Topical dermatological preparations containing molgramostim for the treatment of non-healing wounds and skin ulcers
Indications for use
Non-healing wounds and skin ulcers are typically associated with diabetes mellitus, venous insufficiency, pressure, and ischemia. Together, these affect more than 1% of the industrialized world’s population. In the US they may affect up to 6 million people, and at least as many are affected in EU.
Pathology, symptoms and consequences
Common to the causes of non-healing wounds and ulcers is the deficient local blood supply, which fails to provide the nutritional means of keeping the cells involved in healing fully active. White blood cells and macrophages fail in their housekeeping functions, and the macrophages fail to provide their normal stimulation of repair functions. The consequences are that the skin remains ulcerated for months or even years, seriously impairing the patient’s quality of life because of physical disability, pain, and having to devote considerable time just to dress the ulcers and control weeping exudation. The economic costs to society are huge (total annual cost in the US estimated at USD 3 billion).
It should be noted that all chronic wounds and ulcers are colonized by bacteria, but more than half may at some stage be more aggressively infected by pathogenic bacteria including Staphylococcus aureus and Pseudomonas aeruginosa. This means that Reponex’s clinical development project is divided into two parts:
1a. Molgramostim dermatological preparations for wounds that are not seriously infected.
1b. Molgramostim combinations for bacterially infected wounds.
This is a complex matter on which textbooks and review articles are continually being written. Treatment includes debridement of necrotic tissue, infection control and local wound care. For each category of non-healing wound, specialized treatment modalities have to be implemented. For diabetic foot ulcers, for example, attention has to be paid to mechanical off-loading, tight blood glucose control and patient education on foot care. For venous ulcers, special measures typically include mechanical compression and limb elevation to reverse tissue edema and improve venous blood flow. Care for ulcers caused by arterial insufficiency is centered on reestablishing blood flow and minimizing further loss of tissue perfusion. For pressure ulcers, off-loading methods or devices are the gold standard of treatment. There is continuing need to improve treatment methods and accelerate healing; it is this aspect which is addressed by Reponex’s clinical development project.
Improved treatment with topical dermatological preparations containing molgramostim
Applying GM-CSF to the non-healing wound tends to restore the failing housekeeping functions of the neutrophils and macrophages and to render the macrophages capable once more of orchestrating the repair processes, thus accelerating healing.
Independent evidence of efficacy
The accelerating effect of locally applied GM-CSF on wound healing has been attested by a large number of studies published since the early 1990s on the off-label use of GM-CSF to this end, more than can conveniently be cited here.
1a. Topical molgramostim preparations for non-infected (bacterially colonized) wounds
i) Molgramostim gel
Reponex believes that there has long been a case for providing a simple topical preparation of molgramostim, such as a cream or gel, that can be applied directly to the wound or ulcer to accelerate healing. Studies of this hitherto off-label use of GM-CSF have varied and sometimes inconvenient protocols from a practical point of view, e.g. involving multiple intradermal injections around the wound margins. Making available a convenient molgramostim preparation for local application fulfills the need of a waiting market.
This product cannot be patented, as the principle is known to prior art without having been appropriately exploited.
ii) Potentiated molgramostim topical preparations with additives
Additives can promote the synthesis and assembly of key extracellular matrix components, such as the interstitial collagens, during wound healing and potentiates the effects of intrinsic cytokines and growth factors involved in wound healing, e.g. basic fibroblast growth factor, by binding them and protecting them from degradation so that their effect in the healing wound is prolonged. This effect may also be expected when applied together with GM-CSF. The components of the topical preparation are expected to act additively or synergistically through their different pathways to accelerate wound and ulcer healing.
Accordingly, Reponex will develop and clinically test topical preparations for accelerating wound healing. These are expected to show greater efficacy than preparations with molgramostim alone.
The combination is a new concept and Reponex has filed the patent application DK PA201470300 “Compositions for promoting the healing of wounds” which seeks protection for this type of composition.
1b. Topical molgramostim combinations for bacterially infected wounds
As stated above, a high proportion of non-healing wounds and skin ulcers will be frankly infected with pathogenic bacteria. While topical molgramostim alone will act to strengthen the local defense against bacterial infection, mediated by neutrophils and macrophages, the elimination of bacteria will be accelerated by the provision of a high local concentration of an effective antibiotic. Fosfomycin is particularly suitable, as its broad spectrum covers most of the relevant pathogenic organisms, including methicillin-resistant Staphylococcus aureus (MRSA), other antibiotic-resistant bacteria and many common strains of Pseudomonas aeruginosa. At the same time, it is remarkably non-toxic to the patient and to the effector cells, the neutrophils and macrophages, that provide the biological defense mechanism. If bacterial culture from the wound should exceptionally detect an organism that is relatively insensitive to fosfomycin, preparations containing an additional antibiotic can be used.
The use of topical antibiotics in wound healing is sometimes regarded as counterproductive, in that bacterial resistance to the antibiotic may develop quite rapidly, making further treatment ineffective and maybe generating another resistant strain that could persist in the community. These considerations are not expected to apply to the topical use of fosfomycin, which will be applied in a high local concentration. Any bacterial resistance that develops will be due to the suppression of a biochemical pathway within the bacterium which itself leads to a weakening of the virulence and viability of the organism. Thus the widespread use of fosfomycin in other countries has not led to an increase in resistant strains in the community.
Nevertheless, to preserve maximum efficacy, Reponex will recommend that the antibiotic preparation be used for 1-week periods, separated by 3-week periods during which the molgramostim preparations without antibiotic are used.
The combination of molgramostim with fosfomycin is a new concept and Reponex has filed the patent application DK PA201470059 “Compositions to promote the healing of skin ulcers and wounds”, which seeks protection for this type of composition.
No significant adverse effects have been reported for the topical use of the active substances in the proposed preparations. Systemic side effects after topical administration of GM-CSF, e.g. in the form of neutrophil leukocytosis, are not expected, as GM-CSF is not expected to pass from the wound base into the systemic circulation because of its large molecular size and the diffusion barriers to its translocation.
Negotiations are in progress with a strategic partner in the dermatological field. On reaching the necessary manufacturing and testing agreements, the development will proceed directly to clinical phase II studies in Europe, which are expected to take approximately 18 months. Agreements on clinical testing has been concluded with a Danish University Hospital.
Dermatological Department and Center for Wound Healing, Bispebjerg Hospital, Copenhagen, Denmark; Administrative chief physician Tonny Karlsmark, MD, Professor Finn Gottrup, MD. An international partner will also be sought.
Relevant publications: 1. Gottrup F, Karlsmark T (eds) (2008) Sår – baggrund, diagnose og behandling. 2nd ed., Copenhagen: Munksgaard. 2. Gottrup F, Jørgensen B, Karlsmark T (2009) News in wound healing and management. Curr Opin Support Palliat Care 3:300-304