Leaflet BOEY 1400U powder for solution for injection

Pharmacotherapeutic group: Muscle relaxants, other peripherally acting agents, ATC code: not yetassigned

TrenibotulinumtoxinE exerts its effect by blocking neuromuscular transmission. After intramuscularinjection, the toxin undergoes rapid binding to specific cell surface receptors on motor nerve terminals.

After binding, toxin is transported across the plasma membrane via receptor-mediated endocytosis andthe proteolytic light chain is then released into the cytosol, where it acts by cleaving SNAP-25, a pre-synaptic protein involved in vesicle docking and fusion required for acetylcholine transmitter release.

By disrupting SNAP-25, the toxin inhibits acetylcholine release from nerve terminals, resulting inpartial chemical denervation and a localised reduction in muscle activity.

The clinical effects of Boey begin to manifest 8 hours post-injection with a peak around day 7 afterinjection. Recovery generally occurs within 2-3 weeks as primary nerve terminals recover.

A Phase 1, double-blind study was conducted with sequential administration of Boey 700 units orplacebo on Day 1 followed by a botulinum toxin A 20 Allergan units (units are toxin-specific) on Day30 in a total of 90 subjects with moderate to severe glabellar lines. The pharmacodynamic effect, asassessed using Facial Wrinkle Scale (FWS), was similar between treatment groups, regardless ofwhether the subject initially received Boey or placebo.

In five glabellar line studies, 2 104 subjects treated with Boey had samples analysed for antibodyformation. Among Boey-treated subjects who received single or repeat treatments (up to threetreatments), one subject (< 0.1%) developed binding antibodies. This subject received three treatmentsof Boey 700 units at 6-week interval and was negative for neutralising antibodies. This subject did notdemonstrate cross-reactivity to botulinum toxin type A. Across all studies, no subject (0%) developedneutralising antibodies. Overall, anti-drug antibodies (ADA) were very rarely detected. There was noevidence of ADA impact on safety or efficacy, and risk of cross-reactivity to botulinum toxin type A islow; however, data are still limited.

A total of 725 adult subjects with moderate to severe glabellar lines associated with corrugator and/orprocerus muscle activity, who were psychologically impacted by their glabellar lines, were included intwo randomised, multi-centre, double-blind, placebo-controlled studies of identical design (N=498,

Study M21-500; N=227, Study M21-508). Adult subjects were enrolled on baseline Day 1 (Hour 0).

Subjects were eligible for treatment with Boey at the Day 43 Visit if retreatment criteria were met,including moderate to severe glabellar lines at maximum frown.

In these two studies, the majority of subjects were female. All races (White, Black, Asian, and others)and ethnicity (Hispanic and non-Hispanic) were included. Subjects were 20 to 81 years old, with amean age of 46 years.

The primary efficacy instrument to assess glabellar line severity at maximum frown was the 4-point

Facial Wrinkle Scale (FWS) (0=none, 1=mild, 2=moderate, 3=severe) used by both the investigatorand subject. The investigator and subject assessments were performed independently.

The co-primary efficacy measure (treatment responder rate) was defined as the percentage of subjectsachieving a ≥ 2-grade improvement from baseline in glabellar line severity at maximum frown at Day7 based separately on investigator and subject assessments using FWS.

Both co-primary efficacy measures showed statistically significant improvements with the Boey groupcompared to placebo group for both studies M21-500 and M21-508, including all randomised subjectswith baseline FLO-11 Total Transformed Score ≤ 50. Results are included below (Table 2).

