The antibacterial and cytotoxic activity of the human cathelicidin peptide LL-37 is inhibited by plasma. Because LL-37 does
not undergo rapid degradation in human plasma, we postulated that this ...inhibition results from binding of LL-37 to unidentified
proteins. An LL-37 binding plasma protein has now been isolated by affinity chromatography. SDS-polyacrylamide gel electrophoresis
of proteins that bound to an LL-37 column revealed one band with a molecular mass of about 26 kDa, and amino acid sequence
analysis identified the protein as apolipoprotein A-I (apoA-I). Biomolecular interaction analysis using surface plasmon resonance
showed that LL-37 and isolated apoA-I bind with an apparent K
d in the low micromolar range. 50 μ m of apoA-I inhibits the antibacterial activity of 50 μ m LL-37 by about 50% of the inhibition exhibited by plasma. In addition, anti-apoA-I IgG completely blocks the plasma inhibition
of LL-37 antibacterial activity up to a peptide concentration of 25 μ m and blocks most of the plasma inhibition at higher LL-37 concentrations. These results indicate that apoA-I is the main LL-37
binding protein in human plasma and may work as a scavenger of LL-37, thus suggesting a novel mechanism involved in the regulation
of a cathelicidin peptide.
Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a ...potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC(50)=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC(50) 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).
The determinants of insulin-like growth factor (IGF) binding to its binding proteins (IGFBPs) are poorly characterized in terms of important residues in the IGFBP molecule. We have previously used ...tyrosine iodination to implicate Tyr-60 in the IGF-binding site of bovine IGFBP-2 (Hobba, G. D., Forbes, B. E., Parkinson, E. J., Francis, G. L., and Wallace, J. C. (1996) J. Biol. Chem. 271, 30529–30536). In this report, we show that the mutagenic replacement of Tyr-60 with either Ala or Phe reduced the affinity of bIGFBP-2 for IGF-I (4.0- and 8.4-fold, respectively) and for IGF-II (3.5- and 4.0-fold, respectively). Although adjacent residues Val-59, Thr-61, Pro-62, and Arg-63 are well conserved in IGFBP family members, Ala substitution for these residues did not reduce the IGF affinity of bIGFBP-2. Kinetic analysis of the bIGFBP-2 mutants on IGF biosensor chips in the BIAcore instrument revealed that Tyr-60 → Phe bIGFBP-2 bound to the IGF-I surface 3.0-fold more slowly than bIGFBP-2 and was released 2.6-fold more rapidly than bIGFBP-2. We therefore propose that the hydroxyl group of Tyr-60 participates in a hydrogen bond that is important for the initial complex formation with IGF-I and the stabilization of this complex. In contrast, Tyr-60 → Ala bIGFBP-2 associated with the IGF-I surface 5.0-fold more rapidly than bIGFBP-2 but exhibited an 18.4-fold more rapid release from this surface compared with bIGFBP-2. Thus both the aromatic nature and the hydrogen bonding potential of the tyrosyl side chain of Tyr-60 are important structural determinants of the IGF-binding site of bIGFBP-2.
Signalling through the leptin receptor has been shown to activate the SH2 domain-containing tyrosine phosphatase SHP-2 through tyrosine phosphorylation. The human leptin receptor contains five ...tyrosine residues in the cytoplasmic domain that may become phosphorylated. We show here using BIAcore studies, wherein binding of peptides to SHP-2 was detected, that peptides corresponding to sequences containing phosphotyrosines 974 and 986 (LR974P and LR986P, respectively) from the leptin receptor cytoplasmic domain were the only two peptides that bound to the enzyme. Binding of LR974P to SHP-2 was inhibited in a dose-dependent fashion by orthovanadate, whereas binding of LY986P was not, indicating that the enzyme binds to these peptides through different sites. Only the leptin receptor-derived peptide corresponding to tyrosine 974 was dephosphorylated by recombinant purified SHP-2. Time courses of the reaction were complex, and fitted a two exponent rate equation. Preincubation of SHP-2 with LR986P markedly activated the enzyme at early time points and time courses of the activated enzyme fitted a single exponential first order rate equation. We propose that LR974P binds to the active site of SHP-2, whereas LR986P may bind to the N- and C-terminal SH2 domains of SHP-2, thus activating the phosphatase activity. These data support a model in which SHP-2 binds to phosphotyrosine 986 in the activated leptin receptor and is activated to dephosphorylate phosphotyrosine 974, downregulating signalling events emanating from SH2 domain-containing proteins that bind here.
