Preparations containing molgramostim with fosfomycin for intra-intestinal administration to treat Crohn’s disease
Indication for use
Crohn’s disease The prevalence of Crohn’s disease in the USA and Europe is estimated at approximately 2 million patients.
Pathology, symptoms and consequences
Crohn’s disease is a type of inflammatory bowel disease (IBD) that may affect any part of the gastrointestinal tract, but is particularly common in the mid-to-distal ileum and colon. Its cause is attributed to a combination of environmental, immune and bacterial factors in genetically susceptible individuals. An abnormal interaction between the intestinal bacterial flora and the local immune defense is thought to provoke a prolonged inflammatory response which may gravely damage the integrity of the intestinal mucosa and the underlying bowel wall. One characteristic of the disease is that exacerbations are associated with raised titers of autoantibodies directed against GM-CSF, which may result in a local impairment of GM-CSF signaling, which is necessary for maintaining the integrity of the mucosa and the defenses against intestinal bacteria, which may in these circumstances take on a pathogenic role. Symptoms include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever and weight loss. Other inflammatory complications may occur outside the gastrointestinal tract. The inflamed bowel may be subject to fibrosis and constriction, causing episodes of bowel obstruction. The disease is debilitating, confers a greater risk of bowel cancer and may shorten life.
Glucocortocosteroids can be used for limited periods to reduce inflammation during exacerbations, followed by longer term use of agents such as sulfasalazine, or cytotoxic immuno-suppressants such as methotrexate, azathioprine and 6-mercaptopurine. Monoclonal antibodies to the inflammatory cytokine TNF-α are also being used. None of these treatments are satisfactory enough to allow a consensus to be formed as to which are the most appropriate treatments.
Improved treatment by the intra-intestinal administration of molgramostim and fosfomycin
Applying GM-CSF locally from the intestinal lumen to the areas of inflamed and damaged mucosa has the capacity to restore the impaired mucosal barrier and local macrophage function without provoking systemic inflammatory effects. At the same time, the local application of fosfomycin, possibly supplemented with a carbapenem to suppress Bacteroides group bacteria, reduces the load of intestinal bacteria that trigger and sustain the abnormal inflammatory response.
Both GM-CSF and antibiotics have been documented to show signs of therapeutic efficacy when systemically applied, but not the extent that it has motivated routine use. It seems clear from the local effects of GM-CSF to restore mucosal barrier function, that the intraluminal delivery route is important for achieving an adequate efficacy.
The challenge is then to design an effective method of delivering GM-CSF into the intestinal lumen so that an effective amount will reach the adjacent intestinal mucosa. The intraluminal and mucosal environment is hostile to an active protein in that it contains a considerable level of protease activity. The GM-CSF will have to be delivered at high dose, possibly accompanied by a protease inhibitor to ensure that an effective amount reaches the mucosal cells and macrophages on which it has to act. However, it must not be given in such a large amount that it will penetrate the mucosa to exert a systemic effect.
A further consideration is to deliver the active ingredient at the appropriate level of intestine to approximately match the sites of the Crohn’s lesions. This can be achieved by means of known technology in the form of capsules with chemical compositions designed to release their contents at different levels of the small intestine. Lesions of the colon can in general be treated by giving the active substances in the form of an enema.
Reponex has filed the patent application DK PA201470416 “Compositions for the treatment of inflammatory bowel disease”, which seeks protection for the compositions outlined above in the treatment of Crohn’s disease, these compositions to be administered into the lumen of the inflamed bowel. The application also covers the possibility of applying these compositions to the treatment of other types of IBD.
Independent support for the treatment principle
After the filing of the patent application, an independent Italian group published support of the treatment principle focused on patients with Crohn’s disease (Bernasconi et al. “Critical role of the GM-CSF signaling pathway in macrophage pro-repair activities.” Pathobiology 2014 81:183-189).
Systemic side effects after the intra-intestinal administration of GM-CSF are not expected, as GM-CSF will have great difficulty in penetrating into the systemic circulation in an intact, active form. No significant systemic side effects are expected from the antibiotics, as they have a long record of oral and intravenous administration and are given at lower intraluminal doses than those used systemically.
Reponex has access to the active ingredients. Some work on testing the optimal delivery methods will be necessary before a clinical phase II study can commence. The clinical phase II study may be longer than usual, as it will be expected to include a dosage adjustment component.
Department of Medicine, Nykøbing Falster Hospital, Denmark; Consultant physician Stig Bondesen MD. Gastro Unit, Department of Surgery, Herlev Hospital, Copenhagen, Denmark; Professor Jacob Rosenberg, MD, DMSc.