- Email: [email protected]
OnabotulinumtoxinA (Botox) displays superior activity to incobotulinumtoxinA drug product (Xeomin) in multiple in vitro and in vivo assays
S10
Abstracts / Toxicon 123 (2016) S2eS90
Reference Berg G, Gottwall T, Hammar M, Lindgren R. Climacteric symptoms among women aged 60-62 in Linkoping, Sweden, in 1986. Maturitas. 1988;10(3):193199. 22. CENTRAL EFFECTS OF BOTULINUM NEUROTOXIN Matteo Caleo*, Laura Restani. CNR Neuroscience Institute, Pisa, Italy * Corresponding author: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy. E-mail address:[email protected].
Introduction and objectives: Recently, evidence in animal models has indicated retrograde transport of BoNT/A to the central nervous system (CNS) after peripheral administration. BoNT/A appears to be transcytosed following retrograde transport, but the specific CNS targets remain unexplored. Methods: We performed BoNT/A injections into the whisker pad and hind limb muscles of adult rats. We used detection of cleaved synaptosomalassociated protein 25 kDA (SNAP)-25 as an assay of BoNT/A trafficking. We combined immunostaining for BoNT/A-truncated SNAP-25 with markers of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic synaptic terminals. Results: BoNT/A-cleaved SNAP-25 appeared in the facial nucleus and spinal cord following injection of the neurotoxin into the whisker pad and hind limb muscles, respectively. Co-localization analysis in the facial nucleus demonstrated preferential uptake and proteolytic activity of BoNT/A in cholinergic terminals. Conclusions: These data provide evidence for synapse-specific central effects of BoNT/A. This knowledge is important for a complete understanding of the mechanisms of action of this neurotoxin. Keywords: Cholinergic synapses; Facial nucleus; Retrograde axonal transport; SNAP-25; Transcytosis 23. EFFECT OF BOTULINUM TOXIN INJECTIONS ON GAIT OF CHILDREN WITH HEREDITARY SPASTIC PARAPLEGIA Anja Van Campenhout a,*, Pheline Neut b, Eirini Papageorgiou c. Department of Orthopaedics, University Hospital Leuven, Department of Development and Regeneration, University of Leuven, Leuven, Belgium; b Department of Biomedical Sciences, University of Leuven, Leuven, Belgium; c Department of Rehabilitation Sciences, University of Leuven, Clinical Motion Analysis Laboratory, University Hospital Leuven, Leuven, Belgium a
* Corresponding author: Department of Orthopaedics, University Hospital Leuven, Department of Development and Regeneration, University of Leuven, Leuven, Belgium. E-mail address:[email protected].
Introduction and Objectives: Children with hereditary spastic paraplegia (HSP) present with spasticity and muscle weakness of the lower limbs leading to progressive gait problems. This pathology is caused by different genes, giving rise to slightly different clinical presentations and evolution. It has been demonstrated that the use of botulinum neurotoxin type A (BoNT-A) injections can decrease spasticity of the muscles of HSP patients, but the evolution of their gait after the treatment has not been reported. The objective of this retrospective study was to analyze whether BoNT-A injections can influence the gait of children with HSP and to document the outcome for the different genetic etiologies of HSP. Methods: Children with HSP who had a first BoNT-A injection in the lower limb muscles were retrospectively included if they had a three-dimensional gait analysis (3D GA) (Vicon, Oxford, UK) before and 2 to 3 months after the procedure. Patients who had lower limb surgery or had received an intrathecal baclofen (ITB) pump were excluded. Spasticity was assessed using the Modified Ashworth Scale (MAS) for all the injected lower limb muscle groups. The primary outcome measure for gait was the Gait Profile Score (GPS). The Movement Analysis Profile (MAP) and selected gait parameters were recorded as secondary outcome measures. Results: Thirty-four of 106 children with HSP received BoNT-A; 12 of the thirty-four fulfilled all the inclusion criteria. These 12 children (age: 7, 3 years [y]; range 2-14 y); Gross Motor Function Classification System
