The Breakthrough Drug for Crohn’s Disease・・・Is This the First Step Toward a Cure of This Disease?

Translated by Dr. Taigo Kato

This time, I would like to introduce a paper describing a new drug for Crohn’s disease that was published in the March 19th issue of “The New England Journal of Medicine.” This report came out from Roma University in Tor Vergata. The clinical outcome reported in this manuscript is phenomenal.

 Crohn’s disease is caused by an uncontrolled immune response in the gastrointestinal tract. Severe inflammation damages both small and large intestines. The main manifestations of this disease are abdominal pain and diarrhea. Sometimes patients experience gastrointestinal bleeding due to ulcers. In the worst cases, deep ulceration results in perforation of the bowel, which leads to peritonitis.

   Generally, Crohn’s disease appears between ages 10 and 30, and is difficult to completely cure.  Patients typically have a very poor quality of life with frequent remissions and exacerbations. In severe cases, patients need to have surgical treatment to resect the severely damaged bowel.

  The cause of the illness is related to microbial flora under the influence of the patient’s diet. In addition, we have identified genetic factors associated with this disease. Our laboratory reported the difference in HLA molecules that are key factors for rejection after organ/bone marrow transplantation, and the genetic substitutions in the TNFSF15 gene which encodes one of cytokines modulating immune response.

 I would like to explain what was reported in the paper. This anti-sense DNA drug targets a molecule called SMAD7 that was known to be an important immune modulator in the gastrointestinal tract and to be highly activated in the affected intestine.  In the normal gastrointestinal tract, a cytokine called TGF beta negatively regulates the immune response. However, in patients with Crohn’s disease, SMAD7 is overexpressed and suppresses the function of TGF beta, which leads to an imbalance of the immune system.

 Crohn’s disease is one of many autoimmune diseases.  In patients with autoimmune disease, their immune response becomes overactive due to the imbalance between activation and suppression in the immune system.  In the clinical trial of this report, the authors applied oral administration of anti-sense DNA consisting of 21 nucleic acids corresponding to SMAD7, which was expected to suppress the function of SMAD7 and activate the TGF-beta pathway.


The Effort to Eliminate Incurable Diseases


I thought that this kind of nucleic acid drug was immediately chopped up by deoxyribonuclease secreted from the pancreas.  However, they modified DNA to escape rapid degradation. Honestly, it is hard for me to believe, but the rate of clinical response was significantly higher among patients receiving 40mg/day (>55%) or 160mg/day (>65%) than those receiving placebo (10%) or just 10mg/day of drug (12%) for 2 weeks.

   In the same journal, Dr. Vermeire from Belgium evaluated the data in this report.  The remission rates of between 55 and 65% for the 40mg and 160mg dose of this drug are unprecedented when compared with those reported in large clinical studies of infliximab (32.5% remission at week 6), adalimumab (36% remission at week 4).  Although we should evaluate this data in a careful manner because patient characteristics were not necessarily similar in these clinical trials, Dr. Vermeire mentioned that 2-week treatment of this drug sometimes achieves a remission and is able to maintain the effect for 3 months even without medication, and he described that this is the first step towards a complete cure of Crohn’s disease.

Researchers continue their efforts to turn “incurable diseases” into “curable diseases.”