TRIALISTMD ยท Drug Intelligence Platform
FDA APPROVED 2022
Botulinum Toxin Type A ยท Dermatology / Aesthetics ยท Glabellar Lines
DaxibotulinumtoxinA-lanm
DAXXIFYโข ยท Revance Therapeutics, Inc.
A first-in-class 150 kDa botulinum toxin type A without accessory proteins, formulated with a proprietary 35-amino acid stabilizing peptide excipient (RTP004) that confers exceptional thermal stability and extended duration of effect. The first neuromodulator to demonstrate median duration of response exceeding 6 months in clinical trials โ differentiated from onabotulinumtoxinA and other BoNT-A products by its novel formulation without albumin or human serum. Carries the class Boxed Warning for distant spread of toxin effect. Approved for glabellar lines in adults only; not approved for spasticity.
Drug Overview
BLA 761127
โ BOXED WARNING โ DISTANT SPREAD OF TOXIN EFFECT: The effects of DAXXIFY and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects, reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening; deaths have been reported. DAXXIFY is not approved for spasticity or any condition other than glabellar lines.
Indication
Glabellar Lines
Temporary improvement in moderate-to-severe glabellar lines with corrugator and/or procerus muscle activity in adult patients (โฅ18 years)
Mechanism
BoNT-A / SNAP25 Cleavage
Inhibits acetylcholine release at the NMJ; internalizes into nerve terminal, cleaves SNAP25, blocks synaptic vesicle docking and ACh release
Primary Efficacy (Week 4)
74%
Treatment success (โฅ2-point composite improvement on IGA-FWS + PFWS) vs 0% placebo in both SAKURA-1 and SAKURA-2; p<0.0001
Key Differentiator
Extended Duration
Median duration of response ~6 months in pivotal trials; formulated with novel RTP004 peptide excipient instead of albumin
Mechanism of Action & Differentiating Features
Section 12.1 / Section 11DaxibotulinumtoxinA-lanm is a purified 150 kDa botulinum neurotoxin type A without accessory proteins, derived from Clostridium botulinum type A. Upon intramuscular injection, the toxin is internalized into the nerve terminal and translocates into the neuronal cytosol where it cleaves SNAP25 โ a SNARE protein essential for synaptic vesicle membrane docking and acetylcholine release. This produces a dose-dependent decrease in muscle function. Recovery is gradual via degradation of the neurotoxin light chain and axonal sprouting, leading to eventual muscle reinnervation. The key formulation innovation is the 35-amino acid stabilizing peptide excipient RTP004, which prevents surface adsorption and promotes thermal stability, enabling room-temperature storage and the extended clinical duration observed in trials.
Novel formulation (Section 11): Each DAXXIFY vial contains daxibotulinumtoxinA-lanm with L-histidine (0.14 mg), L-histidine-HCl monohydrate (0.65 mg), polysorbate 20 (0.1 mg), RTP004 peptide (11.7 mcg), and trehalose dihydrate (36 mg). Unlike onabotulinumtoxinA (BOTOX) which uses human serum albumin as a stabilizer, DAXXIFY is albumin-free. Stored at room temperature or refrigerated โ no mandatory cold chain for unopened vials.
Non-interchangeability (Section 5.2): The potency Units of DAXXIFY are specific to the preparation and assay method utilized. They are NOT interchangeable with onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, rimabotulinumtoxinB, or prabotulinumtoxinA-xvfs. Units cannot be compared or converted across products.
Competitive Landscape โ Injectable Neuromodulators for Glabellar Lines (US)
| Product | INN / Toxin Type | Excipient / Stabilizer | FDA Approval (GL) | Typical Duration |
|---|---|---|---|---|
| DAXXIFY (Revance) | daxibotulinumtoxinA-lanm (BoNT-A, no accessory proteins) | RTP004 peptide (albumin-free) | Sep 8, 2022 (BLA 761127) | ~24 weeks median (pivotal trials); up to 6 months |
| BOTOX Cosmetic (AbbVie) | onabotulinumtoxinA | Human serum albumin, NaCl | Apr 15, 2002 | ~3โ4 months |
| DYSPORT (Galderma) | abobotulinumtoxinA | Human serum albumin, lactose | Apr 29, 2009 | ~3โ4 months |
| XEOMIN (Merz) | incobotulinumtoxinA (naked toxin) | Human serum albumin, sucrose (no complexing proteins) | Jul 20, 2011 | ~3โ4 months |
| JEUVEAU (Evolus) | prabotulinumtoxinA-xvfs | Human serum albumin, NaCl | Feb 1, 2019 | ~3โ4 months |
Source: FDA label BLA 761127, Ref ID 5042005; BLA 761127 Multi-disciplinary Review, Ref ID 5041522 and 5041615. Duration estimates for competitor products based on labeling and published data; not derived from head-to-head comparisons. DAXXIFY approved September 8, 2022 following resubmission in response to Complete Response Letter (manufacturing deficiencies resolved). No new clinical data were submitted in the resubmission; efficacy and safety established from first review cycle.
