The last decade or so has seen dramatic progress in the science of inflammatory bowel disease. Now that progress is being translated into medicines and other treatments, some of which are soon to come to market. A recent paper looks at the directions IBD treatment might take in the near future.
The Crohnology blog has run a couple of posts lately looking at new drugs for Crohn’s and new drugs for UC. For anyone still scratching their heads about some of those drugs [author raises hand], this paper helps us understand the kinds of drugs that are in development, and what they promise to do.
The paper, by Dr. Gerhard Rogler, is titled, “Where are we heading to in pharmacological IBD therapy?”, and was published in the journal Pharmacological Research (full citation below). The paper briefly introduces IBD and current treatments, and then lists future pathways by category, as follows:
- Antibodies against cytokines: these are drugs — like Remicade and Humira — based on blocking immune system signals (i.e. cytokines) using biologic molecules. Remicade and Humira both block the same cytokine, called TNF, and there are other drugs available and in development that work the same way. Still other drugs block different signals: Stelara is an antibody that blocks cytokines IL-12 and IL-23, and there are drugs in development that block IL-13, IL-2R, and so on.
- Antibodies against other molecules: these biologic drugs block molecules that are not specifically part of the immune system, but which allow immune cells to move through tissue. Entyvio, for example, is an antibody against an integrin, a molecule that allows white blood cells to cross into intestinal tissue. Other drugs in development block similar pathways in gut inflammation.
- Anti-chemokine drugs: chemokines are a kind of cytokine (only smaller), and also play a role in the immune system. Anti-chemokine drugs use biologic antibodies to stop the immune response that drives inflammation. CCX282-B and MDX-1100 are chemokine antibodies currently in development.
- Oral antibodies: anyone tired of injections and infusions will be happy to know that oral antibodies are in development. Oral antibodies work like injected antibodies, except they come in pill form. AVX-470 is an antibody to TNF that is in trials.
- Recombinant proteins: where the above drugs all seek to block ‘bad’ molecules created by the body, recombinant proteins seek to replicate good molecules to control the immune system. IL-10 and IL-11 are both proteins the body produces that help to regulate inflammation, but clinical trials have not been promising.
- Anti-fibrotic therapies: fibrotic diseases are involve scar formation and excessive connective matrix due to tissue damage (like inflammation). Anti-fibrotic drugs are in development for other diseases, but may prove useful in treating IBD.
- Natural compounds: some natural chemicals have shown promise in treating IBD, including anthocyanins derived from billberries, curcurmin, and a myrrh and chamomile mixture.
- Antisense therapies: because proteins like cytokines and chemokines are formed via DNA instructions, one way to block those proteins is to block the instructions. Antisense — or anti-sense — works like a black marker in DNA, crossing out the recipe for a specific molecule. Antisense drugs can be taken orally; Mongersen is probably the best know example, targeting the instructions for a protein called SMAD7.
- Kinase inhibitors: certain diseases, including some cancers and some inflammatory disease, involve proteins that have an extra group of phosphate added. Kinases are molecules that help add phosphates to those proteins, so inhibiting kinase keeps that from happening and prevents the protein from contributing to disease. The kinase inhibitor drug Tofacitinib targets the Janus kinase 3 (JAK3) molecule, and is in clinical trials for IBD.
- Small molecules: much the way that some drugs target bad cytokines and some replicate good cytokines, the same can be done for small molecules. Where Entyvio blocks a specific integrin protein, another drug — AJM300, introduces a related integrin into the body. Another example is laquinimod. These drugs are taken orally.
- Barrier support/barrier repair: because the layers of mucus in IBD patients’ guts are much thinner than normal people’s, some drugs try to improve this important barrier between the gut tissue and intestinal contents. One drug, Phosphatidylcholine (also known as lecithin) has shown promise in trials.
- Stem cell transplantation: this involves destroying the patient’s immune system and replacing with a donor’s through stem cell transpants. This has been tried in some extremely sick Crohn’s patients, with success.
- Fecal microbiota transplant: also known as the poo transplant, this involves repopulating the gut’s microbiome with material from a healthy donor. While this is already in use and very effective for C. Diff. overgrowth, there is also some research into whether it is helpful in patients with IBD.
- Helminth therapy: helminth therapy introduces parasitic worms into the gut, on the theory that the inflammation reaction driving IBD needs an appropriate target. Although this has shown some promise, it needs more research.
Dr. Rogler points out that for the last 15 years, anti-TNF therapies (like Remicade and Humira) have been state of the art for treating IBD. However, this may soon change, as current research bears fruit and new drugs become available.
“These are exciting times in the IBD field,” writes Dr. Rogler, but he adds that it is important for patients, physicians, and others concerned with the disease to keep up-to-date on the latest and best treatments.
The paper is Rogler, G. “Where are we heading to in pharmacological IBD therapy?” Pharmacological Research 100 (2015). Abstract online. A copy of the article was provided by the author.