Berdazimer Sodium: A Novel Nitric Oxide-Releasing Drug in Dermatology

Introduction

Molluscum contagiosum (MC) is a prevalent, usually self-resolving viral skin infection caused by the molluscipoxvirus, primarily impacting children, individuals with immunosuppression, and adults who are sexually active. This condition generates a substantial healthcare burden and psychosocial stigma resulting in quality-of-life issues requiring therapeutic interventions.[1,2] On January 4, 2024, Food and Drug Administration (FDA) of the United States approved 10.3% berdazimer topical gel as a pioneering treatment for MC in pediatric patients aged one year and older as well as adults.[3] This article provides a thorough overview of the pharmacological aspects and clinical evidence concerning its application in MC and other skin conditions.

Role of Nitric Oxide in Cutaneous Infections

Nitric oxide (NO) is a Janus-faced, transient, diatomic gas, that is, predominantly produced by macrophages.[4] It has demonstrated a wide-ranging antimicrobial activity against viruses, bacteria, parasites, and fungi. At low levels, NO activates the immune response by augmenting the proliferation, differentiation, and apoptosis of immune cells, promoting cytokine proliferation, increasing the expression of adhesion and co-stimulatory factors, and facilitating the synthesis and deposition of extracellular constituents. As the concentration of nitric oxide (NO) increases, it becomes increasingly effective in combating microbial pathogens. This effectiveness stems from NO’s capacity to interact with reactive oxygen intermediates, resulting in the production of reactive nitrogen oxide species (RNOS).[4,5,6]

NO has demonstrated local Immunity against MC, human papillomavirus (HPV), and human herpesviridae, among viral infections.[1] After the virus breaches the host’s defense mechanisms, it triggers different pathways that result in increased activity of an enzyme called inducible nitric oxide synthase (iNOS), leading to the production of nitric oxide (NO). NO exerts direct antiviral effects through diverse mechanisms, including inhibiting viral enzymes via nitrosylation, inducing viral DNA damage through oxidative and nitrosative stress, modulating viral-encoded transcription factors, and activating host signaling pathways.[1,4,5]

Mechanism of Action

The exact mechanism by which berdazimer treats MC is not fully understood. Berdazimer is a topical NO-releasing macromolecule comprising a polysiloxane backbone linked covalently to N-diazeniumdiolate NO donors. It is administered alongside a carboxymethyl cellulose hydrogel, which serves as a donor of proton, facilitating targeted drug delivery.[7] This distinct mechanism allows for NO release upon interplay with proton donors like H₂O, leading to deterioration of the N-diazeniumdiolate entity and eventually minimizing systemic uptake [Figure 1]. It is speculated that berdazimer may exert antiviral effects through processes such as nitrosylation and modulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).[8,9]

Figure 1.

Mechanism of action of berdazimer sodium

In vitro studies have demonstrated that berdazimer inhibits poxvirus replication and reduces the expression of the molluscum immune invasion protein MC160.[9] Furthermore, berdazimer has been found to decrease the activity of E6 and E7 and inhibit HPV 18 amplification in HPV 18-infected primary human keratinocyte raft cultures.[10] Additionally, NO has been shown to inhibit NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and caspase, which are crucial immunoregulatory pathways implicated in the pathogenesis of acne vulgaris.[11,12]

Efficacy

1. Molluscum contagiosum

   In a phase 2 trial lasting 12 weeks, berdazimer sodium at various concentrations and dosing schedules was evaluated in a randomized, vehicle-controlled study involving 256 patients aged 2 to 16. Among these, the group receiving berdazimer sodium at a concentration of 12% in a carboxymethyl cellulose-based hydrogel once daily demonstrated the most favorable benefit-risk profile. In the intention-to-treat analysis, a higher rate of molluscum contagiosum (MC) clearance (37.5% or 18 out of 48 patients) was observed in this group compared to the vehicle (18.2% or 12 out of 66 patients). Changes in MC lesions were noticeable as early as one week into treatment. Conversely, groups receiving berdazimer twice daily at 12% or lower concentrations exhibited reduced efficacy and a higher incidence of reactions at the application site.[2]

   The phase 3 trials Berdazimer sodium in molluscum patients with lesions (B-SIMPLE) 1 and 2, assessing berdazimer sodium in molluscum patients with lesions, failed to achieve statistical significance for the primary endpoint.[13] However, in the subsequent phase 3 multicenter trial, B-SIMPLE 4, a larger sample size of 891 patients was included with a 1:1 allocation ratio, stratifying patients based on the baseline BOTE (Beginning of the end sign) sign. At the 12-week mark, patients in the berdazimer group achieved statistical significance in the primary efficacy endpoint of complete clearance, with 32.4% (144 out of 444) compared to 19.7% (88 out of 447) in the vehicle group. Notably, improved efficacy with berdazimer was observed as early as week two. Additionally, most patients who experienced a reduction of more than 75% in lesions reported satisfaction in the B-SIMPLE 4 trial.[14]