[GMFCS] Levels: 7, Level I; 3, Level II; and 2, Level III), received BoNT-A injections in the adductors (3), psoas (7), medial hamstrings (11), and/or gastrocnemius muscles (8). The muscle selection was defined by the clinical need. Two children had a pathologic SPG3A gene, 2 SPG4, 1 SPG35, and 7, other unknown genetic etiology. On average, GPS and MAP scores remained stable after BoNT-A injection. A significant decrease in cadence was observed with mild decrease in walking speed. Further, there was a significant increase in knee extension at initial contact and during stance. A reduction in the pelvic sagittal range of motion produced an improvement in pelvic stability. The MAS scores of the injected muscles were reduced significantly for hip flexors, hamstrings and gastrocnemius, but not for adductors (but only 3 patients were injected in the adductors). Remarkably, both children with the SPG4 gene showed an increased GPS score (more than the minimal detectable change of 1, 63 for GPS [Beynon 2010]) demonstrating a deteriorated gait after BoNT-A injection. Both children with the SPG3 gene had a reduction (improvement) in GPS score, although no reduction in MAS score for the injected muscles was noted. Conclusions: Children with HSP demonstrated a slower and more extended gait after BoNT-A injections. However, the overall gait measured by GPS did not improve. Furthermore, the results from this pilot study suggest that genetic diagnosis might alter the outcome after BoNT-A injections with worsening of gait in children with SPG4 HSP. However, a larger group and inclusion of measurement of strength is required to explore this finding in greater depth. Keywords: BoNT-A injections; Gait; Hereditary spastic paraplegia; SPG3; SPG4 Reference Beynon S, McGinley JL, Dobson F, Baker R. Correlations of the Gait Profile Score and the Movement Analysis Profile relative to clinical judgments. Gait Posture. 2010; 32(1):129-132. 24. ONABOTULINUMTOXINA (BOTOX) DISPLAYS SUPERIOR ACTIVITY TO INCOBOTULINUMTOXINA DRUG PRODUCT (XEOMIN) IN MULTIPLE IN VITRO AND IN VIVO ASSAYS David Canty, Linh Le, Joanne Wang, Greg Nicholson, Amy BrideauAndersen, Lance Steward, Birgitte Jacky, Ron Broide, Mark Washburn, David Rupp*. Allergan Inc, Irvine, CA, USA * Corresponding author: Allergan, 2525 Dupont Drive, Irvine, CA, 92715, USA. Email address:[email protected].
Objectives: Introduction of incobotulinumtoxinA (IncoA) to the market has led to an ongoing clinical controversy on whether incobotulinumtoxinA is interchangeable with onabotulinumtoxinA (OnaA). This study was conducted to assess in vivo and in vitro activity of 50 U, 100 U, and 200 U vials of IncoA in relation to 100 U OnaA product. Methods: 50 U, 100 U, and 200 U vials of IncoA and 100 U OnaA were diluted and tested at equal botulinum toxin type A product label activity units in 4 distinct assays: rat compound muscle action potential (CMAP), mouse digit abduction score (DAS), cell-based potency assay (CBPA), and light chain activity (LCA) assay. Results: Multiple orthogonal assays demonstrated that the biological activity of Merz Units is less than Allergan Units. Higher doses of IncoA were required to cause 50% inhibition (ID50) in the CMAP assay, demonstrating that OnaA displays greater biological activity compared to IncoA. Superior biological activity was displayed by OnaA in the DAS assay demonstrating statistical differences between OnaA and IncoA. CMAP and DAS data were corroborated by CBPA data. Additionally, greater light chain activity was displayed by 100 U OnaA when evaluated against 50 U, 100 U, and 200 U IncoA. Light chain activities of 50 U, 100 U, and 200 U products were approximately 50% of predicted values. No atypical cleavage products were observed when testing any of the IncoA products, which differs from previous 50 U and 100 U results, and suggests that changes have been made to the product. Conclusions: Data from 4 different assays establish that, on a unit for unit basis, OnaA displays greater biological activity than IncoA confirming that
Abstracts / Toxicon 123 (2016) S2eS90
units of OnaA and IncoA are not interchangeable. Data presented here emphasize that non-interchangeability and product-specific potency must be considered when dosing patients.
