New Options to Manage Epidermolysis Bullosa

Reference: Gurevich I, Agarwal P, Zhang P, et al. In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nat Med. 2022;28(4):780–788. doi:10.1038/s41591-022-01737-y

Rationale: A topical B-VEC containing 2 copies of the COL7A1 coding sequence has been developed. B-VEC-C7 can restore C7 expression in vitro in RDEB keratinocytes and fibroblasts and has restored skin integrity and C7 expression in RDEB skin xenografts and C7-deficient mice. The effects of B-VEC-C7 remain to be tested in patients with RDEB.

Objective: The objective was to describe the development and translational research preparing B-VEC-C7 containing the COL7A1 coding sequence and perform phase 1 and 2 RCTs testing safety, function, and healing efficacy of a topical wound hydrogel containing this COL7A1 vector on patients with RDEB.

Methods: Preclinical studies established restored cell COL7A1 expression and function in RDEB keratinocytes and fibroblasts in vitro and restored skin integrity in COL7A1-deficient mice and xenografts. The current RCT described in detail was conducted per recommendations of the US Food and Drug Administration Center for Biological Evaluation and Research and following review by the Stanford Institutional Review Board. An open-label, placebo-controlled phase 1 (safety) and 2a, 2b, 2c (efficacy) RCT enrolled consenting outpatients at Stanford University between the ages of 10 and 36 years with generalized RDEB and a confirmed COL7A1 gene mutation profile. Nine patients with a total of 33 wounds were evaluated for the primary safety outcomes (mortality, adverse events, and functional and immune responses to B-VEC and COL7A1 expression as measured in patients’ blood, serum, and urine samples). Two patients with 5 wounds withdrew before analysis of the secondary healing efficacy outcome; the secondary outcome was measured as median time to complete wound closure as defined by at least 95% reduction in wound area from enrollment to study weeks 8, 10, or 12, and with healing sustained for 2 weeks.

Topical treatments, applied during dressing changes every 1 to 3 days for 2 consecutive 25-day treatment cycles, included 2 × 10⁸ to 8 × 10⁸ plaque-forming units of the B-VEC-C7 vector containing the COL7A1 coding sequence in 0.2 mL of a heat-sterilized aqueous hydrogel vehicle, covered with a transparent film dressing. One wound on each of the 11 patients with 28 wounds was randomly assigned to receive similarly applied vehicle placebo (n = 10), with the remaining wounds receiving the B-VEC-C7 hydrogel (n = 18).

Healing efficacy was analyzed as (a) a responder analysis of healing efficacy on 21 wounds on 7 patients evaluated as 95% wound closure at weeks 8 and 10 or 10 and 12 after enrollment or (b) time to and duration of 95% wound closure for 28 wounds analyzed at all timepoints and at follow-up, up to 8 months after healing. Wound area was measured from tracings by 2 blinded and 1 non-blinded wound area observers using a telehealth application loaded onto patients’ mobile phones. Wound closure data were compared for the 7 patients completing the study using Kaplan-Meier estimates of median and 95% confidence interval for time to 95% wound closure. The Wilcoxon Rank Sum Test compared mean percent area change from baseline through week 12 of B-VEC-C7 or placebo-treated wounds, with a P value of .05 considered statistically significant.

Results: Primary safety results were acceptable, with expected seropositivity results for patients with B-VEC-C7 and no vector shedding or unexpected inflammation. No tissue-bound immunoreactants were observed using immunofluorescence microscopy. The few adverse events potentially related to B-VEC-C7 treatment (fever, taste artifacts, rash or itching, and application site discharge) resolved on study with no reduction in B-VEC-C7 treatment dose or frequency. From study weeks 4 to 12, the mean percent change of B-VEC-C7–treated wounds exceeded 80% reduction in wound area, with a sustained mean area reduction exceeding 90% during weeks 10 to 12. This pattern differed from that of placebo-treated wounds, which fluctuated between healed and nonhealed states typical of RDEB wounds, ending with a 27% wound area increase by week 12 for placebo-treated wounds compared with a 94% decrease in wound area for B-VEC-C7–treated wounds (P =.02).

Responder analyses confirmed the wound area results, with 11 of 14 (79%) B-VEC-C7 wounds showing 95% closure during study weeks 8 to 12 compared with 0 of 7 wounds treated with the placebo (P =.0026). Wounds treated with B-VEC-C7 closed at least 95% in a median of 13.5 days (range, 8–21) compared with 22.5 days (range, 8–64) for the placebo-treated wounds. B-VEC-C7–treated wounds remained closed for a median of 103 days (range, 94–118) compared with 16.5 days (range, 0–66) for wounds treated with the placebo.

Authors' Conclusions: The results of this phase 1 and 2 RCT revealed that repeated topical exposure of B-VEC-C7 to wounds of patients with RDEB was associated with enduring wound closure and C7 expression and function with minimal adverse events.

