The effect of the hr-EGF on the restoration of damages on peripherals nerves after sever traumas was studied at CIGB in the 90s. Local infiltrations of hr-EGF have shown to be effective to reduce the consequences of neurogenic ischemia, and to protect peripheral soft tissue. Pre-clinical evidences allowed developing the product Heberprot-P®, a pharmaceutical formulation containing hr-EGF to be applied through peri and intralesional infiltration, which constitutes a treatment to accelerate the healing deep and complex ulcers, including ischemic and neuropathic ulcers, derived from this metabolic disorder. After proof of concept demonstrated that Heberprot-P® contributed to the restoration of the granulation tissue, which is the joining material of tissues after open traumas, the CIGB and the National Institute of Angiology and Vascular Surgery (INACV) used this product in a pilot clinical trial, between 2001 and 2002, in 29 diabetic patients. Ischemic and critical neuropathic lesions were treated.
The medical criteria to identify patients as candidates for the treatment were grade 3 or 4 ulcers or amputation residual bases, as defined by the Wagner’s classification. All the ulcers had to exceed 20 cm2 and 25 days of torpid evolution after hospital admission, with granulation failure and atonic contours aspect following repeated sharp debridements 4 and conventional treatment. Residual amputation bases had to show clinical evidences of ischemia and exceed 30 cm2 and 15 days without improvement after frequent debridements and other conventional approaches. In addition, patients had to meet one of the following criteria:
- Target lower extremity with an inadequate blood perfusion as shown by an ankle–brachial index pressure (ABI) <0.7 and a transcutaneous oxygen tension below 30 mmHg, absence of palpable posterior tibialis or dorsal pedis pulse.
- Patients with ABI >0.7 but being considered difficult cases with a high risk of amputation due to extensive neuropathy, failing to granulate with standard wound care and with previous amputations.
No distinction was given to the topographic localisation of the wound on the lower extremity. Patients were included irrespective of their diabetes evolution time and type, specific medication for the diabetes control, gender or age. Patients with malignant diseases as well as pregnant or nursing women, patients with autoimmune diseases (except for type 1 diabetes) or psychiatric disorders or those receiving corticosteroids medication were excluded (Berlanga Acosta, Jorge. et al., (2006). Epidermal growth factor intralesional infiltrations can prevent amputations in patients with advanced diabetic foot wounds. International Wound Journal 3 (3): 232-239).
Despite the limitations of the data, the fact that 86% of the patients, most of them ischemic, showed a productive granulation at the eighth infiltration session and that amputation was prevented in 58% of the study population remarks the efficacy of the infiltrative intervention. Amazing results were obtained during a second clinical trial Fase I-II with 41 patients. 50% of wound healing was observed, and lower limbs amputations were avoided in 66% of patients treated with Heberprot-P® (Fernández-Montequín José F. et al., (2007). Intralesional Injections of Citoprot-P (recombinant human Epidermal Growth Factor) in Advanced Diabetic Foot Ulcers with Risk of Amputation. International Wound Journal Dec; 4 (4): 326-327). After these encouraging results, more than 800 Cuban DFU patients have been treated with Heberprot-P®, and the national extension of the product to 498 hospitals, and the integral management of DFU, are current CIGB’s priorities in collaboration with National Direction of Post-grade and the National Group of Active Screening headquartered at the Minister of Public Health (MINSAP). A randomised, double-blinded, and controlled with placebo clinical trial Phase III was done. Positive results of safety and efficacy one again were obtained, and the product has been approved for commercialization in Cuba. The therapy with Heberprot-P® fills the gap of an unmet medical need for treatment of complex DFU with wound areas between 1 and 80 cm2 in neuropathic and neuro-ischemic patients.
The advantages of this treatment are currently unique at global level:
- Stimulates constant and progressive granulation and healing.
- Reduces the number of debridement and surgical interventions.
- Reduces the number of recidives.
- Reduces the healing time, and therefore, complications derived, such as gangrene and infections, since Heberprot-P® prevents that open wounds become deeper, which would require more debridement and amputation.
- Heberprot-P® prevents that open wounds become deeper, which would require more debridement and amputation.
- Reduces hospitalization costs.
- Improves patient’s life quality.
This result of the Cuban Biotechnology fills all requirements to be introduced not only in the Cuban Health System, but also in countries where DM and its associated complications show a pandemic incidence, with a direct impact on the healing and cure of complex wounds. The novelty of this invention has been claimed by the CIGB in a patent presented in Argentina, Brasil, Canadá, Indonesia, Japón, Malasia, México, Tailandia y Chile. Otorgada en: Australia, China, Corea del Sur, Cuba, Europa, EEUU, Hong Kong, India, Rusia, Singapur, Sudáfrica y Ucrania, and granted in USA, Cuba, México, South Africa, Europe, Russia, Ukrany, China, South Korea, Hong Kong, India, Singapur and Autralia. Heberprot-P® offers an actual and effective solution to a serious medical and social problem.
The costs of diabetes-related foot ulcers and amputations in the US, Germany and the UK have been estimated to be 11 billion USD, 5 billion Euros, and 456 million USD, respectively (Gordois A, et al. “The health care costs of diabetic peripheral neuropathy in the US”. Diabetes Care 2003, 26 (6): 1790-1795; “The healthcare costs of diabetic peripheral neuropathy in healthcare costs of diabetic peripheral neuropathy in the UK”. The Diabetic Foot 2003, 6 (1): 62-73; Nord D. “Cost-effectiveness in wound care”. Zentralbl Chir. 2006, 131 (Suppl 1): S185-8). The costs of ulcer care for 2 years were estimated to be 27 987 USD/patient (Ramsey SD, et al. “Incidente, outcomes, and costs of foot ulcers in patients with diabetes”).
Diabetes Care 1999, 22 (3): 382-387). A wide variability of cost data has also been reported in literature. It has been estimated a cost ranging 14 641 – 17 096 USD/patient for DFU chronic patients, and 13 758 USD/patient for patients with osteomyelitis. The cost of debridement in patients with lower-extremity ulcers was estimated in the range between 5064 and 7104 USD/patient. Data from Sweden, suggested a wider range of DFU costs between 1000 and 17 500 USD/patient, and costs of amputations in the range 16 500 – 66 200 USD/patient (Tennvall RG, Apelqvist J. “Health-economic consequences of diabetic foot lesions”. Clin. Inf. Dis. 2004, 34 (Suppl 2): S132-9). In other studies, the cost of ulcer healing was estimated as 16 500 USD/patient, for patients whose wounds healed without severely impaired circulation (ischemia); and as 27 000 USD/patient for those with ischemia. Minor amputation had 44 000 USD/patient health-related costs, and the cost of a major amputation was 63 000 USD/patient (Apelqvist J, et al. “Long-term costs for foot ulcers in diabetic patients in a multidisciplinary setting”. Foot Ankle Int. 1995, 16 (7): 388-394). Reports on the current costs of Wargner’s grades III and IV ulcer treatments have not been found in literature.