LetibotulinumtoxinA (LETYBO) — Drug Profile | TrialistMD

Acetylcholine release inhibitor · Neuromuscular blocking agent

LetibotulinumtoxinA

LETYBO (letibotulinumtoxinA-wlbg)

An acetylcholine release inhibitor and neuromuscular blocking agent (botulinum toxin type A; 900 kDa) indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients. Approved February 29, 2024 via BLA 351(a).

Applicant

Hugel, Inc.

BLA Number

761225

Approval Date

February 29, 2024

Review Division

DDD (OII)

IND Number

IND 123178

Drug Profile

Drug Class

BTX-A

Botulinum toxin type A; SNAP25 cleavage

Molecular Weight

900 kDa

Noncovalent multimeric complex; 6 proteins

Dosage Form

50/100 U

White freeze-dried powder; single-dose vial

Route

Intramuscular; 5 sites; 20 Units total

Drug Identification

Established / Proper Name	letibotulinumtoxinA-wlbg
Proposed Trade Name	LETYBO
Pharmacologic Class	Acetylcholine release inhibitor; neuromuscular blocking agent
Molecular Weight	~900 kDa (noncovalent multimeric complex; 6 proteins)
Source Organism	Clostridium botulinum (fermentation)
Toxin Type	Botulinum toxin type A
Active Ingredient	letibotulinumtoxinA-wlbg
Inactive Ingredients	Albumin human; sodium chloride
Marketed Name Outside US	Botulax® (Korea; marketed since 2010)
US License Number	2237
Manufacturer	Hugel, Inc., 61-20 Sinbuk-ro, Sinbuk-eup, Chuncheon, 24206 Korea

Mechanism of Action

Neuromuscular Blockade via SNAP25 Cleavage: letibotulinumtoxinA blocks cholinergic transmission at the neuromuscular junction by inhibiting acetylcholine release. After IM injection, the toxin is internalized into the nerve terminal, translocates into the neuronal cytosol, and cleaves SNAP25 — a protein essential for synaptic vesicle docking and acetylcholine release — producing a dose-dependent decrease in muscle function.

Primary Target	SNAP25 (Synaptosomal-Associated Protein 25)
Action	Prevents ACh vesicle membrane fusion; blocks cholinergic NMJ transmission
Mechanism (cellular)	Internalization → translocation to neuronal cytosol → SNAP25 cleavage
Onset of Effect	Gradual; dose-dependent decrease in muscle function
Recovery Mechanism	Neurotoxin degradation + axonal sprouting → muscle reinnervation → slow reversal
Preclinical Comparator	Onset and duration of paralysis comparable to onabotulinumtoxinA at all timepoints (3, 7, 14, 21, 28 days) and doses (2, 4, 8 U/animal) in rat model (Study CP-001)

Approved Indication

FDA-Approved Indication	Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients
Population	Adults (18–75 years in trials)
Line Severity	Moderate to severe at maximum frown (GLS ≥2)
Not Approved For	Spasticity or any conditions other than glabellar lines
Pediatric Use	Safety and effectiveness not established in pediatric patients; full waiver granted (extremely low prevalence of glabellar lines in pediatric population)

Competitive Landscape — FDA-Approved BoNT Products for Glabellar Lines

Product (INN)	FDA Approval	Dosing	Pivotal Efficacy (responder rate)	Key Safety
BOTOX Cosmetic (onabotulinumtoxinA)	2002	20 U IM; 5 sites × 4 U	Study 1: 61%; Study 2: 46%	Spread of toxin; dysphagia; breathing difficulties
Dysport (abobotulinumtoxinA)	2009	50 U IM; 5 sites × 10 U	GL1: 55%; GL2: 52%; GL3: 60%	Spread of toxin; dysphagia; breathing difficulties
Xeomin (incobotulinumtoxinA)	2011	20 U IM; 5 sites × 4 U	GL1: 60%; GL2: 48%	Spread of toxin; dysphagia; breathing difficulties
Jeuveau (prabotulinumtoxinA-xvfs)	2019	20 U IM; 5 sites × 4 U	EV-001: 67%; EV-002: 70%	Spread of toxin; dysphagia; breathing difficulties
LETYBO (letibotulinumtoxinA-wlbg)	2024	20 U IM; 5 sites × 4 U	BLESS I: 47%; II: 49%; III: 65%	Spread of toxin; standard BTX-A warnings

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 1. Physician’s Inserts from Drugs@FDA.

Study Population Overview

Three Pivotal Phase 3 Trials (BLESS I, II, III): Identically designed, randomized, double-blind, placebo-controlled studies. Total randomized: 1,276 subjects (957 LETYBO, 319 placebo); Full Analysis Set (FAS): 1,271 subjects (954 LETYBO, 317 placebo). Each study comprised a double-blind phase followed by an open-label extension phase.

BLESS I (NCT02677298)

708

531 LETYBO / 177 Placebo
CPH-301-201030
US (9 sites), Germany, Poland (9 sites) — 18 centers

BLESS II (NCT02677805)

213

160 LETYBO / 53 Placebo
CPH-302-201030
US — 6 centers

BLESS III (NCT03985982)

355

266 LETYBO / 89 Placebo
CPH-303-201400
US (6 sites), Austria (1 site) — 7 centers

Subject Disposition

Parameter	BLESS I (Letybo / Placebo)	BLESS II (Letybo / Placebo)	BLESS III (Letybo / Placebo)
Randomized	531 / 177	160 / 53	266 / 89
Received Treatment	529 (99.6%) / 175 (98.9%)	160 (100%) / 53 (100%)	266 (100%) / 89 (100%)
FAS (primary analysis)	528 / 175	160 / 53	266 / 89
Completed Double-Blind Phase	500 (94.2%) / 160 (90.4%)	147 (91.9%) / 48 (90.6%)	249 (93.6%) / 84 (94.4%)
Completed Entire Study	456 (85.9%) / 145 (81.9%)	136 (85.0%) / 43 (81.1%)	227 (85.3%) / 80 (89.9%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 5. Non-responder imputation for FAS.

