Gut reaction: seeking new treatments for IBD
Inflammatory bowel disease is affecting an increasing number of people. Dr Sarah Houlton describes the latest advances in treatments for this painful and distressing condition
Inflammatory bowel disease is affecting an increasing number of people. Dr Sarah Houlton describes the latest advances in treatments for this painful and distressing condition
Inflammatory bowel disease (IBD) is the all-encompassing term for a range of distressing conditions, notably Crohn's disease and ulcerative colitis. They are rare in early childhood, but young adults and over 65s are particularly at risk of developing IBD. Neither sex is more susceptible than the other, but racial background is a factor. White people are at greater risk than black, and the number of cases in people of Asian origin but born in the UK is increasing. This implies that both genetics and environmental factors play a part in triggering IBD.
It is estimated that around 1 to 1.5 people in 1000 in Western Europe suffer from ulcerative colitis, and a slightly lower number - about 1 in 1,500 - from Crohn's disease. Both conditions are becoming increasingly common.
In Crohn's disease, also referred to as regional ileitis, sections of the intestinal tract become thickened, inflamed and ulcerated. It usually affects the terminal part of the ileum. Between the sites of inflammation, the intestine remains normal. In its chronic form, the condition can lead to the intestine becoming partially obstructed, resulting in maladsorption of food, as well as pain and diarrhoea. Common complications include fistulae developing between adjacent loops of the intestine or the anus, or even between the intestine and other organs such as the bladder or the skin. Crohn's disease is usually controlled using drugs, but if the damage becomes particularly severe, surgical removal of part of the intestine will be necessary.
In ulcerative colitis sufferers, both the rectum and colon become inflamed and ulcerated. The ulcers may be deep, spreading sideways under the lining of the colon. Its severity varies over time, with relapses being treated with drugs and bed rest. As with Crohn's disease, in extreme cases, surgical intervention becomes necessary.
The cause is as yet unknown, but there are many theories, and it is almost certain that it develops in people with a genetic disposition to it who are exposed to environmental triggers. It is clear that both ulcerative colitis and Crohn's disease are multifactorial conditions, with several genes implicated alongside environmental factors. Infectious agents - possibly the rod-shaped Gram-positive organism Mycobacterium paratuberculosis and the measles virus - have also been implicated in triggering IBD, though no proof of a causal link has yet been found.
There is also evidence that an intolerance to the bacteria that normally reside within the digestive tract is a factor; people with Crohn's often have antibodies against common organisms like baker's yeast, and memory T cells present in their bloodstream that think these organisms are foreign and attack them. Patients who have taken antibiotics in the previous year appear to be more at risk of developing Crohn's disease, and an appendectomy seems to offer some protection against ulcerative colitis. Smoking appears to protect against ulcerative colitis, but is a risk factor in Crohn's disease.
inflammation process
Many different cell types are involved in the inflammation process within the gut, attracted to the area by the cytokines and other substances secreted by the gut wall, as well as the expression of receptors on the blood vessels. The initial treatment for the active form of both colitis and Crohn's is usually an aminosalicylic acid derivative and a corticosteroid, often administered as an enema if the disease is confined to the lower end of the digestive tract.
A wide range of different drug classes is used to treat IBD, including:
• steroids, such as hydrocortisone, budesonide, and prednisolone;
• 5-aminosalicylic acid derivatives, like sulphasalazine, mesalazine, balsalazide and olsalazine;
• medicines that act on the immune system, such as azothioprine and 6-MP;
• the monoclonal antibody infliximab;
• drugs that give symptomatic relief, including analgesics, and antidiarrhoeals, plus antibiotics to fight bacterial infection, including ciprofloxacin, clarithromycin and metronidazole.
side-effects
Steroid therapy is usually given to patients suffering from an acute attack, as a high oral or intravenous dose of steroids has been proved to lower the death rate in severe cases. Around 80% of Crohn's and colitis patients respond to steroid treatment. However, side-effects are common; many of these can be avoided if the drugs are given as an enema to patients whose disease is confined to the lower end of the colon or the rectum.
Newer steroids have been developed with more specific actions that reduce the incidence of side-effects, notably budesonide (AstraZeneca/Provalis), which has high levels of localised anti-inflammatory effects.
