Heberprot-P: A Novel Product for Treating Advanced Diabetic Foot ...

Heberprot-P: 

A Novel Product for Treating Advanced Diabetic Foot Ulcer 

DIABETIC FOOT ULCER: A SERIOUS COMPLICATION 

Diabetes mellitus (DM) is a noncommunicable endocrine disease 

increasing in global incidence. Lower extremity ulceration is a 

main complication and often leads to amputation.[1] 

In DM, failure in the repair process of distal peripheral soft tissues 

leads to the characteristic appearance of chronic wounds. 

These exhibit protracted cellular and noncellular infl ammatory 

reactions that hinder transition to the granulation phase, inhibiting 

edge contraction and slowing re-epithelialization. Hyperglycemia 

is the proximal trigger of numerous processes that lead to a proinfl 

amed, pro-oxidant and pro-degradative phenotype in such diabetic 

wounds.[2,3] 

Evidence shows that diabetic patients have decreased concentrations 

of growth factors in their tissues, notably epidermal 

growth factor (EGF). This shortage impairs natural wound healing 

and leads to chronic nonhealing wounds, diabetic foot ulcers 

(DFU), which in later stages can require limb amputation. More 

than half of DFU patients also have peripheral vascular disease, 

characterized by impaired lower limb blood circulation that leads 

to lack of oxygenation in the foot (known as ischemic foot). Ischemic 

DFUs are the most diffi cult to treat and at highest risk of 

amputation. 

DM is the leading cause of nontraumatic amputation in the US,[4] 

resulting in more than 70,000 amputations in 2008.[5] In Brazil, 

DM is now thought to affect more than 7% of the adult population, 

and many of these patients fi nd it diffi cult to maintain good glycemic 

control.[6] The estimated diabetic population in Cuba is about 

450,000; and there are 15,000 new cases of DFU every year. 

Between 3000 and 5000 of these patients are at risk of amputation.[7] 

MEDICC Review, January 2013, Vol 15, No 1 

Special Article 

Jorge Berlanga DVM MS PhD, José I. Fernández MD, Ernesto López MS, Pedro A. López MD PhD, Amaurys del Río MD, 

Carmen Valenzuela MS, Julio Baldomero MD, Verena Muzio MD PhD, Manuel Raíces PhD, Ricardo Silva PhD, 

Boris E. Acevedo MD PhD, Luis Herrera MD PhD 

ABSTRACT 

Diabetic foot ulcer is a principal diabetic complication. It has been shown 

that diabetic patients have decreased growth factor concentrations in 

their tissues, particularly epidermal growth factor. Growth factor shortage 

impairs wound healing, which leads to chronic nonhealing wounds 

and sometimes eventual amputation. Ischemic diabetic foot ulcer is the 

most diffi cult to treat and confers the highest amputation risk. 

Injecting epidermal growth factor deep into the wound bottom and contours 

encourages a more effective pharmacodynamic response in terms 

of granulation tissue growth and wound closure. Epidermal growth factor 

injected into the ulcer matrix may also result in association with extracellular 

matrix proteins, thus enhancing cell proliferation and migration. 

Heberprot-P is an innovative Cuban product containing recombinant 

human epidermal growth factor for peri- and intra-lesional infi ltration; evidence 

reveals it accelerates healing of deep and complex ulcers, both 

ischemic and neuropathic, and reduces diabetes-related amputations. 

Clinical trials of Heberprot-P in patients with diabetic foot ulcers have 

shown that repeated local infi ltration of this product can enhance healing 

of chronic wounds safely and effi caciously. As a result, Heberprot- 

P was registered in Cuba in 2006, and in 2007 was included in the 

National Basic Medications List and approved for marketing. It has 

been registered in 15 other countries, enabling treatment of more than 

100,000 patients. 

Heberprot-P is a unique therapy for the most complicated and recalcitrant 

chronic wounds usually associated with high amputation risk. 

Local injection in complex diabetic wounds has demonstrated a favorable 

risk–benefi t ratio by speeding healing, reducing recurrences and 

attenuating amputation risk. Further testing and deployment worldwide 

of Heberprot-P would provide an opportunity to assess the product’s 

potential to address an important unmet medical need. 

