Context Data quantifying the impact of metreleptin therapy on survival in nonHIVrelated generalized lipodystrophy (GL) and partial lipodystrophy (PL) are unavailable. Objective This study aimed to estimate the treatment effect of metreleptin on survival in patients with GL and PL. Design/Setting/Patients Demographic and clinical characteristics were used to match metreleptin-treated and metreleptin-naïve patients with GL and PL. Differences in mortality risk were estimated between matched cohorts of metreleptin-treated and metreleptin-naïve patient cohorts using Cox proportional hazard models. Sensitivity analyses assessed the impact of study assumptions and robustness of results. Outcome Measures This study assessed time to mortality and risk of mortality. Results The analysis evaluated 103 metreleptin-naïve patients with characteristics matched to 103 metreleptin-treated patients at treatment initiation. Even after matching, some metabolic and organ abnormalities were more prevalent in the metreleptin-treated cohort due to bias toward treating more severely affected patients. A Cox proportional hazards model associated metreleptin therapy with an estimated 65% decrease in mortality risk (HR 0.348, 95% CI: 0.134-0.900; P = 0.029) even though the actual number of events were relatively small. Results were robust across a broad range of alternate methodological assumptions. Kaplan-Meier estimates of time to mortality for the metreleptin-treated and the matched metreleptin-naïve cohorts were comparable. Conclusions Metreleptin therapy was associated with a reduction in mortality risk in patients with lipodystrophy syndromes despite greater disease severity in treated patients, supporting the view that metreleptin can have a positive disease-modifying impact. Confirmatory studies in additional real-world and clinical datasets are warranted.

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Parkinson's disease psychosis (PDP) is a clinical condition that affects patients diagnosed with Parkinson's disease (PD) and has a spectrum of neuropsychiatric symptoms distinct from the hallmark motor symptoms. Although prior studies have reported on the prevalence of PDP in select European nations, variations in study design complicate study-to-study comparisons. In this study, we surveyed 1,667 medical practitioners across France, Germany, Italy, Spain, and the UK (collectively, the EU-5) to estimate the prevalence of PDP or symptoms of psychosis among patients with PD. Analysis of the survey data suggest approximately 29% of the general PD population in the EU-5 exhibit signs of PDP. Among the PD population, country-specific rates of PDP are estimated at 30% in France, 27% in Germany, 34% in Italy, 30% in Spain and 21% in the UK. These rates appear in line with those reported in prior country-specific studies. Results from the subset of 437 neurologists who proceeded to take the full survey suggest the symptoms of PDP are disruptive to patients or their respective caregivers in approximately 53% of cases. These results provide a resource that enables cross-country comparison of PDP rates across these major European nations.

Over half of patients with Parkinson’s disease (PD) develop symptoms of psychosis during the course of their disease. Existing guidelines include recommendations for managing symptoms of psychosis in patients with PD. However, the extent to which such recommendations translate to clinical practice in major European nations is unclear. The current study describes trends in the clinical management of patients diagnosed with PD psychosis (PDP) based on survey responses and patient chart reviews from 437 neurologists across France, Germany, Italy, Spain, and the UK (collectively, the EU-5). Surveyed neurologists reported that PDP typically manifests four or more years after the diagnosis of PD, with the most commonly reported initial symptoms being moderately disruptive visual hallucinations, agitation, and illusions/false sense of presence. PD medications adjustment was the most common first-line intervention, applicable to an estimated 59–79% of patients for the initial management of PDP depending on country. Responses from surveyed neurologists suggest PD medications adjustment is a temporary solution for many patients with PDP and that there is considerable variability in subsequent lines of intervention. The current report provides a resource for understanding the patterns of care and treatment for PDP across these major European nations.

