1. Safety, Efficacy and Duration of Effect of RT002, a Botulinum Toxin Type A for Injection, to Treat Glabellar Lines: The Phase 2 BELMONT Study
Authors:
Jean D. Carruthers, MD, University of British Columbia, Vancouver, BC, Canada
Arthur Swift, MD, The Westmount Institute of Plastic Surgery, Montreal, QC, Canada
Nowell Solish, MD, University of Toronto, Toronto, ON, Canada
Vince Bertucci, MD, University of Toronto, Toronto, ON, Canada
Alastair Carruthers, MD, University of British Columbia, Vancouver, BC, Canada

2. DISCLOSURES Consultants and Researchers with : ALLERGAN ALPHAEON
MERZ REVANCE
ZELTIQ

3. BELMONT Study Design Multi-center, double-blind, active and placebo-controlled trial
Protocol Title: A Phase 2, Randomized, Double-Blind, Dose Ranging, Active and Placebo Controlled, Multi-Center Study to Evaluate the Safety and Efficacy and Duration of RT002, a Botulinum Toxin Type A for Injection, to Treat Glabellar Lines
Key Features: Phase 2, DaxibotulinumtoxinA for Injection (RT002) Dose Ranging, Active OnabotulinumtoxinA (BOTOX® Cosmetic) Comparator and Placebo Controlled
Objectives:
To determine the safety and efficacy of a single treatment of DaxibotulinumtoxinA for Injection (RT002) at three dosage levels for the treatment of glabellar lines versus OnabotulinumtoxinA
DaxibotulinumtoxinA: 20U, 40U, 60U
OnabotulinumtoxinA: 20U
Placebo
To assess the duration of effect of a single treatment of DaxibotulinumtoxinA at three dosage levels versus OnabotulinumtoxinA
*BOTOX® is a registered trademarks of Allergan, Inc.

4. Facial Wrinkle Severity
Study Population & Scales Subjects with moderate to severe glabellar lines
At entry, subjects required to have moderate or severe glabellar lines (GL) as assessed by the Investigator and subject
Investigator Global Assessment-Facial Wrinkle Severity (IGA-FWS)
Subject’s assessment of Patient Facial Wrinkle Severity (PFWS)
IGA-FWS and PFWS also key efficacy endpoints
Global Aesthetic Improvement Scale (GAIS) for Investigator and Subject also used as efficacy endpoints
IGA-FWS
Rating Score
Facial Wrinkle Severity
None 1
Mild 2
Moderate 3
Severe
Photo guide exhibiting the grades of wrinkle severity used for Investigator training and reference
PFWS
Rating Score
Wrinkle Severity
Description
None
No wrinkles 1
Mild
Very shallow wrinkles 2
Moderate
Moderate wrinkles 3
Severe
Deep wrinkles
Investigator and Subject GAIS
Rating Score
Wrinkle Improvement -3
Very Much Worse -2
Much Worse -1
Worse
No Change 1
Improved 2
Much Improved 3
Very Much Improved

5. BELMONT Study Assessments
Efficacy evaluations versus baseline
Every 4 weeks for up to 36 weeks using Investigator Global Assessment-Facial Wrinkle Severity (IGA-FWS)
All subjects were followed for at least 24 weeks
Primary Efficacy Assessments
≥ 1-point improvement IGA-FWS
Duration of response
Risk-to-benefit ratio
Secondary Efficacy Assessments
Investigator (IGA-FWS)
Subject Global Aesthetic Improvement Scale (GAIS)
Patient Facial Wrinkle Scale (PFWS) 5

6. Demographics Placebo (N=54) Daxibot* 20U (N=54) Daxibot* 40U (N=53)
Onabot** U (N=54)
Age (years)
49.1 (32 to 64)
49.0 (30 to 64)
49.9 (30 to 63)
47.5 (30 to 64)
50.0 (36 to 63)
Male
9 (16.7%)
5 ( 9.3%)
7 (13.2%)
11 (20.8%)
6 (11.1%)
Female
45 (83.3%)
49 (90.7%)
46 (86.8%)
42 (79.2%)
48 (88.9%)
Race: White
46 (85.2%)
47 (87.0%)
50 (94.3%)
48 (90.6%)
IGA-FWS: moderate
34 (63.0%)
35 (66.0%)
30 (56.6%)
31 (57.4%)
IGA-FWS: severe
20 (37.0%)
18 (34.0%)
23 (43.4%)
23 (42.6%)
PFWS: moderate
36 (66.7%)
33 (62.3%)
37 (69.8%)
29 (53.7%)
PFWS: severe
18 (33.3%)
20 (37.7%)
16 (30.2%)
25 (46.3%)
*Daxibot = DaxibotulinumtoxinA, RT002
**Onabot = OnabotulinumtoxinA, BOTOX®
Table 14.1.1; Table 

