A Phase 2 Trial of the Drug Tofacitinib, One of a New Class of Experimental Drugs Known as JAK Inhibitors, Indicates an Easing of Symptoms of Ulcerative Colitis
A phase 2 trial of Tofacitinib, a drug that is one of a new class of experimental drugs known as JAK inhibitors that suppress chronic inflammation, indicates that patients with moderate to severely active ulcerative colitis are more likely to respond to or experience remission of the disease than those who were given a placebo, according to a study published in the August 15, 2012 issue of The New England Journal of Medicine.
Ulcerative colitis is an inflammatory bowel disease that affects the lining of the large intestine or colon and rectum in about 700,000 Americans of all age groups. Symptoms include abdominal pain and cramping, blood and pus in the stool, diarrhea, fever, rectal pain, and weight loss.
Ulcerative colitis increases the chance of developing colon cancer. The National Institute of Health (NIH) recommends that those with the disease be given a colonoscopy following diagnosis, and a follow-up colonoscopy every one or two years after that.
While the majority of patients respond to available standard treatments, at least 20 percent don’t and others need to have treatment administered intravenously. About half experience flare ups of the disease so severe that in some cases a last resort treatment of surgery to remove the colon is required. Clearly, a need exists for new and effective medication and treatment.
The drug Tofacitinib affects a group of proteins in the white blood cells to suppress the immune system. Manufactured by Pfizer, the drug company that funded this study, Tofacitinib was approved for use in November 2012 by the FDA to treat rheumatoid arthritis.
The research protocol was designed and led by the University of California San Diego, School of Medicine. “Ulcerative colitis causes severe bouts of illness that adversely affect a patient’s quality of life at home and work,” says William Sandborn, MD, lead study researcher and chief of the Division of Gastroenterology at the UC San Diego School of Medicine and Director of the Inflammatory Bowel Disease Center at UC San Diego Health System. “Oral treatment with Tofacitinib resulted in improvement and remission in some patients,” he says.
The study was conducted at 51 centers in 17 countries – United States, Belgium, Brazil, Chile, Czech Republic, Denmark, France, Hungary, Israel, Italy, Mexico, The Netherlands, Poland, Slovakia, South Africa, Sweden, and the UK – during the period from January of 2009 to September of 2010. In each study, participants were 194 individuals 18 years of age and older who had previously been treated for ulcerative colitis with conventional therapy and had experienced moderate to severely active symptoms.
Study participants were assigned either to get a dose of Tofacitinib or a placebo with neither the researchers nor the study participants knowing who was in which group. Those who were given Tofacitinib were given the drug at doses of 0.5mg, 3mg, 10mg, or 15mg twice a day for eight weeks, while those who received the placebo were also given doses twice a day for the same eight weeks. Each group was followed for four weeks after the final treatment, and benefits for those who were being given the drug began to be seen after just two weeks of treatment.
At the start of the trial and at eight weeks, participants were given a sigmoidoscopy, an examination of the rectum and part of the colon. Blood, urine, and stool samples were also taken to measure inflammation.
Over eighty percent of the participants or 157 people completed the eight-week trial. More than ¾ of those in the treatment group responded to the medication, with 41 percent going into remission. Ten percent of the placebo group went into remission.
The symptoms of ulcerative colitis were rated on a scale of 0 to 12, with 12 indicating the most damage. The drug was considered to have been effective if a study participant had a 3 or more decrease in their symptom score or if they had a 30 percent or more drop in score from the score at the start of the study and a decrease in rectal bleeding.
The rates of response to Tofacitinib directly correlated with dosage. Those given a 0.5mg dose had the lowest response rate, while those given a 15mg dose saw the greatest benefit. Of those taking the highest dose, 78 percent experienced a reduction in symptoms in eight weeks compared to 42 percent in the placebo group.
Among the individuals treated with Tofacitinib, influenza and respiratory infection with common cold type of symptoms were the most reported side effects. Several people experienced headaches, a couple saw their symptoms worsen, and two people developed an abscess.
A rise in both good and bad cholesterol took place as dosages increased, and three patients had low white blood cell counts, a sign of the possibility of infection.
David A. Greenwald, MD, Associate Director in the Division of Gastroenterology at Montefiore Medical Center says it appears that the drug is safe, shows promise, and will be evaluated more in a Phase 3 type of trial. “The clinical response and remission are promising results, and the drug seems to be effective when added to some therapies that don’t appear to be working.” In the next trial, he says, the drug will be used as an alternative to other drugs.”