DAS fold increase in units required for comparable OnaA ED50 Value N¼3
CBPA fold increase in units required for comparable OnaA EC50 Value N¼2, N¼3c
LCA % of 100 U OnaA light chain values N¼3c
50 U 2.0, 2.1, 1.4 IncoA b(P¼0.032)
Not Tested
1.2, 1.2
100 U 1.6, 1.6, 1.2 IncoA b(P¼0.077)
Not Tested
1.6, 1.6, 0.9 b (P¼0.254)
200 U 1.5, 2.0, 1.2 IncoA b(P¼0.234)
1.7 b(P¼<0.001)
1.4, 1.3
26% of 100 U OnaA b (P¼0.0001) 53% of 100 U OnaA b (P¼0.0008) 95% of 100 U OnaA b (P¼0.3129)
CMAP fold increase in units required for comparable OnaA ID50 valuea N¼3
a
Unpaired 2-tailed t-test for all test results (N¼9, P¼0.005). Unpaired 2-tailed t-test. c Predicted LCA values for 50 U, 100 U, and 200 U IncoA would be 50%, 100%, and 200%, respectively, if OnaA and IncoA units were interchangeable. b
Keywords: CBPA; CMAP; DAS; IncobotulinumtoxinA; OnabotulinumtoxinA 25. BOTULINUM NEUROTOXIN (BONT) IN PARKINSONISM: THE WHEN, HOW, AND WHICH FOR BONT INJECTIONS Francisco Cardoso. Movement Disorders Unit, Neurology Service, UFMG, Av Pasteur 89/1107, Belo Horizonte, MG, 30150-290, Brazil. E-mail address:[email protected] The core clinical feature of Parkinson’s disease (PD), the most common cause of parkinsonism, is bradykinesia in association with at least one of the following features: tremor, rigidity, and postural instability. The mainstays of PD treatment are the use of pharmacological agents, rehabilitation techniques and, in selected cases, surgery. There are some other features, however, that can be successfully treated with BoNT injections. A significant proportion of PD patients present with sialorrhea that is refractory to clinical treatment. Controlled trials of intraglandular injections of both BoNT A and B show that this is an effective and safe treatment for drooling in PD. Dystonia is also often seen in PD patients, where the most common types are blepharospasm, apraxia of eyelid opening, oromandibular dystonia, and foot dystonia. In most instances, the latter is a feature of the disease whereas the others are commonly part of the spectrum of levodopa-induced dyskinesias. If these forms of dystonia fail to respond to conventional PD treatment, clinical practice shows that they can be successfully controlled with BoNT injections. There is, however, a need for controlled trials to support the effectiveness of BoNT in this scenario. Finally, urinary urgency or incontinence caused by overactive detrusor is seen in at least 30% of PD patients. Several open-label studies show that intradetrusor injections of BoNT provide a 6-month improvement of the urinary incontinence. There are also rare causes of parkinsonism with features amenable to treatment with BoNT injections. Many individuals with Progressive Supranuclear Palsy (PSP) present with focal dystonias treatable with BoNT injections. Among them, the most common form is eyelid dystonia, often referred to as apraxia of eyelid opening. Corticobasal syndrome, an uncommon atypical parkinsonism, typically causes painful hand dystonia that can be treated with BoNT injections. 26. SAFETY AND DURATION OF SEVERITY REDUCTION IN GLABELLAR LINES FOLLOWING AN INJECTION OF DAXIBOTULINUMTOXINA: RESULTS OF BELMONT STUDY Jean Carruthers a, Steve Yoelin b, Carol Y. Chung c, *, Roman G. Rubio c. Department of Ophthalmology and Visual Sciences, University of British
a
Columbia, Vancouver, BC, Canada; Therapeutics, Newark, CA, USA
S11 b
Newport Beach, CA, USA;
c
Revance
* Corresponding author: Revance Therapeutics, 7555 Gateway Boulevard, Newark, CA, 94560, USA E-mail address:[email protected].