Thanks to an enteric coating on the capsules, its release can be delayed until it reaches the relevant part of the digestive tract. Steroid treatment is usually stopped (with slow withdrawal to avoid side-effects) after the acute attack has subsided, as this does not help to maintain remission.
The second class of medicines that is extremely beneficial in IBD is the 5-aminosalicylic acid (5-ASA) derivatives. Around 60 years ago the rheumatoid arthritis drug sulfasalazine was found to improve the symptoms of IBD.
On oral administration, the majority of the dose passes through to the colon, where the pro-drug is broken down into 5-ASA.
Its use is limited by its side-effects, which are largely caused by the sulphapyridine carrier part of the molecule, but 5-ASA itself (also referred to as mesalazine) is unstable in solution, and so cannot be used directly.
Newer pro-drugs have been developed since, whose carrier part does not have the same side-effect profile. On bacterial breakdown in the colon, Pharmacia's olsalazine releases two molecules of ASA, and Shire's balsalazide one plus an inert carrier. These both act largely in the colon and rectum and are much better tolerated than sulphasalazine.
Several different controlled release formulations of mesalazine are also available. Procter & Gamble and Provalis have both developed forms with an enteric coating that act on the ileum, and Ferring formulated it inside microspheres that release the drug gradually as it passes through the gut. Choosing the right formulation is essential if the drug is to act at the correct target site.
Because immune reactions are implicated in IBD, immunoactive agents have use in its treatment. 6-Mercaptopurine and its pro-drug azathioprine, both from GlaxoSmithKline, slow down immune reactions, and appear to act by indirectly blocking DNA synthesis in T-lymphocytes. They also have a direct action on the white blood cells implicated in inflammation. The slow onset of action means it can take three or four months before they have any real effect. They are largely used to reduce steroid dosage, and are very useful for inducing remission and preventing relapse in both Crohn's and ulcerative colitis patients.
Two other immunoactive drugs have some use, despite not being specifically licensed for use in IBD. Cyclosporin (Neoral/Sandimmun, Novartis) is well known as the antirejection medicine that transformed the fate of organ transplant patients, and can have a beneficial effect in patients with severe ulcerative colitis that has not responded to steroid therapy.
Methotrexate, the fourth immunoactive drug used for IBD, has long been used in immune diseases such as rheumatoid arthritis and cancer, and seems to be able to reduce the steroid dosage in steroid-dependent Crohn's disease. It has recently been shown that giving a low maintenance dose maintained remission in Crohn's patients.
monoclonal antibodies
The latest development in drug therapy for IBD is the use of monoclonal antibodies. The target for antibodies that will help IBD patients are the cytokines that are overproduced in sufferers, particularly tumour necrosis factor α (TNF-α). Elevated levels of TNF-α have been found in the faeces of children with IBD, and cells from the gut wall have been shown to produce higher levels of the cytokine in affected people. Schering-Plough discovered the humanised monoclonal antibody infliximab which can neutralise TNF-α, and it has been available on the UK market since 1999 for treating severe cases of Crohn's disease, particularly those that are resistant to steroid therapy or immunosuppressants.
Clinical trials showed it can have dramatic results patients given a single infusion of infliximab showed a 64% improvement, compared with 17% on placebo; 33% who received the antibody achieved remission, and only 4% of the placebo group. It healed long-standing fistulas in some patients that proved resistant to conventional treatments. Side-effects include an increasing likelihood of the patient picking up opportunistic infections, but the dramatic effects it has been shown to have in otherwise difficult to treat patients indicate that it is a definite step forward.
clinical trials
Other monoclonal antibodies for TNF-α are also in development. D2E7 is being developed by Abbott, having been licensed from Cambridge Antibody Technology, and is currently in Phase II. CDP 571 (in Phase III) and CDP 870 are both under investigation at Celltech. The latter is in Phase II and is a co-development with Pharmacia. It is an antibody fragment coupled to PEG as a carrier, and hence is potentially much cheaper to produce than a full antibody; it is being developed for treating rheumatoid arthritis, but may well have value in Crohn's patients.
