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DRUG PROFILE
Nitric Oxide Releasing Agent · Topical Small Molecule · Dermatology / Virology
Berdazimer
ZELSUVMI™ · EPIH SPV, LLC (developed by Novan, Inc.)
A first-in-class topical nitric oxide (NO) releasing agent consisting of berdazimer sodium gel (Tube A) mixed with a proton-donating hydrogel (Tube B) immediately before application. The first and only FDA-approved prescription topical treatment specifically indicated for molluscum contagiosum (MC) — a highly transmissible poxvirus infection predominantly affecting children — with established efficacy and a favorable systemic safety profile based on subnanomolar systemic exposure under maximal use conditions.
Drug Overview
§1 · NDA 217424
No Boxed Warning. ZELSUVMI carries no boxed warning. The safety profile is dominated by local application site reactions (primarily burning/stinging, erythema, and pruritus). No significant systemic safety signals were identified across three Phase 3 trials. Systemic exposure under maximal use conditions (484 cm² treatment area) was subnanomolar, supporting waiver of chronic systemic toxicology studies.
Indication
Molluscum Contagiosum
Adults and pediatric patients ≥1 year of age; topical treatment of all treatable MC lesions once daily for up to 12 weeks
Mechanism
NO Releasing Agent
Berdazimer sodium releases nitric oxide upon mixing with the proton-donating hydrogel; exact MOA for MC treatment is unknown
Formulation
Two-Tube Topical Gel
Tube A: 10.3% berdazimer (14 g); Tube B: hydrogel (17 g) — mixed 1:1 (0.5 mL each) immediately before use
Primary Efficacy (Trial NI-MC304)
32.4% vs 19.7%
Complete clearance at Week 12; Δ +12.8% (95% CI 7.1%, 18.6%); p<0.0001
Mechanism of Action
§1.1 · Section 12.1ZELSUVMI is a nitric oxide (NO) releasing agent. Berdazimer sodium (NVN1000) is a macromolecular silica-based polymer backbone with covalently bound diazeniumdiolate moieties that release nitric oxide upon protonation. When the berdazimer gel (Tube A) is mixed with the proton-donating hydrogel (Tube B), NO is released locally at the site of MC lesions. Nitric oxide is a highly reactive signaling molecule with antimicrobial, antiviral, and immunomodulatory properties across a broad concentration spectrum. The precise mechanism by which NO exerts its effect on the molluscum contagiosum virus (MCV) is unknown per the prescribing information.
Two-component system (label Section 11): Tube A contains 240 mg berdazimer sodium per gram of gel (inactive: cyclomethicone, hexylene glycol, hydroxypropyl cellulose, isopropyl alcohol). Tube B is the hydrogel that triggers NO release (inactive: benzoic acid, carboxymethylcellulose sodium, cyclomethicone, ethanol 13% v/v, glycerin, potassium phosphate monobasic, purified water). The mixed gel must be applied immediately — premixed storage is not permitted.
Label note (Section 12.1 & 12.2): The mechanism of action for the treatment of molluscum contagiosum is unknown. The pharmacodynamics of ZELSUVMI are unknown. No QTc prolongation concern: a dedicated QT study using a higher-strength product (SB204 12%) at ~33× the expected MC treatment area showed no clinically relevant QTc prolongation.
Therapeutic Landscape — Topical Therapies for Molluscum Contagiosum
§1.2| Agent | Class / MOA | Route | Status (US) | Notes |
|---|---|---|---|---|
| Berdazimer (ZELSUVMI) | NO releasing agent (topical) | Topical QD ×12 wk | FDA Jan 5, 2024 (NDA 217424) | First FDA-approved Rx topical for MC; ≥1 year |
| Cantharidin (Ycanth) | Mitotic inhibitor (vesicant) | Topical in-office | FDA Jul 26, 2023 (NDA 212905) | HCP-administered; ≥2 years; blistering mechanism |
| Imiquimod 5% (Zyclara/generic) | TLR7/8 agonist (immune modulator) | Topical 3×/wk | Off-label (FDA approved for genital warts/AK) | No FDA indication for MC; used off-label |
| Podophyllotoxin (generic) | Antimitotic (off-label) | Topical | Off-label | Not evaluated in randomized MC trials |
| Curettage / Cryotherapy | Procedural (destructive) | In-office procedure | Standard of care (no FDA approval required) | Painful in children; risk of scarring; no controlled trials |
Source: FDA Prescribing Information NDA 217424, Ref ID 5304861. FDA Multi-disciplinary Review NDA 217424, Ref ID 5304936. Competitive landscape based on FDA approval records. Berdazimer was developed under IND 137015. Prior to ZELSUVMI approval, no FDA-approved prescription topical therapy existed specifically for molluscum contagiosum.