Baseline Demographics (FAS)

Characteristic	BLESS I Letybo (N=528) / Placebo (N=175)	BLESS II Letybo (N=160) / Placebo (N=53)	BLESS III Letybo (N=266) / Placebo (N=89)
Mean Age (years)	49.3 / 48.7	52.0 / 52.4	52.2 / 49.4
Median Age (years)	49 / 49	52.5 / 51	53 / 52
Age Range (years)	19–75 / 21–74	27–75 / 29–73	21–75 / 22–75
18–64 years	462 (87.5%) / 157 (89.7%)	141 (88.1%) / 45 (84.9%)	233 (87.6%) / 81 (91.0%)
65–75 years	66 (12.5%) / 18 (10.3%)	19 (11.9%) / 8 (15.1%)	33 (12.4%) / 8 (9.0%)
Female	483 (91.5%) / 155 (88.6%)	150 (93.8%) / 45 (84.9%)	248 (93.2%) / 80 (89.9%)
Male	45 (8.5%) / 20 (11.4%)	10 (6.3%) / 8 (15.1%)	18 (6.8%) / 9 (10.1%)
White	482 (91.3%) / 153 (87.4%)	153 (95.6%) / 50 (94.3%)	236 (88.7%) / 79 (88.8%)
Black or African American	33 (6.3%) / 18 (10.3%)	3 (1.9%) / 1 (1.9%)	25 (9.4%) / 7 (7.9%)
Asian	7 (1.3%) / 3 (1.7%)	2 (1.3%) / 1 (1.9%)	4 (1.5%) / 1 (1.1%)
Not Hispanic or Latino	497 (94.1%) / 166 (94.9%)	126 (78.8%) / 45 (84.9%)	200 (75.2%) / 67 (75.3%)
Hispanic or Latino	25 (4.7%) / 8 (4.6%)	33 (20.6%) / 7 (13.2%)	66 (24.8%) / 22 (24.7%)
Region: US	268 (50.8%) / 95 (54.3%)	160 (100%) / 53 (100%)	225 (84.6%) / 79 (88.8%)
Region: EU	260 (49.2%) / 80 (45.7%)	0 / 0	41 (15.4%) / 10 (11.2%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 7. EU: Germany and Poland in BLESS I; Austria in BLESS III.

Baseline Disease Characteristics (FAS)

Characteristic	BLESS I Letybo / Placebo	BLESS II Letybo / Placebo	BLESS III Letybo / Placebo
GLS-I = 3 (Severe) at max frown	384 (72.7%) / 133 (76.0%)	112 (70.0%) / 37 (69.8%)	202 (75.9%) / 67 (75.3%)
GLS-I = 2 (Moderate) at max frown	144 (27.3%) / 42 (24.0%)	48 (30.0%) / 16 (30.2%)	64 (24.1%) / 22 (24.7%)
GLS-S = 3 (Severe) at max frown	401 (75.9%) / 121 (69.1%)	121 (75.6%) / 42 (79.2%)	196 (73.7%) / 64 (71.9%)
GLS-S = 2 (Moderate) at max frown	127 (24.1%) / 54 (30.9%)	39 (24.4%) / 11 (20.8%)	70 (26.3%) / 25 (28.1%)
Previous Use of Botulinum Toxin: No	345 (65.3%) / 116 (66.3%)	105 (65.6%) / 42 (79.2%)	169 (63.5%) / 53 (59.6%)
Previous Use of Botulinum Toxin: Yes	183 (34.7%) / 59 (33.7%)	55 (34.4%) / 11 (20.8%)	97 (36.5%) / 36 (40.4%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 8. A higher proportion of subjects had severe (74%) vs moderate (26%) glabellar lines. Demographics were generally balanced across treatment groups.

Study Design

Design	Randomized, double-blind, placebo-controlled; two-part: double-blind phase + open-label extension
Randomization	3:1 (LETYBO : placebo) at Day 0 (baseline)
Double-Blind Phase	Single injection session with evaluations at Weeks 1, 2, 4, 8, and re-evaluation visits (starting Week 12, every 4 weeks)
Open-Label Extension	Up to 3 additional retreatments with 20 U LETYBO over 48 weeks; minimum 3-month interval between treatments; up to 4 total treatment cycles
Total Study Duration	Up to 60 weeks
Treatment Duration	At least 12 weeks per cycle (until retreatment eligibility)
Injection Sites	5 sites: 2 per corrugator supercilii muscle (inferomedial + superior middle), 1 in procerus muscle
Dose (active)	4 Units per site × 5 sites = 20 Units total
Volume per Site	0.1 mL
Primary Analysis Population	Full Analysis Set (FAS): all randomized subjects receiving ≥1 injection; ITT principle
Supportive Population	Per Protocol Set (PPS): FAS minus significant protocol deviations; ~84–90% Letybo, ~85–91% placebo
Statistical Method	Cochran-Mantel-Haenszel (CMH) test stratified by study center; Mantel-Haenszel common risk difference and 95% CI (reviewer-corrected)
Missing Data Handling	Primary: non-responder imputation (NRI); Sensitivity: observed values only, LOCF, worst-case imputation

Glabellar Line Scale (GLS)

Primary Endpoint Instrument: 4-point grading scale assessed independently by both investigator (GLS-I) and subject (GLS-S) at maximum frown. The same scale and descriptors used for both assessors. The PI also refers to this scale as the Facial Wrinkle Scale (FWS) in the medical review.

GLS Score	Descriptor	Line Severity at Maximum Frown
0 — None	Smooth area	No visible lines between the eyebrows
1 — Mild	Shallow lines	One or more thin or shallow lines
2 — Moderate	Medium depth	One or more lines of medium depth
3 — Severe	Deep/pronounced	One or more deep and pronounced lines

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 4. GLS-I = Investigator assessment; GLS-S = Subject (patient) assessment.

Key Inclusion / Exclusion Criteria

Key Inclusion Criteria

Healthy adults aged 18–75 years
Moderate to severe glabellar lines at maximum frown (GLS ≥2) by both investigator and subject
Ability to substantially lessen glabellar lines by physically spreading them apart
Corrugator and/or procerus muscle activity contributing to glabellar lines

Key Exclusion Criteria

Ptosis (drooping eyelids or eyebrows)
Deep dermal scarring in treatment area
Inability to substantially lessen glabellar lines by spreading
Marked facial asymmetry
Excessive dermatochalasis
Surgical alterations to facial anatomy
Active infection at injection site(s)
Neuromuscular disorders (ALS, myasthenia gravis, Lambert-Eaton)
Pregnancy or breastfeeding

Supportive Studies

Study	Design	Population / Country	N	Purpose
HG-11-01	Double-blind, randomized, active-controlled (Botox comparator)	Mod-severe glabellar lines; 18–75 yrs; Korea	272	Safety/efficacy (Korea approval); supportive safety data for BLA
HG-13-02 (HG-12-02)	Post-marketing surveillance	Mod-severe glabellar lines; 18–65 yrs; Korea	815	Additional post-marketing safety data

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 3. Phase 3 dose selection for BLESS studies was supported by HG-11-01 results demonstrating similar efficacy to onabotulinumtoxinA (Botox) at 20 Units.