7. Subject Disposition Per Protocol Population
77 subjects excluded from Per Protocol population
0 subjects violated inclusion/exclusion criteria
2 subjects received incorrect dose/treatment
14 subjects used a prohibited medication
5* subjects did not attend at the primary endpoint, Week 24 visit
57 subjects attended the Week 24 visit off schedule (+/- 5 days)
Subjects excluded from PP
Similar across treatment groups (12, 14, 10, 10, 11)
Not unusual for long term studies
* Subjects may have more than one reason for exclusion

8. Summary of Safety
All five groups exhibited an excellent overall safety profile in interim data
No serious adverse events
Adverse events were predominantly localized, transient and mild in severity and typically injection related (erythema and pain)
Most common adverse events by subject
DaxibotulinumtoxinA dosed at 20U and 40U exhibited NO EYELID PTOSIS
OnabotulinumtoxinA had 1.9% ptosis (N=1)
DaxibotulinumtoxinA at 60U had 7.5% ptosis (N=4)
Placebo
N=54
Onabot
Daxibot 20U
N=53
Daxibot 40U
Daxibot 60U
Headache 3 10 6 4
Erythema 5 8

9. 100% Response Rates For All DaxibotulinumtoxinA Doses
Week 4 Investigator Efficacy Analyses (PP)
Placebo
N=35
Onabot
N=34
Daxibot 20U
N=39
Daxibot 40U
N=41
Daxibot 60U
N=42
≥ 1 pt 3%
95%
100%
≥ 2 pt 0%
76%
74%
85%
95%*
None or Mild
93%
97%
98%
* Statistically significant vs. OnabotulinumtoxinA. Study not powered for statistical significance at Week 4 9

10. Primary Efficacy Analyses (Week 24)
Placebo (N=35)
Daxibot 20U (N=34)
Daxibot 40U (N=39)
Daxibot 60U (N=41)
Onabot 20 U (N=42)
> 1 Point Improvement vs Baseline IGA-FWS N 35 34 39 41 42
Yes
1 (2.9%)
6 (17.6%)
14 (35.9%)
12 (29.3%)
8 (19.0%) No
34 (97.1%)
28 (82.4%)
25 (64.1%)
29 (70.7%)
34 (81.0%)
p-value vs Placebo
0.048
<.001
0.003
0.030
p-value vs onabotulinumtoxinA
0.854
0.089
0.328
Duration of Response based on > 1 Point Improvement vs Baseline IGA-FWS (Kaplan-Meier)
Median (weeks)
0.0
20.0
23.6
20.9
18.8
95% Confidence Interval
N/A
(17.0,24.0)
(19.6,24.7)
(20.0,24.1)
(15.9,20.0)
0.430
0.020
0.148
Risk to Benefit Ratio
Number of Treatment-Related Adverse Events 8 15 11 22 21
Sum of No. of Response Weeks 16
707
903
923
785
Ratio
0.514
0.022
0.012
0.025
0.027
Table 

11. Carruthers Study: Responder Rate at Maximum Frown By Trained Observer
The peak responder rate occurred between 2 and 4 weeks and ranged from 85% in the 10 U group to 100% in the 40 U group.
At Month 3, the responder rate was still near 40% in the 30 and 40 U groups but had fallen to 5% in the 10 U group.
At month 4, 25% of patients in the 30 and 40 U groups were still rated as responders.
The differences seen among the 4 treatment groups were statistically significant at months 1, 2, and 3 (p < .0294).
There was a significant linear trend at months 1, 2, 3, and 4 reflecting a linear dose-dependent response (p < .0212).
Carruthers A, Carruthers J, Said S., Division of Dermatology, University of British Columbia, Vancouver, B.C., Canada.
Double-Blind, Randomized, Parallel Group, Dose-Ranging Study of Botulinum Toxin Type A in the Treatment of Glabellar Lines, 2001

