DaxibotulinumtoxinA-lanm (Daxxify™): A Comprehensive Overview

Nicole Salame, MD¹; Ariel E. Eber, MD²; Jeffrey Dover, MD, FRCPC^2,3

¹Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
²SkinCare Physicians, Chestnut Hill, MA, USA
³Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

Conflict of interest: Nicole Salame and Ariel Eber have no conflicts to disclose.
Jeffrey Dover has served as an investigator in the SAKURA trials and advises for Revance Therapeutics.

Abstract:
Botulinum toxin A (BoNTA) is produced by Clostridium botulinum and widely used for aesthetic indications requiring neuromuscular blockade. For dynamic facial lines, BoNTA is effective and safe, but also temporary, requiring repeat injections approximately every 3-4 months for maintenance of effects. There is a desire by both patients and providers for a longer-lasting neurotoxin to prevent periods of suboptimal correction. Approved by the US Food and Drug Administration (FDA) in September 2022, daxibotulinumtoxinA for injection (DAXI or Daxxify™) is the first long-lasting BoNTA formulated with a 150-kDa BoNTA (RTT150) and proprietary stabilizing excipient peptide (RTP004) in place of human serum albumin. DAXI is approved for treatment of moderate to severe glabellar lines. The median duration of effect was 6 months and results lasted as long as 9 months in some patients. Its unique formulation and prolonged effectiveness positions DAXI as a safe, novel BoNTA for improved durability and patient satisfaction.

Keywords: neuromodulator, neurotoxin, botulinum toxin, daxibotulinumtoxinA, rhytids, glabellar lines, forehead lines, lateral canthal lines, aesthetics, dermatology

Introduction

Botulinum toxin type A (BoNTA) is derived from Clostridium botulinum and has a variety of medical and aesthetic indications. BoNTA has been widely used in the United States (US) and Canada for the treatment of dynamic rhytids since its initial Food and Drug Administration (FDA) approval for glabellar lines in 1989. BoNTA inhibits muscle contraction by blocking neurotransmitter release in the neuromuscular junction, preventing formation of deep facial lines. This blockade is not permanent, necessitating repeat injections every 3-4 months to maintain the aesthetic benefit. Patient surveys have identified a desire for longer-lasting neuromodulators to reduce periods of suboptimal correction.¹

DaxibotulinumtoxinA-lanm for intramuscular use (DAXI or Daxxify™) is a novel peptide-formulated BoNTA engineered with a proprietary stabilizing excipient peptide (RTP004) in place of human serum albumin (HSA). On September 8, 2022, the US FDA approved DAXI as the first and only long-acting neuromodulator for the treatment of glabellar lines with a median duration of 6 months and up to 9 months for some patients.² Its innovative formulation, prolonged durability, and overall performance has caused excitement among early practitioners for DAXI’s potential in the realm of BoNTA treatment.

The Novelty of DAXI

While DAXI shares similarities with other BoNTA formulations approved in the US, it has important characteristic differences [Table 1]. DAXI is the first BoNTA entirely produced and formulated in the US. Its biochemical structure is unique; containing a highly purified 150-kDa core BoNTA (daxibotulinumtoxinA, or RTT150), a proprietary synthetic stabilizing peptide (RTP004), and other excipients including a surfactant (polysorbate-20), buffers, and sugar.¹ Importantly, DAXI’s unit definition is based on testing of biologic activity of the proprietary product with an individualized patented reference standard, rendering unit conversion to other BoNTA formulations impossible.

Table 1. Comparison of characteristics of BoNTA used for aesthetic injection in the United States.

DAXI’s unique proprietary excipient, RTP004, is a 35-amino highly positively charged peptide in place of HSA. While other neurotoxin products require HSA to prevent BoNTA from aggregating and/or adsorbing to glass surfaces, RTP004 fulfills this role by stabilizing daxibotulinumtoxinA via strong electrostatic bonds. RT004’s core domain consists of 15 lysine residues flanked on each side by a protein transduction domain (PTD). Positively charged amino acids in the PTD region form non-covalent, electrostatic interactions with negatively charged surface of the core BoNTA, preventing aggregation and defeating the need for HSA. The absence of HSA also allows DAXI to remain stable at room temperature for up to 3 years before reconstitution.

In addition to replacing HSA, RTP004 also contributes to DAXI’s efficacy and durability. RTP004’s strong electrostatic interaction and stabilization of core neurotoxin permits DAXI’s effect with a similar or lesser amount of product compared to other BoNTA preparations. RTP004’s positive charge also allows DAXI to bind to negative neurons and extracellular matrix proteins, facilitating localization of product and reduced diffusion from injection sites. Lastly, RTP004’s positive charge facilitates DAXI’s high-affinity binding to negatively-charge presynaptic nerve terminals, allowing for increased neurotoxin uptake into the neuron and prolonged efficacy.