Baseline & Trial Characteristics
§2 · Table 20–22, NDA 217424 Medical Review (Ref ID 5304936)Total Enrolled (3 Trials)
1,598
ITT population across NI-MC301 (N=352), NI-MC302 (N=355), NI-MC304 (N=891); all US centers
Median Age (NI-MC304)
~5.7 yrs
3% <2 yrs; 96% aged 2–17 yrs; predominantly pediatric population across all three trials
Avg Baseline Lesion Count
20.2
Range 3–70; 18.2 in NI-MC301/302, 21.8 in NI-MC304; majority had <20 lesions
AD Comorbidity
~13%
Prior AD/eczema history in ~12–15% of subjects across trials; majority had no AD comorbidity
Trial Design Summary
§2.1 · Section 8.1.1| Parameter | NI-MC301 | NI-MC302 | NI-MC304 (Pivotal) |
|---|---|---|---|
| NCT Number | NCT03927716 | NCT03927703 | NCT04535531 |
| Randomization | 2:1 (SB206:vehicle) | 2:1 (SB206:vehicle) | 1:1 (SB206:vehicle) |
| Sample Size | N=352 (236 / 116) | N=355 (237 / 118) | N=891 (444 / 447) |
| No. of Centers | 33 (all US) | 33 (all US) | 55 (all US) |
| Primary Endpoint | Complete clearance Wk 12 | Complete clearance Wk 12 | Complete clearance Wk 12 |
| Key Secondary Endpoint | Complete clearance Wk 8 | Complete clearance Wk 8 | Complete clearance Wk 8 |
| Stratification | Investigator type; household | Investigator type; household | + Baseline BOTE score added |
| Missing Data Method | NRI (conservative) | NRI (conservative) | NRI (balanced dropout) |
| Conduct Period | 2019–2020 | 2019–2020 | 2020–2022 (COVID era) |
| Remote Visits | No | No | Week 4 allowed remotely |
| Efficacy Conclusion | Not significant (p=0.3637) | Marginal (p=0.0510) | Significant (p<0.0001) ✓ |
Demographic Characteristics (NI-MC304 ITT, N=891)
§2.2 · Table 20, NDA 217424 Medical Review| Characteristic | Berdazimer (N=444) | Vehicle (N=447) |
|---|---|---|
| Mean age (SD), years | 6.6 (4.50) | 6.5 (4.34) |
| Median age (range) | 5.6 (0.9–47.5) | 6.0 (1.3–49.0) |
| Age <2 years, n (%) | 16 (3.6%) | 12 (2.7%) |
| Age 2–<6 years, n (%) | 220 (49.5%) | 213 (47.7%) |
| Age 6–<12 years, n (%) | 178 (40.1%) | 201 (45.0%) |
| Age 12–<18 years, n (%) | 24 (5.4%) | 15 (3.4%) |
| Age ≥18 years, n (%) | 6 (1.4%) | 6 (1.3%) |
| Female, n (%) | 216 (48.6%) | 234 (52.3%) |
| White, n (%) | 387 (87.2%) | 382 (85.5%) |
| Black or African American, n (%) | 21 (4.7%) | 28 (6.3%) |
| Hispanic or Latino, n (%) | 94 (21.2%) | 87 (19.5%) |
Baseline Disease Characteristics (NI-MC304 ITT)
§2.3 · Table 21, NDA 217424 Medical Review| Characteristic | Berdazimer (N=444) | Vehicle (N=447) |
|---|---|---|
| Mean baseline lesion count (SD) | 23.1 (17.60) | 20.5 (16.18) |
| Median lesion count (range) | 18.5 (3–70) | 15.0 (3–69) |
| <20 lesions, n (%) | 229 (51.6%) | 267 (59.7%) |
| ≥20 lesions, n (%) | 215 (48.4%) | 180 (40.3%) |
| Mean time since onset (months) | 12.0 | 13.1 |
| Baseline BOTE score = 0 (no inflammation), n (%) | 225 (50.7%) | 222 (49.7%) |
| Baseline BOTE ≥1 (mild–very severe), n (%) | 219 (49.3%) | 225 (50.3%) |
| AD/eczema history, n (%) | 67 (15.1%) | 56 (12.5%) |
| Dermatologist investigator, n (%) | 260 (58.6%) | 265 (59.3%) |
| Mean treatment compliance (%) | 91.4% | 94.8% |
Source: NDA 217424 Multi-disciplinary Review, Ref ID 5304936. BOTE = Beginning-of-the-End (clinical sign of impending spontaneous resolution). NI-MC304 had higher baseline lesion counts in the berdazimer arm vs vehicle (23.1 vs 20.5) due to randomization imbalance. Compliance lower in active arm, consistent with application site reaction–driven interruptions. All three trials conducted at US centers only.
Clinical Efficacy
§3 · Section 14 / Table 2 (Label); Table 25 (Medical Review, Ref ID 5304936)
Primary endpoint & statistical framework: The primary efficacy endpoint was the proportion of subjects achieving complete clearance (total MC lesion count = 0) at Week 12. Key secondary endpoint: complete clearance at Week 8. Primary analysis used GEE logistic regression with exchangeable working correlation structure (accounting for household correlation). Missing data handled by non-responder imputation (NRI). FWER controlled hierarchically across two confirmatory trials (NI-MC304 and NI-MC302).
Wk 12 CCR — NI-MC304 (Primary)
32.4%
vs 19.7% vehicle; Δ +12.8% (95% CI 7.1–18.6%); p<0.0001
Wk 8 CCR — NI-MC304 (Secondary)
19.6%
vs 11.6% vehicle; Δ +7.5% (95% CI 3.0–12.0%); p=0.0012
Wk 12 CCR — NI-MC302 (Primary)
30.0%
vs 20.3% vehicle; Δ +9.2% (95% CI −0.04–18.4%); p=0.0510
NI-MC301 (not significant)
25.8%
vs 21.6% vehicle; Δ +4.3% (95% CI −5.0–13.6%); p=0.3637 — conservative NRI with imbalanced dropout
Complete Clearance Rate — Pivotal Trial NI-MC304
§3.1 · ITT Population, GEE Logistic Regression, NRI
NI-MC304 (NCT04535531) · N=891 · 1:1 Randomization · p<0.0001
55 US centers; stratified by investigator type, household size, BOTE score
Week 12 — Complete Clearance Rate (Primary Endpoint)
Treatment difference: +12.8% (95% CI 7.1%, 18.6%) · p<0.0001
Week 8 — Complete Clearance Rate (Key Secondary Endpoint)
Treatment difference: +7.5% (95% CI 3.0%, 12.0%) · p=0.0012
Complete Clearance Rate — Supportive Trial NI-MC302
§3.2 · ITT Population, GEE Logistic Regression, NRI
NI-MC302 (NCT03927703) · N=355 · 2:1 Randomization · p=0.0510
33 US centers; marginally missed primary p<0.05 threshold; Week 8 secondary supportive
Marginally missed primary endpoint significance threshold; conservative NRI with higher missing data in active arm (16% vs 12.7%). Multiple sensitivity analyses and Week 8 secondary were supportive. FDA concluded efficacy demonstrated.
