AZZALURE Powder for solution for injection Ref.[27680] Active ingredients: Botulinum toxin type A

Pharmacotherapeutic group: Other muscle relaxants, peripherally acting agents
ATC code: M03AX01

The primary pharmacodynamic effect of Clostridium botulinum toxin type A is due to chemical denervation of the treated muscle resulting in a measurable decrease of the compound muscle action potential, causing a localised reduction of, or paralysis in, muscle activity.

Botulinum toxin type A is a muscle relaxant that temporarily weakens the muscles' activity. After injection, botulinum toxin type A works by blocking the transport of the neurotransmitter acetylcholine across the neuromuscular junction, located between the nerve end and the muscle fibre. The mode of action of botulinum toxin type A involves four main stages, all of which must function correctly for activity to occur. The action results in stopping the muscular contraction of the targeted muscles. The effect lasts for sustained periods until the junction has recovered and muscle activity returns.

Clinical data

During the clinical development of Azzalure, more than 4500 patients were included in the different clinical trials and approximately 3800 patients were exposed to Azzalure.

Glabellar lines

In clinical studies, 2032 patients with moderate to severe glabellar lines have been treated at the recommended dose of 50 Speywood units. Of these, 305 were treated with 50U in two pivotal Phase III double-blind placebo-controlled studies and 1200 treated with 50U in a long-term open-label repeated dose Phase III study. The remaining patients were treated in supportive and dose-ranging studies.

The median time to onset of response was 2 to 3 days following treatment, with the maximum effect observed at day thirty. In both pivotal placebo-controlled phase III studies, Azzalure injections significantly reduced the severity of glabellar lines for up to 4 months. The effect was still significant after 5 months in one of the two pivotal studies.

Thirty days following injection, the assessment of the investigators showed that 90% (273/305) of patients had responded to treatment (exhibited no or mild glabellar lines at maximum frown), compared to 3% (4/153) placebo-treated patients. Five months after injection, 17% (32/190) of patients treated with Azzalure were still responding to treatment compared to 1% (1/92) of placebo treated patients in the concerned study. The patients' own assessment at maximum frown after thirty days gave a response rate of 82% (251/305) for those treated with Azzalure and 6% (9/153) for those treated with placebo. The proportion of patients exhibiting a two-grade improvement according to the investigator assessment at maximum frown, was 77% (79/103) in the one pivotal Phase III study where this was assessed.

A subset of 177 patients had moderate or severe glabellar lines at rest prior to treatment. Assessment by investigators of this population, thirty days after treatment, showed that 71% (125/177) of Azzalure-treated patients were considered responders versus 10% (8/78) of placebo-treated patients.

The long-term repeat dose open label study showed that the median time to onset of response of 3 days was maintained across repeated dose cycles. The responder rate at maximum frown as determined by the investigator at day 30 was maintained over repeated cycles (ranging between 80% and 91% over the 5 cycles). The responder rate at rest over repeated dose cycles was also consistent with the single dose studies, with 56% to 74% of Azzalure-treated patients considered by investigators to be responders thirty days after treatment.

Lateral Canthal lines

In clinical studies, 308 patients with moderate to severe lateral canthal lines at maximum smile have been treated at the recommended dose of 30 Speywood units per side in double blind studies. Of these, 252 were treated in a Phase III double-blind placebo controlled study and 56 patients were treated in a double-blind Phase II dose-ranging study.

In the phase III study, Azzalure injections significantly reduced the severity of lateral canthal lines compared with placebo (p≤0.001) at 4, 8 and 12 weeks (assessed at maximum smile by the investigators). For the subjects' assessment of satisfaction with the appearance of their lateral canthal lines, there was a statistically significant difference between Azzalure and placebo (p≤0.010) in favour of Azzalure at 4, 8, 12 and 16 weeks.

The primary efficacy endpoint was at 4 weeks following injection: the assessment of the investigators showed that 47.2% (119/252) of patients had responded to treatment (no or mild lateral canthal lines at maximum smile), compared to 7.2% (6/83) placebo-treated patients.

In a post-hoc analysis, at the same time point, 4 weeks following injection, 75% (189/252) of Azzalure treated patients had at least 1 grade improvement at maximum smile compared with only 19% (16/83) of placebo-treated subjects.

A total of 315 subjects entered the open label extension phase of the Phase III study in which they could be treated concomitantly for both lateral canthal lines and glabellar lines.

Patients treated with Azzalure in the double-blind and open label phases of the Phase III received a median of 3 treatments for lateral canthal lines. The median interval between injections for lateral canthal lines, which was largely determined by the protocol design, ranged from 85 to 108 days. The results showed that efficacy is maintained with repeated treatments over the period of one year.

The patient satisfaction levels at weeks 4, 16 and 52 show after the first treatment with Azzalure that 165/252 subjects (65.5%) were either very satisfied or satisfied with the appearance of their LCLs.

At week 16, 4 weeks after either a second Azzalure treatment for those randomised to Azzalure in Part A or the first treatment for those randomised to placebo the proportion who were very satisfied or satisfied was 233/262 (89.0%). At week 52 when subjects could have had up to five cycles of Azzalure treatment with the last one being at week 48 the proportion of very satisfied/satisfied subjects was 255/288 (84.7%).

No patient tested positive for toxin-neutralising antibodies after receiving repeated treatments with Azzalure over one year.