Safety, Pharmacodynamic Response, and Treatment Satisfaction With OnabotulinumtoxinA 40 U, 60 U, and 80 U in Subjects With Moderate to Severe Dynamic Glabellar Lines.

BACKGROUND: OnabotulinumtoxinA 20 U reduces glabellar line (GL) severity at maximum frown for approximately 3 to 4 months. Small studies have suggested that >20-U doses may increase the efficacy and duration of response for GLs. OBJECTIVES: The aim of this study was to evaluate safety, pharmacodynamic response, and treatment satisfaction with onabotulinumtoxinA doses ≥20 U for GLs. METHODS: This 48-week, double-blind study compared 40, 60, and 80 U onabotulinumtoxinA vs 20 U and placebo in women with moderate or severe dynamic GLs on the Allergan Facial Wrinkle Scale. The following parameters were evaluated: the percentage of subjects with investigator-assessed ≥1-grade Facial Wrinkle Scale improvement from baseline at maximum frown (responders) at Week 24; the estimated median duration of response; the proportion of mostly/very satisfied responders on the Facial Line Satisfaction Questionnaire follow-up Items 1 to 5; and treatment-emergent adverse events. RESULTS: The modified intent-to-treat population (N = 226) had a mean age of 48.0 years, with similar baseline GL severity between treatment groups. Week 24 responder rates were 0% for placebo and 16.0%, 32.0%, 30.6%, and 38.5% for onabotulinumtoxinA 20, 40, 60, and 80 U, with significant (P < 0.05) differences for 40 and 80 U vs 20 U. Median duration of response was longer with all higher doses vs 20 U (≥24.0 vs 19.7 weeks; P < 0.05 vs 20 U at Week 24). Facial Line Satisfaction Questionnaire results indicated high subject satisfaction. The incidence and severity of treatment-emergent adverse events did not exhibit a dose-response effect. CONCLUSIONS: GL treatment with onabotulinumtoxinA doses >20 U demonstrated longer duration of response and higher patient-reported satisfaction vs the on-label 20-U dose with no apparent impact on safety variables.

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.

Real-World Dosing of OnabotulinumtoxinA and IncobotulinumtoxinA for Cervical Dystonia and Blepharospasm: Results from TRUDOSE and TRUDOSE II.

The real-world use of onabotulinumtoxinA and incobotulinumtoxinA for cervical dystonia and blepharospasm treatment was assessed in two separate retrospective studies using identical protocols (TRUDOSE and TRUDOSE II). The studies were conducted in Mexico, Norway, and United Kingdom and designed to evaluate dose utilization of the two botulinum toxins in clinical practice. Eighty-three patients treated with both onabotulinumtoxinA and incobotulinumtoxinA for ≥2 years for each botulinum toxin were included, (52, cervical dystonia; 31, blepharospasm). All patients switched from onabotulinumtoxinA to incobotulinumtoxinA for administrative/financial reasons. A range of dose ratios (incobotulinumtoxinA to onabotulinumtoxinA) was reported; with the majority of dose ratios being >1. The mean dose ratio was >1 regardless of the study site or underlying clinical condition. The inter-injection interval was significantly longer for onabotulinumtoxinA versus incobotulinumtoxinA when assessed for all patients (15.5 vs. 14.3 weeks; p = 0.006), resulting in fewer onabotulinumtoxinA treatments over the study time period. Consistent with product labeling, no single fixed-dose ratio exists between incobotulinumtoxinA and onabotulinumtoxinA. The dosage of each should be individualized based on patient needs and used as per product labeling. These real-world utilization data may have pharmacoeconomic implications.

Real-World Assessment of Dexamethasone Intravitreal Implant in DME: Findings of the Prospective, Multicenter REINFORCE Study.

BACKGROUND AND OBJECTIVE: Dexamethasone intravitreal implant (DEX) (Ozurdex; Allergan plc, Dublin, Ireland) is approved for the treatment of diabetic macular edema (DME). This study assessed the real-world effectiveness, safety, and reinjection interval of DEX in adult patients with DME. PATIENTS AND METHODS: This was a phase 4, prospective, multicenter (18 U.S. sites), observational study. RESULTS: The study population comprised 177 patients (180 eyes; 93.8% previously treated). Baseline mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were 54.4 letters and 424.6 µm, respectively. DEX was administered as monotherapy or with other DME therapy (55%/45%). The mean reinjection interval was 5.0 months. Mean maximum BCVA change from baseline after the first three DEX injections was +9.1 letters, +7.7 letters, and +7.0 letters, respectively (P < .001); 36.0% of eyes achieved 15-letter or greater BCVA improvement. Mean maximum CRT change from baseline was -137.7 µm (P < .001). CONCLUSION: DEX used alone or with other DME therapy improved visual and anatomic outcomes in DME patients in clinical practice, with no new safety concerns. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:425-435.].