Week 12 — Complete Clearance Rate (Primary Endpoint)
Treatment difference: +9.2% (95% CI −0.04%, 18.4%) · p=0.0510
Week 8 — Complete Clearance Rate (Key Secondary Endpoint)
Treatment difference: +7.8% (95% CI 1.8%, 13.8%)
Non-Significant Trial NI-MC301
§3.3 · Context & Interpretation
NI-MC301 (NCT03927716) · N=352 · 2:1 Randomization · NOT SIGNIFICANT
33 US centers; imbalanced dropout attenuated treatment effect under NRI
Treatment difference: +4.3% (95% CI −5.0%, 13.6%) · p=0.3637
FDA conclusion on NI-MC301: Highly imbalanced missing data (16.1% berdazimer vs 3.4% vehicle) with conservative NRI likely attenuated the treatment effect. Multiple sensitivity analyses consistently showed numerical advantages for the active arm. The non-significant result in NI-MC301 does not detract from the overall efficacy evidence established by NI-MC304 and NI-MC302 per 21 CFR 314.126. Substantial evidence of effectiveness was demonstrated.
Efficacy Summary Table — All Three Trials
§3.4 · Table 25, NDA 217424 Medical Review (Label Table 2)| Endpoint | NI-MC304 Berdazimer (N=444) | NI-MC304 Vehicle (N=447) | Treatment Diff. (95% CI) | NI-MC302 Berdazimer (N=237) | NI-MC302 Vehicle (N=118) | Treatment Diff. (95% CI) |
|---|---|---|---|---|---|---|
| Complete Clearance Wk 12 (Primary) | 32.4% | 19.7% | +12.8% (7.1%, 18.6%) p<0.0001 | 30.0% | 20.3% | +9.2% (−0.04%, 18.4%) p=0.0510 |
| Complete Clearance Wk 8 (Key Secondary) | 19.6% | 11.6% | +7.5% (3.0%, 12.0%) p=0.0012 | 13.9% | 5.9% | +7.8% (1.8%, 13.8%) |
| Complete Clearance Wk 12 (NI-MC301 — not significant) | 25.8% (N=236) | 21.6% (N=116) | +4.3% (−5.0%, 13.6%) p=0.3637 — Not significant | |||
Complete Clearance Rate Time-Course — NI-MC304
§3.5 · Chart.js · Source: NDA 217424 Medical Review, Ref ID 5304936Complete Clearance Rate (%) Over Time — NI-MC304 (ITT, NRI)
Source: FDA Medical Review NDA 217424 (Ref ID 5304936), Table 25 / Figure summarizing CCR over time. Week 8 and Week 12 values directly from FDA label Table 2. Week 4 value: Not reported in text tables — marked null. Berdazimer N=444; Vehicle N=447.
Patient-Reported Outcomes
§3.6 · PRO Instruments| PRO Instrument | Finding | Timepoint |
|---|---|---|
| Patient/Caregiver Global Assessment (PaGA) | Not reported as a registered secondary endpoint; supportive data collected | Not reported |
| CDLQI / DLQI | Not formally evaluated as pre-specified endpoint in Phase 3 trials | Not reported |
| Pruritus severity | Assessed as part of BOTE score (Beginning-of-the-End sign); not an independent PRO endpoint | Baseline through Week 12 |
PRO note: No formal patient-reported outcome instruments (DLQI, CDLQI, NRS itch/pain) were pre-specified as secondary endpoints in the Phase 3 trials. The PRO data in the FDA Medical Review are limited to the BOTE (Beginning-of-the-End) score as a stratification variable and clinical sign of impending spontaneous resolution.
Source: FDA Prescribing Information NDA 217424 (label Table 2), Ref ID 5304861. FDA Multi-disciplinary Medical Review NDA 217424, Ref ID 5304936. GEE = generalized estimating equation; NRI = non-responder imputation; ITT = intent-to-treat; CCR = complete clearance rate. Complete clearance defined as total MC lesion count = 0 at assessment.
Safety Profile
§4 · Section 6.1 (Label); Integrated Summary of Safety (ISS), Ref ID 5304936
No Boxed Warning. No boxed warning is present in the ZELSUVMI prescribing information. The safety profile is dominated by local application site reactions — local, dose-related, and manageable. No significant systemic safety signals were identified across three Phase 3 trials (N=1,596 subjects).
Safety Population (Controlled Trials)
1,596
916 berdazimer + 680 vehicle; pooled Trials 1, 2, and 3 (NI-MC304, NI-MC302, NI-MC301)
Long-term Exposure (OLE)
Not reported
No open-label extension study; treatment duration up to 12 weeks in controlled trials
Treatment Duration
Up to 12 wks
Once-daily application; subjects with missing data counted as non-responders (NRI)
Most Common ADR (≥1%)
App. Site Pain
18.7% (burning/stinging); vs 4.8% vehicle. Application site erythema 11.7% second most common.
§4.1 — Boxed Warning
Section 5 (Label)
No Boxed Warning. ZELSUVMI (berdazimer) topical gel has no boxed warning in the FDA-approved prescribing information (NDA 217424, Ref ID 5304861, Revised 01/2024).
§4.2 — Warnings & Precautions
Section 5.1- Application Site Reactions including Allergic Contact Dermatitis (5.1): Application site reactions have occurred in ZELSUVMI-treated patients. Suspect allergic contact dermatitis if pain, pruritus, swelling, or erythema at the application site persists for longer than 24 hours. If allergic contact dermatitis occurs: discontinue ZELSUVMI and initiate appropriate therapy.