KEYWORDS Diabetic foot ulcer, Heberprot-P, amputation, healing, 

unmet medical need, rhEGF, Cuba 

In 2007, treatment of DM and its complications in the USA generated 

some $116 billion in direct and $58 billion in indirect costs. 

[8] At least one third of direct costs were linked to DFU treatment. 

[9] There, estimated two-year followup costs for a DFU amputee 

range from $80,000 to $110,000.[10] 

Antimicrobial agents, surgical techniques and a broad variety 

of therapeutic approaches based on drugs and devices have 

been applied to DFUs.[11–14] These interventions have shown 

limited clinical success, even when included in a comprehensive 

wound care program,[15] and there is no evidence of 

impact on amputation rates. Short-term recurrences remain a 

problem hampering clinical effectiveness of some contemporary 

therapies.[16] 

Topical application of human growth factor dates back almost 30 

years, when it sparked hopes of a ‘magic bullet’ for tissue healing. 

Two main factors quenched that initial excitement: the almost 

simultaneous fi nding from basic science that growth factors were 

involved in malignant growth[17] and disappointing results from a 

rigorous clinical trial in which EGF was topically administered to 

acute, experimentally-induced, controlled wounds in healthy volunteers.[18] 

The need to precondition the chronic wound bed and 

to ensure local growth factor bioavailability for subsequent receptor 

stimulation and downstream signaling activation emerged as 

paradigmatic concepts.[19,20] 

RATIONALE FOR GROWTH FACTOR WOUND 

INFILTRATION 

In Cuba, epithelial response to daily topical administration of 

three different EGF concentrations formulated in a semisolid 

cream was examined; results suggested a possible reduction 

of EGF bioavailability by proteases derived from noninfected, 

Peer Reviewed 

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acute, controlled wounds.[21] This was somewhat surprising 

as other studies had already established proteolysis affecting 

growth factors and their receptors in chronic circumstances.[22,23] 

It is worth noting that previous studies had 

also documented the need for prolonged interaction between 

EGF and its receptor to achieve a significant granulation tissue 

response in controlled wounds in mice.[24] Our initial 

research indicated 125 I-EGF was rapidly cleared from the 

application site, probably by protease-driven cleavage and 

receptor-mediated endocytosis. Mean residence time values 

suggested that over 60% of the amount administered could 

have disappeared as early as two hours after administration. 

[25] The message of these studies was that even acute, clean 

and controlled wounds may not represent a hospitable substrate 

for growth factor physical and chemical integrity. Previous 

disappointing clinical results may have been due to local 

bioavailability limitations.[26,27] 

Such knowledge prompted the hypothesis that injecting EGF 

deep into the wound base and walls would allow for greater 

pharmacodynamic response in terms of granulation tissue 

growth and wound closure. In further studies, single or repeated 

EGF systemic or local injections produced clear-cut cytoprotective 

and proliferative responses, suggesting an intrinsic ability 

of EGF at supraphysiological concentrations to trigger biological 

events necessary for tissue repair.[28–30] 

Injecting EGF into the tissue, down and inside the base and 

walls (including the dermo-epidermal junction), possibly also 

reduces its degradation following topical application and 

contact with wound exudate. These experiments identified 

three layers of cellular response potential along the longitudinal 

axis of granulation tissue. Fibroblasts populating 

the more superficial stratum expressed far more prohibitin 

and far less EGF receptor. Advanced glycosilated endproducts 

and elastase also appeared overexpressed next to the 

wound surface than in deeper cells strata. It is likely that 

topographic positioning along the wound bed axis dictates 

fibroblasts’ intrinsic ability to respond to a mitogenic signal. 

Notably, prohibitin is a renowned inhibitor of cell cycle progression.[31] 

Contemporary evidence supports that EGF 

injected into the ulcer matrix may result in an association 

complex with extracellular matrix proteins, thus enhancing 

cell proliferation and migration.[32] 

Classic studies have shown that growth factor effectively 

counteracts senescence of chronic ulcer-derived fi broblasts— 

including diabetic ulcer fi broblasts—and stimulates proliferation.[33,34] 

Appropriate wound bed preparation through sharp 

debridement and infection elimination is required prior to infi ltration. 