Primary Efficacy Endpoint

Primary Endpoint Definition (Week 4): Proportion of subjects achieving a GLS score of 0 or 1 (none or mild) AND an improvement of ≥2 points from baseline at maximum frown, assessed concurrently by BOTH the investigator (GLS-I) AND the subject (GLS-S). FDA statistical reviewers termed this the “multi-component responder rate.” Analysis method: CMH test stratified by study center (two-sided p=0.05); Mantel-Haenszel common risk difference with 95% CI.

Primary Endpoint Results at Week 4 (FAS, NRI)

Study	LETYBO Multi-component Responder n/N (%)	Placebo n/N (%)	Treatment Difference (MH)	95% CI	p-value
BLESS I	246/528 (46.6%)	0/175 (0%)	47.0%	(42.7%, 51.4%)	<0.0001
BLESS II	78/160 (48.8%)	1/53 (1.9%)	45.1%	(36.0%, 54.3%)	<0.0001
BLESS III	172/266 (64.7%)	0/89 (0%)	65.2%	(59.3%, 71.2%)	<0.0001

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 9. Reviewer analysis using Mantel-Haenszel stratified by study center. NRI for missing data. All three studies met pre-specified primary endpoint; results statistically superior to placebo. PI (Ref ID 5337801) reports Newcombe CIs (unstratified); reviewer-corrected MH CIs shown here.

Multi-component responder rate (GLS 0/1 + ≥2-point improvement at max frown, Week 4). Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 9.

Individual Components of Primary Endpoint (Week 4)

Component	BLESS I LETYBO / Placebo	BLESS II LETYBO / Placebo	BLESS III LETYBO / Placebo
Investigator Assessment (GLS-I 0 or 1; ≥2-pt improvement)	348/528 (65.9%) / 1/175 (0.6%)	120/160 (75.0%) / 1/53 (1.9%)	209/266 (78.6%) / 1/89 (1.1%)
Subject Assessment (GLS-S 0 or 1; ≥2-pt improvement)	290/528 (54.9%) / 0/175 (0%)	83/160 (51.9%) / 1/53 (1.9%)	183/266 (68.8%) / 0/89 (0%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 9. Investigator assessment responder rates were 10–23% higher than subject assessment rates in the LETYBO arm across studies.

Sensitivity Analyses — Primary Endpoint

Analysis Method	BLESS I LETYBO / Placebo	BLESS II LETYBO / Placebo	BLESS III LETYBO / Placebo
Primary (NRI)	46.6% / 0%	48.8% / 1.9%	64.7% / 0%
Observed Values Only	47.2% / 0%	50.6% / 2.0%	65.2% / 0%
LOCF	47.2% / 0%	50.6% / 1.9%	64.7% / 0%
Worst-Case Imputation	46.6% / 4.0%	48.8% / 9.4%	64.7% / 3.4%

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Tables 11–13. All sensitivity analyses showed consistent results; missing data had limited impact on efficacy conclusions due to large effect size and small proportion of subjects with missing data (0.8–3.8%).

Secondary Efficacy Endpoints (FAS)

Hierarchical Testing (BLESS I and II): Pre-specified hierarchical procedure. BLESS I: procedure did not stop until SE4 (Week 20; p=0.169). BLESS II: procedure stopped after SE1 (Week 12; p=0.173). BLESS III: all secondary endpoints exploratory only.

Secondary Endpoint	BLESS I LETYBO / Placebo	Treatment Diff. (95% CI)	BLESS II LETYBO / Placebo	Treatment Diff. (95% CI)	BLESS III LETYBO / Placebo (exploratory)
SE1: Multi-component Responder Rate at Week 12 (NRI)	67/528 (12.7%) / 0/175 (0%)	12.2% (9.3%, 15.0%); p<0.0001	7/160 (4.4%) / 0/53 (0%)	3.6% (0.6%, 6.6%); p=0.173 (Stop)	56/266 (21.1%) / 1/89 (1.1%); 19.4% (13.8%, 25.0%)
SE2: Multi-component Responder Rate at Week 16 (observed)	22/501 (4.4%) / 0/159 (0%)	4.5% (2.6%, 6.3%); p=0.006	5/149 (3.4%) / 0/48 (0%)	2.9% (-0.0%, 5.7%) [exploratory after SE1 stop]	27/254 (10.6%) / 1/84 (1.2%); 8.6% (4.1%, 13.2%)
SE3.1: ≥1-pt improvement at rest (GLS-I; Week 4)	333/473 (70.4%) / 27/160 (16.9%)	54.8% (47.7%, 61.9%); p<0.0001	95/141 (67.4%) / 3/47 (6.4%)	58.5% (47.4%, 69.6%)	163/215 (75.8%) / 8/66 (12.1%); 62.4% (52.8%, 72.0%)
SE3.2: ≥1-pt improvement at rest (GLS-S; Week 4)	412/502 (82.1%) / 17/167 (10.2%)	72.5% (66.7%, 78.2%); p<0.0001	113/148 (76.4%) / 9/52 (17.3%)	57.7% (44.7%, 70.7%)	214/255 (83.9%) / 11/82 (13.4%); 69.4% (60.6%, 78.1%)
SE4: Multi-component Responder Rate at Week 20 (observed)	6/503 (1.2%) / 0/158 (0%)	1.2% (0.2%, 2.2%); p=0.169 (Stop)	2/148 (1.4%) / 0/48 (0%)	1.3% (-0.7%, 3.2%) [exploratory]	NA

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 15. SE3 applicable only for subjects with GLS at rest ≥1 at baseline. Mantel-Haenszel weights stratified by center.

