Update on Non-Interchangeability of Botulinum Neurotoxin Products.

The growing use of botulinum neurotoxins (BoNTs) for medical and aesthetic purposes has led to the development and marketing of an increasing number of BoNT products. Given that BoNTs are biological medications, their characteristics are heavily influenced by their manufacturing methods, leading to unique products with distinct clinical characteristics. The manufacturing and formulation processes for each BoNT are proprietary, including the potency determination of reference standards and other features of the assays used to measure unit potency. As a result of these differences, units of BoNT products are not interchangeable or convertible using dose ratios. The intrinsic, product-level differences among BoNTs are compounded by differences in the injected tissues, which are innervated by different nerve fiber types (e.g., motor, sensory, and/or autonomic nerves) and require unique dosing and injection sites that are particularly evident when treating complex therapeutic and aesthetic conditions. It is also difficult to compare across studies due to inherent differences in patient populations and trial methods, necessitating attention to study details underlying each outcome reported. Ultimately, each BoNT possesses a unique clinical profile for which unit doses and injection paradigms must be determined individually for each indication. This practice will help minimize unexpected adverse events and maximize efficacy, duration, and patient satisfaction. With this approach, BoNT is poised to continue as a unique tool for achieving individual goals for an increasing number of medical and aesthetic indications.

Pain, disability, and quality of life in participants after concurrent onabotulinumtoxinA treatment of upper and lower limb spasticity: Observational results from the ASPIRE study.

INTRODUCTION: Upper and lower limb spasticity is commonly associated with central nervous system disorders including stroke, traumatic brain injury, multiple sclerosis, cerebral palsy, and spinal cord injury, but little is known about the concurrent treatment of upper and lower limb spasticity with botulinum toxins. OBJECTIVE: To evaluate onabotulinumtoxinA (onabotA) utilization and to determine if concurrent onabotA treatment of the upper and lower limbs has supported improvements in participants with spasticity. DESIGN: Sub-analysis of a 2-year, international, prospective, observational registry (ASPIRE, NCT01930786). SETTING: International clinic sites (54). PARTICIPANTS: Adult spasticity participants across etiologies, who received ≥1 concurrent onabotA treatment of the upper and lower limbs during the study. INTERVENTION: Participants were treated with onabotA at the clinician's discretion. OUTCOMES: Baseline characteristics and outcomes of disability (Disability Assessment Scale [DAS]), pain (Numeric Pain Rating Scale [NPRS]), participant satisfaction, physician satisfaction, and quality of life (QoL; Spasticity Impact Assessment [SIA]) were evaluated. Adverse events were monitored throughout the study. RESULTS: Of 744 participants enrolled, 730 received ≥1 dose of onabotA; 275 participants received treatment with onabotA in both upper and lower limbs during ≥1 session; 39.3% of participants were naïve to onabotA for spasticity. The mean (SD) total dose per treatment session ranged from 421.2 (195.3) to 499.6 (188.6) U. The most common baseline upper limb presentation was clenched fist (n = 194, 70.5%); lower limb was equinovarus foot (n = 219, 66.9%). High physician and participant satisfaction and improvements in pain, disability and QoL were reported after most treatments. Nine participants (3.3%) reported nine treatment-related adverse events; two participants (0.7%) reported three serious treatment-related severe adverse events. No new safety signals were identified. CONCLUSION: More than a third of enrolled participants received at least one concurrent onabotA treatment of the upper and lower limbs, with reduced pain, disability, and improved QoL after treatment, consistent with the established safety profile of onabotA for the treatment of spasticity.

Real-world differences in dosing and clinical utilization of OnabotulinumtoxinA and AbobotulinumtoxinA in the treatment of upper limb spasticity.