Baseline & Trial Characteristics
Table 12โ13, BLA 761127 Medical ReviewTotal Enrolled (Phase 3)
609
SAKURA-1 (N=303) and SAKURA-2 (N=306); identical trial designs; 2:1 DAXXIFY:placebo randomization
Mean Age
50 years
Range 21โ75 years; age groups 18โ45 (29%), 46โ55 (39%), 56โ75 (32%); adults only (โฅ18 years)
Female
87%
Predominantly female (174/201 in SAKURA-1 DAXXIFY arm); 86% Caucasian; consistent with aesthetic neuromodulator trial demographics
Prior BoNT-A Use
~45โ59%
45.8% in SAKURA-1, 59.3% in SAKURA-2 (DAXXIFY arms); comparable rates in placebo arms
Trial Design Summary
Section 8.1.1 / Studies 1620301 and 1620302| Parameter | SAKURA-1 (Study 1620301) | SAKURA-2 (Study 1620302) |
|---|---|---|
| Study type | Randomized, double-blind, placebo-controlled Phase 3 | Randomized, double-blind, placebo-controlled Phase 3 (identical design) |
| Randomization ratio | 2:1 (DAXXIFY:placebo) | 2:1 (DAXXIFY:placebo) |
| Sample size | N=303 (201 DAXXIFY / 102 placebo) | N=306 (204 DAXXIFY / 102 placebo) โ note: 1 placebo subject treated with DAXXIFY in error |
| Dose | 40 Units (5 ร 8 U IM) or placebo | 40 Units (5 ร 8 U IM) or placebo |
| Follow-up | 24โ36 weeks post-treatment | 24โ36 weeks post-treatment |
| Assessment visits | Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36 | Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36 |
| Discontinuation rule | Subjects discontinued after Week 24 if IGA-FWS AND PFWS both returned to baseline | Same as SAKURA-1 |
| Primary endpoint | 2-point composite response (IGA-FWS + PFWS โค1 AND โฅ2-grade improvement) at Week 4 | Same as SAKURA-1 |
| Key secondary endpoints | IGA-FWS โค1 and IGA-FWS + PFWS โค1 at Weeks 2, 4, 8, 12, 16, 20, 24 | Same as SAKURA-1 |
| Statistical test | Cochran-Mantel-Haenszel, stratified by center; M-H confidence intervals | Same as SAKURA-1 |
| Missing data | “Worst/best outcome” imputation; multiple imputation (MCMC) as sensitivity analysis | Same as SAKURA-1 |
| Completion (Week 4) | 196/201 (98%) DAXXIFY; 97/102 (95%) placebo | 203/204 (99%) DAXXIFY; 99/102 (97%) placebo |
| Full study completion | 182/201 (91%) DAXXIFY; 93/102 (91%) placebo | 191/204 (94%) DAXXIFY; 93/102 (91%) placebo |
Demographics (Pooled SAKURA-1 + SAKURA-2, DAXXIFY arms)
Table 12| Characteristic | SAKURA-1 DAXXIFY (N=201) | SAKURA-2 DAXXIFY (N=204) | SAKURA-1 Placebo (N=102) | SAKURA-2 Placebo (N=102) |
|---|---|---|---|---|
| Mean age (range) | 50.9 yrs (23โ74) | 49.6 yrs (21โ73) | 49.0 yrs (22โ74) | 50.5 yrs (27โ75) |
| Age 18โ45, n (%) | 58 (28.9%) | 62 (30.4%) | 32 (31.4%) | 30 (29.4%) |
| Age 46โ55, n (%) | 68 (33.8%) | 91 (44.6%) | 41 (40.2%) | 42 (41.2%) |
| Age 56โ75, n (%) | 75 (37.3%) | 51 (25.0%) | 29 (28.4%) | 30 (29.4%) |
| Female, n (%) | 174 (86.6%) | 183 (89.7%) | 88 (86.3%) | 87 (85.3%) |
| White, n (%) | 173 (86.1%) | 180 (88.2%) | 81 (79.4%) | 92 (90.2%) |
| Black / African American, n (%) | 10 (5.0%) | 9 (4.4%) | 8 (7.8%) | 3 (2.9%) |
| Asian, n (%) | 7 (3.5%) | 11 (5.4%) | 2 (2.0%) | 5 (4.9%) |
| Hispanic or Latino, n (%) | 47 (23.4%) | 19 (9.3%) | 25 (24.5%) | 10 (9.8%) |
