The impact of multiple sclerosis severity on health state utility values: Evidence from Australia.

BACKGROUND: The measurement of health state utility values (HSUVs) for a representative sample of Australian people with multiple sclerosis (MS) has not previously been performed. OBJECTIVES: Our main aim was to quantify the HSUVs for different levels of disease severities in Australian people with MS. METHOD: HSUVs were calculated by employing a 'judgement-based' method that essentially creates EQ-5D-3L profiles based on WHOQOL-100 responses and then applying utility weights to each level in each dimension. A stepwise linear regression was used to evaluate the relationship between HSUVs and disease severity, classified as mild (Expanded Disability Status Scale (EDSS) levels: 0-3.5), moderate (EDSS levels: 4-6) and severe (EDSS levels: 6.5-9.5). RESULTS: Mean HSUV for all people with MS was 0.53 (95% confidence interval (CI): 0.52-0.54). Utility decreased with increasing disease severity: 0.61 (95% CI: 0.60-0.62), 0.51 (95% CI: 0.50-0.52) and 0.40 (95% CI: 0.38-0.43) for mild, moderate and severe disease, respectively. Adjusted differences in mean HSUV between the three severity groups were statistically significant. CONCLUSION: For the first time in Australia, we have quantified the impact of increasing severity of MS on health utility of people with MS. The HSUVs we have generated will be useful in further health economic analyses of interventions that slow progression of MS.

Once-daily liraglutide (1.2 mg) compared with twice-daily exenatide (10 µg) in the treatment of type 2 diabetes patients: An indirect treatment comparison meta-analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists provide effective hyperglycemia management in patients with type 2 diabetes. In a randomized head-to-head trial, liraglutide 1.8 mg q.d. led to greater reductions in HbA1c than exenatide 10 µg b.i.d. There are no direct comparisons of liraglutide 1.2 mg q.d. and exenatide b.i.d.; therefore, in the present study, an indirect comparison and meta-analysis were undertaken. METHODS: A systematic literature search was performed for randomized controlled trials of liraglutide 1.2 mg q.d. or exenatide b.i.d. with HbA1c as an outcome and ≥25 subjects. Key data were extracted and analyzed. A random-effects model was used to incorporate heterogeneity between studies. RESULTS: Three liraglutide 1.2 mg q.d. (n = 1060) and 10 exenatide b.i.d. (n = 2609) placebo-controlled studies were identified, allowing indirect comparison with placebo as the common arm. Baseline characteristics were mean age ~55 years, disease duration ~7 years, HbA1c ~8%, and body mass index ~32 kg/m2 . Compared with exenatide b.i.d., liraglutide 1.2 mg was associated with significantly greater reductions from baseline in HbA1c (-0.29%; 95% confidence interval [CI] -0.53, -0.05) and fasting plasma glucose (-0.92 mmol/L; 95% CI -1.43, -0.41), with shorter duration of nausea (3 vs 14 days; P = 0.002) and fewer withdrawals (odds ratio 0.34; 95% CI 0.22, 0.52). The incidence of adverse events (including nausea) and withdrawals because of adverse events were similar between treatments. CONCLUSIONS: Liraglutide 1.2 mg provided a significantly greater reduction in HbA1c than exenatide 10 µg b.i.d. The significantly shorter duration of nausea with liraglutide than exenatide may be appreciated by patients.

Bioanalytical platform comparison using a generic human IgG PK assay format.

A comparison of four different ligand-binding assay technology platforms (ELISA, Meso Scale Discovery®, Gyros® and AlphaLISA®) was conducted using quantitative assays for the measurement of a human IgG1 monoclonal antibody (MAb) in rat serum. The assays used common reagents for Fc-specific measurement to determine total levels of a human IgG MAb drug analyte, and all were fully optimized for use on each platform. Mock MAb study samples were prepared and analyzed using all platforms to assess assay performance. Assay parameters such as sensitivity, dynamic range, minimum required dilution and sample volume as well as other considerations such as per-run cost, technology availability, requisite equipment and necessary reagent modifications were evaluated toward the determination of a default go-to assay platform for monoclonal antibody biotherapeutics in this laboratory. Based primarily on superior assay performance, Meso Scale Discovery and Gyros were selected from the four technologies evaluated as our default platforms for non-regulated (discovery) study support. As an adjunct, immunoaffinity LC-MS/MS was explored as an alternate platform for generic Fc quantitation and was found to perform similarly to the ligand-binding assays.

Pharmacokinetic, biodistribution, and biophysical profiles of TNF nanobodies conjugated to linear or branched poly(ethylene glycol).

Covalent attachment of poly(ethylene glycol) (PEG) to therapeutic proteins has been used to prolong in vivo exposure of therapeutic proteins. We have examined pharmacokinetic, biodistribution, and biophysical profiles of three different tumor necrosis factor alpha (TNF) Nanobody-40 kDa PEG conjugates: linear 1 × 40 KDa, branched 2 × 20 kDa, and 4 × 10 kDa conjugates. In accord with earlier reports, the superior PK profile was observed for the branched versus linear PEG conjugates, while all three conjugates had similar potency in a cell-based assay. Our results also indicate that (i) a superior PK profile of branched versus linear PEGs is likely to hold across species, (ii) for a given PEG size, the extent of PEG branching affects the PK profile, and (iii) tissue penetration may differ between linear and branched PEG conjugates in a tissue-specific manner. Biophysical analysis (R(g)/R(h) ratio) demonstrated that among the three protein-PEG conjugates the linear PEG conjugate had the most extended time-average conformation and the most exposed surface charges. We hypothesized that these biophysical characteristics of the linear PEG conjugate accounts for relatively less optimal masking of sites involved in elimination of the PEGylated Nanobodies (e.g., intracellular uptake and proteolysis), leading to lower in vivo exposure compared to the branched PEG conjugates. However, additional studies are needed to test this hypothesis.

Cost-effectiveness of colorectal cancer screening: comparison of community-based flexible sigmoidoscopy with fecal occult blood testing and colonoscopy.

BACKGROUND AND AIMS: To determine the cost-effectiveness of screening for colorectal cancer using flexible sigmoidoscopy once every 10 years, compared with annual and biennial rehydrated Hemoccult fecal occult blood testing and colonoscopy once every 10 years, or no screening. METHODS: A Markov model was developed in order to simulate the progression of a cohort of asymptomatic, average-risk individuals aged 55-64 years who were moving through a defined series of states towards death. The main outcome measures were: cases of colorectal cancer averted, colorectal cancer deaths averted, and cost per life-year saved. RESULTS: Colonoscopy averted the greatest number of cases of colorectal cancer (35%), followed by flexible sigmoidoscopy (25%), and annual (24%) and biennial (14%) fecal occult blood testing. Colonoscopy averted the greatest number of deaths from colorectal cancer (31%), followed by annual fecal occult blood testing (29%), flexible sigmoidoscopy (21%) and biennial fecal occult blood testing (19%). Flexible sigmoidoscopy was the most efficient in terms of cost per life-year saved (16,801 Australian dollars), followed by colonoscopy (19,285 Australian dollars), biennial (41,183 Australian dollars), and annual (46,900 Australian dollars) fecal occult blood testing. CONCLUSIONS: Flexible sigmoidoscopy and colonoscopy are cost-effective strategies for reducing the disease burden of colorectal cancer.