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DaxibotulinumtoxinA for injection (DAXI)
DaxibotulinumtoxinA for Injection (DAXI; Revance Therapeutics, Inc., Newark, CA) represents the first truly differentiated botulinum toxin formulation in the United States, the only type A botulinum toxin (BoNTA) wholly manufactured in the United States, and the first to be formulated without human serum albumin. The product is based around a 150 kDa type A core neurotoxin, produced from Hall strain Clostridium botulinum without the use of animal protein in the bacterial medium, and purified using a three-stage column purification process.
At the heart of the formulation is a proprietary 35-amino acid peptide excipient (RTP004) (see Fig. 10.1 ). This peptide is primarily composed of lysine and arginine residues, is highly positively charged, and forms a strong non-covalent association with negatively charged regions of the 150 kDa neurotoxin. The peptide, along with other excipients, is critical for preventing the neurotoxin from adhering to the glass vial walls and for protecting the neurotoxin from aggregation and thermal denaturation—functions historically requiring the inclusion of human serum albumin in a formulation. The other excipients include polysorbate 20 (a surfactant), a buffer, and a sugar (for protection during lyophilization). Furthermore, evidence suggests that the peptide may increase the affinity of the neurotoxin for nerve terminals and may also drive affinity for negatively charged elements of the extracellular matrix, such as proteoglycans. Enhanced affinity for structures in the injection area may permit the peptide and neurotoxin to remain localized to the injected site, perhaps increasing the probability of a toxin molecule being internalized into a neuron. DAXI is dried by lyophilization, appears as a powdered cake in the bottom of the vial, and is stable in this form at a controlled room temperature (22°C to 25°C) for up to 3 years prior to reconstitution.
Structure of DAXI peptide excipient, RTP004. DAXI, DaxibotulinumtoxinA for Injection; PTD, protein transduction domain.
As with all BoNTA products, the definition of a unit of biological activity is proprietary, and units of DAXI cannot be compared or converted to units of other BoNTA products. This is illustrated by the fact that a 100 U vial of DAXI contains only 0.46 ng of core neurotoxin, whereas a 100 U vial of onabotulinumtoxinA has been shown to contain approximately 0.90 ng of core neurotoxin. The glabellar line dose of 40 U DAXI therefore contains 0.18 ng neurotoxin and as described below, demonstrates a median of 6 months’ clinical duration in glabellar lines, compared with the 3 to 4 months’ duration reported with an almost identical amount of core neurotoxin in the 20 U onabotulinumtoxinA dose. This illustrates the impact of formulation on the clinical performance of botulinum toxin products, as has been previously reported. Systematic dose conversion between botulinum toxin products cannot be assumed as DAXI has shown significant efficacy in cervical dystonia at a dose of 125 U (0.57 ng neurotoxin), whereas the approved dose for onabotulinumtoxinA is 236 U (estimated as 2.21 ng core neurotoxin).
DAXI clinical program: Treatment of glabellar lines
The DAXI clinical program in glabellar lines included a phase 1/2 dose-escalation study, a phase 2 dose-ranging study that also compared DAXI with onabotulinumtoxinA 20 U, and three phase 3 studies (two identical, double-blind, placebo-controlled pivotal trials, SAKURA 1 and SAKURA 2, and an open-label, repeat-dose safety study, SAKURA 3). A total of 3139 adults participated in this development program, with 4444 DAXI treatments administered in 2994 subjects. The DAXI phase 3 clinical program in glabellar lines was the largest to date in aesthetics.
In SAKURA 1 and 2, a total of 609 adults with moderate or severe glabellar lines at maximum frown were enrolled, received a single treatment, and were followed for up to 36 weeks. Results from SAKURA 1 and SAKURA 2 were highly consistent and demonstrated DAXI to be significantly more effective than placebo in achieving the primary endpoint (proportion of subjects who achieved a ≥2-point improvement from baseline in glabellar line severity at maximum frown based on both the Investigator Global Assessment-Frown Wrinkle Severity [IGA-FWS] and Patient Frown Wrinkle Severity [PFWS] scores at week 4: 74% vs. 0% of subjects in SAKURA 1, and 74% vs. 1% in SAKURA 2 ( P < .0001 vs. placebo for both studies).
At weeks 4 and 24, none or mild glabellar lines at maximum frown based on IGA-FWS score were achieved by 98% and 32% of DAXI-treated subjects, respectively (vs. 4% and 2% of placebo-treated subjects based on pooled SAKURA 1 and 2 data; P < .0001 vs. placebo for both time points). Median duration of effect—defined as time to loss of none or mild glabellar line severity at maximum frown based on both IGA-FWS and PFWS scores—was 24.0 weeks. Median time to return to baseline glabellar line severity (or worse) at maximum frown based on both IGA-FWS and PFWS scores was 27.1 weeks. Treatment-related adverse events (AEs) were primarily mild, with the most common treatment-related AEs being headache and injection site AEs (pain, erythema, edema). Eyelid ptosis was observed in 2.2% of subjects.
In the SAKURA 3 open-label study evaluating single and repeat treatments of DAXI 40 U in 2691 subjects, efficacy outcomes (proportion of subjects who achieved none or mild glabellar line severity at maximum frown over time based on IGA-FWS score), duration of effect (time to loss of none or mild glabellar line severity at maximum frown based on both IGA-FWS and PFWS scores), and safety were consistent with those reported in the phase 2 and 3 pivotal trials ( Fig. 10.2 ). SAKURA 3 confirmed the DAXI safety profile seen in the SAKURA 1 and SAKURA 2 trials, with no new safety signals observed. Headache and injection site AEs (pain, erythema, edema) were the most common treatment-related AEs. The frequency of AEs tended to decrease over subsequent DAXI treatments. Treatment-related eyelid ptosis occurred with 0.9% of DAXI treatments; most cases (82.4%) were mild in severity. No subjects developed neutralizing antibodies to DAXI in the SAKURA program.
DAXI has also been evaluated in a phase 2, 36-week, open-label dose-escalation study for the treatment of forehead lines after treatment of glabellar lines. Doses of 12 U, 18 U, 24 U, and 30 U were evaluated in cohorts of approximately 15 subjects. At week 4, 86%, 87%, 94%, and 100% of subjects achieved none or mild forehead line severity in each of the four dose groups, respectively, by investigator assessment. Median duration until loss of none or mild response on both investigator and patient assessment for week 4 responders was 20 weeks for the 18 U, 24 U, and 30 U doses, suggesting that an 18 U dose may provide an optimal balance of efficacy and duration for forehead lines. Most subjects reported high rates of satisfaction. No dose response was observed for AEs, and the most frequently reported AEs were injection site edema, injection site erythema, and headache. One case of eyelid ptosis occurred after glabellar line injection.
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