Exposure-Response Relationship between Von Willebrand Factor (VWF) Activity and Bleeding Events Following Prophylaxis with Recombinant VWF (rVWF, vonicog alfa) in Patients with Severe Von Willebrand Disease (VWD)

Background: rVWF (vonicog alfa; Vonvendi ®,Baxalta US Inc, a Takeda company, Lexington, MA, USA) is a purified recombinant VWF concentrate approved for on-demand (OD) treatment of hemorrhage and management of surgical bleeding in adults with VWD. The efficacy and safety of rVWF prophylaxis has also been evaluated in a recent open-label phase 3 trial in adults with severe VWD (NCT02973087). Aims: To evaluate the exposure-response (ER) relationship between VWF activity (measured by VWF:ristocetin cofactor [RCo]), endogenous factor VIII (FVIII) activity (measured by FVIII:C), and spontaneous bleeding events (sBEs) in patients with severe VWD receiving rVWF prophylaxis for up to 1 year. Methods: The modeling framework involved developing population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models and conducting simulations to characterize VWF activity/PK and FVIII activity/PD, then developing an ER model for VWF and FVIII activities in association with sBEs. The population PK and PK/PD models were developed using data from 100 unique patients receiving intravenous rVWF in 4 completed clinical studies (NCT00816660; NCT01410227; NCT02283268; NCT02973087). The PK and PK/PD analyses were used to generate model parameters and evaluate predictors of heterogeneity for PK/VWF:RCo and PD/FVIII:C time profiles. The ER relationship was evaluated using sBEs from the phase 3 rVWF prophylaxis trial (NCT02973087) in 23 adults with severe VWD (VWF:RCo <20 IU/dL) requiring VWF therapy to manage BEs during the year before study entry: 13/23 patients were previously treated OD with a VWF (Prior OD group) and 10/23 had received plasma-derived VWF (pdVWF) prophylaxis (Switch group). For this ER evaluation, a repeated time-to-event (RTTE) model was used, including a piecewise exponential additive model, and the covariate effect of previous treatment (OD with a VWF or prophylaxis with pdVWF) was explored. Model selection was performed by comparing the goodness of fit of linear and nonlinear ER models based on the PK and PK/PD models' predicted values for 1) VWF:RCo and FVIII:C trough levels; 2) average VWF:RCo and FVIII:C levels in dosing interval; and 3) average VWF:RCo and FVIII:C levels over 24 h following rVWF treatment, with comparisons of these levels before sBE onset in patients with and without sBEs. The PK and PK/PD models were also used to derive the VWF:RCo and FVIII:C levels for pdVWF, and these were applied to the ER model. The impact of the dosing regimens (twice weekly [BIW] or once weekly [QW]) on the ER for rVWF and pdVWF were investigated based on population simulations. Hazard ratios (HRs) for the probability of bleeding were generated as a function of median VWF activity at steady state for patients with type 3 VWD. Results: The RTTE model with a linear ER function linking the average levels of VWF:RCo or FVIII:C over 24 h before sBE onset was selected as the best model. A statistically significant ER relationship was observed (p<0.05) for the ER model with VWF:RCo, in which higher exposure to VWF:RCo was associated with a lower risk of sBE occurrence. The covariate effect of previous treatment (OD with a VWF or prophylaxis with pdVWF) was not statistically significant (p=0.6732). Simulations suggested that the HR per 10 IU/dL increment in the average exposure of VWF:RCo 24 h before an sBE was 0.673 (95% CI: 0.454-0.999). The HR per 20 IU/dL increment in the average exposure of VWF:RCo 24 h before an sBE was 0.453 (95% CI: 0.206-0.998). In addition, the predicted risk of a sBE for the 50 IU/kg QW regimen of rVWF and pdVWF was 30% and 43% higher, respectively, compared with the 50 IU/kg BIW regimen of rVWF (ie, reference regimen). The predicted risk of bleeding with the 50 IU/kg BIW regimen of pdVWF was 20% higher compared with the 50 IU/kg BIW regimen of rVWF. A trend was observed for the ER relationship based on FVIII:C (average levels of FVIII over 24 h before the sBE) suggesting a lower risk of sBEs with increased FVIII:C, which was however not statistically significant. Conclusions: Analysis of exposure to VWF:RCo or FVIII:C vs sBE occurrence indicated a causal association between VWF:RCo and sBEs; higher VWF:RCo was associated with a lower sBE risk. This relationship was independent of the patients' previous treatment (OD with a VWF or prophylaxis with pdVWF). Once further supported with additional data, this ER model could be utilized for individualized dosing strategies to optimize patient outcomes with rVWF prophylaxis. Disclosures Wang: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Özen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Mellgård: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Marier: Certara Strategic Consulting: Current Employment. Barriere: Certara Strategic Consulting: Current Employment. Vasilinin: Certara Strategic Consulting: Current Employment. Bhattacharya: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.: Current Employment. OffLabel Disclosure: Abstract reports results from a population ER analysis using data from a clinical trial investigating the efficacy and safety of rVWF prophylaxis. rVWF is not currently authorized for use as a prophylactic treatment.