Baseline Disease Characteristics
Table 13| Characteristic | SAKURA-1 DAXXIFY (N=201) | SAKURA-2 DAXXIFY (N=204) | SAKURA-1 Placebo (N=102) | SAKURA-2 Placebo (N=102) |
|---|---|---|---|---|
| Prior BoNT type A use, n (%) | 92 (45.8%) | 121 (59.3%) | 45 (44.1%) | 60 (58.8%) |
| IGA-FWS Moderate at baseline | 123 (61.2%) | 129 (63.2%) | 66 (64.7%) | 67 (65.7%) |
| IGA-FWS Severe at baseline | 78 (38.8%) | 75 (36.8%) | 36 (35.3%) | 35 (34.3%) |
| PFWS Moderate at baseline | 120 (59.7%) | 106 (52.0%) | 64 (62.7%) | 49 (48.0%) |
| PFWS Severe at baseline | 81 (40.3%) | 98 (48.0%) | 38 (37.3%) | 53 (52.0%) |
Efficacy Scale Definitions
Table 9| Score | Descriptor | Definition |
|---|---|---|
| 0 โ None | No wrinkles | No visible glabellar wrinkles at maximum frown |
| 1 โ Mild | Very shallow wrinkles | Barely perceptible wrinkles at maximum frown |
| 2 โ Moderate | Moderate wrinkles | Moderate visible wrinkles at maximum frown |
| 3 โ Severe | Deep and furrowed wrinkles | Deep, furrowed glabellar wrinkles at maximum frown |
Enrollment criteria: Subjects aged 18โ75 with moderate or severe glabellar lines at maximum frown on BOTH IGA-FWS and PFWS (score โฅ2 on both scales). Excluded: eyelid ptosis, deep dermal scarring, excessive dermatochalasis, inability to lessen glabellar lines by physically spreading them apart. Subjects were multicenter (US-only based on site roster).
Source: BLA 761127 Multi-disciplinary Review, Ref ID 5041522. IGA-FWS = Investigator Global Assessment-Frown Wrinkle Severity; PFWS = Patient Frown Wrinkle Severity; BoNT = botulinum neurotoxin. Demographics generally balanced across treatment groups. Higher proportion of Hispanic subjects in SAKURA-1 vs SAKURA-2 noted (23% vs 9%); consistent efficacy across subgroups confirmed.
Clinical Efficacy
Section 14.1 (Label) / Table 14, 20 (Medical Review)Primary Endpoint (Wk 4) โ SAKURA-1
73.6%
vs 0% placebo; ฮ +74.2% (95% CI 68.2โ80.2%); p<0.0001
Primary Endpoint (Wk 4) โ SAKURA-2
74.0%
vs 1.0% placebo (1 crossover subject); ฮ +72.9% (95% CI 66.6โ79.1%); p<0.0001
IGA-FWS Response (Wk 4) โ SAKURA-2
91.7%
IGA-FWS score โค1 (none/mild) at Week 4; SAKURA-1: 87.6%; individual component (less stringent than composite)
Duration of Effect
~24 wks
Median duration of treatment success maintained through approximately 24 weeks in pivotal trials; some subjects responded through 36 weeks
Primary Efficacy โ 2-Point Composite Response at Week 4
ITT Population (as-randomized); Cochran-Mantel-HaenszelSAKURA-1 (STUDY 1620301) โ N=303 ยท p<0.0001
Treatment success: score โค1 (none/mild) on both IGA-FWS and PFWS AND โฅ2-grade improvement from baseline on both scales at Week 4. Zero placebo responders.
Week 4 โ 2-Point Composite Treatment Success (Primary)
IGA-FWS โค1 (Investigator)
PFWS โค1 (Patient-Reported)
SAKURA-2 (STUDY 1620302) โ N=306 ยท p<0.0001
Identical design to SAKURA-1. Note: one subject randomized to placebo was inadvertently treated with DAXXIFY; included in placebo arm (as-randomized) for efficacy analysis. As-treated analysis: 74.2% vs 0%.