Subgroup Analyses — Primary Endpoint at Week 4 (FAS)

Subgroup	BLESS I LETYBO / Placebo	BLESS II LETYBO / Placebo	BLESS III LETYBO / Placebo
Age 18–64 years	222/462 (48.1%) / 0/157 (0%)	73/141 (51.8%) / 1/45 (2.2%)	155/233 (66.5%) / 0/81 (0%)
Age 65–75 years	24/66 (36.4%) / 0/18 (0%)	5/19 (26.3%) / 0/8 (0%)	17/33 (51.5%) / 0/8 (0%)
Female	230/483 (47.6%) / 0/155 (0%)	77/150 (51.3%) / 1/45 (2.2%)	166/248 (66.9%) / 0/80 (0%)
Male	16/45 (35.6%) / 0/20 (0%)	1/10 (10.0%) / 0/8 (0%)	6/18 (33.3%) / 0/9 (0%)
White	216/482 (44.8%) / 0/153 (0%)	75/153 (49.0%) / 1/50 (2.0%)	157/236 (66.5%) / 0/79 (0%)
Black or African American	22/33 (66.7%) / 0/18 (0%)	2/3 (66.7%) / 0/1 (0%)	12/25 (48.0%) / 0/7 (0%)
Not Hispanic/Latino	233/497 (46.9%) / 0/166 (0%)	60/126 (47.6%) / 0/45 (0%)	121/200 (60.5%) / 0/67 (0%)
Hispanic/Latino	10/25 (40.0%) / 0/8 (0%)	18/33 (54.5%) / 1/7 (14.3%)	51/66 (77.3%) / 0/22 (0%)
Botulinum Toxin Naïve	160/345 (46.4%) / 0/116 (0%)	49/105 (46.7%) / 1/42 (2.4%)	106/169 (62.7%) / 0/53 (0%)
Previous Botulinum Toxin Use	86/183 (47.0%) / 0/59 (0%)	29/55 (52.7%) / 0/11 (0%)	66/97 (68.0%) / 0/36 (0%)
US	146/268 (54.5%) / 0/95 (0%)	78/160 (48.8%) / 1/53 (1.9%)	153/225 (68.0%) / 0/79 (0%)
EU	100/260 (38.5%) / 0/80 (0%)	N/A	19/41 (46.3%) / 0/10 (0%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 16. Treatment effect for females was higher than males; effect for subjects <65 yrs was higher than ≥65 yrs in all three studies. Small sample sizes in male and ≥65-yr subgroups limit reliable estimation. Results consistent across most subgroups.

BLESS III Sensitivity — Excluding Site 110

Protocol Deviation — Site 110 (BLESS III): A site audit in January 2020 identified that an unblinded staff member performed blinded safety assessments at Site 110 (44 Letybo, 7 placebo subjects). Sensitivity analysis excluding Site 110 yielded 147/222 (66.2%) vs 0/82 (0%), treatment difference 66.1% (95% CI: 59.7%, 72.5%), p<0.0001 — nearly identical to primary analysis (65.2%; 59.3%, 71.2%). Minimal impact on efficacy conclusions.

Open-Label Extension — Drug Exposure

Treatment Cycle	BLESS I (N=704)	BLESS II (N=213)	BLESS III (N=355)	Combined (N=1272)
1st treatment (DB LETYBO + all OL)	704 (100%)	213 (100%)	355 (100%)	1272 (100%)
3rd study treatment	616 (93.5%)	181 (92.8%)	265 (82.0%)	1062 (83.5%)
4th study treatment	464 (70.4%)	149 (76.4%)	139 (43.0%)	752 (59.1%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 17. ISS Population: 1,272 total; 955 DB LETYBO + 317 placebo; 1,177 OL LETYBO. Total BoNT/A-DP exposures at marketed 20U dose: 1,380 subjects (including 134 from HG-11-01). 546 subjects received all 4 treatment cycles.

Boxed Warning

⚠ DISTANT SPREAD OF TOXIN EFFECT: The effects of all botulinum toxin products, including LETYBO, may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. Symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. LETYBO is not approved for the treatment of spasticity or any conditions other than glabellar lines.

Safety Database

Double-Blind Safety Population: 911 LETYBO and 310 placebo subjects from BLESS I, II, III. Open-Label Safety Population: 1,129 subjects. Total BoNT/A-DP exposures at 20U: 1,380 subjects across all studies.

Deaths

No deaths in any study phase

Tx-Related SAEs

No SAEs judged treatment-related

Any TEAE (DB)

23.6%

LETYBO vs 19.4% Placebo

Headache (AR)

Most common adverse reaction; PI Table 2

Adverse Reactions (PI Table 2) — Double-Blind Period

Adverse Reaction	LETYBO (N=911) n (%)	Placebo (N=310) n (%)
Headache* (any)	17 (2%)	2 (1%)
Brow ptosis** (any)	3 (<1%)	0
Eyelid ptosis	3 (<1%)	0
Blepharospasm	2 (<1%)	0

* Includes headache, head discomfort, migraine, and procedural headache. ** Includes brow ptosis and brow heaviness. Source: FDA PI BLA 761225 (Ref ID 5337801), Table 2. Adverse reactions reported in more than one subject in the LETYBO group vs placebo.

Common TEAEs ≥1% — Double-Blind Period (Pooled BLESS I, II, III)

Preferred Term	LETYBO (N=911) n (%)	Placebo (N=310) n (%)
Any TEAE	215 (23.6%)	60 (19.4%)
Upper respiratory tract infection*	47 (5.2%)	12 (3.9%)
Headache†	31 (4.3%)	5 (1.6%)
Injection site reaction‡	11 (1.2%)	6 (1.9%)
Urinary tract infection	9 (1.0%)	0

* Includes nasopharyngitis, URTI, sinusitis, laryngitis, tonsillitis, pharyngitis, pharyngitis streptococcal. † Includes headache, head discomfort, migraine, procedural headache. ‡ Includes contusion, facial pain, folliculitis, haematoma, injection site pain/bruising/hematoma/pruritus, swelling. Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 26.