Valuing and pricing the components of combination therapies can be difficult due to competition law issues, difficulty implementing different prices for the same product in alternative uses, and ...attributing value to each component of the combination. We propose a value attribution solution that allows all combination components to be priced according to their relative value in the combination.OBJECTIVEValuing and pricing the components of combination therapies can be difficult due to competition law issues, difficulty implementing different prices for the same product in alternative uses, and attributing value to each component of the combination. We propose a value attribution solution that allows all combination components to be priced according to their relative value in the combination.We developed a value attribution solution that is universal, symmetrical, and neutral to each combination constituent, regardless of whether it is the backbone or the add-on; and complete, meaning it will always attribute the full value of the combination between the component parts. Moreover, it can be applied to any number of components in the combination (e.g. triplets or quadruplets). We compared this solution to two other existing approaches.METHODSWe developed a value attribution solution that is universal, symmetrical, and neutral to each combination constituent, regardless of whether it is the backbone or the add-on; and complete, meaning it will always attribute the full value of the combination between the component parts. Moreover, it can be applied to any number of components in the combination (e.g. triplets or quadruplets). We compared this solution to two other existing approaches.The results of the proposed value attribution solution sit between those of the two other value attribution approaches as it combines elements of each. As the degree of additivity moves further away from one in either direction, then our general approach ratios also move, reflecting the impact of the incremental value.RESULTSThe results of the proposed value attribution solution sit between those of the two other value attribution approaches as it combines elements of each. As the degree of additivity moves further away from one in either direction, then our general approach ratios also move, reflecting the impact of the incremental value.The proposed value attribution solution for combination therapies differs from two existing approaches by being universally applicable and allowing for symmetry when neutral to the constituent components of the combination. To optimally contribute to policy debate and practice, various requirements for its implementation need to be well understood including how to overcome (1) partial information, (2) whether its assumptions can be relaxed, and (3) implementation issues.CONCLUSIONThe proposed value attribution solution for combination therapies differs from two existing approaches by being universally applicable and allowing for symmetry when neutral to the constituent components of the combination. To optimally contribute to policy debate and practice, various requirements for its implementation need to be well understood including how to overcome (1) partial information, (2) whether its assumptions can be relaxed, and (3) implementation issues.
Abstract Purpose Our objective was to assess the cost-effectiveness of evolocumab in patients at high risk of cardiovascular (CV) events from the Spanish National Health System perspective. Methods A ...Markov model was used to assess the cost-effectiveness (incremental ∆ cost per ∆ quality-adjusted life-year QALY; or cost utility) of evolocumab plus standard of care (SoC; statins) versus SoC, assuming lifetime treatment. Cohorts with baseline LDL-C >100 mg/dL and familial hypercholesterolemia (FH) or CV event history (secondary prevention SP) were considered. Lifetime CV event rates were predicted either (1) using risk equations considering local risk factors (Spanish Familial Hypercholesterolemia Cohort Study) adjusted to reflect the increased risk of FH patients or (2) using CV event rates from local registries (Information System for the Development of Research in Primary Care) for SP patients. LDL-C relative reductions from evolocumab trials (Evolocumab 140 mg Q2W (bi-weekly) and 420 mg QM (monthly)) were converted into CV event reductions using rate ratios per millimole per liter (mmol/L; 38.67 mg/dL) from a meta-analysis of statin trials (Cholesterol Treatment Trialists’ Collaboration). Findings Predicted 10-year/lifetime CV risks were 50%/95% (FH) and 62%/82% (SP) for SoC and 27%/83% (FH) and 44%/69% (SP) for evolocumab plus SoC. Predicted 10-year/lifetime major CV event risks were 42%/86% (FH) and 47%/67% (SP) for SoC and 21%/68% (FH) and 31%/52% (SP) for evolocumab plus SoC. Predicted per patient-year rates of non-fatal/fatal CV events were 2.2/0.8 (FH) and 1.1/0.6 (SP) for SoC and 1.2/0.6 (FH) and 0.7/0.5 (SP) for evolocumab plus SoC. Predicted CV event reductions per mmol/L were 17% (FH) and 15% (SP). Evolocumab treatment was associated with increased QALYs and costs compared with SoC (FH: ∆cost, €65,369; ∆QALY, 2.12; incremental cost-effectiveness ratio ICER, €30,893; SP: ∆cost, €42,266; ∆QALY, 0.93; ICER, €45,340). Implications Evolocumab plus to SoC may provide a cost-effective option for LDL-C lowering in FH and SP patients in Spain.