Week 4 โ 2-Point Composite Treatment Success (Primary)
IGA-FWS โค1 (Investigator)
PFWS โค1 (Patient-Reported)
Efficacy Summary Table
Table 14 and 20, BLA 761127 Medical Review (Label Table 4)| Endpoint | SAKURA-1 DAXXIFY (N=201) | SAKURA-1 Placebo (N=102) | SAKURA-1 ฮ (95% CI) | SAKURA-2 DAXXIFY (N=204) | SAKURA-2 Placebo (N=102) | SAKURA-2 ฮ (95% CI) |
|---|---|---|---|---|---|---|
| Treatment Success Wk 4 (2-pt composite IGA + PFWS) | 148 (73.6%) | 0 (0%) | +74.2% (68.2โ80.2%) p<0.0001 | 151 (74.0%) | 1 (1.0%) | +72.9% (66.6โ79.1%) p<0.0001 |
| IGA-FWS โค1 Wk 4 (Investigator only) | 176 (87.6%) | 1 (1.0%) | โ | 187 (91.7%) | 3 (2.9%) | โ |
| PFWS โค1 Wk 4 (Patient only) | 155 (77.1%) | 0 (0%) | โ | 156 (76.5%) | 1 (1.0%) | โ |
| All secondary endpoints (IGA-FWS โค1 and IGA+PFWS โค1 at Wks 2โ24) | All pre-specified secondary endpoints statistically significant in sequential testing (Weeks 2, 4, 8, 12, 16, 20, 24) in both trials | |||||
Subgroup Analysis โ Primary Endpoint at Week 4
Table 19| Subgroup | SAKURA-1 DAXXIFY | SAKURA-1 Placebo | SAKURA-2 DAXXIFY | SAKURA-2 Placebo |
|---|---|---|---|---|
| Age 18โ45 years | 50/58 (86%) | 0/32 (0%) | 49/62 (79%) | 1/30 (3%) |
| Age 46โ55 years | 45/68 (66%) | 0/41 (0%) | 70/91 (77%) | 0/42 (0%) |
| Age 56โ75 years | 53/75 (71%) | 0/29 (0%) | 32/51 (63%) | 0/30 (0%) |
| Female | 134/174 (77%) | 0/88 (0%) | 136/183 (74%) | 1/87 (1%) |
| Male | 14/27 (52%) | 0/14 (0%) | 15/21 (71%) | 0/15 (0%) |
| White | 126/173 (73%) | 0/81 (0%) | 133/180 (74%) | 1/92 (1%) |
| Black / African American | 8/10 (80%) | 0/8 (0%) | 8/9 (89%) | 0/3 (0%) |
| Asian | 6/7 (86%) | 0/2 (0%) | 7/11 (64%) | 0/5 (0%) |
| Hispanic or Latino | 39/47 (83%) | 0/25 (0%) | 15/19 (79%) | 1/10 (10%) |
Duration of effect context: Label Figure 2 shows the proportion of subjects with IGA-FWS โค1, PFWS โค1, and treatment success over 36 weeks. The composite treatment success (solid line) peaked at Weeks 2โ4 (~74%) and declined gradually. Subjects who returned to baseline on both IGA-FWS and PFWS before Week 36 were counted as non-responders from that point forward. The secondary endpoints (IGA-FWS โค1 alone) remained elevated through Week 24 in both trials, consistent with a longer duration of investigator-assessed improvement than the stringent composite endpoint. SAKURA-OLS (open-label repeat-dose study, N=2691) confirmed consistent efficacy across up to 3 treatment cycles with no attenuation of response over retreatments.
Source: FDA label BLA 761127, Ref ID 5042005 (Table 4, Figure 2) and BLA 761127 Multi-disciplinary Review, Ref ID 5041522 (Tables 14, 20). ITT = intent-to-treat. Treatment success defined as IGA-FWS and PFWS score โค1 (none or mild) AND โฅ2-grade improvement from baseline on both scales. Composite “treatment success” endpoint is stringent โ individual IGA-FWS response rates were 10โ15% higher than composite rates. All secondary endpoints met in both trials using sequential multiplicity control.
Safety Profile
Section 6.1 / 6.2 (Label) / Tables 27โ34 (Medical Review)
โ BOXED WARNING โ Distant Spread of Toxin Effect: Symptoms consistent with botulism (asthenia, generalized weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, breathing difficulties) reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening; deaths reported. Risk greatest in children treated for spasticity. No serious adverse reactions of distant spread were reported in DAXXIFY clinical studies at 40 Units for glabellar lines, but these reactions remain possible.
Most Common Adverse Reactions โฅ1% (Pooled SAKURA-1 + SAKURA-2 โ Label Table 3)
N=406 DAXXIFY, N=203 Placebo| Adverse Reaction | DAXXIFY N=406 | Placebo N=203 | Notes |
|---|---|---|---|
| Headache | 26 (6%) | 4 (2%) | Most common ADR; pooled data (9.4% in medical review broader TEAE analysis). Includes tension headache. |
| Eyelid Ptosis | 9 (2%) | 0 (0%) | Local spread; 1% in SAKURA-OLS repeat-dose. Risk reduction: avoid injecting <1 cm above superior orbital rim. |
| Facial Paresis | 5 (1%) | 0 (0%) | Includes facial asymmetry; also 1.2% in SAKURA-OLS. Incidence did not increase with multiple retreatments. |
| Injection Site Reactions | 6% (pooled) | 6% (pooled) | Rates similar between DAXXIFY and placebo (not listed in label Table 3 as excess ADR). ISR components: pain 3.7%, erythema 1.2%, oedema 1.2%. Most mild and transient. |
TEAE Overview โ SAKURA-1 + SAKURA-2 (Medical Review Table 27)
| TEAE Category | DAXXIFY N=406 | Placebo N=203 |
|---|---|---|
