The drug development process as modified by drug repositioning
pharmaceutics. When delivered directly to its site of action in the organ concerned, it does not readily pass into blood stream. This protects the patients from the adverse effects that it might have when given systemically, e.g. by intravenous infusion or subcutaneous injection.
Standard drug development process
Reponex Pharmaceuticals drug development process
Reponex’s position bypasses preclinical and clinical phase I testing
Reponex’s position is such that all the components of its pharmaceutical preparations have long since been evaluated for safety and suitability for human use by the routes by which they are to be given. Regarding the biological active ingredient, GM-CSF in the form of sargramostim (recombinant human GM-CSF expressed in yeast) has had its safety for inhalation by humans attested by prior clinical use; the closely related molgramostim to be used by Reponex (recombinant human GM-CSF expressed in E. coli), will have completed this evaluation by the start of clinical phase II studies. Reponex has access to preclinical data on the safety of molgramostim inhalation in non-human primates, and further clinical phase I data on human inhalation of molgramostim.
The safety of inhaled fosfomycin has been confirmed in published human studies.
This means that Reponex’s active pharmaceutical ingredients will not require further clinical phase I testing and that the clinical development projects outlined below can enter directly into clinical phase II testing.
Overview of prioritized Reponex clinical projects
|Indication/IP||Number of patients|
|1a. Non-healing wounds and skin ulcersDK PA201470300 “Com-positions for promoting the healing of wounds”.||Up to 12 million in EU and USA.|
|1b. Bacterially infect-ed non-healing wounds and skin ulcersDK PA201470059 “Com-positions to promote the healing of skin ulcers and wounds”.||Up to 6 million cases per year estimated in EU and USA.|
|2. Lung dysfunction from radiation and cancer chemotherapyWO2012136224; WO2013029627 “Com-positions and methods for treating or prevent-ing radiation of chemo-therapy induced pulmo-nary dysfunction”.||Estimated 200,000 cases per year in EU and USA.|
|3. Crohn’s diseaseDK PA201470416 “Com-positions for the treat-ment of inflammatory bowel disease”.||Up to 2 million cases in EU and USA.|
|4. Bacterial peritonitisDK PA201470473 “Com-positions for the treat-ment of peritonitis”.||Estimated 200,000 cases/year in EU and USA.|
|5. Acute and chronic bacterial lung infectionsDK PA201470113 “Com-positions for treating lung infections by airway administration”.||Estimated 820,000 cases/year in EU and USA (excluding bronchiectasis in COPD, which has a prevalence of 9-17 million).|
Reponex’s clinical pipeline
This consists of the five clinical development projects shown in the preceding overview Table. Common to
the projects is the use of recombinant human GM-CSF, molgramostim, which is applied locally to the site of the pathology on which it is intended to act, and can therefore be used in much smaller doses than systemic administration. In four of the projects, molgramostim is combined with the antibiotic fosfomycin, and sometimes with an additional antibiotic, which is applied locally with the molgramostim in the same preparation. Fosfomycin has been chosen as the lead antibiotic because of its exceptionally broad antibacterial spectrum and its remarkable lack of toxicity, so that it allows molgramostim to exert its stimulating action on defensive effector cells without this being abrogated by any cytotoxic effect of the antibiotic. In the dermatological project, the molgramostim may be applied together with the wound-healing substances hyaluronan and sucralfate, which have a documented independent effect to promote
wound healing through other mechanisms than molgramostim, while also being capable of protecting
molgramostim from degradation and prolonging its action. These projects illustrate Reponex’s three-limb strategy of drug repositioning, rerouting and recombination.
Secure supply of pharmaceutical-grade molgramostim
An essential aspect of the rapid start-up of the proposed clinical development projects is that Reponex has negotiated access to pharmaceutical grade molgramostim from an independent pharmaceutical Company. This company will be the initial and in all probability the long-term source of the pharmaceutical-grade molgramostim necessary for Reponex’s clinical projects and subsequent sales. An agreement to this effect has been made with the strategic partner.
Access to toxicological data from animal studies and clinical phase I results for molgramostim
Reponex has access to toxicological data generated from an animal study and a clinical phase 1 study on inhaled molgaramostim. This data is expected to confirm the safety of inhaled molgramostim. The safety of inhalation and other modes of topical administration, including dermatological use, of a closely similar type of recombinant human GM-CSF (sargramostim, expressed in yeast cells) has already been extensively documented by off-label use of this registered pharmaceutical agent.
Clinical phase II studies
Reponex’s access to the molgramostim clinical phase I data will enable the company to proceed directly to clinical phase II studies of its preparations, depending on the resources that can be mounted to initiate the studies.
Independent external evidence of efficacy and safety of locally applied GM-CSF
For some of the projects, existing studies by independent external groups provide evidence for the safety and efficacy of the certain aspects of the proposed local treatment. Evidently, these cannot cover all the aspects of Reponex’s treatments, which would otherwise not be patentable. The supporting independent evidence is referenced under the specific project descriptions.