However, Celltech received a setback when at the end of July it was announced that the Phase III trials showed a lower than expected level of inflammation reduction in the intestine. The company remains confident that it will receive a licence of some form for the drug, possibly for serious, acute cases of Crohn's, though further clinical trials may be required, and it is now unlikely to reach the market by the original target date of 2003.
Many other medicines in a range of novel classes are also being investigated. The success of infliximab against Crohn's proved that TNF-α is implicated in the condition, and drugs that act on this and other cytokines are being developed. For example, Serono's r-TBP-1 is a protein TNF-α inhibitor, currently in Phase II trials. And CytoAb from Protherics, another protein inhibitor, is in Phase I.
Thalidomide has been shown to have some use too, as it is believed to prevent TNF-α synthesis in the gut wall, and early studies by Celgene have shown it to give improvements in patients with severe Crohn's disease. Celgene is also developing a range of selective cytokine inhibitory drugs, or SelCIDS, that may decrease TNF-α production.
Isis Pharmaceuticals' ISIS 104838 is an antisense inhibitor of TNF-α that is in Phase I, while SangStat's peptide TNF-α inhibitor RDP58 has reached Phase II.
Other cytokines are also implicated in the IBD process. Cambridge Antibody Technology is developing J695, a monoclonal antibody for interleukin 12 (IL-12), which is believed to be a key mediator of IBD; clinical trials are again being carried out by Abbott.
Interleukin 6 is being investigated by Chugai, and it has a humanised monoclonal antibody in preclinical trials for IBD. And Abgenix is looking at interleukin 8, and its MAb ABX-IL-8 is also in preclinical studies.
complex condition
Other monoclonal antibodies are being investigated too. Elan's natalizumab blocks a4 integrin, and may reduce the infiltration of inflammatory cells, and it is now in Phase III trials. MLN-02 from Millennium Pharmaceuticals acts on a receptor on leucocytes, and is in Phase II for both Crohn's and ulcerative colitis. The same receptor target is being investigated by GlaxoSmithKline, whose SB 638698 is in Phase I trials.
IBD is a complex condition with many contributing factors, so various other mechanisms are also being studied. Cellular adhesion molecules are the target of Isis Pharmaceuticals' ISIS 2302, an antisense compound also known as alicaforsen, which is in Phase III trials for active Crohn's disease. The drug blocks the formation of the receptor that enables white cells to adhere to the walls of the blood vessels.
Another mechanism implicated in IBD is the CD40 pathway, which has a role both in antibody responses, and in the cell-to-cell contact processes that take place within the affected bowel. Chiron has developed a monoclonal antibody, TNX-100, that blocks this pathway, It has been licensed to Tannox, and is currently in Phase I trials for Crohn's disease.
Phytopharm's P54, a plant extract, is also in Phase I in IBD. It indirectly blocks the expression of the NFkB genes involved in inflammation, and may reduce the need for steroids in IBD patients. Oxis Pharmaceuticals has developed a small molecule drug candidate, BTX-51072, that mimics the enzyme glutathione peroxidase, which traps reactive oxygen. It has given some improvement in patients who have failed to respond to first line therapeutic options.
Other compounds in development include GlaxoSmithKline's p38 kinase inhibitor SB-281832, and Pfizer's neurokinin 1 antagonist C-96345, which blocks a peptide released by nerves in inflamed areas. Both of these products are in Phase I trials.
vaccine treatment
A further potential treatment option is the administration of naturally occurring cytokines, such as the interferon IL-10, keratinocyte growth factor, and transforming growth factor b. Schering Plough, for example, has developed a recombinant form of IL-10, given the name tenovil, which is in Phase III trials. And Serono is carrying out Phase II trials on interferon β1α in patients with ulcerative colitis.
Vaccines are another treatment possibility, and a vaccine against Mycobacterium paratuberculosis is being investigated at St George's hospital in London. Meanwhile, M&E Biotech is developing the vaccine MS-101 as a potential treatment for Crohn's disease as it may neutralise TNF-α. Another idea would be a vaccine that increases the resistance of the mucosa to attack.
A vaccine that could deliver genes to replace faulty ones may also be possible, as the human genome project has already pinpointed several genes that are implicated in increased susceptibility to IBD. This is still a long way in the future but, as with many troublesome conditions, knowledge gained from the unravelling of the human genome may ultimately hold the key to a permanent cure.
