Scientific Update Laxman Bahroo, MD

Transcription

1 Scientific Update Laxman Bahroo, MD Associate Professor Director; Botulinum Toxin Clinic Director; Neurology Residency Program Medstar Georgetown University Hospital Washington, D.C.

2 Disclosures Advisory Board and Consultant/independent contractor: Allergan plc, Acadia Pharmaceuticals, Inc., Cynapsus Therapeutics, Inc., Ipsen Biopharmaceuticals, Inc., Lundbeck, Teva Pharmaceuticals, and US WorldMeds LLC. Speaker s Bureau participant: AbbVie Inc., Allergan plc, Acadia Pharmaceuticals, Inc., Ipsen Biopharmaceuticals, Inc., Lundbeck, Teva Pharmaceuticals, UCB, and US WorldMeds LLC.

3 Objectives 1. Discuss the structure and function of botulinum toxin 2. Briefly review history 3. Review current botulinum toxin products available in US 4. Discuss study comparing multiple preparations 5. Discuss ongoing studies for botulinum toxins and future indications **Discussion of off label uses of botulinum toxins

4 Botulinum Toxin Structure 7 serotypes A G found in nature Heavy Chain and light chain complex held by disulfide bonds Accessory proteins: hemaggluttinin and nonhemaggluttinin proteins Manual of Botulinum Toxin Therapy. Cambridge University Press; 2 edition (March 31, 2014)

5 Botulinum Toxin Structure Light Chain (enzyme) Light Chain (50 kd) Heavy Chain delivery/binding Heavy Chain (100 kd) Available:

6

7

8 History of Botulinum Toxin Justinus Kerner MD Studied botulism, known as sausage poisoning Botulus is Latin for sausage Published 2 monographs on the effect of botulism and found the causes of death to be cardiac failure or respiratory arrest The capacity of nerve conduction is interrupted by the toxin in the same way as in an electric conductor by rust Manual of Botulinum Toxin Therapy. Cambridge University Press; 2 edicon (March 31, 2014).

9 From Poison to Therapeutic Agent Clostridium botulinum linked to botulism Crude form of type A isolated by Herman Sommer, MD Botulinum toxins shown to block neuromuscular transmission BoNT-A: Preclinical research by Allan Scott and Edward Schantz MD BoNT-A: First experimental use in humans by Allan Scott, MD s FDA approves Glabellar lines 2002 FDA approves Primary Axillary Hyperhydrosis FDA approves Dysport 1920s s Botox & Myobloc FDA approved for Cervical Dystonia FDA approves ULS & Chronic Migraine New formulation of Botox (low protein) FDA Approved 1997 FDA approves Xeomin 2011 NDO Overactive Bladder FDA approves Botox for Strabismus & blepharospasm

10 Various Preparations of Botulinum Toxins Available:

11 Unique Names for Botulinum Toxins Onabotulinum toxin A Botox Abobotulinum toxin A Dysport Incobotulinum toxin A Xeomin Rimabotulinum toxin B Myobloc Using brand names as they are easier to mention and more recognized.

12 Comparison of US Toxin Formulations Botox Dysport Xeomin Myobloc OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA RimabotulinumtoxinB Vacuum Drying Lyophilization Lyophilization Soluble (500 units / 0.1ml) 900 kd complex 300 /600 kd complex 150 kd 600 kd 100 unit 300 unit 50 unit 2500 unit 200 unit 500 unit 100 unit 5000 unit units

13 Comparison of US Toxin Formulations Botox OnabotulinumtoxinA Dysport AbobotulinumtoxinA Xeomin IncobotulinumtoxinA Myobloc RimabotulinumtoxinB SNAP-25 SNAP-25 SNAP-25 VAMP Cosmetic Chronic Migraine Cosmetic Cervical Dystonia Cosmetic Blepharospasm Cervical Dystonia Blepharospasm Cervical Dystonia Cervical Dystonia ULS Neurogenic and non neurogenic Overactive Bladder

14 Benefits of Multiple Preparations Multiple options for patients Increased funding for scientific and clinical research Increased disease states studied Improved patient access to botulinum toxin therapy