DAXI in Clinical Trials

Glabellar Lines

Studies from the DAXI Glabellar Lines Clinical Program recruited 2994 subjects who underwent a total of 4444 DAXI treatments. The program included a phase 1/2 dose-escalation study,³ the Belmont phase 2 dose-ranging study (NCT02303002) comparing DAXI (20U, 40U, 60U) to onabotulinumtoxinA (20U) or placebo,^4,5 two phase 3 pivotal trials (SAKURA 1, NCT03014622 and SAKURA 2, NCT03014635)^6,7 and one large, phase 3 open-label safety (OLS) study (SAKURA 3, NCT03004248) evaluating the safety and efficacy of DAXI 40U.^2,8

Results supported DAXI’s safety, improved efficacy, and prolonged sustained duration of up to 24 weeks before returning to none or mild glabellar line (GL) severity and 28 weeks before returning to baseline. Results were consistent between studies and upon repeat-dosing in the OLS. A subgroup analysis comparing those who had prior BoNTA treatments (treatment-experiences) to those who had not (treatment-naïve) found similar response, duration, and tolerance to DAXI.⁹ Data also revealed greater efficacy with DAXI 40U as compared to onabotulinumtoxinA 20U, despite similar mass of core neurotoxin (each 0.18 ng),² suggesting that the aforementioned effects of RTP004 peptide and absence of HAS permitted increased efficacy for a similar given amount of core neurotoxin.

Forehead Lines, Eyebrow Positioning and Lateral Canthal Lines

Promising results from the Glabellar Lines Clinical Program prompted studies evaluating DAXI for treatment of forehead lines (FHL) and eyebrow position. An open-label, dose-escalating phase 2 trial evaluated treatment of FHL after GL treatment found that 86%, 87%, 94%, and 100% of patients had none or mild FHL severity by investigator assessment with 12U, 18U, 24U, and 30U doses, respectively.¹⁰ Mean time to loss of none or mild line severity by both investigator and patient assessments was 20 weeks for 18U, 24U, and 30U dose.¹⁰

A post-hoc analysis of the phase 2 FHL dose-escalating study and the SAKURA 3 OLS study found that adults receiving DAXI 40U for GL also experienced reductions in FHL and either positive or no impact on eyebrow position.¹¹ A separate post-hoc analysis of the phase 2 FHL dose-escalation study found that precise injection of DAXI 40U to the corrugator supercilii and procerus muscles with avoidance of the frontalis can achieve aesthetically pleasing eyebrow position with prolonged duration.¹²

Because the upper facial lines are often treated together in real-world practice to improve outcomes and patient satisfaction, a separate phase 2 study was conducted to evaluate the simultaneous treatment of GL, FHL, and lateral canthal lines (LCL) with DAXI.¹³ DAXI was found to be safe and effective for simultaneous treatment of upper facial lines with no differences in response rates for GL, FHL, or LCL.¹³ Mean time to loss of none or mild upper facial line severity was 25 weeks for GL, 24 weeks for FHL, and about 28 weeks for LCL.¹³ Optimal DAXI doses of 18U and 24U allowed for effective duration while ensuring some movement remains in the upper facial lines;¹³ at 30U, patients can achieve no forehead line movement. To achieve a patient’s desired aesthetic outcome, DAXI dose may be selected along a range of 18U-30U based on patient preferences for sustained movement.¹³

Adverse Events

Adverse events from daxibotulinumtoxinA studies were mild and included erythema, facial discomfort, and headache. In studies involving FHL,¹³ no cases of eyelid or eyebrow ptosis were observed. Similarly, in dose escalation studies, no patients experienced eyelid ptosis with DAXI 40U for GL,⁴ 30U for FHL,¹⁰ or 48U for LCL.¹⁴ In the large, phase 3 OLS study of repeated DAXI 40U dosing for GL, eyelid ptosis was seen in only 0.9% of treatments.⁸

Immunogenicity

Although DAXI lacks HSA, the presence of RTP004 excipient has potential implications on immunogenicity. Data from SAKURA 1, 2 and 3 found presence of anti-daxibotulinumtoxinA binding antibodies in 0.8% of subjects without evidence of neutralizing antibodies.¹⁵ Anti-RTP004 antibodies were found in 1.3% of subjects with low titer (<1:200) transient neutralizing antibodies.¹⁵ No patients had antibodies to both daxibotulinumtoxinA and RTP004.¹⁵ Presence of either antibody did not impact DAXI efficacy, and no patients reported immune-related adverse effects.¹⁵

Conclusion & Future Considerations

DAXI’s unique biochemical formulation with novel excipient peptide RTP004 in place of HSA, improved efficacy, safety, and prolonged duration utilizing a similar or potentially lower amount of core neurotoxin, supports DAXI’s role as a novel, pioneering BoNTA for treatment of dynamic facial lines. Future studies may focus on expanding DAXI for other cosmetic indications, including lower facial lines, neck lines, and in combination with other BoNTA and its use for functional disorders.

Acknowledegment

The authors gratefully acknowledge Revance Therapeutics for providing data in preparing this manuscript.

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