§4.2 — Adverse Reactions ≥1% (Pooled Trials 1, 2, 3)
Label Table 1; Day 1 through Week 12; TEAEs| Adverse Reaction | Berdazimer N=916 | Vehicle N=680 | Total Berdazimer (%) | ||||
|---|---|---|---|---|---|---|---|
| Mild | Moderate | Severe | Mild | Moderate | Severe | ||
| Any TEAE | 220 (24.0%) | 192 (21.0%) | 16 (1.7%) | 118 (17.4%) | 47 (6.9%) | 4 (0.6%) | 46.7% |
| Application Site Pain† (burning/stinging) | 113 (12.3%) | 56 (6.1%) | 2 (0.2%) | 30 (4.4%) | 3 (0.4%) | 0 | 18.7% |
| Application Site Erythema | 48 (5.2%) | 55 (6.0%) | 4 (0.4%) | 7 (1.0%) | 2 (0.3%) | 0 | 11.7% |
| Application Site Pruritus | 36 (3.9%) | 15 (1.6%) | 1 (0.1%) | 5 (0.7%) | 2 (0.3%) | 0 | 5.7% |
| Application Site Exfoliation | 18 (2.0%) | 26 (2.8%) | 2 (0.2%) | 0 | 0 | 0 | 5.0% |
| Application Site Dermatitis | 16 (1.7%) | 26 (2.8%) | 3 (0.3%) | 3 (0.4%) | 2 (0.3%) | 0 | 4.9% |
| Application Site Swelling | 17 (1.9%) | 14 (1.5%) | 1 (0.1%) | 3 (0.4%) | 1 (0.1%) | 0 | 3.5% |
| Pyrexia | 14 (1.5%) | 6 (0.7%) | 0 | 6 (0.9%) | 1 (0.1%) | 0 | 2.3% |
| Application Site Erosion | 7 (0.8%) | 5 (0.5%) | 3 (0.3%) | 1 (0.1%) | 0 | 0 | 1.6% |
| Application Site Discoloration | 13 (1.4%) | 1 (0.1%) | 0 | 1 (0.1%) | 0 | 0 | 1.5% |
| Application Site Vesicles | 5 (0.5%) | 9 (1.0%) | 0 | 0 | 1 (0.1%) | 0 | 1.5% |
| Application Site Irritation | 7 (0.8%) | 4 (0.4%) | 0 | 0 | 0 | 0 | 1.2% |
| Application Site Infection | 4 (0.4%) | 4 (0.4%) | 2 (0.2%) | 2 (0.3%) | 1 (0.1%) | 0 | 1.1% |
† Application site pain includes burning and stinging sensations. Adverse reactions reported ≥1% of subjects and more frequently than vehicle. Source: FDA label NDA 217424 Table 1, Ref ID 5304861.
§4.3 — Key Safety Considerations
No Systemic Safety Signals
Analysis of ISS (three Phase 3 trials combined) identified no significant systemic safety signals. Waiver granted for 6-month systemic rodent repeat-dose toxicology based on subnanomolar systemic exposure at maximal clinical use.
Methemoglobin Monitoring
Methemoglobin levels (biomarker for systemic NO exposure) ranged 0–3.2% in Phase 1 maximal use study (NI-MC101) and Phase 2 study (NI-MC201). No clinically meaningful elevations observed; no apparent dose-response relationship.
Mutagenicity Finding (Ames Assay)
Berdazimer was mutagenic in the bacterial mutagenicity (Ames) assay. However, it was NOT clastogenic in the in vitro chromosomal aberration assay (human peripheral blood lymphocytes) or in vivo micronucleus assay (rats). No drug-related tumor findings in 2-year mouse dermal carcinogenicity study at doses up to 4% berdazimer gel.
Reproductive Toxicity (Animal Data)
Oral berdazimer increased fetal malformations in rats (189 mg/kg/day, in setting of severe maternal toxicity) and rabbits (284 mg/kg/day). Clinical relevance is unknown given significantly lower topical vs. oral bioavailability. No effects on male/female fertility in rats at oral doses up to 189 mg/kg/day.
Pregnancy — No Human Data
No human pregnancy data available. Animal data show fetal effects only at doses associated with severe maternal toxicity via oral route. Given subnanomolar systemic topical exposure, risk is expected to be low. No data on berdazimer excretion into breast milk.
Pediatric Safety
Safety established in pediatric patients ≥1 year; 904 pediatric subjects (including 29 <2 years) exposed to berdazimer across trials. Age-appropriate safety profile with same application site reaction predominance. Not established in infants <1 year.
§4.4 — Deaths
No deaths were reported in the three Phase 3 controlled trials (NI-MC301, NI-MC302, NI-MC304). Source: NDA 217424 Medical Review, Ref ID 5304936.
§4.5 — Discontinuations Due to AEs
Higher dropout rates in the berdazimer arm across trials NI-MC301 and NI-MC302 were predominantly due to withdrawn consent/assent and lost to follow-up — not adverse events per se. Only 5 subjects (1.1%) in NI-MC304 discontinued due to adverse events vs. 3 (0.7%) in vehicle. Application site reactions were manageable and did not generate a systematic discontinuation signal.
§4.6 — Laboratory Abnormalities
No clinically relevant laboratory abnormalities were identified. Methemoglobin levels remained within normal range (0–3.2%) throughout Phase 1 maximal use study. No treatment-related changes in plasma nitrate levels indicative of significant systemic NO exposure. No standard laboratory panel (CBC, CMP) anomalies were attributed to berdazimer treatment. Source: NDA 217424 Medical Review, Ref ID 5304936.
§4.7 — Immunogenicity
Not applicable. Berdazimer sodium is a small-molecule inorganic polymer, not a biologic agent. No immunogenicity (ADA/NAb) assessments were conducted or required.