Introduction: Injectable daxibotulinumtoxinA (RT002) is composed of a purified 150-kDa botulinum toxin type A formulated without additives in a lyophilized powder containing a proprietary peptide excipient. Safety and duration of frown line reduction of RT002 at 20, 40 or 60 units (U) compared with placebo or onabotulinumtoxinA (onabot) 20 U were evaluated in this randomized, double-blind, multicenter study (ClinicalTrials.gov Identifier: NCT02303002). Methods: Adults 30-64 years of age with moderate-to-severe glabellar lines were randomized to receive a single injection of RT002 20, 40, or 60 U, placebo, or onabot, and were followed for 24-36 weeks. Duration of response was depicted with Kaplan-Meier curves and compared between arms using the log-rank test. Results: A total of 268 patients were included in the intent-to-treat analysis; 191 were included in the per-protocol (PP) analysis. In the PP analyses, response (defined as having a 1 point improvement in Investigator Global Assessment-Facial Wrinkle Severity [IGA-FWS]) assessments was achieved in 100% of RT002-treated subjects at Weeks 2, 4, and 8, and was maintained by half of the RT002 40 U subjects for 24 weeks. Conversely, the response rate in the onabot arm decreased gradually from 98% at Week 2 to 90% at Week 8, and 52% had lost the response by 19 weeks. Consistent results were found in PFWS and Global Aesthetic Improvement Scale (GAIS) assessments. Adverse events (AE) were predominantly localized, transient and mild, and none were serious. Treatment-related AEs were observed as follows: a severe migraine occurred in a RT002 20 U subject; the onabot arm had the highest rate of headache (13%), injection site erythema (9%) and injection site edema (4%); facial asymmetry was reported in 2%-4% of the RT002 subjects (all resolved in 2-11 days); and eyelid ptosis occurred in 4 RT002 60 U subjects and 1 onabot subject. Conclusions: RT002 40 U had the most favorable risk-benefit profile in the study. Compared to onabot, RT002 had a greater rate and duration of response. Keywords: Botulinum toxin; DaxibotulinumtoxinA; Glabellar frown lines 27. SAFETY AND TOLERABILITY OF ONABOTULINUMTOXINA IN THE TREATMENT OF FACIAL LINES: STATISTICAL META-ANALYSIS OF POOLED DATA FROM GLOBAL REGISTRATION STUDIES OF TREATMENT OF CROW’S FEET LINES AND GLABELLAR LINES IN MORE THAN 3900 PARTICIPANTS Jean Carruthers a,*, Mitchell F. Brin b, Koen De Boulle c, Steven Liew d, Alastair Carruthers a, Alexander Rivkin e, Yan Wu f, Irina Yushmanova b, Terry I. Boodhoo b, Kathy Zhuang b, Conor J. Gallagher b, Elisabeth Lee b. a University of British Columbia, Vancouver, BC, Canada; b Allergan plc, Irvine, CA, USA; c Aalst Dermatology Clinic, Aalst, Belgium; d Private Practice, Sydney, NSW, Australia; e Private Practice, Los Angeles, CA, USA; f Peking University First Hospital, Beijing, China * Corresponding author: University of British Columbia, 2329 West Mall, Vancouver, BC, V6T 1Z4, Canada. E-mail address:[email protected].
Objective: A meta-analysis of pre-2009 registration studies (N¼1678; Brin 2009) evaluated safety/tolerability of onabotulinumtoxinA for glabellar lines (GL) and crow’s feet lines (CFL). We pooled safety data from pre- and post-2009 registration studies, focusing on those in CFL and CFL+GL combined. Methods: Safety data were pooled for 3946 participants from 15 onabotulinumtoxinA studies. Of 3338 participants from 11 randomized, doubleblind, placebo-controlled (DBPC) studies, 2394 received onabotulinumtoxinA for GL (n¼665), CFL (n¼1324), and CFL+GL (n¼405); the remaining participants received placebo. A total exposure (TE) population included onabotulinumtoxinA-treated participants (n¼3189) from the DBPC studies plus 4 wherein all participants received onabotulinumtoxinA. Results: Participants in the DBPC population were predominantly Caucasian (59.9%), Asian (33.6%), and female (85.1%); median age was 47.0 (21.885.0) years. Age and gender demographics were similar for DBPC studies in
Abstracts / Toxicon 123 (2016) S2eS90
Reference Berg G, Gottwall T, Hammar M, Lindgren R. Climacteric symptoms among women aged 60-62 in Linkoping, Sweden, in 1986. Maturitas. 1988;10(3):193199. 22. CENTRAL EFFECTS OF BOTULINUM NEUROTOXIN Matteo Caleo*, Laura Restani. CNR Neuroscience Institute, Pisa, Italy * Corresponding author: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy. E-mail address:[email protected].
