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More people are being diagnosed with Crohn’s disease and ulcerative colitis than ever before, but researchers aren’t exactly sure why. A variety of factors including genetics, weakened immune systems and the environment may be at play.

In this podcast produced for this year’s Crohn’s and Colitis Awareness Week, Cathy Ferrone, director of patient advocacy at Celgene, and Laura Wingate, senior vice president of Education, Support and Advocacy at the Crohn’s and Colitis Foundation, discuss the rise in worldwide incidence rates of inflammatory bowel disease and why research in this area remains so important.

 

 


CATHY FERRONE FROM CELGENE AND LAURA WINGATE FROM CROHN’S AND COLITIS FOUNDATION DISCUSS THE RISE IN INFLAMMATORY BOWEL DISEASE.

 

To learn more about the lifelong struggle of having an inflammatory bowel disease, read “What It’s Really Like to Live with Ulcerative Colitis.”

To explore the Crohn’s & Colitis Foundation’s resources available to patients, caregivers and health care professionals, visit their website at http://www.crohnscolitisfoundation.org/ or call 1-888-My-Gut-Pain.
 

Many of the 1.6 million Americans living with inflammatory bowel disease (IBD) struggle to find an effective treatment, leaving them with pain, fatigue and other symptoms that directly affect their lives but may not be obvious to others. Although more than 380 active clinical trials are exploring investigational treatment options for the two most common forms of IBD—Crohn’s disease and ulcerative colitis—many patients either don’t know of these studies or don’t understand the possible benefits of participating.

As patients and advocates work to bring visibility to this disease during this year’s Crohn’s and Colitis Awareness Week (December 1-7), Dr. Bruce Sands, a gastroenterologist at Mount Sinai Hospital and the Icahn School of Medicine at Mount Sinai in New York, explains why some people living with IBD could benefit from discussing clinical trials with their doctors.

DR. BRUCE SANDS, A GASTROENTEROLOGIST AT MOUNT SINAI Hospital and the Icahn School of Medicine at Mount Sinai IN NEW YORK, EXPLAINS WHY SOME PEOPLE LIVING WITH IBD COULD BENEFIT FROM DISCUSSING CLINICAL TRIALS WITH THEIR DOCTORS.

DR. BRUCE SANDS, A GASTROENTEROLOGIST AT MOUNT SINAI Hospital and the Icahn School of Medicine at Mount Sinai IN NEW YORK, EXPLAINS WHY SOME PEOPLE LIVING WITH IBD COULD BENEFIT FROM DISCUSSING CLINICAL TRIALS WITH THEIR DOCTORS.

Why are some people living with IBD unaware that there are clinical trials for their disease?

“IBD clinical trials usually recruit patients who have active, flaring disease. But many patients on existing therapies who may still be flaring are not being cared for by doctors involved with trials. So these doctors may not be prepared to discuss clinical trials as an option. These patients can consider getting another opinion from a doctor at a medical center that offers IBD clinical trials. A good resource for IBD patients to learn more is ClinicalTrials.gov.”

How do you address patients’ concerns about enrolling in a trial?

“Patients feel more comfortable about enrolling when they understand the process. I try to explain the different stages to them. Such as, in Phase 1, researchers focus on evaluating the safety of a new treatment. A treatment doesn’t get to Phase 2 or Phase 3 until we know more about the medication’s safety. At each later stage, more patients take part, and researchers gain better knowledge of the treatment’s safety and efficacy profile.”

“Sometimes, patients hesitate to take part because they worry they will receive a placebo and be left untreated. I tell them that in almost every IBD trial, the investigational therapy is added on top of their existing medication. So they will not be left untreated. Furthermore, most studies allow all participating patients access to the investigational medication after eight to 12 weeks.”

We continue to see progress by studying investigational medications that may provide patients with better symptom relief and disease control.

What do you tell patients who qualify for a clinical trial?

“I explain that there are two big reasons why they should consider enrolling in a clinical trial. First, a clinical study may give them access to a medication that works for them.”

“Second, if people with Crohn’s disease and ulcerative colitis don’t enroll in trials, we will never see advances in the treatment of these diseases. Voluntary patient participation has been essential to the development of new treatment options over the last two decades and will continue to be so in the future.”

Why is it important that we continue to explore new treatments for Crohn’s and ulcerative colitis?