§4.8 — Special Populations Safety
Section 8| Population | Guidance |
|---|---|
| Pregnancy (8.1) | No human pregnancy data. Animal oral studies showed fetal malformations only at doses causing severe maternal toxicity (rats: 189 mg/kg/day fetal NOAEL 95 mg/kg/day; rabbits: 284 mg/kg/day fetal NOAEL 142 mg/kg/day). Clinical relevance unknown given subnanomolar topical systemic exposure vs. oral bioavailability. |
| Lactation (8.2) | No data on presence of berdazimer or metabolites in human or animal milk. Consider developmental benefits of breastfeeding alongside maternal need for treatment. |
| Pediatric Use (8.4) | Safety and efficacy established for patients ≥1 year. 1,575 pediatric subjects in trials (904 berdazimer); includes 29 subjects <2 years (1 subject <1 year). Not established in infants <1 year. |
| Geriatric Use (8.5) | Of ZELSUVMI-treated subjects in clinical trials, none were 65–74 years of age; 1 was ≥75 years. Insufficient data to determine whether elderly respond differently from younger adults. |
| Renal/Hepatic Impairment | Not studied. Given negligible systemic exposure, dose adjustment not expected to be required. |
§4.9 — Nonclinical Safety Summary
Section 13.1
Carcinogenicity
2-year dermal mouse carcinogenicity study (daily topical administration up to 4% berdazimer gel). No drug-related tumor findings. Source: PI §13.1, NDA 217424.
Genotoxicity
Mutagenic in bacterial mutagenicity (Ames) assay. NOT clastogenic in in vitro chromosomal aberration assay (human peripheral blood lymphocytes) or in vivo micronucleus assay (rats). Overall genotoxicity classification: equivocal/context-dependent. Source: PI §13.1.
Reproductive Toxicity
No berdazimer-related effects on male or female fertility and early embryonic parameters in rats at oral doses up to 189 mg/kg/day. Fetal skeletal/visceral malformations in rats only at 189 mg/kg/day (severe maternal toxicity present). Fetal NOAEL rat: 95 mg/kg/day; rabbit: 142 mg/kg/day. Source: PI §8.1, §13.1.
Cardiac Safety (QTc)
No clinically relevant QTc prolongation observed in dedicated QT study conducted with SB204 12% gel at ~33× the expected MC treatment area. No QTc concern for ZELSUVMI at approved clinical dose. Source: NDA 217424 Medical Review, Ref ID 5304936.
Source: FDA label NDA 217424 Table 1, Ref ID 5304861 (prescribing information) and NDA 217424 Multi-disciplinary Medical Review, Ref ID 5304936. No contraindications identified. No drug-drug interaction studies conducted; not warranted given subnanomolar systemic exposure.
Pharmacology & Pharmacokinetics
§5 · Section 12 / Table 15 (NDA 217424 Medical Review, Ref ID 5304936)Systemic Absorption (hMAP3)
Negligible
0/34 subjects had quantifiable plasma hMAP3 on Day 1; only 2/34 on Day 15 (Cmax 5.12 and 33.9 ng/mL). LLOQ = 5 ng/mL
Tmax (hMAP3, Day 15)
~2 hours
Observed in the 2 subjects with quantifiable concentrations. AUC0–3 calculated as 75.5 h·ng/mL for 1 subject only
Plasma Nitrate
Flat / No Δ
Mean plasma nitrate levels similar on Days 1 and 15; flat during PK sampling (baseline through 1, 3, 6 hrs post-application)
Methemoglobin
0–3.2%
Observed range in Phase 1 maximal use study (NI-MC101) and Phase 2 (NI-MC201); no clinically significant elevations
Distribution / Metabolism / Excretion
Not Studied
No distribution, metabolism, or excretion studies conducted. Plasma protein binding not determined. DDI studies not warranted.
Maximal Use Study Area
484 cm²
~5× the mean treatment area in Phase 3 trials (~98 cm²); mean lesion count 34 vs 20.2 in Phase 3. Mean dose ~3 mL/day
§5.1 — Absorption
Section 12.3
Percutaneous absorption: Systemic absorption of berdazimer following topical application is negligible. In a maximal use PK study (NI-MC101, N=34, ages 2–12 years), subjects applied ZELSUVMI once daily for two weeks to a total treatment area of 484 cm² (mean lesion count=34), applying a mean dose of approximately 3 mL/day. No subjects had quantifiable plasma hMAP3 concentrations on Day 1; two subjects had quantifiable concentrations on Day 15 (LLOQ = 5 ng/mL). Mean plasma nitrate levels remained stable at background/endogenous levels throughout. No apparent differences in methemoglobin levels were observed throughout the study.
§5.2 — Distribution
No distribution studies were conducted. Berdazimer sodium is applied topically and acts locally at the skin surface. Plasma protein binding in humans was not determined. Given negligible systemic absorption, systemic distribution is not clinically relevant. Source: NDA 217424 Medical Review, Ref ID 5304936.
§5.3 — Metabolism
| Parameter | Details |
|---|---|
| Primary metabolic mechanism | Proton-mediated hydrolysis of diazeniumdiolate (NONOate) moieties, releasing nitric oxide and the structural backbone marker hMAP3 (hydrolyzed N-methylaminopropyl-trimethoxysilane) |
| Metabolic enzymes (CYP) | No formal CYP metabolism studies conducted. Not applicable given negligible systemic exposure. |
| Active metabolites | Nitric oxide (pharmacologically active at target site); hMAP3 used as bioanalytical structural marker for systemic exposure assessment |
| Formal metabolism studies | Not conducted; waived by FDA given negligible systemic exposure |
§5.4 — Elimination
No formal excretion studies conducted. Topical product applied locally; low systemic exposure precludes meaningful assessment of systemic elimination. No accumulation detected (plasma hMAP3 exposure not appreciably accumulating after 5 daily topical administrations — confirmed in animal models). Source: NDA 217424 Medical Review, Ref ID 5304936.