Introduction and objectives: Recently, evidence in animal models has indicated retrograde transport of BoNT/A to the central nervous system (CNS) after peripheral administration. BoNT/A appears to be transcytosed following retrograde transport, but the specific CNS targets remain unexplored. Methods: We performed BoNT/A injections into the whisker pad and hind limb muscles of adult rats. We used detection of cleaved synaptosomalassociated protein 25 kDA (SNAP)-25 as an assay of BoNT/A trafficking. We combined immunostaining for BoNT/A-truncated SNAP-25 with markers of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic synaptic terminals. Results: BoNT/A-cleaved SNAP-25 appeared in the facial nucleus and spinal cord following injection of the neurotoxin into the whisker pad and hind limb muscles, respectively. Co-localization analysis in the facial nucleus demonstrated preferential uptake and proteolytic activity of BoNT/A in cholinergic terminals. Conclusions: These data provide evidence for synapse-specific central effects of BoNT/A. This knowledge is important for a complete understanding of the mechanisms of action of this neurotoxin. Keywords: Cholinergic synapses; Facial nucleus; Retrograde axonal transport; SNAP-25; Transcytosis 23. EFFECT OF BOTULINUM TOXIN INJECTIONS ON GAIT OF CHILDREN WITH HEREDITARY SPASTIC PARAPLEGIA Anja Van Campenhout a,*, Pheline Neut b, Eirini Papageorgiou c. Department of Orthopaedics, University Hospital Leuven, Department of Development and Regeneration, University of Leuven, Leuven, Belgium; b Department of Biomedical Sciences, University of Leuven, Leuven, Belgium; c Department of Rehabilitation Sciences, University of Leuven, Clinical Motion Analysis Laboratory, University Hospital Leuven, Leuven, Belgium a
* Corresponding author: Department of Orthopaedics, University Hospital Leuven, Department of Development and Regeneration, University of Leuven, Leuven, Belgium. E-mail address:[email protected].
Introduction and Objectives: Children with hereditary spastic paraplegia (HSP) present with spasticity and muscle weakness of the lower limbs leading to progressive gait problems. This pathology is caused by different genes, giving rise to slightly different clinical presentations and evolution. It has been demonstrated that the use of botulinum neurotoxin type A (BoNT-A) injections can decrease spasticity of the muscles of HSP patients, but the evolution of their gait after the treatment has not been reported. The objective of this retrospective study was to analyze whether BoNT-A injections can influence the gait of children with HSP and to document the outcome for the different genetic etiologies of HSP. Methods: Children with HSP who had a first BoNT-A injection in the lower limb muscles were retrospectively included if they had a three-dimensional gait analysis (3D GA) (Vicon, Oxford, UK) before and 2 to 3 months after the procedure. Patients who had lower limb surgery or had received an intrathecal baclofen (ITB) pump were excluded. Spasticity was assessed using the Modified Ashworth Scale (MAS) for all the injected lower limb muscle groups. The primary outcome measure for gait was the Gait Profile Score (GPS). The Movement Analysis Profile (MAP) and selected gait parameters were recorded as secondary outcome measures. Results: Thirty-four of 106 children with HSP received BoNT-A; 12 of the thirty-four fulfilled all the inclusion criteria. These 12 children (age: 7, 3 years [y]; range 2-14 y); Gross Motor Function Classification System