Adverse Reactions ≥1% — Double-Blind and Open-Label Periods

Preferred Term	DB: LETYBO (N=911)	DB: Placebo (N=310)	OL Cycle 2 (N=1129)	OL Cycle 3 (N=1020)	OL Cycle 4 (N=722)
Any Adverse Reaction	33 (3.6%)	8 (2.6%)	28 (2.5%)	23 (2.3%)	7 (1.0%)
Headache*	17 (1.9%)	2 (0.6%)	15 (1.3%)	8 (0.8%)	2 (0.3%)
Injection site reaction	11 (1.2%)	6 (1.9%)	5 (0.4%)	4 (0.4%)	3 (0.4%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Tables 28 and 30. Headache AR was more frequent in younger subjects (<65 yrs: 4.6% vs ≥65 yrs: 1.4%) and in treatment-naïve subjects (5.1% vs 2.5% pre-treated). AR incidence did not increase with multiple retreatments.

Injection Site Reactions — Double-Blind Period

Injection Site Reaction	LETYBO (N=911) n (%)	Placebo (N=310) n (%)
Any injection site reaction	6 (0.7%)	2 (0.6%)
Injection site pain	3 (0.3%)	1 (0.3%)
Contusion (bruising)	2 (0.2%)	1 (0.3%)
Haematoma	1 (0.1%)	1 (0.3%)
Swelling	1 (0.1%)	1 (0.3%)
Injection site bruising	1 (0.1%)	1 (0.3%)
Facial pain	0	1 (0.3%)
Folliculitis	1 (0.1%)	0
Injection site haematoma	1 (0.1%)	0
Injection site pruritus	1 (0.1%)	0

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 29.

Serious Adverse Events (Double-Blind Period)

SAEs in LETYBO group (DB)	10/911 (1.1%) subjects; none treatment-related
SAEs in Placebo group (DB)	1/310 (0.3%) subject; not treatment-related
SAE pattern	All by PT reported for 1 subject except cholecystitis, osteoarthritis, and coronary artery disease (2 subjects each)
SAEs in OL period	21 subjects overall (1.9%); rate decreased with subsequent cycles: Cycle 1: 1.1%, Cycle 2: 1.1%, Cycle 3: 0.7%, Cycle 4: 0.4%
Treatment-Related SAEs	None
Deaths	None

Adverse Events of Special Interest — Toxin Spread

AESI (Preferred Term)	DB: LETYBO (N=911) n (%)	DB: Placebo (N=310) n (%)	OL: LETYBO (N=1129) n (%)
LOCAL SPREAD
Eyelid ptosis	3 (0.3%)	0	6 (0.5%)
Brow ptosis and heaviness	3 (0.3%)	0	1 (0.1%)
Vision blurred	1 (0.1%)	0	1 (0.1%)
Photophobia	0	0	1 (0.1%)
Diplopia	0	0	1 (0.1%)
DISTANT SPREAD
Bradycardia	1 (0.1%)	0	0
Dysarthria	1 (0.1%)	0	0
Constipation	1 (0.1%)	0	1 (0.1%)
Dyspnoea	0	0	1 (0.1%)
Muscular weakness	0	1 (0.3%)	0
Dysphagia	0	1 (0.3%)	0

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 21. Total 24 AESIs across studies (excluding 1 subject from BLESS III Site 110). 12 in DB period (10 after LETYBO, 2 after placebo); 12 in OL period. None of the AESIs were considered serious or severe. DB clinical reviewer noted disagreement with investigator causality assessment for several eyelid/brow ptosis events, stating temporal relationship could not rule out treatment-relatedness.

Cardiovascular Adverse Events

Preferred Term	DB: LETYBO (N=955) n (%)	DB: Placebo (N=317) n (%)	OL: LETYBO (N=1177) n (%)
Any cardiac disorder	4 (0.4%)	1 (0.3%)	4 (0.3%)
Arrhythmia	1 (0.1%)	0	1 (0.1%)
AV block first degree	1 (0.1%)	1 (0.3%)	0
Bradycardia	1 (0.1%)	0	0
Palpitations	1 (0.1%)	0	0
Coronary artery disease	0	0	2 (0.2%)
Acute myocardial infarction	0	0	1 (0.1%)
Angina unstable	0	0	1 (0.1%)
Hypertension	2 (0.2%)	0	10 (0.8%)

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Table 23. None of the cardiac events was judged treatment-related; none was consistent with MACE. ECG assessment showed no clinically meaningful differences between groups or QT prolongation.

Warnings and Precautions (PI §5)

Spread of toxin effects; dysphagia and breathing difficulties can be life-threatening; death reported. Seek immediate medical attention if respiratory, speech, or swallowing difficulties occur.
Potency Units of LETYBO are NOT interchangeable with other botulinum toxin products; cannot be compared or converted.
Serious adverse reactions (excessive weakness, dysphagia, aspiration pneumonia, fatal outcomes) reported with unapproved uses.
Hypersensitivity reactions: anaphylaxis, serum sickness, urticaria, soft tissue edema, dyspnea. Discontinue and initiate appropriate therapy.
Cardiovascular adverse reactions (arrhythmia, MI) with some fatal outcomes; use caution in pre-existing cardiovascular disease.
Increased risk with pre-existing neuromuscular disorders (ALS, myasthenia gravis, Lambert-Eaton syndrome); monitor for increased neuromuscular compromise.
Dysphagia and dyspnea including respiratory failure; may occur hours to weeks post-injection; deaths from severe dysphagia reported.
Use caution with inflammation at injection site, excessive weakness/atrophy in target muscles, marked facial asymmetry, surgical alterations, excessive dermatochalasis, deep dermal scarring.
Ophthalmic adverse reactions: dry eye, reduced tear production, reduced blinking, corneal disorders; refer to ophthalmologist if persistent dry eye symptoms.
Contains human albumin (derivative of human blood); remote risk for viral disease transmission and variant CJD/CJD. No cases identified for licensed albumin products.

Immunogenicity

Subjects evaluated (Phase 3 pivotal studies)	1,129 subjects (DB + OL phases)
Pre-existing antibodies at Screening/Baseline	3 subjects (<1%)
Antibody development post-treatment	2 subjects (<1%) — end of study
Neutralizing antibodies detected	None (all titer values zero)
Impact on efficacy/safety	No apparent association between antibody development and reduced efficacy or adverse events
PI-reported ADA incidence (1,195 subjects)	4 subjects (0.3%) developed antibodies; no neutralizing ADA detected in tested samples
Supportive study (HG-11-01; Korea)	No positive antibody samples among 271 subjects; samples collected at Baseline and Week 16
Caveats	Small number of antibody-positive subjects limits definitive conclusions; ADA detection dependent on assay sensitivity/specificity

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Section 6.2.1 and Table 2; FDA PI (Ref ID 5337801). PI and medical review differ slightly in the total N reported (1,195 vs 1,129) due to inclusion/exclusion of supportive studies.