§5.5 — PK Summary Table (hMAP3 as Structural Marker)
Table 15 / Table 49, NDA 217424 Medical Review| PK Parameter | Details |
|---|---|
| Analyte | hMAP3 (hydrolyzed N-methylaminopropyl-trimethoxysilane) — specific structural marker for berdazimer sodium backbone. Also: plasma nitrate ion (NO metabolism), methemoglobin (systemic NO exposure biomarker) |
| Bioanalytical method | High-performance LC/MS/MS; LLOQ 5 ng/mL for hMAP3, 300 ng/mL for nitrate |
| Study population | NI-MC101: N=34 children aged 2–12 years with MC; maximal use field treatment (484 cm²) |
| hMAP3 Day 1 | 0/34 subjects had quantifiable concentrations (all <LLOQ of 5 ng/mL) |
| hMAP3 Day 15 | 2/34 subjects had quantifiable concentrations; Cmax: 5.12 and 33.9 ng/mL; Tmax ~2 h; AUC0–3 = 75.5 h·ng/mL (1 subject) |
| Accumulation | No accumulation detected (plasma hMAP3 exposure not appreciably accumulating after 5 daily topical administrations — confirmed in animal models) |
| Plasma nitrate | Levels remained stable at background/endogenous levels across Days 1 and 15; no treatment-related increase |
| Special population PK | No dedicated studies in renal impairment, hepatic impairment, or geriatric populations; not warranted given negligible systemic exposure |
| Drug-drug interactions | No DDI studies conducted; not warranted due to subnanomolar systemic exposure |
| QTc | No clinically relevant QTc prolongation observed in dedicated QT study (SB204 12% gel, ~33× expected MC treatment area) |
§5.6 — Drug–Drug Interactions
No DDI studies conducted: No drug-drug interaction studies were performed for berdazimer. Given subnanomolar systemic exposure following topical application, clinically relevant drug interactions are not expected. FDA did not require DDI studies as part of the NDA 217424 review. Source: NDA 217424 Medical Review, Ref ID 5304936.
§5.7 — Mechanism of Action
Section 12.1Berdazimer sodium (NVN1000) is a macromolecular silasesquioxane polymer with covalently bound diazeniumdiolate (NONOate) moieties that release nitric oxide upon contact with protons. In the two-tube system, when the berdazimer sodium gel (Tube A) is mixed with the proton-donating hydrogel (Tube B), protonation of the NONOate groups triggers NO release directly at the skin surface. NO is a highly reactive diatomic radical with established antimicrobial, antiviral, and immunostimulatory properties. At low/signaling concentrations, NO activates guanylate cyclase and modulates immune responses; at higher concentrations it exerts cytotoxic effects via reactive nitrogen species. The exact mechanism by which this NO release clears molluscum contagiosum virus (MCV, a poxvirus) lesions is not established per the prescribing information.
Nonclinical virology: In vitro studies with berdazimer sodium (0–7 µg/mL) and its hydrolysis product hMAP3 (0–3 µg/mL) showed concentration-dependent inhibitory effects against MCV. The IC50 for berdazimer sodium was estimated as >7 µg/mL. The IC50 for hMAP3 was not calculable at concentrations tested. Source: NDA 217424 Medical Review, Ref ID 5304936.
§5.8 — Pharmacodynamics
Section 12.2
Pharmacodynamics unknown (label Section 12.2): The pharmacodynamics of ZELSUVMI are formally described as unknown per the FDA-approved prescribing information. No dose-response or PK/PD relationship has been established. No formal exposure-response analysis was conducted in the NDA 217424 review due to negligible systemic exposure. The drug is administered at a fixed topical dose (0.5 mL each tube, QD) without PK-guided titration.
Molecular characteristics (Section 11): Berdazimer sodium is a white to off-white powder — a partially hydrolyzed silasesquioxane copolymer with empirical formula [(C₄H₉N₃NaO₃.₅Si)₃(C₄H₁₀NO₁.₅Si)₁(SiO₂)₆(HO₀.₅)₅]₀.₁ₙ. Due to the insoluble polymeric nature of the molecule, molecular formula, molecular mass, and average molecular weight cannot be determined by conventional methods.
Source: NDA 217424 Clinical Pharmacology Review (Section 6.2.2, Table 15), Non-Clinical Review (Section 5), and Label Section 12. Phase 1 maximal use PK study NI-MC101: open-label, N=34, ages 2–12 years. All US centers. OCP review completed by Division Director Suresh Doddapaneni (OCP). No outstanding Clinical Pharmacology issues precluded approval. Ref ID 5304936.
Dosing, Administration & Contraindications
§6 · Section 2, 4, 5 / Label (Ref ID 5304861)Recommended Dose
0.5 mL + 0.5 mL
Equal volumes from Tube A (berdazimer) and Tube B (hydrogel) — mix immediately before application
Frequency
Once Daily
Apply to each MC lesion; continue up to 12 weeks; treat new lesions as they arise
Population
≥1 Year
Adults and pediatric patients 1 year of age and older; not established in infants <1 year
Duration
Up to 12 wks
Maximum treatment duration per PI; apply to all treatable MC lesions including new ones throughout treatment
§6.1 — Standard Dosing & Preparation
Section 2.1 / 2.2Standard Dosing
- Dispense equal amounts (0.5 mL) of gel from Tube A and Tube B on the dosing guide.
- Immediately put caps back on Tube A and Tube B tightly after dispensing.
- Mix together on the dosing guide using circular motion while counting to 20.
- Immediately apply ZELSUVMI as an even thin layer to each MC lesion.
- Apply once daily for up to 12 weeks. No loading dose required.
- No titration schedule — fixed topical dose throughout treatment.
Dose Modifications
- No dose modifications recommended for renal impairment — not studied; negligible systemic exposure.
- No dose modifications recommended for hepatic impairment — not studied; negligible systemic exposure.
- No weight-based or age-based dose adjustments — same dose for adults and pediatric patients ≥1 year.
- If allergic contact dermatitis occurs: discontinue ZELSUVMI and initiate appropriate therapy.
Preparation & Administration
- Wash and dry hands before applying.
- Place Dosing Guide on a clean, flat surface.
- Squeeze gel from Tube A (blue lane) and Tube B (yellow lane) covering the entire respective lanes.
- Mix both gels in the center of Dosing Guide using circular motion (~20 seconds). Clumping is normal.