HEBERPROT-P IMPROVES HEALING AND REDUCES 

AMPUTATIONS IN PATIENTS WITH SEVERE DFU 

Following earlier research, scientists at the Center for Genetic 

Engineering and Biotechnology (CIGB, the Spanish acronym) in 

Havana developed Heberprot-P, a patented pharmaceutical composition 

whose parenteral formulation is based on rhEGF. The 

product is administered in DFU patients by intralesional infi ltration 

to accelerate healing of deep and complex ulcers, either neuropathic 

or ischemic.[35] 

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Based on the rationale that rhEGF can enhance healing of chronic 

wounds following repeated local infi ltrations,[36] various clinical 

trials using Heberprot-P in DFU patients have been conducted, 

demostrating safety and effi cacy.[37–43] Infi ltration with rhEGF 

for diabetic wound healing does not replace standard procedures 

but should be incorporated into comprehensive wound care along 

with medical interventions to correct patients’ glycemia and creatinine. 

In a compassionate study with terminal ulcer patients in 2001– 

2002, the fi rst clinical evidence using EGF infi ltration for diabetic 

foot ulcers and amputation residual bases emerged.[37] All lesions 

were chronic, complex and recalcitrant, Wagner scale stages 3 

and 4.[36] Effi cacy demonstrated in these types of wounds paved 

the way for solid clinical development, which culminated in a 

nationwide, double-blind, placebo-controlled phase III clinical trial, 

duly registered with the appropriate Cuban regulatory agency.[39] 

Since then, EGF local injection has been used for complex diabetic 

wounds in various Cuban clinical trials, demonstrating a 

favorable risk–benefi t balance by speeding healing, reducing 

recurrences and attenuating amputation risk.[43] Adverse effects 

were preponderantly mild to moderate (65.6% mild, 28.6% moderate, 

and only 3.7% severe), with pain and burning sensation 

at administration site the most frequent. Pain reported was mild 

to moderate in intensity and was not associated with treatment 

suspension. A dose-effect relation associated with appearance of 

shivering and chills was consistently obtained in all trials at both 

doses used (25 μg and 75 μg) and in the pooled analysis; intensity 

was mild to moderate and symptom appearance was not associated 

with treatment suspension.[39] 

EGF infi ltration increased and accelerated healing in poor-prognosis 

wounds toward a rapid and sustained response (Figure 1). 

More than 80% granulation was obtained globally with Heberprot- 

P, in comparison with less than 60% with standard care alone. Of 

patients treated with Heberprot-P at 75 μg, three times per week 

until complete granulation (or during 8 weeks) in association with 

standard care, 77% healed; while only 56% healed with placebo 

injections and standard care.[40] Seminal clinical trials are summarized 

in Table 1. 

As a result, Heberprot-P was registered in Cuba in 2006, and 

in 2007 was included in the National Basic Medications List 

and approved for marketing. Heberprot-P has also been registered 

in 15 other countries (Table 2) enabling treatment of over 

100,000 patients. Registration and market approval submissions 

are in process in countries such as Brazil, Russia, China, 

South Africa, and the Arab states of the Persian Gulf. A Spanish 

phase II clinical trial for the DFU indication, approved by the 

Spanish Drug Agency under European Good Clinical Practices, 

concluded recently (publication pending), with the aim of moving 

to a pivotal phase III clinical trial in Europe. 

EFFECTIVE COMPREHENSIVE DFU TREATMENT: 

AN UNMET MEDICAL NEED 

Adjuvant therapies and advanced technologies can be used in 

addition to standard care as a second line of treatment when 

appropriate. These include some topical drugs but are mostly 

medical devices: living skin equivalents, specialized dressings, 

hyperbaric oxygen therapy and negative pressure devices. These 

interventions provide moderate improvement over standard treat- 

MEDICC Review, January 2013, Vol 15, No 1

Figure 1: Severe diabetic foot ulcers treated with Heberprot-P 

Ischemic Patient A 

Before fi rst injection of Heberprot-P: 11.9 cm 2 

After seven weeks’ treatment: 1.1 cm 2 

At week 11: healed 

Photos: Dr A del Río Martín 

(available in color online at www.medicc.org/mediccreview/berlanga.html) 

Table 1: Seminal clinical trials with Heberprot-P 


Ischemic Patient B 

Before fi rst injection of Heberprot-P: 21.8 cm 2 

After seven weeks’ treatment: 0.5 cm 2 

At week 11: healed 


Trial Details Results Ref. 

