A New Paradigm in Severe Burn Treatment – FDA Approves Anacaulase (NexoBrid®)

In December 2022, the US Food and Drug Administration (FDA) approved MediWound’s biologic license application (BLA) for anacaulase-bcdb (NexoBrid®), a bromelain-based biological product indicated for eschar removal in adults with deep partial thickness and/ or full thickness thermal burns.1

NexoBrid is formulated as topic gel and contains a sterile mixture of proteolytic enzymes, which selectively eliminates burn eschar within four hours without causing harm to surround viable tissue. 

Thermal burns result from tissue exposure to an external heat source and burns that occur at higher temperatures or for extended contact times result in deeper, more severe injuries.2 Severe burns are associated with long-term morbidity and mortality.3,4 With deep dermal and full-thickness burns, the dermis can become stiff and unyielding, and this necrotic tissue is referred to as an eschar. The presence of eschar creates challenges in the accurate diagnosis of burn depth and contributes to local and systemic complications. Early burn eschar removal via excisional debridement followed by autografting is considered standard of care but can result in serious potential consequences.2,5,6 While effective, excisional debridement is often traumatic, resulting in loss of viable tissue, blood and heat, and requiring specialized surgical personnel and facilities, and is often delayed until an accurate diagnosis of burn depth is reached confirming the necessity for surgery. 

NexoBrid was developed to provide a non-surgical alternative to excisional debridement. Early phase studies signalled promising results with NexoBrid’s selective removal of burn eschar after a single 4-hour application, resulting in a clean wound bed, reducing the time to complete debridement and need for excisional debridement, as well as reducing burn-induced elevated compartment and interstitial pressures.7–9 In partial thickness burns, this manner of enzymatic debridement leaves behind sufficient non-injured dermis that can epithelialize spontaneously, decreasing the need for excisional debridement and autografting. 

The US regulatory nod was largely based on DETECT (NCT02148705),10 a Phase III US clinical study which evaluated the efficacy and safety of NexoBrid in adult patients with deep partial-thickness or full-thickness thermal burns over 3% to 30% of their total body surface area (TBSA). 

The study met its primary endpoint of incidence of ≥95% eschar removal compared to gel vehicle, as well as all secondary endpoints, which include shorter time to eschar removal, lower incidence of surgical eschar removal and lower blood loss compared to surgical and non-surgical standard of care, including both surgical and non-surgical eschar removal methods, with highly statistically significant results. 11 A safety endpoint of non-inferiority in time to >95% wound closure compared with patients treated with standard of care was also achieved. In addition, non-inferiority was established between NexoBrid and standard of care in cosmesis and function of burn scars at 12- and 24-month follow-up time points. Overall, NexoBrid appears to be safe and generally well tolerated.11 NexoBrid may be applied initially to an area of up to 15% body surface area. A second application of NexoBrid may be applied 24 hours later, with a total treated area for both applications of up to 20% TBSA.

NexoBrid was approved for use in Europe in 2013 and has secured market authorisation in over 43 countries to date. Bromelain-based enzymatic debridement with NexoBrid has established itself as a reliable and useful alternative to surgical eschar removal and is most beneficial in mid-to-deep dermal burns.6 In 2020, a multi-professional expert panel of European plastic surgeons and burn care specialists published a consensus guideline update on the use of NexoBrid for eschar removal. The guidelines reflect the increasing body of evidence and clinical experience with the therapeutic.6

The panel identified studies addressing the advantages of enzymatic debridement which include the reduction of procedural blood loss, the need for autologous skin grafting and the number of wounds with further surgical excision, by preserving more viable dermis compared to the standard of care.12 Additionally, enzymatic debridement was found to have the advantage of reducing the rate of burn wound infection and the length of hospital stay compared to the standard of care.13 Further, the immediate application of enzymatic debridement in circumferential burns to the extremity was investigated by Fischer et al. who demonstrated its effectiveness and safety for the prevention of burn-induced compartment syndrome in clinical practice, thereby reducing the need and burden of surgical escharotomy.14