- Apply mixed gel immediately to all MC lesions as a thin, even layer.
- Allow to dry for 10 minutes before dressing. Avoid swimming/bathing for 1 hour.
- Wash hands after application (unless hands are being treated).
- Do not apply to uninvolved skin. Avoid transfer to eyes.
- Topical use only. Not for ophthalmic, oral, or intravaginal use.
Missed Dose
- No specific missed dose instructions are stated in the prescribing information.
- Clinically: apply as soon as remembered, then continue regular once-daily schedule.
- Do not apply double doses to make up for a missed dose (general topical guidance).
Storage & Handling
- Prior to dispensing: Refrigerate at 2°C–8°C (36°F–46°F) until dispensed.
- After dispensing: Store at room temperature 20°C–25°C (68°F–77°F) in a dry location.
- Discard 60 days after removal from refrigeration.
- Do not freeze. Keep away from open flame (product contains alcohol).
- Do not premix or store mixed ZELSUVMI.
How Supplied (Section 16)
- Carton NDC: 71403-103-31
- Tube A (14 g, blue label): Berdazimer sodium gel. NDC 71403-113-14. 240 mg berdazimer sodium/g gel.
- Tube B (17 g, yellow label): Hydrogel (translucent to opaque white). UPC 71403-0000-17.
- Dosing Guide: Included in carton; reusable — do not discard.
§6.4 — Contraindications
Section 4
None. ZELSUVMI (berdazimer) topical gel has no contraindications identified in the FDA-approved prescribing information (PI §4, NDA 217424, Ref ID 5304861, Revised 01/2024).
§6.5 — Warnings Relevant to Dosing
Section 5.1- Application Site Reactions including Allergic Contact Dermatitis (5.1): Application site reactions have occurred in ZELSUVMI-treated patients. Suspect allergic contact dermatitis if pain, pruritus, swelling, or erythema at the application site persists for longer than 24 hours. If allergic contact dermatitis occurs: discontinue ZELSUVMI and initiate appropriate therapy. Application site reactions were the most common reason for clinician review of treatment.
§6.6 — Drug Interactions Affecting Dosing
No drug interactions identified: No drug-drug interaction studies were conducted for berdazimer. Given negligible systemic exposure (subnanomolar) following topical application, no dose adjustments for concomitant medications are required or expected. No interactions with topical products at application site have been formally studied.
§6.7 — Administration Instructions Summary
| Parameter | Recommendation |
|---|---|
| Application technique | Thin, even layer applied to each MC lesion using fingertip; mixed on dosing guide — do NOT mix directly on skin |
| Application areas | All treatable MC lesions including new ones; avoid uninvolved skin; avoid application near/in eyes, mouth, vagina |
| Post-application wait | 10 minutes before clothing/dressing; 1 hour before swimming, bathing, or washing treated areas |
| Concomitant topicals | Not formally studied; no specific guidance on spacing with emollients/moisturizers; apply ZELSUVMI to clean, dry skin |
| Caregiver instructions | Caregiver/parent should wash hands after applying ZELSUVMI unless hands are being treated |
| Open wounds | Do not apply to open wounds; rinse with water if accidental exposure |
| Eye exposure | Rinse with water if gel gets in eye; contact healthcare provider |
§6.8 — Special Populations
Section 8| Population | Guidance |
|---|---|
| Pregnancy (8.1) | No human pregnancy data. Animal oral studies showed fetal malformations only at doses causing severe maternal toxicity. Clinical relevance unknown given subnanomolar topical systemic exposure. |
| Lactation (8.2) | No data on presence of berdazimer or metabolites in human or animal milk. Consider developmental benefits of breastfeeding alongside maternal need for treatment. |
| Pediatric Use (8.4) | Safety and efficacy established for patients ≥1 year. 1,575 pediatric subjects in trials (904 berdazimer). Not established in infants <1 year. |
| Geriatric Use (8.5) | Insufficient data (1 subject ≥75 years); no geriatric-specific dosing recommendation. |
| Renal/Hepatic Impairment | Not studied; dose adjustment not expected to be required given negligible systemic exposure. |
Source: FDA Prescribing Information NDA 217424, Ref ID 5304861, Revised 01/2024. Manufactured for EPIH SPV, LLC, Wilmington, Delaware 19801. U.S. Patents: www.novan.com/patents. Patient information line: 1-855-330-7546. For SUSPECTED ADVERSE REACTIONS contact LNHC, Inc. at 1-800-499-4468 or FDA MedWatch at 1-800-FDA-1088.
Regulatory History
§7 · NDA 217424 — 505(b)(1) Standard ReviewRegulatory Pathway
NDA 505(b)(1)
Full NDA with complete safety and efficacy data package generated by the applicant. New Molecular Entity (NME). Standard Review designation.
Reviewing Division
DDD/OII
Division of Dermatology and Dentistry, Office of Immunology and Inflammation, CDER
NME Status
New Molecular Entity
Berdazimer sodium — first NO-releasing macromolecular silasesquioxane polymer approved for topical dermatologic use
PDUFA Goal Date Met
Jan 5, 2024
Submitted Jan 5, 2023; approved on the PDUFA goal date. Review completed Jan 4, 2024 (multi-disciplinary review signed).
§7.2 — NDA Key Facts Table
| Aspect | Detail |
|---|---|
| Application Number | NDA 217424 (Orig1s000) |
| Application Type | NDA 505(b)(1) — Full application with complete data package |
| Applicant | EPIH SPV, LLC, Wilmington, Delaware 19801 |
| Original Developer | Novan, Inc. (code name NVN1000 / SB206) |
| IND Number | IND 137015 (shared with SB204 acne program) |
| Submission Date | January 5, 2023 |
| PDUFA Goal Date | January 5, 2024 |
| Actual Approval Date | January 5, 2024 |
| Review Division | Division of Dermatology and Dentistry (DDD), Office of Immunology and Inflammation (OII), CDER |
| Review Type | Standard Review |
| Breakthrough Therapy Designation | Not reported / Not granted |
| Fast Track Designation | Not reported / Not granted |
| Orphan Drug Designation | Not applicable |
| Advisory Committee | Not convened for this NDA |
| Medical Review Ref ID | 5304936 |
| PI Ref ID | 5304861 |
§7.3 — Regulatory Timeline
IND 137015 OPENED
IND 137015 Opened (SB204 for Acne)
Berdazimer development initially for acne vulgaris under SB204 (same polymer backbone, different concentration). Early IND discussions with FDA informed MC program design.