Novel oncology treatment strategies increasingly use medicines with distinct but complementary mechanisms of action in combination or in close sequence. Payers, when confronted with higher total cost ...of providing combination regimens involving multiple therapies and usually longer treatment durations, are reluctant to reimburse them, particularly when they perceive the expected incremental benefits from adding a new medicine (the add-on) to a currently reimbursed medicine (the backbone) not to represent value for money to the health system. Nevertheless, depending on how value is attributed to the add-on versus the backbone, a clinically effective medicine used as part of a regimen that increases treatment duration might be found “not cost-effective at zero price.” This phenomenon, signaling a policy problem not a pricing issue, first needs to be better understood before a generalizable and transparent solution can be presented.
This article sets out when this policy challenge arises and describes general principles that any proposed solution to the value attribution problem must satisfy.
We develop a simplified conceptual framework and use this to address 2 topics. The first is to understand the origin of problems posed by the current approach for attributing value in incremental cost-effectiveness analyses of combination regimens. The second is to discuss 2 new approaches in the literature designed to address the challenge.
We find that neither meets our criteria, meaning that further work is needed to resolve the issue. Finally, we briefly discuss the implications of relaxing the simplifying assumptions in our conceptual framework.
•The root cause of the “not-cost-effective-at-zero-price” phenomenon in combination regimens is that most combinations have an increase in overall survival relative to treatment duration that is proportionately the same or less than that of the monotherapy.•A new approach to address the value attribution problem is required to overcome challenges faced by attributing combination value, while accepting the price of the backbone as given.•Any proposed value attribution approach should produce plausible and reasonable attribution of value regardless of whether the outcomes of the combination regimen are equal, smaller, or greater than the sum of its parts.
ABSTRACT
Randomized trials have shown marked reductions in low‐density lipoprotein cholesterol (LDL‐C), a risk factor for cardiovascular disease (CVD), when evolocumab is administered. We ...hypothesized that evolocumab added to standard of care (SOC) vs SOC alone is cost‐effective in the treatment of patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic CVD (ASCVD) with or without statin intolerance and LDL‐C >100 mg/dL. Using a Markov cohort state transition model, primary and recurrent CVD event rates were predicted considering population‐specific trial‐based mean risk factors and calibrated against observed rates in the real world. The LDL‐C–lowering effect from population‐specific phase 3 randomized studies for evolocumab was used together with estimated LDL‐C–lowering effect on CVD event rates per 38.67‐mg/dL LDL‐C lowering from a statin‐trial meta‐analysis. Costs and utilities were included from published sources. Evolocumab treatment was associated with both increased cost and improved quality‐adjusted life‐years (QALY): HeFH (incremental cost: US$153 289, incremental QALY: 2.02, incremental cost‐effectiveness ratio: US$75 863/QALY); ASCVD (US$158 307, 1.12, US$141 699/QALY); and ASCVD with statin intolerance (US$136 903, 1.36, US$100 309/QALY). Evolocumab met both the American College of Cardiology/American Heart Association (ACC/AHA) and World Health Organization (WHO) thresholds in each population evaluated. Sensitivity and scenario analyses confirmed that model results were robust to changes in model parameters. Among patients with HeFH and ASCVD with or without statin intolerance, evolocumab added to SOC may provide a cost‐effective treatment option for lowering LDL‐C using ACC/AHA intermediate/high value and WHO cost‐effectiveness thresholds. More definitive information on the clinical and economic value of evolocumab will be available from the forthcoming CVD outcomes study.
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