   An integrated analysis of the three-phase trials further demonstrated the superiority of berdazimer over the vehicle, with a clearance rate of 30.0% compared to 19.8%. This analysis encompassed 1598 patients, with 917 in the berdazimer group and 681 in the vehicle group, all aged over six months and presenting with 3-70 MC lesions.[13] Moreover, a combined meta-analysis of the four randomised controlled trial (RCT) corroborated these findings, showing a significant increase in complete clearance rates in the berdazimer group compared to the vehicle, with percentages of 30% versus 20%, respectively.[15]

2. External genital warts

   In a phase 2 trial, which was double-blind and randomized, SB206 (berdazimer sodium plus carboxymethyl cellulose hydrogel) was evaluated among 108 participants with extragenital warts. The study revealed a notably higher efficacy of 12% SB206 when administered once daily compared to the vehicle (33.3% versus 4.3%). Participants were assigned in a ratio of 3:1 to receive SB206 at concentrations of 4% once or twice daily, 8% once daily, 12% once daily, or the vehicle.[16] According to a network meta-analysis, SB206 exhibited efficacy comparable to that of traditional topical agents like imiquimod and podophyllotoxin. However, more extensive and meticulously designed studies are warranted to assess SB206’s effectiveness in treating external genital warts.[17]

3. Acne vulgaris

   In a phase 2 randomized controlled double-blind study involving 150 participants, SB204 at concentrations of 1% and 4% were compared with the vehicle in a 1:1:1 ratio. The study found a significant absolute change in the non-inflammatory lesion count from baseline to 12 weeks in the SB204 groups compared to the vehicle. However, there was no statistically significant difference observed in the investigator global assessment (IGA) scores.[11]

4. Miscellaneous

   SB414 2% has been reported to possess antimicrobial and anti-inflammatory effects, reducing Th-2, Th-22, Th-1 and Th-17 activity in filaggrin-deficient murine models of atopic dermatitis.[18] In a phase 2 RCT involving 222 participants with interdigital tinea pedis, SB208 at concentrations of 2%, 4%, and 16% were compared with a vehicle. SB208 at 4% and 16% demonstrated statistically significant efficacy compared to the vehicle. Further trials are planned for onychomycosis.[19]

Dosage and Administration

The FDA has approved berdazimer 10.3% gel for the management of MC. It is commercially available in two tubes: First tube contains berdazimer gel, and the second one consists of a hydrogel. To use, an equal amount of 0.5 ml from each tube should be dispensed and mixed thoroughly. The patient should then apply an even, thin layer of the mixture immediately and allow it to dry for ten minutes. It is essential that patients do not use any stored premixed mixture. Furthermore, patients should refrain from washing, swimming, or bathing for one hour after application. The drug should be applied once daily to each MC lesion for up to twelve weeks. It’s important to note that berdazimer is approved for topical use only and should not be used orally, intravaginally, or in the eyes.[3,7]

Adverse Effects

The adverse effect profile of berdazimer has been summarized in Table 1.[11,13]

Table 1.

Adverse effects reported with berdazimer sodium in various randomized control trials

Most frequent adverse effects reported by ≥2% of berdazimer topical gel, 10.3% recipient

Application site reactions

• Pain (including burning or stinging sensations)

• Erythema

• Itching,

• Exfoliation

• Dermatitis

• Swelling

Adverse effects reported in <2% of berdazimer topical gel, 10.3% recipients

Application site reactions

• Vesicles

• Erosion

• Discoloration

• Irritation

• Infection

Miscellaneous

• Pyrexia

• Vomiting

• Upper respiratory tract infection

• Headache

• Dysmenorrhea

• Nasopharyngitis

Safety Profile

The safety and efficacy of berdazimer have not been determined in children younger than one year of age. While there are no absolute contraindications for berdazimer administration, previous studies in the literature have lacked sufficient participation from geriatric patients to determine its safety in that age group. Additionally, the information regarding the use of berdazimer in pregnant and lactating women is currently limited.[3,7]

Conclusion and Future Directions

MC is a frequently encountered viral infection that poses significant therapeutic challenges. Berdazimer 10.3% gel, the first FDA-approved agent that can be administered by patients or caregivers for molluscum contagiosum, has a good efficacy and safety profile. In the future, additional trials are warranted to ascertain the efficacy of the drug against established treatment modalities.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.