According to prescribing information, potency units are not interchangeable between botulinum toxin A products. This exploratory study compared real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA in adults with upper limb spasticity. In this retrospective study, 101 clinicians provided chart data via online surveys for 215 US post-stroke patients treated for upper limb spasticity with ≥3 onabotulinumtoxinA or abobotulinumtoxinA doses (phase 1: 9/18/2020-12/10/2020; phase 2: 9/30/2021-12/7/2021). Most participating clinicians were physicians (70.3%) specializing in neurology (71.3%) or physiatry (20.8%). In the onabotulinumtoxinA (n = 107) and abobotulinumtoxinA (n = 108) groups, ∼75% of patients had moderate-to-severe spasticity. A range of onabotulinumtoxinA:abobotulinumtoxinA dose ratios (1:2.2 [95% CI: 1.8, 2.6] to 1:4.1 [95% CI: 3.0, 6.0]) was observed across muscles. For the most recent dose, mean number of muscles injected was greater for onabotulinumtoxinA (4.3) versus abobotulinumtoxinA (3.1; P = 0.0003). For onabotulinumtoxinA versus abobotulinumtoxinA, the proportion of injections was 81.3% versus 63.9% (P = 0.0067) in forearm muscles and 23.4% versus 3.7% (P = 0.0001) in hand muscles. Mean injection intervals were similar (onabotulinumtoxinA: 102.0 days; abobotulinumtoxinA: 99.1 days). Differences in real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA for upper limb spasticity were observed. There was no standard dose-conversion ratio, consistent with each product's prescribing information.

Efficacy and safety of an alternative onabotulinumtoxinA injection paradigm for refractory overactive bladder.

AIMS: In studies utilizing a 20-injection-site paradigm of onabotulinumtoxinA treatment for overactive bladder (OAB), some patients performed clean intermittent catheterization (CIC). An alternative injection paradigm of fewer injections targeting the lower bladder may reduce the need for CIC by maintaining upper bladder function. This study evaluated the efficacy and safety of an unapproved alternative 10-injection-site paradigm targeting the lower bladder. METHODS: In this phase 4, double-blind, parallel-group study, patients with OAB and urinary incontinence (UI) for ≥6 months with ≥3 episodes of urinary urgency incontinence (no more than 1 UI-free day) and ≥8 micturitions per day over 3 days during screening were randomized 2:1 to onabotulinumtoxinA 100 U or placebo injected at 10 sites in the lower bladder. RESULTS: Of 120 patients, 78 in the onabotulinumtoxinA group and 39 in the placebo group had efficacy assessments. In the double-blind phase, mean change from baseline at week 12 in daily frequency of UI episodes was greater with onabotulinumtoxinA (-2.9) versus placebo (-0.3) (least squares mean difference [LSMD]: -2.99, p < 0.0001). Achievement of 100% (odds ratio [OR]: 6.15 [95% confidence interval, CI: 0.75-50.37]), ≥75% (OR: 7.25 [2.00-26.29]), and ≥50% improvement (OR: 4.79 [1.87-12.28]) from baseline in UI episodes was greater with onabotulinumtoxinA versus placebo. Reductions from baseline in the daily average number of micturitions (LSMD: -2.24, p < 0.0001), nocturia (LSMD: -0.71, p = 0.0004), and urgency (LSMD: -2.56, p < 0.0001) were greater with onabotulinumtoxinA than with placebo. Treatment benefit was improved or greatly improved in the onabotulinumtoxinA group (74.0% of patients) versus placebo (17.6%) (OR: 13.03 [95% CI: 3.23-52.57]). Mean change from baseline in Incontinence Quality of Life score was greater with onabotulinumtoxinA versus placebo (LSMD: 24.2, p = 0.0012). Two of 78 (2.6%) patients in the onabotulinumtoxinA group used CIC during the double-blind period; no females used CIC during the double-blind period. Commonly reported adverse events (≥5%) were urinary tract infection (UTI), dysuria, and productive cough for both groups; rate of UTI was higher with onabotulinumtoxinA versus placebo. CONCLUSION: In patients treated with onabotulinumtoxinA for OAB with UI, an unapproved alternative injection paradigm targeting the lower bladder demonstrated efficacy over placebo, with a low incidence of CIC.

The Effects of Age, Gender, and Postvoid Residual Volume on Catheterization Rates After Treatment with OnabotulinumtoxinA for Overactive Bladder.