| Any TEAE โ Mild | 208 (51.2%) | 51 (25.1%) |
| Any TEAE โ Moderate | 56 (13.8%) | 16 (7.9%) |
| Any TEAE โ Severe | 5 (1.2%) | 0 (0%) |
| Headache (incl. tension) | 38 (9.4%) | 5 (2.5%) |
| Upper respiratory tract infection | 28 (6.9%) | 10 (4.9%) |
| Injection site reaction (all types) | 25 (6.2%) | 13 (6.4%) |
| Eyelid ptosis | 9 (2.2%) | 0 (0%) |
| Influenza | 6 (1.5%) | 2 (1.0%) |
| Urinary tract infection | 5 (1.2%) | 0 (0%) |
| Facial paresis / asymmetry | 5 (1.2%) | 0 (0%) |
| SAEs (treatment-related) | 0 | 0 |
| Deaths | 1 death in SAKURA-OLS โ not considered treatment-related | |
Repeat-Dose Safety (SAKURA-OLS, N=2691)
84-week open-label repeat-dose safety study: 2691 subjects received โฅ1 treatment with 40 Units DAXXIFY; 882 received 2 treatments; 568 received 3 treatments. Adverse reactions reported in 535/2691 subjects (20%). The AE profile was similar to single-dose pivotal trials. Injection site reactions most common (9% โ pain 4%, erythema 3%, oedema 3%, bruising 1%). Headache 5%, edema 2%, erythema 2%, eyelid ptosis 1%. Incidence of adverse reactions did not increase with multiple retreatments. No distant spread of toxin reported; local spread of toxin events declined with successive treatment cycles (eyelid ptosis: 1.0% cycle 1, 0.79% cycle 2, 0.70% cycle 3).
Warnings & Precautions
Section 5- Spread of Toxin Effect (5.1) โ BOXED WARNING: Toxin effects may spread from injection site; symptoms hours to weeks post-injection including dysphagia, respiratory difficulties, generalized weakness. Deaths reported (other botulinum products). Not approved for spasticity or any condition other than glabellar lines.
- Non-Interchangeability (5.2): Units of DAXXIFY are NOT interchangeable with BOTOX, DYSPORT, XEOMIN, MYOBLOC, or JEUVEAU. Cannot compare or convert Units across products.
- Serious ADRs with Unapproved Use (5.3): Excessive weakness, dysphagia, aspiration pneumonia including fatal outcomes reported with unapproved botulinum toxin use. DAXXIFY not approved for any condition other than glabellar lines.
- Hypersensitivity Reactions (5.4): Anaphylaxis, serum sickness, urticaria, soft tissue edema, dyspnea reported with BoNT products. Discontinue and treat immediately.
- Cardiovascular System (5.5): Arrhythmia and MI including fatal outcomes reported with BoNT products. Use caution in patients with pre-existing cardiovascular disease.
- Pre-Existing Neuromuscular Disorders (5.6): Monitor patients with peripheral motor neuropathic diseases, ALS, myasthenia gravis, or Lambert-Eaton syndrome โ at increased risk of clinically significant effects including severe dysphagia and respiratory compromise.
- Dysphagia and Breathing Difficulties (5.7): Can occur hours to weeks post-injection. Deaths as complication of severe dysphagia reported with BoNT products. Aspiration risk in patients with pre-existing swallowing compromise.
- Ophthalmic Adverse Reactions (5.9): Dry eye, reduced blinking, corneal disorders reported. If persistent eye symptoms: refer to ophthalmologist.
Immunogenicity
Section 6.2
Pre-existing Antibodies to Toxin
12/2786 subjects (0.4%) had pre-existing binding antibodies to daxibotulinumtoxinA-lanm at baseline.
Pre-existing Antibodies to RTP004
75/2786 subjects (3%) had pre-existing binding antibodies to the RTP004 peptide excipient at baseline.
Treatment-Emergent Binding Antibodies (Toxin)
20/2786 subjects (0.8%) developed treatment-emergent binding antibodies to daxibotulinumtoxinA-lanm across up to 3 treatment cycles.
Neutralizing Antibodies
No subjects developed neutralizing antibodies to DAXXIFY across all phase 3 studies (N=2786). Treatment-emergent binding antibodies to RTP004: 1.2% (33 subjects).
Source: FDA label BLA 761127, Ref ID 5042005; BLA 761127 Medical Review, Ref ID 5041522. AE profile considered similar to other licensed BoNT-A products for the same indication. No new safety signals identified. SAEs in SAKURA-OLS (N=29 subjects, 31 events) were predominantly unrelated to treatment. Reviewer concluded safety database of 2994 subjects (2839 at 40 U) was adequate and exceeded ICH E1A recommendations.
Pharmacology & Pharmacokinetics
Section 12 / LabelSystemic Detection
Undetectable
Cannot be detected in peripheral blood following IM injection at the recommended dose using currently available analytical technology (Section 12.3)
Molecular Weight
150 kDa
Pure neurotoxin without accessory (complexing) proteins. Purified from Clostridium botulinum type A. No hemagglutinins or non-toxic non-hemagglutinin proteins.
