Inhalation preparation of molgramostim for the prevention and treatment of lung dysfunction due to radiation and/or cancer chemotherapy
Indications for use
- Radiation lung injury due to radiotherapy to the chest region, e.g. in the treatment of breast and lung cancer and Hodgkin’s disease.
- Acute and chronic radiation syndrome due to industrial exposure, accidents or hostile acts.
- Lung injury due to or exacerbated by cancer chemotherapy.
The first indication affects 7% of all patients receiving radiotherapy to the chest. There are no published patient numbers for the US and EU, but a crude estimate can be made that there are at least 200,000 cases per year.
Pathology, symptoms and consequences
At radiation doses above about 2 Gy the lungs may be damaged. Free radicals are produced in the cells which exceed scavenging capabilities and airway epithelial cells may die. About 4-12 weeks after a course of radiotherapy an inflammatory response results in edema and infiltration of the lung tissue with inflammatory cells, together with the occlusion of small airways and blood vessels. This is referred to as radiation pneumonitis. These changes are followed by the longer term development of pulmonary fibrosis. With higher radiation doses, as may be seen in nuclear incidents, the time course may be shortened and initial symptoms appear within a few days. These will typically be cough, shortness of breath and chest discomfort or pain. There is increased susceptibility to lung infections, which may be lethal. The damaging process may cease while the patient still retains enough pulmonary function to maintain life, or the disease may progress to acute respiratory distress syndrome and eventual death from pulmonary fibrosis. A similar type of lung damage may be seen with the use of cytotoxic chemotherapeutic agents for cancer. Bleomycin is the agent most commonly involved, but other cytotoxic agents may also damage the lung.
Glucocortocosteroids can reduce the severity of acute radiation pneumonitis, but apart from that, treatment is palliative.
Improved treatment by the inhalation of molgramostim
The lungs have their own host defense system, based on alveolar macrophages, which are also damaged by radiation exposure. While systemic administration of GM-CSF will not restore alveolar macrophage function as it does not penetrate into the alveoli, inhaled GM-CSF can reach the quiescent alveolar macrophages and transform them into fully immunocompetent dendritic cells which orchestrate the natural repair mechanisms in the lungs. It is recommended that preemptive treatment should be initiated after suspected exposure of a radiation dose of at least ∼2 Gy by prompt daily inhalation of molgramostim for at least 2-3 weeks.
Reponex has filed the patent applications WO2012136224 and WO2013029627 “Compositions and methods for treating or preventing radiation or chemotherapy induced pulmonary dysfunction”, which seeks protection for inhaled molgramostim for these indications.
Systemic side effects after intrapulmonary 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 airways into the systemic circulation because of its molecular size.
Reponex has access to the medicinal product and the inhalation device. After agreement has been reached with the clinicians who are to design and run the clinical study, the development will proceed directly to a clinical phase II study in Europe, which is expected to take approximately 36 months.
Department of Respiratory Diseases, Bispebjerg Hospital, Copenhagen, Denmark; Consultant physician Henrik Permin MD.