Background: Transient increases in postvoid residual urine volume (PVR) requiring clean intermittent catheterization (CIC) have occurred with onabotulinumtoxinA treatment for overactive bladder (OAB). Objective: To evaluate onabotulinumtoxinA safety and the effect of age, gender, and maximum PVR (PVRmax) on CIC initiation in adults with OAB and urinary incontinence (UI). Design setting and participants: This was a pooled post hoc analysis of four placebo-controlled, multicenter randomized trials that included adults with idiopathic OAB after first onabotulinumtoxinA treatment (NCT00910845, NCT00910520, NCT01767519, NCT01945489). Patients had at least three urgency UI episodes over 3 d and at least eight micturitions per day, had inadequate management with at least one anticholinergic agent, and were willing to use CIC. Outcome measurements and statistical analysis: We measured the following outcomes: PVRmax within 12 wk after first treatment; CIC incidence; estimated functional capacity; PVR ratio (PVR/estimated functional capacity). Results and limitations: Of 1504 patients, 87.7% were women and 88.8% were White. The mean age was 60.5 yr across 10-yr age groups, baseline PVR was 13.8-35.0 ml, and estimated functional capacity was 293.5-475.7 ml. Mean baseline PVR was 21.3 ml overall versus 34.0 ml in the group that started CIC. The CIC incidence was 6.2% for women (range 1.1-8.4%) and 10.5% for men (range 0-14.6%). Higher CIC rates were observed for PVRmax >350 ml (women 91.9%, men 84.6%) in comparison to PVRmax of 201-350 ml (women 32.5%, men 17.4%) and PVRmax <200 ml (women 1.2%, men 1.6%). Overall, 2/1504 patients (both women) were unable to void spontaneously. The mean PVR ratio was highest at week 2. Some subgroups had small sample sizes. Conclusions: CIC incidence was low overall, was less frequent for women, was rare with PVRmax ≤200 ml, and did not appear to correlate with baseline PVR. Patient summary: After onabotulinumtoxinA treatment for OAB, patients sometimes insert a catheter to help in emptying their bladder after urinating. In this study, few patients needed a catheter, especially when less urine volume remained after urination.

One treatment with onabotulinumtoxinA relieves symptoms of overactive bladder in patients refractory to one or more oral medications.

INTRODUCTION AND HYPOTHESIS: Patients with overactive bladder (OAB) often undergo prolonged treatment with one or more oral OAB medications. OnabotulinumtoxinA (onabotA), a type A botulinum toxin, may provide an appropriate alternative to oral treatments in patients intolerant of or refractory to one or more oral OAB medications. The GRACE study demonstrated real-world benefits of onabotA treatment for OAB in patients refractory to oral medications. This exploratory post hoc analysis of data from the GRACE study aims to determine if treatment history impacts benefit from treatment with onabotA. METHODS: This is a subanalysis of the GRACE study, a prospective observational study (NCT02161159) that enrolled patients with symptomatic OAB inadequately managed by at least one oral OAB medication. Patients had a treatment history of one or more anticholinergics (AC) and/or ß-3 adrenoreceptor agonists (ß-3) for relief of OAB; results were stratified according to treatment history. Patients in this analysis elected to discontinue oral medications upon treatment with onabotA. Safety was followed for 12 months in all patients that received at least 1 dose of onabotA; efficacy was determined over a 12-week period. RESULTS: Compared to baseline levels, significant reductions in urinary incontinence (UI), urgency, micturition, and nocturia were noted as early as 1 week and were sustained at 12 weeks, regardless of the type and number of oral medications taken before treatment with onabotA. At 12 weeks post-onabotA, the mean change from baseline UI episodes/day for those with a treatment history of only one AC was -2.4 (n = 43, p ≤ 0.001); more than one AC, -2.4 (n = 52, p ≤ 0.001); one ß-3, -3.3 (n = 12, p < 0.05); at least one AC and at least one ß-3, -3.2 (n = 56, p ≤ 0.001). Pad and liner use was significantly decreased at 12 weeks post-onabotA across all treatment history groups. Reductions in diaper pant use varied, with less of a reduction in patients with a treatment history of more than one AC compared to patients with a history of at least one AC and one ß-3 (p < 0.05) or those with a history of only one AC (p < 0.05). Overall, a total of 253/288 of patients (88%) reported improvements on the treatment benefit scale 12 weeks after treatment with onabotA, regardless of type and number of prior oral medications. In the population of patients that received at least one dose of onabotA (N = 504), 57 adverse events were reported in 38 patients (7.5%); 9 were serious (1.8%). Urinary retention was reported in 5 patients (1.0%); 1 was severe (0.2%). Symptomatic urinary tract infection was reported in 2 patients (0.4%). CONCLUSIONS: In this exploratory post hoc analysis of real-world data from the GRACE study, there were few significant differences in outcomes based on the type and number of prior oral medications. Thus, patients who are refractory to one or more oral OAB medications may benefit from earlier treatment with onabotA.

OnabotulinumtoxinA effects on trigeminal nociceptors.

