The Role of Biosimilars in Patient Access to Therapeutic Antibodies for Immune Mediated Inflammatory Diseases.

BACKGROUND: Biosimilars have the potential to create competition, lower costs, and increase patient access to biological medications. However, biological medications are sensitive to their manufacturing processes and difficult to precisely characterize, leading to questions about substitution and interchangeability among products. METHODS: This article reviews the role of biosimilars in patient access to therapeutic antibodies. RESULTS: Although pathways for the approval of biosimilars have been developed, important issues remain unresolved. Interchangeability, or the designation of one medicine as clinically similar to and/or substitutable for another, is specified in some countries but restricted or awaiting policy resolution in others. Non-medical switching, or the switching among biological medications to select a less expensive product, for reasons unrelated to patient health and safety, is controversial because of the potential for complications related to repeated switching (e.g., immunogenicity and loss of therapeutic effect), and transfer of prescribing responsibility for patient medications from the physician to the insurance company. Although biosimilars have different names in different countries, the World Health Organization (WHO) calls for nomenclature that incorporates the international nonproprietary name of the original biological medication followed by a distinguishing suffix qualifier. Naming consistency across countries seems sensible, and adoption of the WHO recommended suffix would greatly simplify pharmacovigilance. CONCLUSIONS: Support for the WHO proposal is advised by numerous stakeholders, and resolution of the remaining outstanding issues is urged so that patients and physicians can safely access biosimilars.

Regenerative Medicine: Charting a New Course in Wound Healing.

Significance: Chronic wounds are a prevalent and costly problem in the United States. Improved treatments are needed to heal these wounds and prevent serious complications such as infection and amputation. Recent Advances: In wound healing, as in other areas of medicine, technologies that have the potential to regenerate as opposed to repair tissue are gaining ground. These include customizable nanofiber matrices incorporating novel materials; a variety of autologous and allogeneic cell types at various stages of differentiation (e.g., pluripotent, terminally differentiated); peptides; proteins; small molecules; RNA inhibitors; and gene therapies. Critical Issues: Wound healing is a logical target for regenerative medicine due to the accessibility and structure of skin, the regenerative nature of healing, the lack of good limb salvage treatments, and the current use of cell therapies. However, more extensive knowledge of pathophysiologic targets is needed to inform regenerative strategies, and new technologies must demonstrate value in terms of outcomes and related health economic measures to achieve successful market access and penetration. Future Directions: Due to similarities in cell pathways and developmental mechanisms, regenerative technologies developed in one therapeutic area may be applicable to others. Approaches that proceed from human genomic or other big data sources to models are becoming increasingly common and will likely suggest novel therapeutic avenues. To fully capitalize on the advances in regenerative medicine, studies must demonstrate the value of new therapies in identified patient populations, and sponsors must work with regulatory agencies to develop appropriate dossiers supporting timely approval.

Interactions between cell adhesion and the synaptic vesicle cycle in Parkinson's disease.

Synaptic dysfunction has been identified as an early neuropathologic event in Parkinson's disease. Synapses depend critically on the adhesion of neurons to one another, glial cells, and the extracellular matrix. Cell-cell and cell-matrix adhesions regulate the structure and function of synapses, in part, through interactions with structural elements such as actin and microtubule proteins. These proteins are critical not only for neuronal structure and polarity, but also for the synaptic vesicle cycle, including maintenance of and transfer between vesicle pools, exocytosis, and vesicle recycling. Pathway analyses of genome wide association studies (GWAS) in Parkinson's disease have identified frequent single nucleotide polymorphisms (SNPs) in cell adhesion pathways, suggesting that dysfunction in cell adhesion may play a role in disease pathology. Based on these observations, it may be hypothesized that Parkinson's disease is due to synaptic dysfunction caused by genetic variations in cell adhesion pathways that affect actin and/or microtubule-mediated events in the synaptic vesicle cycle. Furthermore, it is hypothesized that cells with pacemaker-like activity-a characteristic of neurons that degenerate in Parkinson's disease-may depend more on actin for recruiting synaptic vesicles for release than do less active neurons, thereby enhancing their sensitivity to SNPs in cell adhesion pathways and explaining the selectivity of neurodegeneration. Cells may ultimately die due to detachment from the extracellular matrix. This hypothesis suggests that further exploration of cell adhesion pathways and their linkage to neurotransmitter release through cell structural proteins such as actin and microtubules may provide important insights into Parkinson's disease.