Specific Safety Findings

Pregnancies: 4 pregnancies reported as AEs (“exposure during pregnancy”) — 1 during double-blind phase, 3 during open-label phase; all led to study discontinuation; all 4 subjects delivered healthy babies. No drug-related fetal outcomes observed in available data.

Discontinuations due to TEAEs: 8 subjects total (7 LETYBO, 1 placebo). Treatment-related TEAEs leading to discontinuation: headache (1 subject, definitely related); injection site bruising (1 placebo subject, possibly related to injection procedure). Non-treatment-related: Lyme disease (1), actinic keratosis (1); Pregnancies (4).

Laboratory, Vital Signs, ECG: No clinically significant changes in hematology/chemistry from baseline to Week 4 or end of each treatment cycle in either group. No clinically meaningful changes in vital signs or ECG parameters between groups. No QT prolongation detected. No new safety signals identified.

Mechanism of Action

Drug Type	Botulinum toxin type A; 900 kDa noncovalent multimeric complex (6 proteins)
Mechanism	Blocks cholinergic transmission at the neuromuscular junction by inhibiting acetylcholine release; cleaves SNAP25 protein
Cellular pathway	IM injection → internalization into nerve terminal → translocation to neuronal cytosol → SNAP25 cleavage → prevents ACh vesicle membrane fusion → dose-dependent decrease in muscle function
Recovery	Gradual: neurotoxin degradation + axonal sprouting → muscle reinnervation → slow pharmacological reversal
Primary pharmacology comparator	Onset and duration of muscle paralysis comparable to onabotulinumtoxinA at all tested timepoints (3–28 days) and doses (2, 4, 8 U/animal) in rat model. No recovery within 4 weeks after injection of either toxin (Study CP-001).

Pharmacokinetics

No Detectable Systemic Exposure: Using currently available analytical technology, it is not possible to detect letibotulinumtoxinA in the peripheral blood following IM injection at the recommended doses. No clinical pharmacology studies were conducted to characterize bioavailability or PK because anticipated low systemic exposures are undetectable by current bioanalytical methods.

Absorption / Bioavailability	Not characterized; systemic exposure undetectable after recommended IM dose
Distribution	Not characterized; systemic concentrations undetectable
Metabolism	Not characterized
Excretion	Not characterized
Nonclinical PK	No nonclinical PK evaluations performed; systemic concentrations not detectable at clinically relevant doses by any available bioanalytical methods

Pharmacodynamics

Formal PD Studies	No formal pharmacodynamic studies conducted in humans
Human PD characterization	The pharmacodynamic effects of letibotulinumtoxinA in humans have not been characterized by the Applicant
Dose-response	No dose-ranging study conducted; Phase 3 dose (20 U) selected based on supportive study HG-11-01 results (comparable efficacy to onabotulinumtoxinA 20 U)
Dose-exposure-response	No pharmacodynamic or pharmacokinetic dose-/exposure-response data available
Therapeutic individualization	Not necessary; dose adjustment based on intrinsic factors not required

Drug Product Characterization

Active Ingredient	letibotulinumtoxinA-wlbg
Molecular Weight	~900 kDa (noncovalent multimeric complex; 6 proteins)
Toxin Type	Botulinum neurotoxin type A
Source	Clostridium botulinum fermentation
Formulation	Sterile, preservative-free, white freeze-dried powder; single-dose vial
50 Units vial excipients	Albumin human (0.25 mg), Sodium chloride (0.45 mg)
100 Units vial excipients	Albumin human (0.5 mg), Sodium chloride (0.9 mg)
Reconstituted appearance	Clear, colorless; free of particulate matter

Non-Interchangeability

Critical Warning (PI §5.2 and §2.1): The potency Units of LETYBO are specific to the preparation and assay method utilized. They are NOT interchangeable with other preparations of botulinum toxin products. Units of biological activity of LETYBO cannot be compared to or converted into units of any other botulinum toxin product assessed with any other specific assay method.

Drug Interactions

No formal drug interaction studies conducted. Certain drugs may potentiate the effects of LETYBO, resulting in excessive neuromuscular weakness and heightened systemic anticholinergic effects.

Drug Class / Agent	Clinical Concern	Management
Aminoglycosides	Enhanced neuromuscular blockade	Caution; monitor for excessive neuromuscular weakness
Anticholinergic drugs	May heighten systemic anticholinergic effects	Caution; monitor closely
Other botulinum neurotoxin products	Cumulative toxin effects; potentiate blockade	Avoid concurrent use or within several months of LETYBO
Muscle relaxants	Enhanced neuromuscular weakness	Caution before or after LETYBO administration

Source: FDA PI BLA 761225 (Ref ID 5337801) §7.

Nonclinical Toxicology Summary

Study	Species / Duration	Key Findings
Single dose IM toxicity (Study 05-RA-241-1)	Rat; 6, 30, 150 U/kg	Dose-dependent paralysis, decreased body weight; LD50 = 129.5 U/kg (both sexes). Mortality at 150 U/kg.
Single dose IM toxicity (Study 05-DA242)	Beagle dog; 2.5–200 U/kg (escalating)	Minimum lethal dose >200 U/kg in dogs (not appropriate species for botulinum toxin toxicity)
4-week repeat dose IM toxicity (Study 05-RR-243)	Rat; 0, 1.5, 3, 6 U/kg weekly × 4 wks	Paralysis at injection site (hind leg) all dose groups; muscle atrophy; NOAEL <1.5 U/kg/dose (paralysis at all groups)
6-month repeat dose IM toxicity (Study 167857)	Rat; 0, 0.67/3.75, 2.0/7.5, 6.0/15 U/kg monthly	Muscle fiber atrophy/degeneration all dose groups; inflammatory infiltrate; fibrosis; some reversal after 6-month recovery
Embryo-fetal development (Study 08-RP-375)	Rat; 0, 1, 4, 8 U/kg/dose; GD 5–16	Decreased fetal body weight (all doses); ossification delays (mid/high dose). Effects secondary to maternal toxicity. No drug-related malformations. MRHD = 20 U/subject (0.34 U/kg for 60 kg subject); NOAEL not established at ≥1 U/kg (3× MRHD)
Carcinogenicity / Genotoxicity	—	Not conducted; not warranted per ICH S6(R1) for biotechnology-derived products
Common toxicities	—	Muscle paralysis and atrophy — typical for botulinum neurotoxin type A; no new or unique toxicities

Source: FDA Medical Review BLA 761225 (Ref ID 4960826), Section 5. No nonclinical PMRs or PMCs recommended.