BACKGROUND: OnabotulinumtoxinA (onabotA) is approved globally for prevention of chronic migraine; however, the classical mechanism of action of onabotA in motor and autonomic neurons cannot fully explain the effectiveness of onabotulinumtoxinA in this sensory neurological disease. We sought to explore the direct effects of onabotulinumtoxinA on mouse trigeminal ganglion sensory neurons using an inflammatory soup-based model of sensitization. METHODS: Primary cultured trigeminal ganglion neurons were pre-treated with inflammatory soup, then treated with onabotulinumtoxinA (2.75 pM). Treated neurons were used to examine transient receptor potential vanilloid subtype 1 and transient receptor potential ankyrin 1 cell-surface expression, calcium influx, and neuropeptide release. RESULTS: We found that onabotulinumtoxinA cleaved synaptosomal-associated protein-25 kDa in cultured trigeminal ganglion neurons; synaptosomal-associated protein-25 kDa cleavage was enhanced by inflammatory soup pre-treatment, suggesting greater uptake of toxin under sensitized conditions. OnabotulinumtoxinA also prevented inflammatory soup-mediated increases in TRPV1 and TRPA1 cell-surface expression, without significantly altering TRPV1 or TRPA1 protein expression in unsensitized conditions. We observed similar inhibitory effects of onabotulinumtoxinA on TRP-mediated calcium influx and TRPV1- and TRPA1-mediated release of calcitonin gene-related peptide and prostaglandin 2 under sensitized, but not unsensitized control, conditions. CONCLUSIONS: Our data deepen the understanding of the sensory mechanism of action of onabotulinumtoxinA and support the notion that, once endocytosed, the cytosolic light chain of onabotulinumtoxinA cleaves synaptosomal-associated protein-25 kDa to prevent soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated processes more generally in motor, autonomic, and sensory neurons.

Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation.

Imprime PGG (Imprime), an intravenously-administered, soluble ß-glucan, has shown compelling efficacy in multiple phase 2 clinical trials with tumor targeting or anti-angiogenic antibodies. Mechanistically, Imprime acts as pathogen-associated molecular pattern (PAMP) directly activating innate immune effector cells, triggering a coordinated anti-cancer immune response. Herein, using whole blood from healthy human subjects, we show that Imprime-induced anti-cancer functionality is dependent on immune complex formation with naturally-occurring, anti-ß glucan antibodies (ABA). The formation of Imprime-ABA complexes activates complement, primarily via the classical complement pathway, and is opsonized by iC3b. Immune complex binding depends upon Complement Receptor 3 and Fcg Receptor IIa, eliciting phenotypic activation of, and enhanced chemokine production by, neutrophils and monocytes, enabling these effector cells to kill antibody-opsonized tumor cells via the generation of reactive oxygen species and antibody-dependent cellular phagocytosis. Importantly, these innate immune cell changes were not evident in subjects with low ABA levels but could be rescued with exogenous ABA supplementation. Together, these data indicate that pre-existing ABA are essential for Imprime-mediated anti-cancer immune activation and suggest that pre-treatment ABA levels may provide a plausible patient selection biomarker to delineate patients most likely to benefit from Imprime-based therapy.

The importance of the Erk pathway in the development of linker for activation of T cells-mediated autoimmunity.

The ability of the transmembrane adaptor protein linker for activation of T cells (LAT) to regulate T cell development, activation, survival, and homeostasis depends upon phosphorylation of its multiple tyrosine residues. The mutation of tyrosine 136 on LAT abrogates its interaction with phospholipase C-γ1, causing severe ramifications on TCR-mediated signaling. Mice harboring this mutation, LATY136F mice, have significantly impaired thymocyte development; however, they rapidly develop a fatal lymphoproliferative disease marked by the uncontrolled expansion of Th2-skewed CD4(+) T cells, high levels of IgE and IgG1, and autoantibody production. In this study, we assessed the contribution of multiple signaling pathways in LATY136F disease development. The deletion of the critical signaling proteins Gads and RasGRP1 caused a further block in thymocyte development, but, over time, could not prevent CD4(+) T cell hyperproliferation. Also, restoring signaling through the NF-κB and NFAT pathways was unable to halt the development of disease. However, expression of a constitutively active Raf transgene enhanced lymphoproliferation, indicating a role for the Ras-MAPK pathway in LAT-mediated disease.