“We have yet to find a medication that works for every person with IBD. And while some existing treatments may work for some patients at first, their effectiveness can wear off over time. Meanwhile, the incidence of IBD is rising across the globe—in the developed world and also countries such as India and China.”

“Over time, we hope to understand which patients do better with which medications through clinical trials. But at this point, we simply need more treatment options.”

How hopeful are you about the future of IBD treatment?

“More than 200 genes are thought to contribute to the risk of Crohn’s disease and ulcerative colitis. Given that complexity, and how the biology differs from person to person, achieving a cure may be very difficult. While we all hope for a cure someday, we continue to see progress by studying investigational medications that may provide patients with better symptom relief and disease control.”

To learn why targeted therapies could be an important therapeutic option for IBD patients, read “Interest Grows in Targeted IBD Research.”

Dr. William Sandborn, Professor of Medicine and Chief, Division of Gastroenterology and Director, University of California San Diego Inflammatory Bowel Disease Center, believes the use of two co-primary endpoints for Crohn’s disease trials is raising the bar for new treatment options.

Dr. William Sandborn, Professor of Medicine and Chief, Division of Gastroenterology and Director, University of California San Diego Inflammatory Bowel Disease Center, believes the use of two co-primary endpoints for Crohn’s disease trials is raising the bar for new treatment options.

The last two years have seen dramatic changes in how researchers determine the efficacy of new therapies for Crohn’s disease. We’re now seeing findings from the first clinical trials to measure a therapy’s effectiveness through a combination of objective measures of the disease and patients’ evaluations of their own results.

Dr. William Sandborn, Professor of Medicine and Chief, Division of Gastroenterology and Director, University of California San Diego Inflammatory Bowel Disease Center, explains how this combination approach for Crohn’s disease trials is raising the bar for new treatment options.

What are the unmet needs for the treatment of Crohn’s disease?

While current treatment options for Crohn’s disease have demonstrated efficacy, their use may be limited due to multiple factors, including initial lack of response, loss of response over time or safety concerns. For instance, steroids have safety risks which increase if they are used for long periods of time, and the commonly used anti-TNF therapies can become less effective over time and can have serious side effects.

How have the endpoints for Crohn’s clinical trials been changing, and why?

Previously, we relied on a tool that did not accurately reflect the underlying biology of disease. That measurement, called the Crohn’s Disease Activity Index (CDAI), provided a score based on diaries that patients kept regarding their abdominal pain, stool frequency and how they felt overall (well-being). But those symptoms do not reliably correlate with the inflammation and sores in a patient’s bowels called ulcers.

To determine if a treatment is reducing the inflammation and ulceration of the gastrointestinal tract, doctors perform a colonoscopy, a diagnostic procedure used to examine a person’s digestive tract with a camera. As the Food and Drug Administration has sought to improve clinical trials in Crohn’s disease over the past two years, the field has been moving toward looking at both patient reported outcomes (how the patient feels) and the biological improvement that we can see in the intestine, which we call endoscopic improvement.

The Evolution of Endpoints in Crohn's Disease

How does this combination of endpoints compare with those used for clinical trials in other diseases?

Clinicians have been incorporating the patient’s experience and an assessment of the physical aspects of other autoimmune diseases for years. In multiple sclerosis, they look at patients’ descriptions of how they feel and function along with MRI of the brain that measures damage to the brain and nervous system. In arthritis, patients’ reports are combined with a physician examining the patient for joint damage, and for psoriasis physicians examine the patient’s skin inflammation. Crohn’s disease is now catching up with these conditions.

What are some of the challenges of looking at endoscopic changes?

The approach is still evolving, but we’ve done a lot in the past two years. We developed ways to measure endoscopic improvements and are using them in clinical trials for the first time now. While it’s not a perfect tool just yet, we are refining it based on our experience. You need a lot of training to interpret the data from a colonoscopy because it’s somewhat difficult to measure damage with a two-dimensional image. So we’ve been improving that training, and we’re also improving the system by video recording the procedures and having Crohn’s disease experts independently score the severity of the Crohn’s disease.

Ten years from now, I think that we will look back and realize that this was a seminal moment where we began to expect treatments to address the root causes of the disease.

Do you expect endoscopic improvements come before or after patients start feeling better? Why is that?