Botulinum toxin type A products are not interchangeable: a review of the evidence.

Botulinum toxin type A (BoNTA) products are injectable biologic medications derived from Clostridium botulinum bacteria. Several different BoNTA products are marketed in various countries, and they are not interchangeable. Differences between products include manufacturing processes, formulations, and the assay methods used to determine units of biological activity. These differences result in a specific set of interactions between each BoNTA product and the tissue injected. Consequently, the products show differences in their in vivo profiles, including preclinical dose response curves and clinical dosing, efficacy, duration, and safety/adverse events. Most, but not all, published studies document these differences, suggesting that individual BoNTA products act differently depending on experimental and clinical conditions, and these differences may not always be predictable. Differentiation through regulatory approvals provides a measure of confidence in safety and efficacy at the specified doses for each approved indication. Moreover, the products differ in the amount of study to which they have been subjected, as evidenced by the number of publications in the peer-reviewed literature and the quantity and quality of clinical studies. Given that BoNTAs are potent biological products that meet important clinical needs, it is critical to recognize that their dosing and product performance are not interchangeable and each product should be used according to manufacturer guidelines.

Bimatoprost/timolol fixed combination versus latanoprost in treatment-naïve glaucoma patients at high risk of progression: a pilot study.

OBJECTIVE: To compare a fixed combination of 0.03% bimatoprost and 0.5% timolol (BTFC) with latanoprost monotherapy (LM) in treatment-naïve patients with open-angle glaucoma (OAG) and risk factors for glaucomatous progression. METHODS: Patients were enrolled at 15 sites in Spain and Portugal, and were randomized 1:1 to BTFC or LM. Patients instilled one drop of medication once per day at 8 pm for 12 weeks. The primary outcome was change in intraocular pressure (IOP) at 12 weeks. RESULTS: Of 81 patients enrolled, 43 were randomized to BTFC and 38 to LM. Mean (SD) change in IOP from baseline to 12 weeks was significantly greater for BTFC than for LM: -13.5 mmHg (4.48) versus -11.4 mmHg (3.19), respectively (P=0.003). Similarly, at 12 weeks, significantly more BTFC patients than LM patients had IOP reductions of ≥40% (74.4% versus 47.4%, P=0.015) or ≥50% (46.5% versus 15.8%, P=0.003). Adverse events were more frequent with BTFC than with LM (33 versus 13 events), but most were mild in severity. The only serious adverse event (colon cancer) was adjudged unrelated to the study medication. CONCLUSION: BTFC was effective and well tolerated in treatment-naïve patients with OAG at high risk of progression.

A combined analysis of five observational studies evaluating the efficacy and tolerability of bimatoprost/timolol fixed combination in patients with primary open-angle glaucoma or ocular hypertension.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of a fixed combination of bimatoprost 0.03% and timolol (BTFC) in a clinical setting, in a large sample of patients with primary open-angle glaucoma or ocular hypertension and insufficient intraocular pressure (IOP) lowering on prior therapy. METHODS: Patient data were combined (n = 5556) from five multicenter, observational, non-controlled, open-label studies throughout Europe. Patients were identified from 830 sites in Austria, France, Germany, The Netherlands, and Switzerland. Assessments were made at baseline, 6 weeks (in Austrian, German and Swiss centers), and 12 weeks in all centers. RESULTS: BTFC lowered mean IOP from baseline by 5.4 mmHg over the 12-week duration of the studies (P < 0.0001). At study entry, 92.9% of patients were receiving another ocular hypotensive medication. In patients with no previous treatment (n = 311), BTFC reduced IOP by -9.1 mmHg, corresponding to a reduction from baseline of 36.4% (P < 0.0001). In patients receiving prior therapy of a prostaglandin analog, a ß-blocker, or a fixed combination, BTFC reduced IOP by a further 24.5%, 25.9%, and 21.4%, respectively. The majority of patients (90.3%) reported no adverse events. The most common adverse events were conjunctival hyperemia (3.2%) and eye irritation (2.8%). BTFC was rated as "good" or "very good" by 92.5% of physicians and 88.0% of patients. Most patients (96.3%) were equally or more compliant with BTFC than with their previous treatment. CONCLUSION: In routine clinical practice, BTFC achieved consistent IOP lowering in both previously treated and untreated patients with primary open-angle glaucoma or ocular hypertension. BTFC was associated with significant IOP reductions, good tolerability, and good compliance.