The South American Glabellar Experience Study (SAGE): a multicenter retrospective analysis of real-world treatment patterns following the introduction of incobotulinumtoxinA in Argentina.

BACKGROUND: IncobotulinumtoxinA was approved in Argentina in 2007 for the treatment of moderate to severe glabellar lines. OBJECTIVE: The authors evaluate real-world changes in facial aesthetic treatment patterns and patient satisfaction following the introduction of incobotulinumtoxinA in Argentina. METHODS: This multicenter, retrospective chart review conducted in Argentina included women who had received at least 2 treatment cycles of onabotulinumtoxinA (Allergan, Irvine, California) for glabellar lines (period 1) prior to switching to incobotulinumtoxinA (Merz Pharma, GmbH, Frankfurt, Germany (period 2). Subjects were given the option to continue with incobotulinumtoxinA treatments (captured in period 2) or switch back to onabotulinumtoxinA (documented as period 3). Medical records were reviewed for demographics, dosing, reason for switching between products, treatment satisfaction, and interval between injection cycles. RESULTS: One hundred ten women were enrolled and collectively received 662 treatment cycles with botulinum toxin. Subjects were switched to incobotulinumtoxinA at unit doses that were numerically and statistically similar to the onabotulinumtoxinA doses they received in period 1. Most subjects (92%) initially switched to incobotulinumtoxinA because of lower cost. Ninety-two subjects (84%) switched back to onabotulinumtoxinA in period 3, most commonly due to insufficient duration of effect with incobotulinumtoxinA (61/92; 66%). Subjects reported satisfaction with treatment in >90% of their onabotulinumtoxinA visits and in 34% of their incobotulinumtoxinA visits. Median interinjection intervals with onabotulinumtoxinA were 180.3 days (period 1) and 176.9 days (period 3) and 144.3 days with incobotulinumtoxinA in period 2. CONCLUSIONS: In this real-world setting, subjects did not appear to perceive the same facial aesthetic benefits from incobotulinumtoxinA as onabotulinumtoxinA when the products were administered at comparable doses.

Five-year weight loss experience of outpatients receiving laparoscopic adjustable gastric band surgery.

BACKGROUND: This study evaluated the efficacy and safety of laparoscopic adjustable gastric banding (LAGB) in a large cohort of morbidly obese patients followed for up to 5 years. METHODS: Morbidly obese patients, ≥ 16 years of age, who underwent LAGB surgery at the Surgical Weight Loss Clinic in Ontario, Canada, between May 2005 and January 2011 were eligible for this retrospective chart review. Electronic files were searched to identify all patients who met the inclusion/exclusion criteria. Demographics, weights at baseline and follow-up visits (up to 60 months following surgery), and post-operative complications were documented. As follow-up visits occurred at unevenly spaced intervals within and across patients, modeling methods were used to more accurately assess mean % weight loss (WL) and % excess weight loss (EWL) over time. RESULTS: This study included 2,815 patients (82 % female, mean age 43 years, mean baseline BMI 44.6 kg/m(2)) followed for a mean of 21.8 ± 15.4 months. Complications developed in 238 patients (8.5 %), the most frequent being prolapse/slippage (4.2 %), tubing/access port problems (1.2 %), and explantation (1.2 %). Mean %WL and %EWL progressed continuously over the first 2.5 years post-LAGB, plateauing at 20 and 49 %, respectively, for up to 5 years of follow up. Factors associated with increased weight loss were time since surgery, greater baseline weight (excess weight), older age at time of surgery, and male gender. CONCLUSIONS: Weight loss was maintained for up to 5 years in our population of patients who underwent LAGB for the treatment of morbid obesity.

A randomised, double-blind comparison of 20 units of onabotulinumtoxinA with 30 units of incobotulinumtoxinA for glabellar lines.