12. Carruthers Study: Responder Rate at Maximum Frown By Trained Observer
BELMONT
67% Daxibot 40U
BELMONT
53% Daxibot 20U
BELMONT
32% Onabot 20U
The peak responder rate occurred between 2 and 4 weeks and ranged from 85% in the 10 U group to 100% in the 40 U group.
At Month 3, the responder rate was still near 40% in the 30 and 40 U groups but had fallen to 5% in the 10 U group.
At month 4, 25% of patients in the 30 and 40 U groups were still rated as responders.
The differences seen among the 4 treatment groups were statistically significant at months 1, 2, and 3 (p < .0294).
There was a significant linear trend at months 1, 2, 3, and 4 reflecting a linear dose-dependent response (p < .0212).
Carruthers A, Carruthers J, Said S., Division of Dermatology, University of British Columbia, Vancouver, B.C., Canada.
Double-Blind, Randomized, Parallel Group, Dose-Ranging Study of Botulinum Toxin Type A in the Treatment of Glabellar Lines, 2001

13. DaxibotulinumtoxinA 40U Outperforms OnabotulinumtoxinA At All Time Points
DaxibotulinumtoxinA 40U showed higher response rate for None or Mild wrinkles by Investigator Assessment at all time points
Dose Group
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Daxibot 40U
97%
97%*
85%
67%*
46%*
31%*
Onabot 20U
93%
83%
69%
32%
22%
12%
Not Just a Dose Effect…
Dose Group
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Daxibot 20U
97%
88%
82%
53%*
35%
12%
Onabot 20U
93%
83%
69%
32%
22%
* Statistically significant (p<.05) vs OnabotulinumtoxinA

14. Duration of response separates from onabot in every daxibot dose group
Kaplan-Meier Curve: Duration of Response (None or Mild) for IGA-FWS Assessment at Maximum Frown (Per-Protocol Population)

15. Duration of response separates from onabot
Kaplan-Meier Curve: Duration of Response (None or Mild) for IGA-FWS Assessment at Maximum Frown (Per-Protocol Population)
daxibotuinumtoxinA 20U group vs. onabotulinumtoxinA 20U AND Placebo

16. Duration of response separates from onabot
Kaplan-Meier Curve: Duration of Response (None or Mild) for IGA-FWS Assessment at Maximum Frown (Per-Protocol Population)
daxibotulinumtoxinA 40U group vs. onabotulinumtoxinA 20U AND Placebo

17. DaxibotulinumtoxinA 40 U
Example 2-Point Improvement by IGA-FWS & PFWS at Week 4; 1-Point Sustained Duration of Effect
DaxibotulinumtoxinA 40 U
MAXIMUM FROWN
Pre-treatment
Week 4
Week 24
Baseline Scores:
IGA-FWS: 3
PFWS: 3
Week 4 Scores:
IGA-FWS: 0
PFWS: 0
Week 24 Scores:
IGA-FWS: 2
PFWS: 2
Photo ID RT

18. DaxibotulinumtoxinA 40 U
Example 2-Point Improvement by IGA-FWS & PFWS at Week 4; 2-Point Sustained Duration of Effect
DaxibotulinumtoxinA 40 U
MAXIMUM FROWN
Pre-treatment
Week 4
Week 24
Baseline Scores:
IGA-FWS: 2
PFWS: 2
Week 4 Scores:
IGA-FWS: 0
PFWS: 0
Week 24 Scores:
IGA-FWS: 0
PFWS: 0
Photo ID RT

19. Conclusions and Next Steps
DaxibotulinumtoxinA achieves statistically significant 6-month duration of effect with higher responder rates compared to OnabotulinumtoxinA
DaxibotulinumtoxinA achieves 100% investigator and at or near 100% patient response in all doses at the 28-day primary efficacy assessment
DaxibotulinumtoxinA 40U appears well-tolerated with no Ptosis. Efficacy was statistically superior at the majority of time points compared to OnabotulinumtoxinA
DaxibotulinumtoxinA 40U results indicate 31% of subjects maintain none or mild wrinkles compared to OnabotulinumtoxinA at 12% at 6 months
BELMONT results support selection of the DaxibotulinumtoxinA 40U dose to move forward into Phase 3
Revance plans FDA End of Phase 2 Meeting and Phase 3 Initiation in 2H 2016