The company is focused on developing ropocamptide for healing of venous leg ulcers, but also sees a strong potential to develop ropocamptide for use in the treatment of diabetic foot ulcers. Promore Pharma estimates that the probabilities are strong to obtain market authorization for ropocamptide in the treatment of venous leg ulcers based on data from a future Phase III program.
The drug candidate is administered as a gel (active peptide in a synthetic carrier), locally on the wound, two to three times per week by a nurse or in some cases by the patient. Ropocamptide is developed to be used in conjunction with regular dressing changes of the wound. Consequently, it is not necessary to change the principal medical practice in the wound management.
Mechanism of Action
Ropocamptide is part of a human antimicrobial protein (LL-37 cathelicidin) which is an important constituent in the natural wound healing process. In acute wounds, endogenous LL-37 is present in the wound edge, and the amount of the peptide is typically increased within a few hours after an injury (1). During the normal wound healing process, wounds begin to heal from the edge and then toward the wound center; hence it is important that endogenous LL-37 is present in the wound bed. Venous leg ulcers lack endogenous LL-37 in the wound, unlike all acute wounds. By adding ropocamptide to a venous leg ulcer, it is assumed that the body’s wound healing process is restarted and that the chronic wound becomes more like an acute wound that usually heals rapidly. It is not yet determined how endogenous LL-37 stimulates wound healing, but the peptide impacts several biological mechanisms of relevance in wound healing. The peptide attracts inflammatory cells, including monocytes and granulocytes. It is postulated that LL-37 modulates the inflammatory phase of wound healing through release of proteins and peptides that govern the inflammatory sequence (cytokines) (2). Keratinocytes (skin epithelial cells) are activated by LL-37, which in turn results in activation of growth factors in outer skin layer with a consequent cell migration. This is assumed to result in re-epithelization and closure of the wound (3). Additionally, the production of vascular growth factors such as VEGF and the activation of endothelial cells in blood vessels are also important for the formation of new blood vessels that is observed after treatment with ropocamptide (4).
Clinical Study Results
LL-37 has been explored in two randomized blinded clinical trials.
The first of these, a double-blind Phase IIa study (also referred to as a Phase I/IIa trial) included 34 patients with venous leg ulcers; a study where safety and tolerability were the primary endpoint (5). The patients were randomized in four different groups; three dose strengths of LL-37 and placebo. The trial also included secondary endpoints such a wound area size estimations and wound healing rate.
The two lower doses of LL-37 demonstrated high tolerability and were associated with a pronounced healing: the healing rate being almost six-fold higher than for the placebo group. Treatment for one month with the most efficacious dose resulted in a relative wound area reduction of 75 percent. In contrast, the highest dose was associated with local reactions (redness, pain and effusion). The highest dose did not produce a wound healing effect as compared with the placebo group but was not worse than placebo.
The company has thereafter conducted a clinical Phase IIb trial (HEAL LL-37) of ropocamptide in Sweden and Poland. The study included 144 patients with venous leg ulcers that were randomized into three groups (two doses of ropocamptide and placebo) and the treatment time of the trial was 13 weeks. The study showed that larger wounds (≥10cm2) healed significantly faster among patients treated with ropocamptide as compared with placebo. Patients treated with the most effective dose of ropocamptide, which is 0.5 mg/ml, demonstrated a more than three-fold higher frequency of completely healed wounds. At an aggregated level, where wounds of all sizes included in the study were analyzed, no significant differences can be noted at the whole group level between the three treatment groups.
In patients with larger wounds that were treated with 0.5 mg/ml ropocamptide, 28.1% achieved complete wound healing, in the group treated with 1.6 mg/ml ropocamptide 19.6%, whereas only 8.1% of patients in the placebo group showed complete healing. This difference is statistically significant (p <0.05) for the most effective dose group. When analyzing the proportion of patients who achieved 70% healing of their wounds, a statistically significant advantage could be demonstrated for both dose groups of ropocamptide compared to placebo (p<0.05). The mean reduction in wound size after discontinuation of treatment was 33.7% for patients treated with placebo, and 56.3% for patients treated with the most effective dose of ropocamptide (0.5 mg / ml). Regarding safety and tolerability, no serious side events have been noted that can be considered related to the trial drug.
Other Potential Indications
Diabetic Foot Ulcers
It is probable that ropocamptide may also be efficacious in diabetic foot ulcers. Diabetic foot ulcers, just as venous leg ulcers, lack endogenous LL-37 in the wound edge (6). The company therefore assumes that diabetic foot ulcers may present an opportunity for indication broadening.
(1) Dorschner RA, Pestonjamasp VK, Tamakuwala S, Ohtake T, Rudisill J, Nizet V, Agerberth B, Gudmundsson GH, Gallo RL. (2001). Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J Invest Dermatol, 117(1):91-97.
(2) Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE. (2002). The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol, 169(7):3883-3891.
(3) Tokumaru S, Sayama K et al. (2005). Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J Immunol, 175(7):4662-8.
(4) Koczulla R, von Degenfeld G, Kupatt C, Krotz F, Zahler S, Gloe T, Issbrucker K et al. (2003). An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest, 111(11):1665-72.
(5) Grönberg A, Mahlapuu M, Ståhle M, Whately-Smith C, Rollman O. (2014). Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: A randomized, placebo-controlled clinical trial. Wound Repair & Regenerat, 22(5):613-21.
(6) Rivas-Santiago B et al. (2012) Expression of antimicrobial peptides in diabetic foot ulcer. J Derm Sci, 65(1):19-26