15 Multiple Preparations 4 commercially available botulinum toxins in the United States Differences in purification process 1 units is LD50 and is based on proprietary assay (no standardized assay available) Each toxin has a unique dosing range Food & Drug Administration Conversion: Units / doses of each toxin formulation are unique and non-interchangeable Conversion table or ratio are strongly discouraged Black Box Warning Potentially life threatening distant toxin spread after local injection REMS (Risk Evaluation Mitigation Strategy) for patients to understand risk

16 A Study Evaluating Multiple Botulinum Toxin Preparations? Blepharospasm: long-term treatment with either Botox, Xeomin or Dysport. Kollewe K, Mohammadi B, Köhler S, Pickenbrock H, Dengler R, Dressler D. J Neural Transm (Vienna) Mar;122(3):

17 Study Overview 288 patients with blepharospasm 3 toxin preparations: Botox, Dysport and Xeomin Botox and Xeomin 4 units / 0.1ml Dysport 10 units / 0.1ml Evaluated toxin dose, dose ratio Reviewed latency, duration and response Reviewed adverse events across toxins 17

18 Results 18

19 Results 19

20 Lessons From the Study Various Botulinum toxins effectively manage blepharospasm Slight variability in latency and duration but not statistically significant No significant variability in side effects across multiple preparations Significant differences in dosing and dilution Key point: To use botulinum toxins effectively you must be familiar with dose and dilution 20

21 On Label Conditions Treated with Botulinum Toxin On Label On Label Continued 2 placebo controlled trials showing benefit Blepharospasm Cosmetic Hyperhidrosis Strabismus Hemifacial Spasm* Cervical Dystonia Chronic Migraine Upper Limb Spasticity Neurogenic Detrusor Overactivity Detrusor Overactivity

22 Off Label Conditions Treated with Botulinum Toxin Lack 2 placebo controlled trials but there is medical evidence showing benefit Various dystonias Lower Limb Spasticity Pediatric indications Pain syndromes Bruxism Achalasia There are more off label uses of botulinum toxins than on label uses

23 Emerging Indications - Overview Spasticity Upper Limb Lower Limb Pediatric Upper Limb Pediatric Lower Limb Sialorrhea Adolescent Chronic Migraine Neurogenic Detrusor Overactivity Reference for data on subsequent slides:

24 Upper Limb Spasticity (ULS) Botox approved in 2010 Biceps, FCU, FCR, FDS, FDP Dose 360 units Additional muscles approved in 2015 (NEW) Adductor Pollicus and Flexor Pollicus Longus Final Dose 400 units Botox Prescribing InformaCon. Available: hnps://

25 Botox Prescribing InformaCon. Available: hnps://

26 Dysport Upper Limb Spasticity approved in 2015 (NEW) Initial: Placebo vs 500 units vs 1000 units Extension: 500 units vs 1000 units Primary outcome: Modified Ashworth Secondary outcome: Physician Global Impression, Range of motion Dysport Prescribing InformaCon. Available: h"p://dysporthcp.com/adult-uls-efficacy.

27 Muscles and Dosing Dysport Prescribing InformaCon. Available: h"p://dysporthcp.com/adult-uls-efficacy.

28 Xeomin Upper Limb Spasticity (ULS) Approved 2015 (NEW) Placebo vs 400 units Endpoints: Primary Modified Ashworth Scale, Secondary Physician Global Assessment

29 Xeomin Prescribing InformaCon. Available: hnp://

30 Xeomin Prescribing InformaCon. Available: hnp://

31 Botox Lower Limb Spasticity (LLS) Approved in 2016 (NEW) Placebo vs units Endpoint: Primary: Modified Ashworth Scale Secondary: Pain scale, CGI, Goal attainment score (6 points)

32 Botox Prescribing InformaCon. Available: hnps://

33 Botox Prescribing InformaCon. Available: hnps://

34 Dysport Lower Limb Spasticity (LLS) Initial: Placebo vs 1000 units vs 1500 units Extension: 1000 units vs 1500 units (upper and lower) Endpoints: Primary: Modified Ashworth Scale Secondary: CGI, assessment of walking speed Status: Completion of Initial in May 2014 Status: Completion of Extension in late 2015

35 Lower Limb Spasticity Xeomin Placebo vs 400 units Endpoints: Modified Ashworth and CGI Status: Completed - results not available

36 Pediatric Upper Limb Spasticity Botox Placebo vs 3 units /Kg vs 6 units /Kg Age: 2 16 years with cerebral palsy or stroke Exclusion < 10 Kg, previous tendon lengthening surgery or planned surgery Endpoints: Primary: Modified Ashworth Secondary: CGI, Modified Tardieu Status: Completion 2017