Strategic Consultant and Client: Interaction Models

The paper analyzes theoretical models of relations between executive authorities of federal subjects of the Russian Federation, municipalities (client) and organizations providing services for creating social and economic development strategies (strategic consultant). The authors study the evolution of these relations and the market of territorial strategic consulting from the moment of the emergence of territorial strategic planning in Russia to the present. The researchers identify factors causing serious changes in the models of relations “consultant – client” after the adoption of the Federal Law “On Strategic Planning in the Russian Federation” and tightening of public procurement standards. Theoretical constructions are supported by the statements of the heads of several leading Russian consulting teams. The authors have made a simplified classification of consultants, which includes “innovator”, “pragmatist”, “operator of changes”, and a classification of clients, which includes “progressor”, “formalist”, “populist”. The paper identifies essential characteristics of emerging substantive relationships: positioning of the advisor (“innovator” or “outsourcer”), depth of involvement of the parties into the strategizing process, level of client’s boss participation, form and regularity of communications, compatibility of worldviews. The authors identify two basic models. The preferred one is “partnership under the leadership of an consultant” and the ineffective one is “domination of a client with a low interest”. At the same time, the key characteristic is positioning of the consultant, which is connected with the market segmentation of the territorial strategic consulting. The researchers identify the problem of “tiredness” from standard strategic planning and propose options to modify this process. The authors systematize the problems that complicate the formation of an effective model of relations “consultant – client” associated with the selection and hiring of a consulting system according to the rules of public procurement and give recommendations for the improvement of the strategic planning process which are addressed to clients and consultant and are based on approaching to the model of their relations, which has been seen as the most productive.

Strategic management consulting in Hungary

Several Hungarian SMEs are facing problems using management methodologies. The goal of the research is to analyze the Hungarian management consulting market based on two previous Hungarian surveys. Strategic management consulting is one of the most important management consulting topics. The purpose of this research is to understand the Hungarian strategic management consulting market better. Two surveys are compared with each other and the size of the Hungarian strategic consulting market is calculated based on these secondary data. Trends and problems in the industry are also described briefly. The results of this research contribute to better understanding of the developments happening in this industry.

Population Pharmacokinetic Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma or Acute Myeloid Leukemia