Use in Specific Populations

Pregnancy (§8.1)	Insufficient data from case reports to identify drug-associated risk. Systemic exposure not assessed (undetectable). Animal data: decreased fetal body weight and skeletal ossification at maternally toxic doses ≥1 U/kg (3× MRHD) in rats — secondary to maternal toxicity, not fetal teratogenicity. Background risk (US general population): birth defects 2–4%; miscarriage 15–20%.
Lactation (§8.2)	No data on presence in human or animal milk, effects on breastfed infant, or milk production. Systemic exposure not assessed. Consider developmental and health benefits of breastfeeding.
Pediatric Use (§8.4)	Safety and effectiveness not established. Full waiver granted — extremely low prevalence of glabellar lines in pediatric population (age 0–17 years).
Geriatric Use (§8.5)	148 subjects ≥65 years enrolled (12%). No clinically meaningful differences in safety or efficacy vs younger subjects. Insufficient numbers to determine whether older patients respond differently. Subgroup analysis: response rate lower in ≥65 yrs vs 18–64 yrs.

Recommended Dosing

Standard Dose

Total dose: 20 Units per treatment session
5 intramuscular injection sites
4 Units (0.1 mL) per site
2 injections in each corrugator muscle (inferomedial + superior middle)
1 injection in mid-line of procerus muscle

Treatment Frequency

No more frequently than every 3 months
Consider cumulative dose if other botulinum toxins have been used for other indications
Potency units NOT interchangeable with other botulinum toxin products
Single-use vial only; discard remaining solution immediately after use
One injection session per vial; one patient per vial

Reconstitution

Vial Size	Diluent Added	Resulting Concentration
50 Units	1.25 mL	4 Units / 0.1 mL
100 Units	2.5 mL	4 Units / 0.1 mL

Diluent: Preservative-free 0.9% Sodium Chloride Injection, USP. Source: FDA PI BLA 761225 (Ref ID 5337801), Table 1.

Reconstitution Instructions: Slowly inject diluent into vial. Discard vial if vacuum does not pull diluent in. Gently mix by rotating — do not shake vigorously. Reconstituted solution is clear and colorless; discard if cloudy, discolored, or contains particles. Administer within 24 hours after reconstitution; store at 2°C to 8°C in original carton (protect from light). Do not freeze reconstituted LETYBO.

Administration Technique

Pre-injection Assessment: Carefully examine upper eyelid margin for separation or weakness of levator palpebrae superioris. Evaluate range of upper eyelid excursion while manually immobilizing frontalis to assess levator function and frontalis compensation.

Needle Size	30–31 gauge
Volume per Injection Site	0.1 mL (4 Units)
Number of Sites	5 (see PI Figure 1)
Corrugator Injections	2 per corrugator muscle (inferomedial + superior middle of each corrugator); lateral injections ≥1 cm above bony supraorbital ridge
Procerus Injection	1 in mid-line of procerus muscle
Safety Distance	Avoid injecting toxin closer than 1 cm above the central eyebrow
Syringe Preparation	Draw ≥0.5 mL of reconstituted toxin into sterile syringe; expel air bubbles; remove reconstitution needle; attach 30–31G needle; confirm needle patency
Injection Volume Accuracy	Ensure injected volume/dose is accurate; administer in steady, controlled manner

Ptosis Reduction Precautions: Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. Lateral corrugator injections ≥1 cm above bony supraorbital ridge. Avoid injection <1 cm above central eyebrow.

Storage and Handling

Unopened vials — storage	Refrigerator 2°C to 8°C (36°F to 46°F); original carton; protect from light
Unopened vials — do not freeze	Do not freeze
Reconstituted — storage	Refrigerator 2°C to 8°C in original carton; protect from light; ≤24 hours
Reconstituted — do not	Do not freeze reconstituted product
NDC (50 Units)	NDC 81165-050-01 (carton of 1 vial)
NDC (100 Units)	NDC 81165-100-01 (carton of 1 vial)

Contraindications

Known hypersensitivity to any botulinum toxin preparation (including BOTOX, BOTOX Cosmetic, MYOBLOC, DYSPORT, XEOMIN, JEUVEAU, DAXXIFY)
Known hypersensitivity to any component of the LETYBO formulation (albumin human, sodium chloride)
Presence of infection at the proposed injection site(s)

Special Patient Populations — Dosing Considerations

Patients with neuromuscular disorders (ALS, myasthenia gravis, Lambert-Eaton)	Caution; increased risk of clinically significant effects; monitor for neuromuscular compromise after treatment
Patients with pre-existing cardiovascular disease	Caution; reports of arrhythmia and MI with botulinum toxins, some fatal
Patients with compromised respiratory function or dysphagia	Caution; more susceptible to dysphagia/dyspnea complications
Marked facial asymmetry, surgical facial alterations, ptosis, dermatochalasis, deep scarring, thick sebaceous skin	Use with particular caution; increased risk of suboptimal outcomes or adverse events
Cumulative dose with other botulinum toxin indications	Consider cumulative dose when treating glabellar lines if other botulinum toxin products are or have been used for other approved indications
Geriatric patients (≥65 years)	No dose adjustment required; 148 subjects ≥65 yrs in trials showed no clinically meaningful differences; limited data preclude definitive conclusions

BLA Key Facts

Application Number	BLA 761225
Application Type	BLA 351(a) — full Biologics License Application (original submission)
Applicant	Hugel, Inc.
IND Number	IND 123178
Initial BLA Submission	2021 (first review cycle)
Resubmission Date	August 31, 2023
PDUFA Goal Date	February 29, 2024
Actual Approval Date	February 29, 2024
Review Division	Division of Dermatology and Dentistry (DDD)
Office	Office of Immunology and Inflammation (OII)
Office Director (acting)	Nikolay Nikolov, M.D.
Division Signatory (ADTR)	Gordana Diglisic, M.D.
Cross-Discipline Team Leader	Snezana Trajkovic, M.D.
Clinical Reviewer	Tong Li-Masters, M.D., Ph.D.
Review Type	Standard review
Advisory Committee	Not convened
Recommendation	Approval
Medical Review Ref ID	4960826 (original); 5337218 (resubmission)
PI Ref ID	5337801
U.S. License Number	2237

Regulatory Timeline

September 10, 2014

Pre-IND / End of Phase 2 Meeting

FDA provided recommendations on the development program for proposed indication.