Novel Excipient
RTP004
35 amino acid peptide; prevents surface adsorption; promotes thermal stability. Enables room temperature storage of unopened vials. Albumin-free formulation.
Formal PD Studies
None
No formal pharmacodynamics studies conducted with DAXXIFY (Section 12.2). Pharmacological effect inferred from mechanism of action and clinical outcomes.
QTc Assessment
Not Studied
No dedicated QT study conducted; not required given undetectable systemic levels at therapeutic doses
Drug Interactions
No Formal Studies
No formal DDI studies. Caution with aminoglycosides, anticholinergics, other BoNT products, muscle relaxants โ may potentiate neuromuscular blockade.
Mechanism of Action
Section 12.1DAXXIFY blocks cholinergic transmission at the neuromuscular junction by inhibiting the release of acetylcholine (ACh). The mechanism proceeds in sequential steps: (1) binding of the toxin heavy chain to receptors on the presynaptic nerve terminal; (2) receptor-mediated endocytosis and internalization into the nerve terminal; (3) translocation of the light chain into the neuronal cytosol; (4) endopeptidase cleavage of SNAP25 (synaptosomal-associated protein 25 kDa) โ a SNARE protein essential for synaptic vesicle docking and fusion. Cleavage of SNAP25 prevents the docking of ACh-containing vesicles to the plasma membrane, blocking exocytosis and neurotransmitter release, producing a dose-dependent decrease in muscle contractile function. Recovery of neuromuscular activity is gradual and results from two mechanisms: degradation of the neurotoxin light chain in the neurons, and formation of axonal sprouts leading to muscle reinnervation and slow reversal of the pharmacological effects.
Rationale for extended duration (RTP004 peptide): The proprietary 35-amino acid RTP004 peptide excipient was designed to stabilize daxibotulinumtoxinA without albumin. The peptide prevents adsorption of the toxin to container surfaces and enhances thermal stability of the preparation. The clinical consequence is extended duration of effect (median ~6 months in pivotal trials) compared to albumin-stabilized products. The excipient also allows room-temperature storage of unopened vials (20ยฐCโ25ยฐC), or refrigeration at 2ยฐCโ8ยฐC. Pre-existing antibodies to RTP004 were detected in 3% of subjects at baseline, reflecting prior exposure to structurally related peptides. No neutralizing antibodies were detected throughout the development program.
Recovery of neuromuscular function: The mechanism of toxin inactivation and reversal is entirely biological โ no pharmacological antidote for the local neuromuscular effects exists. Recovery occurs via axonal sprouting and reinnervation. In the event of overdose: medical monitoring; botulinum antitoxin (available from CDC, 1-770-488-7100) will not reverse effects already manifest by the time of administration. Symptomatic respiratory support may be required.
Pharmacokinetics Summary
Section 12.3| PK Parameter | Details |
|---|---|
| Systemic detection | Cannot be detected in peripheral blood following IM injection at 40 Units using currently available analytical technology. No quantifiable systemic exposure data available for the approved indication. |
| Absorption | Locally distributed from IM injection site. Systemic absorption minimal or undetectable at therapeutic doses. Toxin undergoes retrograde axonal transport after receptor binding at NMJ. |
| Distribution | Local diffusion from injection site. The extent of diffusion is dose- and volume-dependent โ higher doses or larger injection volumes increase risk of spread to adjacent muscles (local spread). |
| Metabolism | Degraded by normal protein catabolism. Light chain undergoes intraneuronal proteolysis. Heavy chain and accessory proteins cleared locally. |
| Elimination | Recovery of neuromuscular function via axonal sprouting/reinnervation; not via classical drug elimination. Duration of effect in glabellar muscles: clinically effective for approximately 24 weeks (median, composite endpoint). |
| N-CAM (neural cell adhesion molecule) | N-CAM expression in denervated motor end plates and axonal sprouts serves as a molecular marker for recovery โ label section describes return to baseline N-CAM indicating complete reinnervation. |
| Drug-drug interactions | No formal DDI studies conducted. Theoretical potentiation expected with aminoglycosides (block presynaptic ACh release), anticholinergic agents, other BoNT products, and muscle relaxants. No pharmacokinetic DDI possible given undetectable systemic levels. |
Source: FDA label BLA 761127, Ref ID 5042005 (Section 12). No clinical pharmacokinetic data from human studies available for daxibotulinumtoxinA at the approved 40-Unit dose. This is consistent with all other approved botulinum toxin products where systemic concentrations are below the limits of detection of currently available assays. Product description per Section 11: sterile, preservative-free, white to off-white lyophilized powder in single-dose vials (50 U or 100 U) for intramuscular use after reconstitution with preservative-free 0.9% NaCl. U.S. License Number 2101.
