Application of Multicriteria Decision Analysis to Determine the Value of Prophylaxis Relative to On-Demand Treatment in Hemophilia A and Emicizumab versus Replacement Therapy in the Greek Healthcare Setting.

BACKGROUND AND OBJECTIVE: Hemophilia A (HA) is a rare disease that is characterized by congenital underproduction or dysfunction of the endogenous coagulation factor VIII (FVIII). The aim of the present study was to determine the value of prophylaxis versus on-demand treatment strategies for moderate to severe HA (MtSHA) patients and the value of emicizumab in the prophylaxis of MtSHA in Greece, compared with short half-life (SHL) FVIII and extended half-life (EHL) FVIII through multicriteria decision analysis (MCDA). METHODS: A literature review was performed to identify a set of criteria relevant to the therapeutic approaches and therapies under investigation. A performance matrix was populated by two literature reviews and meta-analyses. The criteria selected were hierarchically classified by allocating weights on a 0-100 scale. The performances of therapies were scored at the 100-point scale. The value judgments utilized for weighing and scoring were sourced via a survey among independent multidisciplinary system stakeholders. A linear additive value function was used for the calculation of total value estimates. RESULTS: The participants ranked 'annual number of bleedings per patient' and 'percentage of target joint bleeds' as the most important criteria, while the least important criterion was the 'annual treatment cost' for both assessments. Based on the weights elicited and the performance in each criterion, the overall value score was higher for prophylaxis treatment (58.27) compared with on-demand treatment (40.13). In the other comparison, the most valued treatment was emicizumab (77.05) followed by EHL FVIII (71.52) and SHL FVIII (19.88). According to the participants, the most important factors for managing MtSHA patients are those related to successful management of bleeding events given their contribution to improved quality of life (QoL) and reduced morbidity. CONCLUSIONS: This MCDA has shown that the prophylaxis strategy was perceived as a more valuable option for managing MtSHA patients when compared with the on-demand strategy. Moreover, emicizumab adds higher value and improves patient QoL compared with replacement therapy for MtSHA in Greece. Emicizumab addresses important unmet needs due to its improved efficacy and mode of administration.

Novel processing of Notch 1 within its intracellular domain by a cysteine protease.

In order to study N1 processing, we expressed human N1 (hN1) in HEK293 cells (293-hN1). Following Western blot analysis of 293-hN1 extracts, we detected, in addition to full-length hN1 and the N1 extracellular domain truncated form (N1-TM), a novel extracellular domain truncated form of hN1 with a COOH-terminal deletion, designated hN1-TMdeltaCT. Treatment of cells with the gamma-secretase inhibitor L-685,458 resulted in an accumulation of hN1-TMdeltaCT suggesting that this fragment is a gamma-secretase substrate. To identify the proteolytic activity(ies) that generates hN1-TMdeltaCT, we treated 293-hN1 cells with inhibitors of proteasome, calpains, caspases, serine and cysteine proteases. Despite the presence of a caspase-3 cleavage site within hN1 intracellular domain, none of the caspase inhibitors inhibited hN1-TMdeltaCT production. The proteasomal inhibitors used had also no effect. Incubation of cells with the cysteine protease inhibitor E64d resulted in the accumulation of hN1-TM and the inhibition of hN1-TMdeltaCT production suggesting a precursor-product relationship and that a cysteine protease is involved. Similarly, treatment of cells expressing amyloid precursor protein or E-cadherin with E-64d resulted in the accumulation of COOH-terminal fragments suggesting that these proteins are also processed within their intracellular domain by a cysteine protease. Processing towards hN1-TMdeltaCT requires maturation and transport of hN1 to the cell surface since treatment with brefeldin A inhibited its production and resulted in accumulation of hN1. Processing of hN1 within its intracellular domain could generate fragments that can exert novel functions and/or interfere with the function of hN1 intracellular domain.

Notch 1 interacts with the amyloid precursor protein in a Numb-independent manner.

We hypothesized that the physical interaction between the amyloid precursor protein (APP) and Notch 1 (N1) may be mediating the reported cross-talk between the respective signaling pathways. Immunoprecipitation of mouse N1 (mN1) or extracellular domain truncated mN1 (mN1-TM, mimics TACE-produced membrane-bound C-terminal fragment) specifically coprecipitated APP(751). Conversely, immunoprecipitation of APP(751) specifically coprecipitated mN1, furin-generated membrane-bound mN1 C-terminal fragment (f.mN1-TM), or mN1-TM. The London mutation of APP did not affect the APP(751)/mN1 interaction. Coexpression of APP(751) and mN1 did not affect APP processing or production of mN1 intracellular domain (mNICD). The APP(751)/mN1 interaction was Numb-independent, insofar as it was observed in HEK293 cells that lack detectable levels of Numb and was unaffected by the expression of exogenous Numb or deletion of the APP cytoplasmic domain, including the Numb-binding YENPTY sequence. This interaction was unaffected even when the N-terminal 647 amino acids of APP were replaced by a sequence of secreted alkaline phosphatase. These data combined with data showing interaction between mN1-TM and APP(751) suggest that their transmebrane domains and short sequences around them are sufficient for the interaction and that APP(751) and mN1 interact in cis. Our results imply novel functions of APP and/or N1 that derive from their interaction.

Presenilin 1 and cadherins: stabilization of cell-cell adhesion and proteolysis-dependent regulation of transcription.

Presenilin-1 (PS1) has gained intensive attention in relation to Alzheimer's disease, since it has been shown that PS1 mutations are linked to familial Alzheimer's disease (FAD), and that PS1 is a member of the high molecular weight complex of gamma-secretase, which generates the carboxyl end of beta-amyloid peptide (gamma-cleavage). A parallel line of evidence suggests that upon formation of cell-cell contacts, presenilin colocalizes with cadherins at the cell surface and stabilizes the cadherin-based adhesion complex. Under conditions stimulating cell-cell dissociation, cadherins are processed by a PS1/gamma-secretase activity, promoting disassembly of adherens junctions, and resulting in the increase of cytosolic beta-catenin, which is an important regulator of the Wnt/Wingless signaling pathway. PS1 also controls the cleavage of a number of transmembrane proteins at the interface of their transmembrane and cytosolic domains (epsilon-cleavage), producing intracellular fragments with a putative transcriptional role. Remarkably, cleavage of N-cadherin by PS1 produces an intracellular fragment that downregulates CREB-mediated transcription, indicating a role of PS1 in gene expression. PS1 mutations associated with FAD abolish production of the N-cadherin intracellular fragment and thus fail to suppress CREB-dependent transcription. These findings suggest an alternative explanation for FAD that is separate from the widely accepted 'amyloid hypothesis': dysfunction in transcription regulatory mechanisms.