BACKGROUND: Biological activity data indicate that the units of incobotulinumtoxinA are not equivalent to those of onabotulinumtoxinA. OBJECTIVE: This study compared 20 units of onabotulinumtoxinA with 30 units of incobotulinumtoxinA in the treatment of glabellar lines. METHODS AND MATERIALS: In this multicenter, randomised, double-blind study, subjects with moderate or severe glabellar lines received a single treatment with 20 units of onabotulinumtoxinA (n = 112), or 30 units of incobotulinumtoxinA (n = 112). The primary endpoint was the percentage of subjects with a reduction of ≥ 1 point on the Facial Wrinkle Scale at maximum contraction as rated by injectors on day 28 post injection. The same variable was evaluated on days 84, 98, and 112. RESULTS: At the primary endpoint, 20 units of onabotulinumtoxinA was as effective as 30 units of incobotulinumtoxinA (96% vs. 95% responders, respectively; difference in proportion of responders = 0.02, 95% confidence interval [CI] - 0.04, 0.07). At subsequent time points, a trend towards a higher percentage of responders was observed in the group treated with 20 units of onabotulinumtoxinA. Given that the 95% CI surpassed the upper equivalence margin at these time points, equivalence was not established. CONCLUSION: These data support the non-interchangeability of units of onabotulinumtoxinA and incobotulinumtoxinA, and the absence of a fixed dose ratio in clinical practice.

Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications.

This meta-analysis evaluated the frequency of neutralizing antibody (nAb) conversion with onabotulinumtoxinA (BOTOX®; Allergan) across five studied indications. The analysis was based on large, controlled or prospective, open-label trials (durations 4 months to ≥2 years). Serum samples were analyzed for nAbs using the Mouse Protection Assay. Subjects who were antibody negative at baseline and had at least one analyzable postbaseline antibody assay result were included. The 16 clinical studies included 3,006 subjects; of these, 2,240 met the inclusion criteria for this analysis. Subjects received 1-15 treatments (mean 3.8 treatments) with onabotulinumtoxinA. Total doses per treatment cycle ranged from 10 or 20 units in glabellar lines to 20-500 units in cervical dystonia. The numbers of subjects who converted from an antibody-negative status at baseline to antibody-positive status at any post-treatment time point were: cervical dystonia 4/312 (1.28%), glabellar lines 2/718 (0.28%), overactive bladder 0/22 (0%), post-stroke spasticity 1/317 (0.32%), and primary axillary hyperhidrosis 4/871 (0.46%). Across all indications, 11/2,240 subjects (0.49%) converted from antibody negative at baseline to positive at one or more post-treatment time points, but only three subjects became clinically unresponsive to onabotulinumtoxinA at some point following a positive assay. Based on these large trials, the frequency of antibody conversion after onabotulinumtoxinA treatment is very low, and infrequently leads to loss of efficacy. © 2010 Movement Disorder Society.

Laparoscopic gastric banding is safe in outpatient surgical centers.

BACKGROUND: Due to constraints on resources and capacity, as well as advances in surgical technique and care, there has been progressive change toward converting surgical procedures to the outpatient setting when feasible. This study was designed to investigate the safety of laparoscopic adjustable gastric banding (LAGB) as an outpatient procedure for morbid obesity in Canada. METHODS: This retrospective analysis included consecutive patients who underwent outpatient LAGB at the Surgical Weight Loss Centre in Ontario, Canada, beginning with our initial experience in February 2005 and continuing to July 2009. Eligible patients were morbidly obese adults whose outpatient clinic surgery had been performed by one of two experienced surgeons. RESULTS: A total of 1,641 patients were included in this analysis. The average presurgical body mass index was 46.7 kg/m2 (range 35.0 to 79 kg/m2). Fifteen patients (0.91%) experienced minor complications during surgery or within 30 days of surgery (dysphagia, n=5; wound infection, n=3; port infection, n=2; all other complications occurred in one patient each). Four patients required transfer to hospital from the clinic on the day of surgery, and three were admitted. None of the complications were serious and all were resolved. The device was explanted in two patients. The average time from sedation to discharge was <4 hours (h). CONCLUSIONS: The ability to treat patients within 4 h and the extremely low complication rates reported here contribute to a growing literature supporting the safe performance of LAGB in an outpatient setting for the treatment of morbid obesity.

Does smoking reduce the risk of Parkinson's disease through stimulation of the ubiquitin-proteasome system?