Reference: Guttmann-Gruber C, Piñón Hofbauer J, Tockner B, et al. Impact of low-dose calcipotriol ointment on wound healing, pruritus, and pain in patients with dystrophic epidermolysis bullosa: a randomized, double-blind, placebo-controlled trial. Orphanet J Rare Dis. 2021;16(1):473. doi:10.1186/s13023-021-02062-2

Rationale: Preclinical studies reported that low-dose calcipotriol (VD3), which is often deficient in patients with RDEB, accelerated healing in RDEB cell culture and inhibited neoplastic cell proliferation. One patient with RDEB reported healing and reduced itching in response to low-dose topical VD3.

Objective: The investigators conducted a double-blind, crossover, placebo-controlled RCT exploring effects of daily topical ointment containing 0.05 ug/g of VD3 on wound healing, microorganisms, and pruritis in patients with RDEB.

Methods: With ethics board approval, the authors recruited 12 consenting patients with RDEB from 2 Austrian University Hospitals, excluding individuals who were pregnant, breastfeeding, participating in other clinical trials, or taking antibiotics or immunosuppressive drugs, or those with known impairments for abnormal liver or kidney function or known disorders of calcium metabolism. Participants were at least 6 years of age with 2 or more target wounds (minimum area, 6 cm²). Patients were instructed to apply 1 gram of either topical VD3 ointment (0.05 ug/g) or the vehicle placebo ointment to the corresponding wound randomly assigned to receive it for 4 weeks, followed by a 2-month washout period when no pharmaceutical agents were applied, then another 4 weeks of topical treatment with the other study ointment. All other EB lesions continued to receive originally prescribed treatments. Patients were clinically assessed for safety issues, and reported pain and pruritis intensity measured on visual analogue scales administered at each clinic visit on study days 0, 14, and 28 of each treatment when wounds were photographed for subsequent area tracings. Wound surface microorganisms were harvested from standardized microbial swabs and analyzed from 5 patients using metagenomics sequencing. Reduction in wound area was analyzed and compared using generalized estimating equations with 2-tailed significance set at P <.05. Fisher’s exact test was used to compare the fraction of wounds completely closed for VD3-treated and placebo-treated wounds within each 28-day treatment period.

Results: Of the 12 patients recruited, 3 patients did not have 2 qualifying wounds and 3 additional patients violated study protocol. In total, 6 patients with 12 wounds were included in the analysis as 2 clusters of 12 wounds each. A significant sustained reduction in patient-reported itch but not pain scores of the VD3-treated RDEB wounds persisted through 28 days of treatment (P <.0001). An originally observed 14-day healing improvement associated with VD3 treatment was not sustained after 28 days of treatment. Wounds reopened as typical for patients with RDEB. The patients experienced no drug-related adverse events or abnormal calcium serum levels. In these patients, the wound microorganisms were predominantly Staphylococcus aureus, less diverse than those of adjacent intact skin.

Authors' Conclusions: This preliminary study reported reduced itching and briefly accelerated healing in response to topical low-dose VD3.

Both studies^1,5 analyzed data on a per-wound, rather than the generally accepted per-patient basis and acknowledged the sample size as an important study limitation, due to the rarity of RDEB in the general population. Despite these limitations, each study highlights a potential benefit for those affected by RDEB. Repeated application of COL7A1 gene coding therapy using a topical B-VEC-C7 formulation resulted in the first enduring healing benefit reported in individuals with RDEB.¹ For the VD3 study,⁵ an analysis of data paired within-subjects may have clarified the result. Despite their methodological challenges, each of these studies reported significant benefit in patients afflicted with a condition formerly unresponsive to RCT tests of efficacy.² The second study⁵ reminds clinicians of the value and importance of addressing the patient’s symptoms, like itching, to improve their quality of life—even if the clinician is unable to address the cause of the wound or heal it. These studies highlight opportunities to further test hypotheses of improved outcomes in patients with RDEB.

As I bid you farewell after 20 years of writing the Evidence Corner and beam you wishes for happy healing, please allow me to share a final thought. Effective wound care follows a path from diagnosing the cause(s) of tissue loss through evidence-based patient and wound care to abolish those causes, then reviewing the outcomes achieved by that care. Each step is vital to successful wound management. Giving caregivers feedback about their patients’ 4-week healing outcomes, which predict diabetic or venous ulcer healing,^6,7 reportedly improved healing time of the ulcers in their care.⁸ If a chronic leg or foot wound has not decreased in area by at least 40% during 4 weeks of care, this alerts wound care professionals that the wound is unlikely to heal in 12 to 24 weeks^6,7 and that referral may be needed to re-examine the diagnosis or to implement treatment interventions with RCT evidence of efficacy. It is well worth the effort to document wound area regularly and use that feedback as needed to restore each wound’s healing trajectory and each patient’s quality of life. Providers and their patients deserve the benefits of knowing accurate wound diagnoses, monitoring wound outcomes, and informing care decisions with RCT evidence of efficacy. Why settle for less?