In general, there is a lag between when the patient feels better and when the bowel begins to heal in response to treatment, so we are learning that we have to wait longer to see those improvements. The emerging data from trials that have used endoscopic improvements suggest somewhere between four to six months might be the right time to evaluate intestinal healing. This evidence is causing us to rethink how we design clinical trials for Crohn’s and how we interpret results.

Aside from endoscopic effects, what are some other factors that are important to consider when analyzing potential new therapies?

Physicians are always looking at a drug’s balance of safety and efficacy. An effective treatment with an acceptable balance of side effects would be considered a step in the right direction. And if two therapies are otherwise similar, most physicians and patients would consider therapies that are taken by mouth, like a pill or tablet, over those given intravenously or through an injection.

Are you optimistic about future treatment options for patients with Crohn’s disease?

The evolution of clinical trial endpoints has been very exciting and is already having a significant impact on our search for new therapies. Ten years from now, I think that we will look back and realize that this was a seminal moment where we began to expect treatments to address the root causes of the disease.

It’s not rare for a patient to be told they have ulcerative colitis only to later find out that they instead have Crohn’s disease.

“It’s difficult for doctors to make a proper diagnosis sometimes because Crohn’s can look very similar to ulcerative colitis,” Dr. Giovanni Monteleone, a gastroenterologist at the University of Rome Tor Vergata, said.

Shared characteristics include diarrhea and abdominal pain caused by inflammation of the digestive tract, but the location of this inflammation differs. In ulcerative colitis, inflammation only affects the large intestine, starting with the rectum—which is located in the lower left abdomen. Meanwhile, Crohn’s disease most commonly involves the terminal ileum—located in the lower right abdomen—although it can affect the entire gastrointestinal tract as well.

Crohn's Disease vs. Ulcerative Colitis

And while ulcerative colitis works its way from the rectum through the colon continuously, Crohn’s disease can cause patches of inflammation surrounded by healthy spots. That patterning can only be identified through a colonoscopy to view the inner lining of the large intestine. Even with this invasive test, about 10 percent of cases are still unclear.

Genetic studies are no help in the matter. “The genetic alterations associated with these diseases are common to both,” Monteleone said. “So we have no genetic diagnostic test to single out a colitis or Crohn’s diagnosis.”

What’s left, then, is simply time. “In those cases, the patient will eventually be diagnosed with one disease or the other as evidence mounts,” Dr. Guillermo Rossiter, senior director of Inflammation and Immunology R&D at Celgene, said.

We have a long way to go in terms of helping the most patients with medical therapies.

For instance, some patients develop anal fistula and fissures—areas of tunneling and painful cracks in the skin around the anus. “That’s a sign that we’re dealing with Crohn’s disease and not colitis,” said Dr. Faten Aberra, a gastroenterologist at the University of Pennsylvania and a committee member at the Crohn’s & Colitis Foundation of America.

At this year’s Annual Scientific Meeting of the American College of Gastroenterology (ACG) in Honolulu, researchers are discussing ways to improve both the diagnosis and treatment of these diseases.

Today, for instance, scientists are looking at how antibodies in a patient’s blood and urine can be used to differentiate these diseases. At ACG, researchers will discuss how symptoms outside the digestive tract can be used to tell these diseases apart.

With the proper diagnosis, doctors can then select the best treatment, from medical options—such as steroids, immunosuppressants and biologics—to more severe surgical procedures to remove diseased sections of the bowels. While up to 75 percent of ulcerative colitis patients will respond to medications, 70 percent of Crohn’s disease patients will undergo surgery.

Even the medical treatment options are far from ideal. “Steroids, immunosuppressants and biologics both have unattractive safety profiles, and patients often become less responsive to biologics over time,” Rossiter said.

New ways to treat inflammatory bowel diseases will of course also be a topic of conversation at ACG. Although medical and surgical treatment can help ease some of the symptoms, none targets the root causes. And there are no cures.

“We need something else to improve the quality of life of these patients,” Monteleone said. “These are nasty conditions that affect their lives; they stay home for long times, cannot work, cannot spend time with their relatives because of their quality of life and hospitalizations.”

Patients have reasons to be hopeful, though, as new treatment options are being developed. And the recent recognition of both Crohn’s and ulcerative colitis as orphan diseases by the U.S. Food and Drug Administration should help expedite the development of several therapies currently in clinical trials.

“We have a long way to go in terms of helping the most patients with medical therapies,” Aberra said. “We can get some patients into remission, but some do not respond at all; we still need to figure out which patients will respond to which medicine.”