October 30, 2015

BLESS I Protocol Submitted

Phase 3 protocol submitted under IND 123178.

November 20, 2015

Full Clinical Hold Placed

IND placed on full clinical hold — insufficient information regarding potency methodology; no parallelism assessment between test and reference standard.

December 21, 2015

Clinical Hold Lifted

Hold lifted after Applicant submitted response (December 1, 2015).

March 16, 2016

Agreed Initial Pediatric Study Plan (iPSP)

Full waiver of pediatric studies granted (ages 0–17 yrs) — glabellar lines extremely rare in pediatric population; studies impossible or highly impractical.

December 20, 2018

Pre-BLA Meeting

Content and format of BLA application discussed.

2021 (first cycle)

Original BLA Submission

Efficacy and safety established during first review cycle (three adequate and well-controlled Phase 3 studies). Clinical data deemed adequate; manufacturing deficiencies identified.

April 12, 2023

Complete Response Letter (CRL) Issued

All deficiencies related to drug substance and drug product manufacturing facilities. No clinical efficacy or safety concerns. Pre-license inspection (PLI) at Hugel Inc. (FEI #3012163998) identified significant outstanding manufacturing risks.

August 31, 2023

BLA 761225 Resubmission

Complete response to FDA manufacturing facility deficiencies. No new clinical efficacy or safety information submitted or required.

February 29, 2024

FDA Approval

LETYBO approved for temporary improvement in appearance of moderate to severe glabellar lines in adult patients. Leap day approval.

Key Review Issues

Manufacturing Deficiencies (CRL — First Cycle): The Complete Response Letter focused entirely on drug substance and drug product manufacturing facility issues identified during pre-license inspection at Hugel Inc. (FEI #3012163998). Deficiencies related to Module 3, identified by OBP and OPMA. No clinical data issues.

Potency Assay / Clinical Hold (IND Phase): Early clinical hold (2015) due to insufficient information on potency methodology — specifically, lack of parallelism assessment between test and reference standard. Resolved December 2015.

Statistical Methodology Correction: FDA statistical reviewers modified CI calculation method. Applicant used unstratified Newcombe confidence limits (inappropriate for 0% placebo responder rates in BLESS I and III). Reviewers applied Mantel-Haenszel stratified by study center. Also corrected one-sided p-value derivation from chi-squared distribution. Neither change affected the efficacy conclusion.

Site 110 Integrity Issue (BLESS III): Protocol non-compliance (unblinded staff performed blinded safety assessments). Sensitivity analysis excluding Site 110 confirmed robustness of primary efficacy conclusion (66.1% vs 65.2%).

Postmarketing Requirements and Commitments

No PMRs or PMCs: No postmarketing requirements or commitments identified for this application from clinical, statistical, or clinical pharmacology perspectives.

Benefit-Risk Assessment

Overall Benefit-Risk	Favorable for glabellar lines indication. Performance similar to other marketed botulinum toxin A products for the same indication.
Efficacy Evidence	Substantial evidence from three adequate and well-controlled Phase 3 trials; consistent primary endpoint results across all three studies (p<0.0001 each)
Safety Profile	Consistent with other approved BoNT-A products; generally well tolerated; no treatment-related deaths or SAEs; no new safety signals identified
Headache (most common AR)	2% (LETYBO) vs 1% (placebo); headache rate higher in treatment-naïve and younger subjects
Immunogenicity	Low rate of ADA formation (0.3%); no neutralizing antibodies detected; no apparent impact on efficacy or safety
Labeling	Standard botulinum toxin warnings and precautions included; label includes relevant safety information for risk management
Global Marketing History	Marketed in Korea as Botulax® since 2010; ~16.7 million vials distributed globally (March 2009 – September 2020) across multiple indications; no new safety signals from global post-marketing experience
Statistical Issues	None affecting efficacy conclusions
Source Documents	Medical Review Ref ID 4960826 (original) / 5337218 (resubmission); PI Ref ID 5337801

LetibotulinumtoxinA

Drug Profile

Drug Identification

Mechanism of Action

Approved Indication

Competitive Landscape — FDA-Approved BoNT Products for Glabellar Lines

Study Population Overview

Subject Disposition

Baseline Demographics (FAS)

Baseline Disease Characteristics (FAS)

Study Design

Glabellar Line Scale (GLS)

Key Inclusion / Exclusion Criteria

Key Inclusion Criteria

Key Exclusion Criteria

Supportive Studies

Primary Efficacy Endpoint

Primary Endpoint Results at Week 4 (FAS, NRI)

Individual Components of Primary Endpoint (Week 4)

Sensitivity Analyses — Primary Endpoint

Secondary Efficacy Endpoints (FAS)

Subgroup Analyses — Primary Endpoint at Week 4 (FAS)

BLESS III Sensitivity — Excluding Site 110

Open-Label Extension — Drug Exposure

Boxed Warning

Safety Database

Adverse Reactions (PI Table 2) — Double-Blind Period

Common TEAEs ≥1% — Double-Blind Period (Pooled BLESS I, II, III)

Adverse Reactions ≥1% — Double-Blind and Open-Label Periods

Injection Site Reactions — Double-Blind Period

Serious Adverse Events (Double-Blind Period)

Adverse Events of Special Interest — Toxin Spread

Cardiovascular Adverse Events

Warnings and Precautions (PI §5)

Immunogenicity

Specific Safety Findings

Mechanism of Action

Pharmacokinetics

Pharmacodynamics

Drug Product Characterization

Non-Interchangeability

Drug Interactions

Nonclinical Toxicology Summary

Use in Specific Populations

Recommended Dosing

Standard Dose

Treatment Frequency

Reconstitution

Administration Technique

Storage and Handling

Contraindications

Special Patient Populations — Dosing Considerations

BLA Key Facts

Regulatory Timeline

Key Review Issues

Postmarketing Requirements and Commitments

Benefit-Risk Assessment

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