Table 2. Co-primary efficacy endpoints: Investigator and subject assessments of glabellarline severity at maximum frown - responder rates (% of subjects achieving ≥2-grade improvement from baseline at Day 7)

Study M21-500 Study M21-508

Boey Boey700 units Placebo 700 units Placebon (%) n (%) n (%) n (%)95% CI 95% CI 95% CI 95% CI

ITT Populationwith Baseline

FLO-11 Total

Transformed

Score ≤ 50 (N=368) (N=130) (N=164) (N=63)

Investigator 265 (72.1%)* 1 (0.8%) 121 (73.6%)* 0 (0%)

Assessment (67.5%, 76.7%) (0.0%, 4.2%) (66.8%, 80.4%) (0.0%, 5.7%)

Subject 224 (61.0%)* 1 (0.8%) 111 (67.9%)* 0 (0%)

Assessment (55.9%, 66.0%) (0.0%, 4.2%) (60.7%, 75.0%) (0.0% 5.7%)

*p < 0.0001 (Boey vs placebo)

The percentages of subjects achieving ≥ 2-grade improvement from baseline over time are shown in

Figure 2. Improvement in glabellar lines started within hours after injection. The peak effect was seenat Day 7 and duration of response lasted 2 to 3 weeks after Boey injection.

Figure 2. ≥2-grade improvement from baseline on the FWS according to subject andinvestigator assessments of glabellar lines severity at maximum frown over time(double-blind period) (Studies M21-500 and M21-508)▪▪▪▪▪▪▪ ≥2-grade Improvement - Subject▬ ▬ ≥2-grade Improvement - Investigatorx Placeboo Boey

Study Timepoint

In M21-500 and M21-508 studies, most subjects (724/725) were younger than 80 years. Subjects inthis age group had treatment responder rates, as assessed by the investigator, of 72.7% (386/531) for

Boey and 0.5% (1/193) for placebo.

In the M21-500 and M21-508 studies, the secondary efficacy measures assessed psychological impact,≥ 1-grade improvement in glabellar lines severity, overall treatment satisfaction, and satisfaction withnatural look. The 11-item Facial Line Outcomes (FLO-11) questionnaire evaluates appearance-relatedpsychological impacts due to glabellar lines including, how bothered they were by their glabellar lines,looking older than they want to look, feeling unattractive, looking older than their actual age, lookingless attractive, looking not well rested, skin not looking smooth, looking tired, looking stressed,looking angry, and feeling good about facial appearance.

Using the FLO-11 total score, 66.6% of subjects in Study M21-500 and 61.9% of subjects in M21-508study reported improvements in appearance-related psychological impacts with Boey compared tosubjects treated with placebo (8.5% and 7.9%, respectively) at Day 7, as assessed by a ≥ 20-pointchange from baseline (p < 0.0001 in both studies).

Using the Facial Lines Satisfaction Questionnaire (FLSQ), overall satisfaction with treatment effect(Item 5), more subjects in M21-500 and M21-508 studies, 58.7% and 68.5%, respectively, reportedbeing Mostly satisfied or Very satisfied with Boey treatment compared to subjects treated with placebo(16.2% and 9.9%, respectively) at Hour 24 (p < 0.0001 in both studies).

Using satisfaction with achieving a natural look (FLSQ Item 4), more subjects in M21-500 and M21-508 studies, 77.7% and 86.0%, respectively, reported being Mostly satisfied or Very satisfied with

Boey treatment compared to subjects treated with placebo (7.7% and 7.9%, respectively) at Day 7(p < 0.0001 in both studies).

Boey also reduced the severity of glabellar lines at rest. In the M21-500 and M21-508 studies, 53.0%and 49.4% had moderate to severe glabellar lines at rest at baseline as assessed by subject andinvestigator, respectively. Of these, 64.6% and 63.2% of Boey-treated subjects were responders at rest

Percentage of Subjects (%)

Day 1 (Hour 0)

Day 2 (Hour 24)

Day 7

Day 14

Day 21

Day 28

Day 35

Day 43with none or mild severity on Day 7, compared with 8.1% and 10.0% of placebo-treated subjects asassessed by subject and investigator, respectively.

The response rate for glabellar lines improvement was similar across all treatment cycles.

There are limited phase 3 clinical data with Boey in patients older than 65 years. Only 7% (38/532) ofsubjects were ≥65 years old and treatment responder rates at Day 7 were lower in this population (58%according to investigator and 37% according to subject).