Introduction KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). Study 20120106 was a 2-part Phase 1 dose-exploration/dose-expansion study of KRT-232 in patients with advanced solid tumors or multiple myeloma (Gluck et al. Invest New Drugs in press; NCT01723020). Study 20120234 was a Phase 1b study evaluating KRT-232 alone and combined with trametinib, in patients with relapsed/refractory AML (Erba et al. Blood Adv 2019; NCT02016729). This population PK analysis quantified the KRT-232 PK time-course and variability, and the contribution of subject covariates to PK variability, using data from Amgen studies 20120106 and 20120234. Methods Study 20120106: Subjects received KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6). Doses were administered once daily (QD) for 7 days in 21-day cycles. PK sampling occurred on Cycle 1 days 1 and 7, at nominal sampling times pre-dose and 1, 3, 5, 7, and 24 h post-dose, and 72 h after the day 7 dose. Study 20120234: Subjects received KRT-232 doses of 60 mg (n=14; n=10 co-administered with 2 mg trametinib once daily, n=4 as single agent), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). KRT-232 was administered QD for 7 days in 14-day cycles. PK sampling occurred on days 1 and 7, at nominal sampling times pre-dose and 1, 2, 4, 6, and 24 h post-dose, and 72 h after the day 7 dose. Population PK modeling was conducted using the first-order conditional estimation (FOCE-I) method in NONMEM® 7.3. Model covariates were selected using a forward addition and backward elimination method, based on significance levels of p<0.05 and p<0.01, respectively. Tested covariates included age, sex, weight, race, ethnicity, creatinine clearance, total bilirubin, AST, ALT, albumin, tumor type, disease stage, ECOG performance status, and the presence/absence of trametinib. Model quality was checked by inspection of model parameters and their confidence intervals, and standard residual-based and simulation-based diagnostics. Results KRT-232 plasma concentrations from 141 subjects with 1783 samples could be described by a two-compartment model with first-order absorption. Apparent oral clearance (CL/F) of KRT-232 was estimated to be 24.9 L/h (CV 61.5%) in subjects with solid tumors. The apparent oral central volume (Vc/F) and peripheral volume (Vp/F) were 62.9 L and 333 L, respectively. The terminal half-life was 17.1 hr. The prediction-corrected visual predictive check in Figure A suggested that the median, 5th and 95th percentiles of the measured plasma KRT-232 concentrations aligned with modeled concentrations for 24 h post-dose; the modeled variability was larger than the measured variability at 72 h post-dose. Residual diagnostics confirmed an adequate model fit. Apparent oral clearance did not change with dose over the studied dose range of 15-480 mg QD, indicating AUC increases were dose-proportional (Figure B). Relative to solid tumor subjects, AML subjects had 61.6% greater steady-state AUC (Figure C). A subject with decreased albumin at the 5th percentile (30 g/L) was modeled to have a 47.7% increase in AUC and an 87.2% increase in Cmin at steady state, relative to a typical subject with a median albumin level of 39 g/L. Trametinib and multiple myeloma model covariates had confidence intervals overlapping the line of unity. Covariates weight, sex, age, race and ethnicity did not affect CL/F or Vc/F. No effects of renal parameters, hepatic parameters, or ECOG performance status on CL/F were detected. Conclusion A two-compartment linear PK model with first-order absorption adequately described KRT-232 PK. Apparent oral clearance did not change with dose, indicating AUC increases were dose-proportional. AML subjects and subjects with decreased albumin had greater steady-state AUC values relative to subjects with solid tumors and normal albumin levels, although the magnitude of these effects were less than 2-fold. Disclosures Ma: Certara Strategic Consulting: Consultancy, Employment. Wada:Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is an investigational small molecule MDM2 inhibitor.

The spatial segmentation of the Russian marketof territorial strategic consulting (TSC)

The localization of organizations providing services in the development of socio-economic strategies of federal and municipal entities of Russia is analyzed and reflected in the schematic maps. The 20162018 period is studied based on data from the official public procurement website, and the 19972018 period based on data from the register of companies involved in strategic research (StratPlan.ru portal). Three groups of organizations all-Russian (omnivores), zonal, and local are identified in terms of their territorial and market behavior mechanisms. Taking into account past experience, including that not reflected on the public procurement website, all-Russian companies are set apart from those active on the territorial and strategic consulting services market in 20162018. The latter include NRU HSE, RANEPA, CJSC ICSER Leontief Centre, LLC Scientific developments, LLC Development and Prudence, ENKO, State Institution Center of Advanced Economic Researches at the Academy of Sciences of the Republic of Tatarstan, LLC AV, LLC Financial and organizational consulting, Fund CSR North-West. Most of Russian suppliers, i.e., those ready to work and already working in many regions and cities have head offices in Moscow, but there are also organizations based in St. Petersburg, Kazan, and Tyumen. Zonal suppliers, i.e., working on the territory of one or two adjacent federal districts, and local suppliers, whose activities are limited to one federal entity, primarily work in the region of their location. Localization is determined by long-term cooperation with the authorities and well-grounded local knowledge.

The Market of Territorial Strategic Consulting in Russia in 2016-2018: Insider’s Notes

The author describes the trends of the service market aimed at working out the strategies for ocioeconomic development of the federal entities and municipalities of Russia. Information on tenders for state and municipal contracts available in the Unified Procurement Information System has been analyzed. The period of 2016-2018 is characterized in detail: the volume of the market, key players, types of market behavior of participants are determined. The authr shows the segmentation of market from the supply side and from the demand side. The tendencies of domination and strengthening of monopolization from the largest state universities - RANEPA (Russian Presidential Academy of National Economy and Public Administration) and Higher School of Economics are revealed. Due to the small size of the market, one large contract can be up to a quarter of the market volume, which accordingly makes its performer a dominant player. It is noted that the tactics of price dumping, as a rule, are unsuccessful. There are indications that most contests are held for a specific winner (a high proportion of “problem-based” contests - with cancellation or change of conditions; presence of companies winning all contests in which they participate, and companies with a high share of victories – over 75 %). The calculated indicators of market competitiveness (the average number of participants in the competition, the share of winners in the total number of participants, the average number of contracts per winner) show a reduction in competition in 2018. The author proposes recommendations on the formation of tender documentation, allowing to neutralize the pressure of the dominant and unscrupulous players, while maintaining quality control of bids.