NEW YORK—September 21 saw Pfizer Inc. announce top-line results from two Phase 3 studies of tofacitinib for the treatment of adults with moderate to severe ulcerative colitis (UC), with both the OCTAVE Induction 1 and OCTAVE Induction 2 studies having met their primary endpoints as measured by the proportion of subjects in remission at week eight compared to placebo. No new or unexpected safety findings for tofacitinib were observed in the studies. Serious adverse events observed were similar to those seen in other clinical development programs for tofacitinib.
The two Phase 3 induction trials of tofacitinib were for 10 mg twice daily (BID) tablets in the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis (OCTAVE) global clinical development program for the treatment of adults with moderate to severe UC. Tofacitinib (brand name Xeljanz) is a prescription medicine that is designed as a Janus kinase inhibitor, more commonly referred to as a JAK inhibitor.
“We are encouraged by the results of the OCTAVE induction studies as ulcerative colitis is a chronic, and at times debilitating, disease that can be difficult to treat” said Dr. Rory O’Connor, , senior vice president and head of Global Medical Affairs, Global Innovative Pharmaceuticals Business for Pfizer. “Pfizer remains committed to advancing the science of Janus kinase inhibition and enhancing understanding of tofacitinib, the first in this new class of medications being investigated for ulcerative colitis. We look forward to sharing the results of our ongoing Phase 3 maintenance study OCTAVE Sustain, when available, which will provide further information on tofacitinib in ulcerative colitis.”
Pfizer is advancing JAK inhibition and pushing for greater understanding of Xeljanz through what it called “a robust clinical development program in a range of immune-mediated inflammatory conditions in the areas of rheumatology, dermatology and gastroenterology.”
OCTAVE Induction 1 and OCTAVE Induction 2 are two identical Phase 3 placebo-controlled studies evaluating induction of remission by oral tofacitinib 10 mg BID in adult patients with moderate to severe UC. A total of 598 patients in OCTAVE Induction 1 and 541 patients in OCTAVE Induction 2 were randomized to tofacitinib 10 mg BID or placebo treatment groups.
The OCTAVE global clinical development program includes three Phase 3 studies, OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain (A3921096), as well as a long-term extension trial, OCTAVE Open (A3921139). Results for OCTAVE Sustain are anticipated by the end of 2016. These four studies will form the potential submission package to regulatory authorities for a potential UC indication.
As Pfizer notes, Xeljanz is the first and only JAK inhibitor approved in more than 40 countries globally to treat moderate to severe rheumatoid arthritis (RA) as a second-line therapy after failure of one or more disease-modifying antirheumatic drugs (DMARDs)—more specifically, it is used typically when methotrexate does not work well for a patient. The benefit:risk profile of Xeljanz in RA has been studied in approximately 6,200 patients in the global clinical development program for such RA indications. Xeljanz may be used as a single agent or in combination with methotrexate or other non-biologic DMARDs. Use of Xeljanz in combination with biologic DMARDs or potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended
A New Drug Application for Xeljanz 11 mg once-daily modified release for the treatment of moderate to severe RA is under review with the U.S. Food and Drug Administration (FDA); the recommended dose is currently 5 mg BID. The drug is not considered safe for use in patients with severe liver problems—it is not yet known if Xeljanz is either safe or effective in people with hepatitis B or C, nor is the safety and efficacy for children a known factor yet.
Pfizer notes that Xeljanz can reduce the immune system’s ability to fight infections, and some people develop serious infections while taking Xeljanz, including tuberculosis (TB), and infections caused by bacteria, fungi or viruses that can spread throughout the body—some deaths have occurred because of this, so healthcare providers should test patients for TB before starting Xeljanz, and monitor them closely for signs and symptoms of TB and other infections during treatment. Other potential complications have included viral reactivation, including cases of herpes virus reactivation; some people who have taken Xeljanz with certain other medicines to prevent kidney transplant rejection have had a problem with certain white blood cells growing out of control, specifically Epstein Barr virus-associated post-transplant lymphoproliferative disorder; and some people taking Xeljanz get tears in their stomach or intestines.
As for the indication currently under investigation by Pfizer, UC is a chronic, often debilitating inflammatory bowel disease that affects millions of people worldwide and is believed to be the result of complex interactions between multiple factors that include the environment, genetic predisposition, immune response and the gut microbiome in the colon or intestines. It can cause abdominal pain, fever, weight loss and chronic, bloody diarrhea. In up to one-third of patients with UC, treatment is not completely successful or complications arise. Under these circumstances, surgery to remove the colon may be considered. Even after surgery, certain symptoms of UC may still persist.