[GMFCS] Levels: 7, Level I; 3, Level II; and 2, Level III), received BoNT-A injections in the adductors (3), psoas (7), medial hamstrings (11), and/or gastrocnemius muscles (8). The muscle selection was defined by the clinical need. Two children had a pathologic SPG3A gene, 2 SPG4, 1 SPG35, and 7, other unknown genetic etiology. On average, GPS and MAP scores remained stable after BoNT-A injection. A significant decrease in cadence was observed with mild decrease in walking speed. Further, there was a significant increase in knee extension at initial contact and during stance. A reduction in the pelvic sagittal range of motion produced an improvement in pelvic stability. The MAS scores of the injected muscles were reduced significantly for hip flexors, hamstrings and gastrocnemius, but not for adductors (but only 3 patients were injected in the adductors). Remarkably, both children with the SPG4 gene showed an increased GPS score (more than the minimal detectable change of 1, 63 for GPS [Beynon 2010]) demonstrating a deteriorated gait after BoNT-A injection. Both children with the SPG3 gene had a reduction (improvement) in GPS score, although no reduction in MAS score for the injected muscles was noted. Conclusions: Children with HSP demonstrated a slower and more extended gait after BoNT-A injections. However, the overall gait measured by GPS did not improve. Furthermore, the results from this pilot study suggest that genetic diagnosis might alter the outcome after BoNT-A injections with worsening of gait in children with SPG4 HSP. However, a larger group and inclusion of measurement of strength is required to explore this finding in greater depth. Keywords: BoNT-A injections; Gait; Hereditary spastic paraplegia; SPG3; SPG4 Reference Beynon S, McGinley JL, Dobson F, Baker R. Correlations of the Gait Profile Score and the Movement Analysis Profile relative to clinical judgments. Gait Posture. 2010; 32(1):129-132. 24. ONABOTULINUMTOXINA (BOTOX) DISPLAYS SUPERIOR ACTIVITY TO INCOBOTULINUMTOXINA DRUG PRODUCT (XEOMIN) IN MULTIPLE IN VITRO AND IN VIVO ASSAYS David Canty, Linh Le, Joanne Wang, Greg Nicholson, Amy BrideauAndersen, Lance Steward, Birgitte Jacky, Ron Broide, Mark Washburn, David Rupp*. Allergan Inc, Irvine, CA, USA * Corresponding author: Allergan, 2525 Dupont Drive, Irvine, CA, 92715, USA. Email address:[email protected].
Objectives: Introduction of incobotulinumtoxinA (IncoA) to the market has led to an ongoing clinical controversy on whether incobotulinumtoxinA is interchangeable with onabotulinumtoxinA (OnaA). This study was conducted to assess in vivo and in vitro activity of 50 U, 100 U, and 200 U vials of IncoA in relation to 100 U OnaA product. Methods: 50 U, 100 U, and 200 U vials of IncoA and 100 U OnaA were diluted and tested at equal botulinum toxin type A product label activity units in 4 distinct assays: rat compound muscle action potential (CMAP), mouse digit abduction score (DAS), cell-based potency assay (CBPA), and light chain activity (LCA) assay. Results: Multiple orthogonal assays demonstrated that the biological activity of Merz Units is less than Allergan Units. Higher doses of IncoA were required to cause 50% inhibition (ID50) in the CMAP assay, demonstrating that OnaA displays greater biological activity compared to IncoA. Superior biological activity was displayed by OnaA in the DAS assay demonstrating statistical differences between OnaA and IncoA. CMAP and DAS data were corroborated by CBPA data. Additionally, greater light chain activity was displayed by 100 U OnaA when evaluated against 50 U, 100 U, and 200 U IncoA. Light chain activities of 50 U, 100 U, and 200 U products were approximately 50% of predicted values. No atypical cleavage products were observed when testing any of the IncoA products, which differs from previous 50 U and 100 U results, and suggests that changes have been made to the product. Conclusions: Data from 4 different assays establish that, on a unit for unit basis, OnaA displays greater biological activity than IncoA confirming that
Abstracts / Toxicon 123 (2016) S2eS90
units of OnaA and IncoA are not interchangeable. Data presented here emphasize that non-interchangeability and product-specific potency must be considered when dosing patients.