On the flip side, the growing clinical use of NexoBrid has also revealed key clinical limitations. Firstly, no evidence currently supports the use of enzymatic debridement in chemical burns, scald burns or high-voltage injuries with potential deep muscle damage. The European expert panel also agreed that while enzymatic debridement of large surfaces may be feasible, it may produce increased surface water loss and adapted resuscitation/ volume management.6 Finally, a case series describing burn treatment in patients with established diabetic foot disease suggested potential limitations as patients developed further eschar and wound deepening a few days after enzymatic debridement. 15

References

1. 761192s000lbl.pdf. Accessed January 15, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761192s000lbl.pdf
2. Walker NJ, King KC. Acute and Chronic Thermal Burn Evaluation and Management. In: StatPearls. StatPearls Publishing; 2022. Accessed January 15, 2023. http://www.ncbi.nlm.nih.gov/books/NBK430730/
3. Revised Estimates of Mortality From the Birmingham Burn Cent… : Annals of Surgery. Accessed January 15, 2023. https://journals.lww.com/annalsofsurgery/Abstract/2014/05000/Revised_Estimates_of_Mortality_From_the_Birmingham.22.aspx
4. Mortality Determinants in Massive Pediatric Burns: An Analys… : Annals of Surgery. Accessed January 15, 2023. https://journals.lww.com/annalsofsurgery/Abstract/1997/05000/Mortality_Determinants_in_Massive_Pediatric_Burns_.12.aspx
5. Sasaki J, Matsushima A, Ikeda H, et al. Japanese Society for Burn Injuries (JSBI) Clinical Practice Guidelines for Management of Burn Care (3rd Edition). Acute Medicine & Surgery. 2022;9(1):e739. doi:10.1002/ams2.739
6. Hirche C, Kreken Almeland S, Dheansa B, et al. Eschar removal by bromelain based enzymatic debridement (Nexobrid®) in burns: European consensus guidelines update. Burns. 2020;46(4):782-796. doi:10.1016/j.burns.2020.03.002
7. Rosenberg L, Lapid O, Bogdanov-Berezovsky A, et al. Safety and efficacy of a proteolytic enzyme for enzymatic burn débridement: a preliminary report. Burns. 2004;30(8):843-850. doi:10.1016/j.burns.2004.04.010
8. Rosenberg L, Krieger Y, Silberstein E, et al. Selectivity of a bromelain based enzymatic debridement agent: A porcine study. Burns. 2012;38(7):1035-1040. doi:10.1016/j.burns.2012.02.011
9. Singer AJ, Taira BR, Anderson R, McClain SA, Rosenberg L. Reepithelialization of Mid-dermal Porcine Burns After Rapid Enzymatic Debridement With Debrase®. Journal of Burn Care & Research. 2011;32(6):647-653. doi:10.1097/BCR.0b013e31822dc467
10. MediWound Ltd. A Multicenter, Multinational, Randomized, Controlled, Assessor Blinded Study, Performed in Subjects With Thermal Burns, to Evaluate the Efficacy and Safety of NexoBrid Compared to Gel Vehicle and Compared to Standard of Care. clinicaltrials.gov; 2019. Accessed January 12, 2023. https://clinicaltrials.gov/ct2/show/NCT02148705
11. Ltd M. MediWound Announces FDA Approval of NexoBrid® for the Treatment of Severe Thermal Burns in Adults. GlobeNewswire News Room. Published December 29, 2022. Accessed January 15, 2023. https://www.globenewswire.com/news-release/2022/12/29/2580838/30505/en/MediWound-Announces-FDA-Approval-of-NexoBrid-for-the-Treatment-of-Severe-Thermal-Burns-in-Adults.html
12. Rosenberg L, Krieger Y, Bogdanov-Berezovski A, Silberstein E, Shoham Y, Singer AJ. A novel rapid and selective enzymatic debridement agent for burn wound management: A multi-center RCT. Burns. 2014;40(3):466-474. doi:10.1016/j.burns.2013.08.013
13. Özcan C, Ergün O, Çelik A, Çördük N, Özok G. Enzymatic debridement of burn wound with collagenase in children with partial-thickness burns. Burns. 2002;28(8):791-794. doi:10.1016/S0305-4179(02)00191-2