Diabetes Mellitus (DM) is serious health problem with a prevalence of 170-194 millions of people worldwide. This figure could double in the coming years; therefore, the statement of diabetes having more deaths than AIDS in the future.

A graze when walking, a small wound or nuisance in the diabetic can generate an ulcerous lesion, one of more common complications of the diabetic patients. DFU represents a significant source of morbidity and mortality in diabetic patients. Traditional treatments include removal of the necrotic tissue (debridement), revascularization and antibiotic therapy. A great number of diabetic patients do not respond to such treatments, mainly if complications exist (infections, lack of blood irrigation characteristic of the diabetic, and other health conditions), often resulting in patients susceptible to amputation.

Foot ulcers develop in approximately 15% of diabetics, and this condition is a leading cause of hospitalization among such patients. Up to 10-15% of those hospitalized patients will wind up with lower-limb amputations. In United States , for instance, in 2005, the number of diabetic patients reached 20 millions and from them, 84 000 suffered amputations. In Cuba , the prevalence of diabetics is approximately 4.5%, accounting 12 000 DFU/year and 1 800 amputations.

Nearly 50% of the amputated population can suffer from a second amputation of the counter-lateral extremity in a period of 2 to 5 years, which involves the loss of the patients' quality of life, as well as considerable expenses for the health system. The problem gets worse as less than 50% of amputated patients survive in the following 5 years.

New modalities of therapy are claimed to reduce the incidence of lower-limb amputations. There has been a great interest in the use of growth factors in the treatment of diabetic foot ulcers and in fact, one growth factor, topical platelet-derived growth factor (PDGF), has been approved by the FDA for the treatment of diabetic foot ulcers. Regranex or Becaplermin approval is solely restricted to neuropathic foot ulcers. Instead, Heberprot-P offers an attractive alternative for end-stage diabetic foot ulcers patients, either ischemic and/or neuropathic, where the amputation is the only available choice.

Scientists at the CIGB have developed the Heberprot-P product, which is supported by a PCT patent application of use for a pharmaceutical composition containing human recombinant epidermal growth factor (EGF) in an injectable formulation, which is administered by means of infiltration for the treatment of diabetic foot ulcer, to accelerate the healing of deep and complex ulcers, either neuropathic or ischemic, with ankle/arm (A/A) pressure index between 0.3-0.8.

Previous preclinical evidences showing efficacy in the neurogenic ischemia and protection of peripheral tissue have been demonstrated. On the rationale that EGF can enhance healing of chronic wounds following repeated local infiltrations, between 2001-2002 a pilot clinical trial in 29 type-II diabetic patients, to whom the decision to amputate had already been taken, was carried out at the National Institute of Angiology and Vascular Surgery. Patients were classified as ischemic-infectious or neuropathic feet, with ulcers bigger than 20 cm 2 (Stages III - IV of Wagner's classification, wound sized from 13-78 cm 2 ), having chronic diabetic wounds, recalcitrant to heal, with scarce or no granulation tissue (GT), exhibiting poor healing events. Heberprot-P was administered according to the schedule proposed. Efficacy criteria to meet were: 1) to generate a productive GT to support an autologous skin graft and 2) to enhance spontaneous wound closure by a second intention. Heberprot-P therapy succeeded in healing and preserving the feet in 17 out of 29 patients, with 58.6% of efficacy. Heberprot-P intralesional infiltration stimulated and originated a granulation tissue, useful for the healing process, the closure of the wounds by second intention or facilitated the accomplishment of a skin-free graft. This effectiveness was also pronounced in patients with a strong ischemic component.

From 2003-2005, a double-blind, controlled and randomized multi-center phase I-II clinical trial was also conducted in Cuba for the safety and efficacy assessment of Heberprot-P, in patients with Wagner's grades III and IV wounds.

The trial was performed to test two EGF doses in type 1 or 2 diabetes patients. Subjects were randomized to receive 75 (group I) or 25 µg (group II) of EGF through intra-lesional injections, three times per week for 5-8 weeks, along with standard wound care. Endpoints were granulation tissue formation, complete healing and need for amputation. Safety was assessed by clinical adverse events and laboratory evaluations.

The hypothesis was confirmed. At both dose levels, percentages of granulation tissue formation equal or superior to 60% were obtained from the second week of treatment. At the treatment stage (up to 8 weeks), granulation tissue formation in 91.3% of patients from group I and in 72.2% of patients from group II was obtained. Major amputation was avoided in 87.3% of patients (91.3% versus 83.3% in groups I and II, respectively). No relation of causality between adverse events and the product was demonstrated. In the follow-up stage, wound healing, measured by complete closure of the wound, was attained in 53.25% overall, and 66% of patients (including both groups of doses) were rescued from amputation.

The product is registered in Cuba since June 2006 and has recently been approved for commercialization. In addition, a double-blind, multi-center, controlled, randomized Phase III clinical trial is ongoing and due to finish by the end of 2007. Upon starting the national extension in Cuba , the product has been applied to more than 250 DFU patients. Partial results show total response in 83.9% of treated patients. Heberprot-P is available at the Angiology Services of all the municipalities from each province, all over the country.

While much more research is needed, we believe it could be an important first step toward creating an attractive alternative for diabetic foot amputation prevention, which remains an unmet medical need.

At the CIGB we have a product and a unique method of treatment, to be given to the diabetic population suffering of these complex wounds. The treatment has the following advantages: 1) stimulate a useful granulation tissue and a progressive and sustainable healing process, 2) reduce the number of debridements and surgical interventions, 3) reduce the number of recidivisms, 4) reduce the time of healing and then, derived complications such as over-infection, gangrene and amputation, 5) reduce the costs by hospital stay and 6) increase the quality of life and the functional recovery of the patient.

This result of the Cuban Biotechnology, supported by the product's strong intellectual property position and novelty, has all the possibilities to be introduced into those countries where the diabetes and its complications constitute a serious health problem, with a direct impact in the healing and cure of these complex wounds; therefore, giving a real and effective solution to a clinical-social problem.

From the economic point of view, this treatment will allow a substantial saving of sources to the health systems while significantly reducing the healing time and then, the risk of amputation, whose direct costs can reach up to $60 000 USD in developed countries by hospital stay, surgery, concomitant medicines and out-hospital rehabilitation services. Other no less important costs (indirect costs), defined as the value of lost productivity and quality of life from those disabled persons for working or that early die as a result of the damages, associated to their extremities, should be also taken into account.