Dosing, Administration & Contraindications
Section 2, 4, 5 / LabelTotal Recommended Dose
40 Units
Per treatment session; 5 equal injections of 8 Units (0.1 mL each) into corrugator and procerus muscles
Injection Sites
5 Sites
2 injections medial corrugator (L+R), 2 injections lateral corrugator (L+R), 1 injection procerus muscle
Retreatment Interval
โฅ3 Months
Administer no more frequently than every 3 months. Consider cumulative dose and concurrent BoNT use for other indications.
Reconstitution โ 50 U Vial
0.6 mL
Add 0.6 mL preservative-free 0.9% NaCl โ 8 Units/0.1 mL. For 100 U vial: add 1.2 mL โ same concentration.
Reconstitution & Administration
Section 2.3 / 2.4Reconstitution Steps
- Slowly inject preservative-free 0.9% NaCl into vial (0.6 mL into 50 U vial; 1.2 mL into 100 U vial). Discard vial if vacuum does not pull diluent in.
- Gently rotate vial to mix. Do not shake. Reconstituted solution should be clear to slightly opalescent, colorless, free of particulate matter.
- Inspect visually before use. Do not use if cloudy, discolored, or contains particles.
- Use within 72 hours of reconstitution. Store unused reconstituted product at 2ยฐCโ8ยฐC, protected from light. Do not freeze reconstituted product.
- Single patient, single session use only. Discard remaining solution immediately after injection.
Injection Technique
- Assess upper eyelid margin and levator palpebrae superioris function before injection. Evaluate levator function and frontalis compensation manually.
- Clean vial stopper with alcohol swab. Withdraw โฅ0.5 mL with sterile syringe. Replace with 30โ33 gauge sterile needle for injection.
- Expel air bubbles. Apply finger pressure on superior medial orbital rim.
- Inject 8 Units (0.1 mL) into each of 5 sites: medial corrugator (ร2), lateral corrugator (ร2), procerus (ร1).
- Ptosis prevention: Do not inject <1 cm above superior orbital rim. Avoid levator palpebrae superioris area. Use accurate volumes. Use steady, controlled injection technique.
Contraindications
Section 4- Hypersensitivity (4.1): Known hypersensitivity to any botulinum toxin preparation, DAXXIFY, or any component of the DAXXIFY formulation (active or inactive ingredients). Cross-reactive hypersensitivity with other BoNT products is a contraindication.
- Infection at Injection Site (4.2): Presence of infection at the proposed injection sites.
Special Populations
Section 8| Population | Guidance |
|---|---|
| Pregnancy (8.1) | No human data. Animal IM studies: fetal growth effects (decreased weight and skeletal ossification) at doses ~40ร MRHD (30 Units/kg in rats); embryofetal NOAEL 10 Units/kg (15ร MRHD). No embryofetal toxicity in rabbits at up to MRHD (~0.48 Units/kg/day). No formal recommendation; weigh risks vs benefits. |
| Lactation (8.2) | No data on presence in human or animal milk, effects on breastfed infant, or milk production. Consider developmental/health benefits of breastfeeding alongside maternal clinical need. |
| Pediatric Use (8.4) | Safety and effectiveness in patients <18 years of age not established. DAXXIFY not approved for pediatric use. |
| Geriatric Use (8.5) | 36/406 subjects in placebo-controlled trials were โฅ65 years. No increase in treatment-related AEs in patients >65 years. Insufficient numbers to determine whether elderly respond differently; caution advised for subgroup analyses showing lower response rates in 56โ75 year age group (63โ71% vs ~80โ86% in 18โ45 year group). |
| Cardiovascular disease | Use with caution. Arrhythmia and MI (some fatal) reported with BoNT products (Section 5.5). |
| Neuromuscular disorders | ALS, myasthenia gravis, Lambert-Eaton syndrome: monitor for exacerbated neuromuscular compromise. Peripheral motor neuropathic disease: increased risk of severe dysphagia and respiratory compromise. |
Storage & Supply
Section 16| Item | Detail |
|---|---|
| Unopened vials | Store at room temperature 20ยฐCโ25ยฐC (68ยฐFโ77ยฐF) OR refrigerated 2ยฐCโ8ยฐC (36ยฐFโ46ยฐF) in original carton, protected from light |
| After reconstitution | Use within 72 hours; store at 2ยฐCโ8ยฐC, protected from light; do not freeze reconstituted product |
| 50 Unit vial NDC | 72960-111-01 (carton containing 1 vial) |
| 100 Unit vial NDC | 72960-112-01 (carton containing 1 vial) |
| Manufacturer | Revance Therapeutics, Inc., Newark, CA 94560. U.S. License Number 2101. |
| Drug interactions | No formal studies. Co-administer with caution: aminoglycosides, anticholinergic drugs, other BoNT neurotoxin products, muscle relaxants โ all may potentiate effects |
Source: FDA label BLA 761127, Ref ID 5042005, Revised 9/2022. PI761127-0.8. Contact Revance Therapeutics at 1-877-373-8669 for adverse event reporting. FDA MedWatch: 1-800-FDA-1088.
