"The U.S. Food and Drug Administration today expanded the approved use for Eylea (aflibercept) injection to treat diabetic retinopathy in patients with diabetic macular edema.
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Mechanism of Action
REGRANEX Gel has biological activity similar to that of endogenous platelet-derived growth factor, which includes promoting the chemotactic recruitment and proliferation of cells involved in wound repair and enhancing the formation of granulation tissue.
Clinical pharmacodynamic studies have not been conducted.
Ten patients with Stage III or IV (as defined in the International Association of Enterostomal Therapy (IAET) guide to chronic wound staging,1,2 lower extremity diabetic ulcers received topical applications of becaplermin gel 0.01% at a dose range of 0.32-2.95 µg/kg (µg/cm2) daily for 14 days. Six patients had non-quantifiable PDGF levels at baseline and throughout the study, two patients had PDGF levels at baseline which did not increase substantially, and two patients had PDGF levels that increased sporadically above their baseline values during the 14 day study period.
Animal Toxicology and/or Pharmacology
In nonclinical studies, rats injected at the metatarsals with 3 or 10 mcg/site (approximately 60 or 200 mcg/kg) of becaplermin every other day for 13 days displayed histological changes indicative of accelerated bone remodeling consisting of periosteal hyperplasia and subperiosteal bone resorption and exostosis. The soft tissue adjacent to the injection site had fibroplasia with accompanying mononuclear cell infiltration reflective of the ability of PDGF to stimulate connective tissue growth, [see INDICATIONS]
The effects of REGRANEX Gel on the incidence of and time to complete healing in lower extremity diabetic ulcers were assessed in four randomized controlled studies. Of 922 patients studied, 478 received either REGRANEX Gel 0.003% or 0.01%. All study participants had lower extremity diabetic neuropathic ulcers that extended into the subcutaneous tissue or beyond (Stages III and IV of the IAET guide to chronic wound staging). Ninety-three percent of the patients enrolled in these four trials had foot ulcers. The remaining 7% of the patients had ankle or leg ulcers. The diabetic ulcers were of at least 8 weeks duration and had an adequate blood supply (defined as Tcp02 > 30 mm Hg). In the four trials, ninety-five percent of the ulcers measured in area up to 10 cm2, and the median ulcer size at baseline ranged from 1.4 cm2 to 3.5 cm2. All treatment groups received a program of good ulcer care consisting of initial complete sharp debridement, a non-weight-bearing regimen, systemic treatment for wound-related infection if present, moist saline dressings changed twice a day, and additional debridement as necessary. REGRANEX Gel 0.003% or 0.01% or placebo gel was applied once a day and covered with a saline moistened dressing. After approximately 12 hours, the gel was gently rinsed off and a saline moistened dressing was then applied for the remainder of the day. Patients were treated until complete healing, or for a period of up to 20 weeks. Patients were considered a treatment failure if their ulcer did not show an approximately 30% reduction in initial ulcer area after eight to ten weeks of REGRANEX Gel therapy.
The primary endpoint, incidence of complete ulcer closure within 20 weeks, for all treatment arms is shown in Figure 1. In each study, REGRANEX Gel in conjunction with good ulcer care was compared to placebo gel plus good ulcer care or good ulcer care alone. In Study 1, a multicenter, double-blind, placebo controlled trial of 118 patients, the incidence of complete ulcer closure for REGRANEX Gel 0.003% (n=61) was 48% versus 25% for placebo gel (n=57; p=0.02, logistic regression analysis).
In Study 2, a multicenter, double-blind, placebo controlled trial of 382 patients, the incidence of complete ulcer closure for REGRANEX Gel 0.01% (n=123) was 50% versus 36% for
REGRANEX Gel 0.003% (n=132) and 35% for placebo gel (n=127). Only REGRANEX Gel 0.01% was significantly different from placebo gel (p=0.01, logistic regression analysis).
The primary goal of Study 3, a multicenter controlled trial of 172 patients, was to assess the safety of vehicle gel (placebo; n=70) compared to good ulcer care alone (n=68). The study included a small (n=34) REGRANEX Gel 0.01% arm. Incidences of complete ulcer closure were 44% for REGRANEX Gel, 36% for placebo gel and 22% for good ulcer care alone.
In Study 4, a multicenter, evaluator-blind, controlled trial of 250 patients, the incidences of complete ulcer closure in the REGRANEX Gel 0.01% arm (n=128) (36%) and good ulcer care alone (n=122) (32%) were not statistically different.
Figure 1. Incidence of Complete Healing
In general, where REGRANEX Gel was associated with higher incidences of complete ulcer closure, differences in the incidence first became apparent after approximately 10 weeks and increased with continued treatment (Table 3).
Table 3: Life Table Estimates of the Incidence (%) of Complete
Healing over Time for Study 2
| REGRANEX Gel 0.01%
| Placebo Gel
In a 3-month follow-up period where no standardized regimen of preventative care was utilized, the incidence of ulcer recurrence was approximately 30% in all treatment groups, demonstrating that the durability of ulcer closure was comparable in all treatment groups. In a randomized, double-blind study of REGRANEX Gel (100 mcg/g once daily for 16 weeks) in patients with Stage III or IV pressure ulcers, the incidence of complete ulcer closure was 15% (28/189) in the becaplermin group and 12% (22/190) in the vehicle control group. This difference was not statistically significant.
In two small, randomized, double-blinded studies of REGRANEX Gel (100 mcg/g once daily for 16 weeks) in patients with venous stasis ulcers, the combined incidence of complete ulcer closure was 46% (30/65) in the becaplermin group and 39% (26/67) in the vehicle control group. This difference was not statistically significant.
1. J. Enterostomal Ther 15:4,1988
2. Decubitis 2:24,1989
Last reviewed on RxList: 5/25/2012
This monograph has been modified to include the generic and brand name in many instances.
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