Researchers at the University of Zurich and Polyphor Ltd. have developed protein epitope mimetics of the antimicrobial peptide protegrin I that specifically target Pseudomonas aeruginosa via a mechanism of action that is distinct from the membrane-disrupting activity of the parent compound. 1 The biotech expects its lead mimetic to enter Phase I testing this year to treat P. aeruginosa infections. P. aeruginosa, a Gram-negative bacterium, is a common cause of opportunistic nosocomial infections, and treatment usually involves a course of antibiotics. But the incidence of resistant strains is rising, resulting in the need for new treatments. 2,3 "Pseudomonas infections that have become multidrug resistant are being treated with polymyxin antibiotics like colistin, which were previously considered too toxic," said Robert Hancock, Canada research chair of the Department of Microbiology and Immunology at The University of British Columbia and director of the university's Centre for Microbial Diseases and Immunity Research. "But even there, we are already seeing strains that are resistant. " He added: "Pseudomonas may be an opportunistic pathogen, but it is causing about 160,000 infections in the U.S. annually. " Protegrin I is an antimicrobial protein, originally isolated from pigs, that induces pore formation in microbial membranes. 4 It has had a checkered clinical past. In 2004, IntraBiotics Pharmaceuticals Inc. (now Ardea Biosciences Inc.) dropped all development of iseganan. The biotech's synthetic version of protegrin I had failed two Phase III trials in oral mucositis, and a Phase II/III trial of the compound to prevent ventilatorassociated pneumonia (VAP) was terminated after an independent datamonitoring committee found higher rates of VAP and mortality in the treatment arm. Researchers at the University of Zurich and Polyphor now have shown that several of the biotech's protegrin I-derived protein epitope mimetics appear to kill P. aeruginosa through functional inhibition of its LPSassembly protein (ostA; lptD; imp), which is involved with incorporating LPS into the outer leaflet of the bacterium's outer membrane. By contrast to protegrin I's membrane-disrupting action, this approach impairs the bacterium's ability to generate its outer membrane in the first place. Polyphor's compounds are synthetic cyclic peptide-like molecules that mimic the β-hairpin and α-helix motifs in a protein's secondary structure comPanies anD institUtions mentioneD Ardea Biosciences Inc. (nasDaQ:rDea), san Diego, calif. PolyMedix Inc.

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Researchers at Duke University are developing a drug delivery technology that is designed to circumvent potential size limitations and manufacturing difficulties associated with pegylation.1 The technology still needs to be tested head-to-head versus pegylation.Pegylation involves attaching a polyethylene glycol (PEG) molecule to a protein or peptide. PEG molecules can reduce protein degradability, immunogenicity and elimination, and thus increase circulating half-life. However, controlling and tailoring pegylation reactions can be complicated and laborious for many proteins. The approach is hard to standardize, as the unique chemical and structural properties of each protein can impose restrictions on the placement and length of PEG molecules. Increasing the size of the polymer chain will increase a protein's half-life, but larger chains are usually more difficult to attach.There also is a trade-off between increased PEG size and reduced biological activity. Finally, the reaction process or protein often needs to be modified to prevent unwanted interactions between the PEG molecules and certain amino acids.The Duke team opted for a different approach: start small, have a single reaction site and use a different polymer. They modified the N-terminus of a protein and attached a small molecule that initiates the polymerization reaction. The modified terminus becomes the only location on the protein that can initiate the controlled growth of a poly(oligo(ethylene glycol) methyl ether methacrylate) (poly[OEGMA]) chain.As proof of concept, the group generated poly[OEGMA]-conjugated myoglobin. In mice, the modified myoglobin showed a 41-fold increase in blood exposure compared with unconjugated myoglobin. The modified myoglobin had an elimination half-life of 18 hours compared with 2 hours for the unconjugated form.The findings were published in the Proceedings of the National Academy of Sciences."We have introduced a novel, general and efficient approach to grow a new therapeutically useful polymer architecture directly from only one universal site on a protein to form polymer conjugates with high yield and good retention of protein activity," said corresponding author Ashutosh Chilkoti. "We believe that this new approach to the synthesis of N-terminal protein conjugates of poly [OEGMA] may be applicable to a large subset of protein and peptide drugs and thereby provide a general methodology for improvement of their pharmacological profiles."Chilkoti is director of the Center for Biologically Inspired Materials and Materials Systems and a professor of biomedical engineering at Duke."From a synthetic point of view, the method is very powerful: it is much easier to grow a very long polymer on a protein than it is to attach a preformed one," said Jeffrey Hubbell, professor of bioengineering and chemical engineering and director of the Institute for Bioengineering at The Swiss Federal Institute of Technology. The poly[OEGMA] advantageThe yield rate for attaching an initiator molecule to myoglobin was about 75%. As a co...