DAS fold increase in units required for comparable OnaA ED50 Value N¼3
CBPA fold increase in units required for comparable OnaA EC50 Value N¼2, N¼3c
LCA % of 100 U OnaA light chain values N¼3c
50 U 2.0, 2.1, 1.4 IncoA b(P¼0.032)
Not Tested
1.2, 1.2
100 U 1.6, 1.6, 1.2 IncoA b(P¼0.077)
Not Tested
1.6, 1.6, 0.9 b (P¼0.254)
200 U 1.5, 2.0, 1.2 IncoA b(P¼0.234)
1.7 b(P¼<0.001)
1.4, 1.3
26% of 100 U OnaA b (P¼0.0001) 53% of 100 U OnaA b (P¼0.0008) 95% of 100 U OnaA b (P¼0.3129)
CMAP fold increase in units required for comparable OnaA ID50 valuea N¼3
a
Unpaired 2-tailed t-test for all test results (N¼9, P¼0.005). Unpaired 2-tailed t-test. c Predicted LCA values for 50 U, 100 U, and 200 U IncoA would be 50%, 100%, and 200%, respectively, if OnaA and IncoA units were interchangeable. b
Keywords: CBPA; CMAP; DAS; IncobotulinumtoxinA; OnabotulinumtoxinA 25. BOTULINUM NEUROTOXIN (BONT) IN PARKINSONISM: THE WHEN, HOW, AND WHICH FOR BONT INJECTIONS Francisco Cardoso. Movement Disorders Unit, Neurology Service, UFMG, Av Pasteur 89/1107, Belo Horizonte, MG, 30150-290, Brazil. E-mail address:[email protected] The core clinical feature of Parkinson’s disease (PD), the most common cause of parkinsonism, is bradykinesia in association with at least one of the following features: tremor, rigidity, and postural instability. The mainstays of PD treatment are the use of pharmacological agents, rehabilitation techniques and, in selected cases, surgery. There are some other features, however, that can be successfully treated with BoNT injections. A significant proportion of PD patients present with sialorrhea that is refractory to clinical treatment. Controlled trials of intraglandular injections of both BoNT A and B show that this is an effective and safe treatment for drooling in PD. Dystonia is also often seen in PD patients, where the most common types are blepharospasm, apraxia of eyelid opening, oromandibular dystonia, and foot dystonia. In most instances, the latter is a feature of the disease whereas the others are commonly part of the spectrum of levodopa-induced dyskinesias. If these forms of dystonia fail to respond to conventional PD treatment, clinical practice shows that they can be successfully controlled with BoNT injections. There is, however, a need for controlled trials to support the effectiveness of BoNT in this scenario. Finally, urinary urgency or incontinence caused by overactive detrusor is seen in at least 30% of PD patients. Several open-label studies show that intradetrusor injections of BoNT provide a 6-month improvement of the urinary incontinence. There are also rare causes of parkinsonism with features amenable to treatment with BoNT injections. Many individuals with Progressive Supranuclear Palsy (PSP) present with focal dystonias treatable with BoNT injections. Among them, the most common form is eyelid dystonia, often referred to as apraxia of eyelid opening. Corticobasal syndrome, an uncommon atypical parkinsonism, typically causes painful hand dystonia that can be treated with BoNT injections. 26. SAFETY AND DURATION OF SEVERITY REDUCTION IN GLABELLAR LINES FOLLOWING AN INJECTION OF DAXIBOTULINUMTOXINA: RESULTS OF BELMONT STUDY Jean Carruthers a, Steve Yoelin b, Carol Y. Chung c, *, Roman G. Rubio c. Department of Ophthalmology and Visual Sciences, University of British
a
Columbia, Vancouver, BC, Canada; Therapeutics, Newark, CA, USA
S11 b
Newport Beach, CA, USA;
c
Revance
* Corresponding author: Revance Therapeutics, 7555 Gateway Boulevard, Newark, CA, 94560, USA E-mail address:[email protected].