2019–2020
Phase 3 Trials NI-MC301 and NI-MC302 Initiated
Concurrent trials; 2:1 randomization (berdazimer:vehicle); 33 US centers each; N=352 and N=355 respectively.
SEPTEMBER 17, 2021
FDA Type C Meeting — Applicant Response
FDA reiterated that partial clearance endpoints would not be accepted for labeling claims. Complete clearance at Week 12 confirmed as primary endpoint. Informed design of NI-MC304.
APRIL 4, 2022
FDA Type B Meeting (IND 137015)
FDA recommended difference in response rates as preferred metric for primary endpoint presentation in labeling (over odds ratio). Informed statistical analysis plan for NI-MC304.
2020–2022
Phase 3 Trial NI-MC304 (Pivotal) Conducted
N=891; 1:1 randomization; 55 US centers; additional BOTE score stratification; COVID-era remote Week 4 visit accommodation. Protocol amendments v2.0 (Jul 2020) and v3.0 (Sep 2020) implemented.
JANUARY 5, 2023
NDA 217424 Submitted and Received
505(b)(1) NDA submitted to FDA. PDUFA goal date set as January 5, 2024. Standard review designation.
JANUARY 4, 2024
Multi-Disciplinary Review Completed
NDA 217424 multi-disciplinary review signed. Summary Review, Clinical Review, Non-Clinical Review, Statistical Review, and Clinical Pharmacology Review completed. Recommendation: Approval.
JANUARY 5, 2024
FDA Approval Granted — NDA 217424
ZELSUVMI (berdazimer) topical gel 10.3% approved for topical treatment of molluscum contagiosum in adults and pediatric patients ≥1 year of age. First FDA-approved prescription topical therapy specifically for MC. Ref ID 5304861 (label), 5304936 (medical review). Label revised 01/2024.
§7.4 — Key Review Issues
Efficacy Across Three Trials (One Failure)
The primary challenge was that NI-MC301 failed to reach statistical significance (p=0.3637), raising questions about whether the evidence package met the two adequate and well-controlled trials standard. FDA concluded that NI-MC302’s Week 8 secondary endpoint and multiple sensitivity analyses provided supportive evidence alongside the pivotal NI-MC304 result.
NRI with Imbalanced Dropout
The conservative NRI approach penalized the active arm disproportionately due to higher dropout in the berdazimer groups (application site reactions). The statistical reviewer confirmed that sensitivity analyses (MMRM, observed cases) consistently supported treatment efficacy in the two confirmatory trials.
Ames Assay Positivity
Berdazimer tested positive in the bacterial mutagenicity (Ames) assay. The non-clinical review resolved this concern by noting negative results in both the in vitro chromosomal aberration assay and the in vivo micronucleus assay, combined with no drug-related tumors in the 2-year mouse carcinogenicity study at topical doses up to 4%.
Primary Endpoint Acceptance
Negotiation of the primary endpoint (complete clearance vs. partial clearance) was a key pre-NDA regulatory discussion. FDA’s Type C meeting (Sep 2021) established complete clearance (lesion count = 0) as the only acceptable primary endpoint for labeling. Partial clearance data were reviewed but not included in labeling claims.
§7.5 — Postmarketing Requirements & Commitments
PMR/PMC: No specific postmarketing requirements (PMRs) or commitments (PMCs) requiring formal study protocols were identified in the publicly available FDA review documents for NDA 217424. Standard pharmacovigilance obligations apply under 21 CFR Part 314.
§7.6 — Regulatory Notes
| Domain | Note |
|---|---|
| Benefit-risk conclusion | FDA concluded favorable benefit-risk balance: the modest but statistically significant and reproducible reduction in complete clearance rate versus vehicle provides meaningful benefit for a condition lacking any FDA-approved prescription topical treatment. Local application site reactions manageable; no systemic safety concerns. |
| Labeling negotiation | Complete clearance endpoint accepted; partial clearance data (≥90% reduction) not included in label claims. Efficacy claim limited to NI-MC304 (confirmed) and NI-MC302 (supportive) per Label Table 2. |
| Immunogenicity labeling | Not applicable — berdazimer is a small-molecule polymer, not a biologic. |
| Statistical issues | GEE with exchangeable working correlation structure accepted; NRI used for primary analysis. Sensitivity analyses with MMRM and MI documented in Medical Review. Household randomization correlation appropriately addressed. |
| Source documents | Prescribing Information: NDA 217424, Ref ID 5304861, Revised 01/2024. Medical Review: NDA 217424, Ref ID 5304936 (completed Jan 4, 2024). |
| Pivotal trials | NI-MC304 (NCT04535531) — primary adequate and well-controlled trial; NI-MC302 (NCT03927703) — supportive adequate and well-controlled trial |
| Failed trial | NI-MC301 (NCT03927716) — did not demonstrate efficacy; conservative NRI with imbalanced dropout; does not detract from overall evidence per FDA |
| U.S. Patents | www.novan.com/patents |
Source: NDA 217424 Multi-disciplinary Review, Ref ID 5304936 (completed Jan 4, 2024). Label NDA 217424, Ref ID 5304861, Revised 01/2024. Section 505(b)(1) of the Federal Food, Drug and Cosmetic Act. All clinical trials conducted in the United States. Review conducted by Division of Dermatology and Dentistry (DDD), Office of Immunology and Inflammation (OII), CDER, FDA.