In terms of other side effects, demyelination, neurologic complications, so people have developed side effects that look similar to multiple sclerosis in some patients who've received TNF inhibitors. And you get into the same issue. There's a relationship between IBD and multiple sclerosis, how do you separate that out? But there are clear-cut cases where patients have developed these neurologic symptoms immediately following anti-TNF therapy. The absolute risk is still very low and, in most cases, the benefit is going to outweigh the risk.

RUSSELL D. COHEN, MD: And, Ed, what about natalizumab, the anti-adhesion molecule therapy? Some safety issues arose with that therapy; can you elaborate on that?

EDWARD V. LOFTUS, MD: Sure. Well, initially, before these safety concerns arose, it appeared to be quite safe and lots of people were talking it up saying, "Wow, look, there's no infection risk. There may not be any risk with malignancies and it appeared to be a significant improvement with respect to safety."

But then what happened was, in late 2004, early 2005, it was reported that there were three cases among patients treated, either Crohn's or multiple sclerosis, three cases of progressive multi-focal leukoencephalopathy, which is a degenerative neurologic disease, which causes either severe debility or it's fatal. And it's estimated that the risk of that is one case approximately per thousand person-years.

RUSSELL D. COHEN, MD: Terrific. I think it's helpful to point out that extensive evaluation of the roughly 3000 patients in the clinical trials with natalizumab did not reveal any further confirmed cases of the PML, which gives us our 1 in a 1000 risk.

Now, Scott, the other issue about safety is patients who have reactions against the drugs themselves. Could you elaborate on that, please?

SCOTT PLEVY, MD: That's correct, Russ. One way of distinguishing all of the biologics that are antibody-based therapies that we're discussing is based on how they were genetically engineered and some of these antibodies contain a murine or a mouse component that's been fused to a human antibody structure to create the actual drug. And the idea behind this is that, if we have mostly human protein within the structure of these antibodies, this would be less immunogenic, less likely to elicit an immune response from patients who were given these products.

So, for instance, infliximab is chimeric, which means that it's 25%, roughly, murine component. When we're talking about natalizumab or certolizumab pegol, these are what we call humanized antibodies or antibody fragment. They contain far less murine component, maybe about 5%. Adalimumab is genetically engineered to have a full human structure, so this is a fully human antibody.

The problems with developing antibodies, as Ed discussed earlier, can really be twofold. Number one would be loss of efficacy, so the antibodies made against these antibodies neutralize its good biologic effects. The other thing is these antibodies have been shown to mediate infusion reactions, in the case of infliximab and natalizumab, and in injection-site reactions, in the case of adalimumab and certolizumab pegol.

So I think one of the bottom lines is that these are all protein-based products and, whenever you administer a large dose of a protein to a human, there is going to be some immune response in select, fortunately the minority of patients. So one of the open questions is whether a fully human antibody is going to be less immunogenic than a chimeric antibody and we don't know the answer to that.

This also becomes important in the context of some of the infectious complications and neoplastic complications Ed was discussing before. Up until this point in our history, we have used biologic therapies in combination with immunomodulators like methotrexate or 6-MP with the notion that the immunomodulators actually protect against the development of antibodies to these compounds. With some of these new safety concerns, in terms of PML, which is a viral infection, ostensibly, and as well as some rare lymphomas that have recently been reported in the pediatric population on combination therapy with infliximab and 6-MP, the notion of combination therapy is now seen in another light. And, certainly, we may be able to treat patients more safely if we can use a biologic as a monotherapy.

We know, from clinical trials, both published and unpublished, if we use a biologic as a monotherapy in a maintenance fashion, we can likely do this. Whether it's going to be as efficacious as combination therapy, we really don't know, but, with some of these new safety concerns, it's become an important question.

RUSSELL D. COHEN, MD: Well, at this point, I'd like to thank my colleagues for joining us for this very interesting discussion that we've had today. And I'd also like to thank the American Gastroenterology Association and you, the audience, for joining us as well. Thank you.