Introduction: Injectable daxibotulinumtoxinA (RT002) is composed of a purified 150-kDa botulinum toxin type A formulated without additives in a lyophilized powder containing a proprietary peptide excipient. Safety and duration of frown line reduction of RT002 at 20, 40 or 60 units (U) compared with placebo or onabotulinumtoxinA (onabot) 20 U were evaluated in this randomized, double-blind, multicenter study (ClinicalTrials.gov Identifier: NCT02303002). Methods: Adults 30-64 years of age with moderate-to-severe glabellar lines were randomized to receive a single injection of RT002 20, 40, or 60 U, placebo, or onabot, and were followed for 24-36 weeks. Duration of response was depicted with Kaplan-Meier curves and compared between arms using the log-rank test. Results: A total of 268 patients were included in the intent-to-treat analysis; 191 were included in the per-protocol (PP) analysis. In the PP analyses, response (defined as having a 1 point improvement in Investigator Global Assessment-Facial Wrinkle Severity [IGA-FWS]) assessments was achieved in 100% of RT002-treated subjects at Weeks 2, 4, and 8, and was maintained by half of the RT002 40 U subjects for 24 weeks. Conversely, the response rate in the onabot arm decreased gradually from 98% at Week 2 to 90% at Week 8, and 52% had lost the response by 19 weeks. Consistent results were found in PFWS and Global Aesthetic Improvement Scale (GAIS) assessments. Adverse events (AE) were predominantly localized, transient and mild, and none were serious. Treatment-related AEs were observed as follows: a severe migraine occurred in a RT002 20 U subject; the onabot arm had the highest rate of headache (13%), injection site erythema (9%) and injection site edema (4%); facial asymmetry was reported in 2%-4% of the RT002 subjects (all resolved in 2-11 days); and eyelid ptosis occurred in 4 RT002 60 U subjects and 1 onabot subject. Conclusions: RT002 40 U had the most favorable risk-benefit profile in the study. Compared to onabot, RT002 had a greater rate and duration of response. Keywords: Botulinum toxin; DaxibotulinumtoxinA; Glabellar frown lines 27. SAFETY AND TOLERABILITY OF ONABOTULINUMTOXINA IN THE TREATMENT OF FACIAL LINES: STATISTICAL META-ANALYSIS OF POOLED DATA FROM GLOBAL REGISTRATION STUDIES OF TREATMENT OF CROW’S FEET LINES AND GLABELLAR LINES IN MORE THAN 3900 PARTICIPANTS Jean Carruthers a,*, Mitchell F. Brin b, Koen De Boulle c, Steven Liew d, Alastair Carruthers a, Alexander Rivkin e, Yan Wu f, Irina Yushmanova b, Terry I. Boodhoo b, Kathy Zhuang b, Conor J. Gallagher b, Elisabeth Lee b. a University of British Columbia, Vancouver, BC, Canada; b Allergan plc, Irvine, CA, USA; c Aalst Dermatology Clinic, Aalst, Belgium; d Private Practice, Sydney, NSW, Australia; e Private Practice, Los Angeles, CA, USA; f Peking University First Hospital, Beijing, China * Corresponding author: University of British Columbia, 2329 West Mall, Vancouver, BC, V6T 1Z4, Canada. E-mail address:[email protected].
Objective: A meta-analysis of pre-2009 registration studies (N¼1678; Brin 2009) evaluated safety/tolerability of onabotulinumtoxinA for glabellar lines (GL) and crow’s feet lines (CFL). We pooled safety data from pre- and post-2009 registration studies, focusing on those in CFL and CFL+GL combined. Methods: Safety data were pooled for 3946 participants from 15 onabotulinumtoxinA studies. Of 3338 participants from 11 randomized, doubleblind, placebo-controlled (DBPC) studies, 2394 received onabotulinumtoxinA for GL (n¼665), CFL (n¼1324), and CFL+GL (n¼405); the remaining participants received placebo. A total exposure (TE) population included onabotulinumtoxinA-treated participants (n¼3189) from the DBPC studies plus 4 wherein all participants received onabotulinumtoxinA. Results: Participants in the DBPC population were predominantly Caucasian (59.9%), Asian (33.6%), and female (85.1%); median age was 47.0 (21.885.0) years. Age and gender demographics were similar for DBPC studies in