Phase I: Exploratory 

Phase II: Treatment 

dose determination 

Phase II: Treatment 

dose determination 

Phase III: Confi rmatory 

trial 

Phase IV: 

Pharmacovigilance 

DFU: diabetic foot ulcer 

Patients with poor prognosis, 25 μg three times a week, 

until granulation or 8 weeks 

25 μg or 75 μg three times a week, until granulation or 

8 weeks 

25 μg or 75 μg three times a week, until healing or 8 

weeks 

Double-blind placebo-controlled multicenter study, 25 

μg versus 75 μg versus placebo (all 3 times a week) 

Good safety pattern 

Promising results in granulation, healing and 

amputation avoidance 

Good safety pattern in both doses 

Trend to greater effi cacy at 75 μg 

Trend to greater effi cacy when treatment is 

prolonged until healing 

Confi rm effi cacy (granulation and healing) and 

safety in patients with Wagner 3−4 DFUs 

Pharmacovigilance study in 1835 patients Confi rmation of safety profi le Unpublished 

Peer Reviewed 

37 

38 

39 

40 

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ments, generally only 15% to 20% healing in less than 20 weeks, 

and may be expensive and time consuming.[44] In ischemic 

patients, surgical revascularization is not suitable for all cases and 

Table 2: Heberprot-P registration year by country 

Country Registration Year 

Cuba 2006 

Algeria 2008 

Argentina 2009 

Uruguay 2009 

Dominican Republic 2009 

Venezuela 2010 

Ecuador 2010 

Mexico 2010 

Paraguay 2010 

Libya 2010 

Colombia 2011 

Guatemala 2011 

Georgia 2011 

Ukraine 2011 

Vietnam 2012 

Philippines 2012 

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Peer Reviewed 

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In the USA, 8.3% of the population—25.8 million people—have 

DM,[46] and therefore an estimated 25% lifetime risk of developing 

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The estimated number of US DFU patients in 2010 was between 

3.9 and 4.6 million. Among these, 2.5 million patients had concomitant 

ischemia and hence were at greater risk of complications.[49] 

Heberprot-P would address the therapeutic needs of this population, 

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wounds that are the most diffi cult to heal. 

Further testing of Heberprot-P—a unique and fi rst-in-class 

therapy to treat the most complicated and recalcitrant chronic 

wounds with a high risk of amputation— would provide an 

opportunity to assess the product’s potential to address this 

vast unmet medical need in different populations and settings 

worldwide. 

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Peer Reviewed 


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THE AUTHORS 

Jorge Berlanga Acosta, veterinarian with a 

master’s degree in pathology and a doctorate in 

pharmacology, Center for Genetic Engineering 

and Biotechnology (CIGB), Havana, Cuba. 

José I. Fernández Montequín, angiologist and 

vascular surgeon, National Institute for Angiology 

and Vascular Surgery, Havana, Cuba. 

Ernesto López Mola, nutritional pharmacist 

with a master’s degree in biotechnology, CIGB, 

Havana, Cuba. 

Pedro A. López Saura, clinical biochemist with 

a doctorate in biology, CIGB, Havana, Cuba. 

Amaurys del Río Martín, medical immunologist, 

CIGB, Havana, Cuba. 

Carmen Valenzuela Silva, mathematician, CIGB. 

Julio Baldomero Hernández, family physician, 

CIGB, Havana, Cuba. 

Verena Muzio González, immunologist with a 

doctorate in biology, CIGB, Havana, Cuba. 

Manuel Raíces Pérez, biologist. Business and 

Projects Development Division, CIGB, Havana, 

Cuba. 

Ricardo Silva Rodríguez, biologist, CIGB, 

Havana, Cuba. 

Boris E. Acevedo-Castro (Corresponding 

author: boris.acevedo@cigb.edu.cu), physician 

with a doctorate in medical sciences, CIGB, 

Havana, Cuba. 

Luis Herrera Martínez, geneticist with a doctorate 

in biology. Director General, CIGB, Havana, 

Cuba. 

Submitted: September 14, 2012 

Approved for publication: January 15, 2013 

Disclosures: All authors except Fernández are 

employed at CIGB, developer of Heberprot-P 

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Heberprot-P: A Novel Product for Treating Advanced Diabetic Foot ...

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