Parkinson's disease is a neurodegenerative condition characterized by tremor, rigidity, bradykinesia, and postural instability. Smoking is an inverse risk factor for Parkinson's disease, although the mechanism for this apparent neuroprotection is not definitively established. Smoking consistently upregulates nicotinic acetylcholine receptor levels in various brain regions known to be involved in Parkinson's disease. The ubiquitin-proteasome system--the system that tags and removes unwanted, misfolded, or damaged proteins from cells--regulates nicotinic receptor levels. The ubiquitin-proteasome system has also been implicated in Parkinson's disease, with aberrant activity identified in both sporadic and familial forms of the disease. The involvement of the ubiquitin-proteasome system in nicotinic receptor regulation and Parkinson's disease pathology suggests a link between the two, which forms the basis of the present hypothesis. Specifically, this paper considers the hypothesis that smoking reduces the risk of Parkinson's disease through the upregulation of nicotinic cholinergic receptors in key brain regions involved in Parkinson's disease. This receptor upregulation is hypothesized to increase activity of the ubiquitin-proteasome system, which is believed to prevent neurodegeneration caused by the accumulation of misfolded or damaged proteins or other consequences of inadequate protein sequestration and/or degradation. This hypothesis is supported by evidence documenting the upregulation of nicotinic receptors in the brains of smokers, neuroprotective effects of nicotine, reduced activity of the ubiquitin-proteasome in Parkinson's disease, and increased activity of the ubiquitin-proteasome system in animals exposed to chronic nicotine. Additional research is needed to test several predictions of the hypothesis, including increased activity of the ubiquitin-proteasome system in key brain regions of smokers.

Comparison of botulinum neurotoxin preparations for the treatment of cervical dystonia.

BACKGROUND: Comparative studies of botulinum neurotoxin preparations to date have generally examined 2 preparations at prespecified dose ratios in relatively homogeneous groups of patients under controlled study conditions. It is unclear whether the differences in adverse-event rates that have been noted under these controlled conditions can be generalized to the broader population of cervical dystonia patients, who are treated with a wider range of doses in a variety of settings. OBJECTIVE: We conducted a systematic review and analysis of the published literature to compare rates of dysphagia and dry mouth in studies of botulinum neurotoxin products. METHODS: We searched the MEDLINE, EMBASE, Biosis, SciSearch, JICST (Japan Science and Technology Center), and Pascal databases from 1985 through 2006 using the terms cervical dystonia, spasmodic torticollis, and botulinum toxin for original English-language studies of Botox, Dysport, or Myobloc in the treatment of cervical dystonia (or spasmodic torticollis) that documented adverse events by treatment or patient. Studies that involved patients with various types of dystonias or movement disorders were included as long as adverse events were reported separately for those with cervical dystonia. Rates of dysphagia with the original preparation of Botox were considered separately from those with the current preparation of Botox. RESULTS: Seventy published articles were included in the analysis (30 Botox, 24 Dysport, 3 Botox + Dysport, 11 Myobloc, 2 Botox + Myobloc). Mean total doses per treatment ranged from 60 to 374 U for Botox, 125 to 1200 U for Dysport, and 579 to 19,853 U for Myobloc. Botox was associated with a significantly lower rate of dysphagia than Dysport, with mean dysphagia rates of 10.5% for original Botox, 8.9% for current Botox, and 26.8% for Dysport (both, P < 0.05). Myobloc was associated with dry mouth (3.2%-90.0%) in 9 of 13 studies, but this adverse event was not reported in a sufficient number of studies of botulinum toxin type A preparations (Botox, n = 2; Dysport, n = 6) to permit statistical comparison. In the weighted analysis, the duration of effect differed between botulinum neurotoxin products (current Botox > Myobloc > original Botox > Dysport; all, P < 0.001), but only 43 (61.4%) of the 70 studies reported duration, and the definitions varied. CONCLUSION: The results of this analysis indicate differences in adverse-event rates between botulinum neurotoxin preparations, suggesting that use of these products should be based on their individual dosing, efficacy, and safety profiles.

Extracellular glutamate decrease in accumbens following cued food delivery.

This study examined the effects of cued vs non-cued food delivery/consumption on extracellular glutamate and dopamine in the nucleus accumbens of food-deprived rats. Animals that always received a food pellet following a series of auditory tones showed a significant decrease in extracellular glutamate following food consumption, whereas animals that had not been previously exposed to tone-food pairing did not (p<0.05). In contrast, extracellular dopamine was significantly increased in the nucleus accumbens during the first time period after food consumption (p<0.05) regardless of whether animals had been exposed to prior tone-food pairing. Results suggest that food delivery/consumption is associated with a decrease in accumbal glutamate if food delivery has been previously paired with predictive environmental cues.