Investigational nitric oxide gel for water warts scores high in phase III trial

A novel nitric oxide-releasing gel, berdazimer 10.3%, proves effective in the treatment of patients with water warts or molluscum contagiosum (MC) skin infection, facilitating clearance of lesions with low adverse event rates, as shown in the phase III B-SIMPLE4 trial.

Applied topically once daily for 12 weeks by patients or caregivers, berdazimer was superior to the vehicle gel in terms of inducing complete lesion clearance (absolute difference, 12.7 percent; odds ratio [OR], 2.0, 95 percent confidence interval [CI], 1.5–2.8; p<0.001). [JAMA Dermatol 2022;doi:10.1001/jamadermatol.2022.2721]

In the intention-to-treat population, 144 of 393 patients (32.4 percent) in the berdazimer group achieved complete lesion clearance at week 12 as opposed to only 88 out of 397 patients (19.7 percent) in the vehicle group. MC clearance led to treatment discontinuation in 64 (14.4 percent) and 40 (8.9 percent) patients in the respective groups.

“Throughout the study … the least-squares (LS) mean percent change from baseline in MC lesion count showed a greater reduction for berdazimer vs vehicle, beginning as early as week 2 and continuing to week 12,” according to the study authors led by Dr Tomoko Maeda-Chubachi of Novan Inc in Durham, North Carolina, US.

The mean percent reduction in lesion count was 27.1 percent with berdazimer vs 5.6 percent with vehicle at week 4, 49.3 percent vs 14.5 percent at week 8, and 57.5 percent vs 31.3 percent at week 12 (p<0.001 for all). By week 24, 51.8 percent of berdazimer-treated patients vs 39.6 percent of those treated with vehicle achieved complete lesion clearance.

There were no safety concerns observed in B-SIMPLE4, and the study drug was well tolerated. The most common adverse events (AEs) were application-site pain and erythema, which were mostly mild to moderate in severity. AEs led to treatment discontinuation in 4.1 percent of patients in the berdazimer group and 0.7 percent of patients in the vehicle group.

“The safety profile of berdazimer was consistently favourable… Transient and reversible erythema, possibly accompanied by a stinging or burning sensation, is an expected pharmacologic effect of topical nitric oxide application. No systemic treatment-related AEs, except crying and insomnia, were [observed] with topical application of berdazimer,” Maeda-Chubachi noted.

Poised as potential first-in-class treatment

B-SIMPLE4 included a total of 891 MC patients, among whom 444 received berdazimer 10.3% (mean age 6.6 years, 51.4 percent male, 87.2 percent White) and 447 received vehicle (mean age 6.5 years, 52.3 percent female, 85.5 percent White).

“The B-SIMPLE4 differs from previous phase III study designs (B-SIMPLE1 and B-SIMPLE2) in four key aspects: (1) a larger sample size (larger than B-SIMPLE1 + B-SIMPLE2 combined); (2) 1:1 vs 2:1 randomization (berdazimer:vehicle); (3) stratification by baseline beginning-of-the-end (BOTE) sign (ie, a BOTE score of 0 vs ≥1); and (4) patient-retention efforts at week 12 to ensure that lesion clearance and AEs were captured at this time point, even in patients who had experienced complete clearance or had an AE before week 12,” according to Maeda-Chubachi.

“Complete lesion clearance at week 12 is a rigorous endpoint, and the 27-percent reduction in mean lesion count by week 4 would likely be perceived by patients and caregivers as meaningful and would encourage them to maintain compliance with the prescribed 12-week therapy,” she added.

In an exit interview, 23 of 30 patients in B-SIMPLE4 who did not achieve complete clearance with berdazimer (or their caregiver) considered the reduction in lesion count at week 12 to be meaningful.

“Highly contagious, MC is a viral infection that may persist for months to years, with lesions appearing and/or spreading to different areas of the body over time. Thus, control of lesion persistence and spread is a cornerstone of therapeutic success and is indicated by complete lesion clearance,” Maeda-Chubachi pointed out.

Berdazimer 10.3% is a novel, topical nitric oxide–releasing medication poised as a potential first-in-class therapy for MC for which there It harnesses the antiviral effects of nitric oxide, so its mechanism of action likely involves protein nitrosylation and NF-κB modulation. [Antimicrob Agents Chemother 2018;62:e01026-17; Antiviral Res 2019;170:104559]

“Currently, there is no FDA-approved medication for MC and available treatments [ie, cantharidin] have notable limitations, such as requiring repeated in-office visits for administration… If approved, berdazimer would provide the only self- or caregiver-administered prescription medication option for MC treatment,” said Maeda-Chubachi. [Actas Dermosifiliogr 2018;109:408-415; JAMA Dermatol 2020;156:1315-1323]