Regulatory History
BLA 761127 โ Biologics License ApplicationApplication Type
BLA (Biologic)
Filed under 351(a) of the Public Health Service Act as a new biologic. Standard Review. First biologic neuromodulator approved with albumin-free formulation using novel peptide excipient.
Reviewing Division
DDD/OII
Division of Dermatology and Dentistry, Office of Immunology and Inflammation, CDER. Team Lead: Tong Li-Masters MD, PhD.
Original PDUFA Goal
Nov 25, 2020
BLA submitted Nov 24, 2019; received Nov 25, 2019. Original PDUFA date Nov 25, 2020. Approval delayed by Complete Response Letter for manufacturing deficiencies.
Final Approval Date
Sep 8, 2022
Approved following resolution of CMC deficiencies in resubmission (Mar 8, 2022). No new clinical efficacy or safety data submitted in resubmission.
Regulatory Timeline
NOVEMBER 24, 2019
BLA 761127 Submitted
Revance Therapeutics submitted BLA 761127 for daxibotulinumtoxinA for the temporary improvement in moderate-to-severe glabellar lines. Received November 25, 2019. Standard Review. PDUFA goal: November 25, 2020.
NOVEMBER 25, 2020
PDUFA Goal Date โ Review Cycle 1 Active
Clinical efficacy and safety review of SAKURA-1, SAKURA-2, and SAKURA-OLS data conducted during this cycle. Efficacy from two adequate and well-controlled trials (SAKURA-1 and SAKURA-2) with 74% treatment success vs 0% placebo established.
OCTOBER 14, 2021
Complete Response (CR) Letter Issued
FDA issued Complete Response Letter to BLA 761127. All deficiencies were related to drug substance and drug product manufacturing facilities โ pre-licensure inspection (PLI) deficiencies. No clinical efficacy or safety deficiencies. No new clinical data requested.
MARCH 8, 2022
BLA 761127 Resubmission
Revance resubmitted BLA 761127 providing Complete Response to PLI observations. Resubmission addressed all CMC manufacturing deficiencies. No new clinical efficacy or safety data included. Review completion date: September 6, 2022.
SEPTEMBER 6, 2022
Multi-Disciplinary Review Completed
Clinical Review Memorandum (Supporting Document #49) signed by Tong Li-Masters MD, PhD, DDD. Product quality team recommended approval; all CMC deficiencies resolved. Recommendation: Approval.
SEPTEMBER 8, 2022
FDA Approval โ BLA 761127
DAXXIFY (daxibotulinumtoxinA-lanm) approved for temporary improvement in the appearance of moderate-to-severe glabellar lines in adult patients. First BoNT product formulated with a novel peptide excipient (RTP004) instead of albumin. Ref ID 5042005 (label), 5041522 and 5041615 (reviews). Label Revised: 9/2022.
Regulatory Submission Summary
| Aspect | Detail |
|---|---|
| Application number | BLA 761127 (Orig1s000) |
| Application type | Biologic License Application (BLA) under 351(a) PHS Act; Standard Review |
| Applicant | Revance Therapeutics, Inc., Newark, CA 94560 |
| Submission / receipt date | November 24โ25, 2019 |
| Original PDUFA goal | November 25, 2020 |
| CR letter date | October 14, 2021 (manufacturing only โ no clinical deficiencies) |
| Resubmission date | March 8, 2022 |
| Review completion | September 6, 2022 |
| Approval date | September 8, 2022 |
| Pivotal trials | SAKURA-1 (Study 1620301; NCT data not specified in review) and SAKURA-2 (Study 1620302) โ identical Phase 3 RCTs; N=609 combined |
| Supporting safety study | SAKURA-OLS (Study 1620303) โ 84-week open-label repeat-dose study; N=2691 subjects, up to 3 treatment cycles |
| Total safety database | 3,139 subjects enrolled; 2,994 exposed to DAXXIFY at any dose; 2,839 at 40 Units (to-be-marketed dose) |
| Primary endpoint accepted | 2-point composite response at Week 4 (IGA-FWS + PFWS โค1 AND โฅ2-grade improvement on both scales) โ FDA-endorsed stringent composite endpoint |
| Reference IDs | 5042005 (label, 9/2022) / 5041522 (multi-disciplinary review) / 5041615 (clinical review memorandum, resubmission) |
| U.S. License Number | 2101 |
Source: BLA 761127 label, Ref ID 5042005, Revised 9/2022; BLA 761127 Multi-disciplinary Review, Ref ID 5041522; BLA 761127 Clinical Review Memorandum (Resubmission), Ref ID 5041615, signed September 6, 2022. Reviewed under Division of Dermatology and Dentistry (DDD), Office of Immunology and Inflammation (OII), CDER, FDA. Team Lead: Tong Li-Masters MD, PhD, DDD. Project Manager: Kimberle Searcy.