37 Pediatric Upper Limb Spasticity Dysport 2 units /Kg vs 8units /Kg vs 16 units/kg Age: 2 17 years with cerebral palsy Inclusion: MAS 2 or greater, elbow, wrist hyper flexion Exclusion < 10 Kg, previous tendon lengthening surgery or planned surgery Endpoints: Primary: Modified Ashworth Secondary: CGI, Modified Tardieu Status: December 2016

38 Pediatric Lower Limb Spasticity Dysport Approved August 2016 (NEW) Study: Initial: Placebo vs 10 units/kg vs 15 units /Kg Extension: 10 units/kg up to 30 units/kg, not exceed 1000 units overall Endpoint: Primary: Modified Ashworth Secondary: CGI, Progress to goal

39 Dysport Pediatric Dosing Dysport Prescribing InformaCon. Available: h"p://dysporthcp.com/adult-uls-efficacy.

40 Pediatric Lower Limb Spasticity Botox Placebo vs 4 units /Kg vs 8 units/kg Age: 2 16 years with cerebral palsy or stroke Exclusion < 10 Kg, previous tendon lengthening surgery or planned surgery Endpoints: Primary: Modified Ashworth Secondary: CGI, Modified Tardieu Status: Completion 2017

41 Myobloc Sialorrhea Phase 3 multicenter trial Evaluating sialorrhea in adults Injections done with surface landmark guidance, ultrasound Placebo vs 2 doses Status: Completion late 2016

42 Xeomin Sialorrhea Phase 2 Placebo vs units Parkinson s disease, Parkinsonism, ALS Endpoints: Measure saliva volume and change in saliva volume at 1 month between placebo and active group Status: Completed November 2013

43 Chronic Migraine Botox approved for Adults with Chronic Migraine Botox study in Adolescents with Chronic Migraine Placebo vs 2 Doses Inclusion: years of age with Chronic Migraine Status: Recruitment complete Expected completion in late 2016

44 Chronic Migraine Endpoints: Primary: Change from baseline in the frequency of headache days Secondary: Change from baseline in the frequency of severe headache days Change from baseline in the total cumulative hours of headache on headache days Percentage of patients with 50% decrease from baseline in the frequency of headache days Percentage of patients who are prescribed oral rescue migraine prophylactic treatment

45 Neurogenic Detrusor Overactivity (NDO) Botox Approved for Neurogenic Detrusor Overactivity in 2011 Approved for Detrusor Overactivity in 2013 Botox study to evaluate role in pediatric neurogenic detrusor overactivity Placebo vs 3 dosing arms Status: Completion: June 2017

46 Pediatric Neurogenic Detrusor Overactivity (NDO) Endpoints: Primary: Change from Baseline in Daily Average Frequency of Daytime Urinary Incontinence Episodes Secondary: Change from Baseline in Maximum Cystometric Capacity (MCC) Percentage of Patients With Involuntary Detrusor Contractions (IDC) Change from Baseline in Maximum Detrusor Pressure During the First IDC Change from Baseline in Detrusor Leak Point Pressure (DLPP) Change from Baseline in Average Urine Volume at First Morning Catheterization Percentage of Patients With Night Time Urinary Incontinence Change from Baseline in Maximum Detrusor Pressure Time to Patient Request for Retreatment Time to Patient Qualification for Retreatment

47 Neurogenic Detrusor Overactivity (NDO) Dysport Phase 3 Trial Patients with MS or spinal Cord injury Dose: Placebo vs 600 units and 800 units End Points: Status: Completion 2021

48 Timeline of Approvals Estimated Approvals Based on phase 3 trials meeting primary endpoints without safety concerns and no issues with FDA approval process LLS Botox Pediatric LLS Dysport LLS Dysport

49 Timeline of Approvals Estimated Approvals continued Pediatric LLS Botox Sialorrhea Myobloc Pediatric ULS Dysport Adolescent Chronic Migraine Botox 2019 Pediatric NDO Botox 2021 NDO - Dysport

50 Summary Numerous Phase 3 trials currently underway Several potential upcoming indications in the next 4 years As botulinum toxin indications expand there will increased scrutiny As the use of botulinum toxins expands there will be increased need for training and education for safe and effective use.

51 Thank You!!