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The multifaceted IL‐2/IL‐2R biology and its modulation by promising therapeutic agents are highly relevant topics in the cancer immunotherapy field. A novel CD25‐Treg‐depleting antibody (Vopikitug, RG6292) has been engineered to preserve IL‐2 signaling on effector T cells to enhance effector activation and antitumor immunity, and is currently being evaluated in the clinic. The Entry into Human‐enabling framework described here investigated the characteristics of RG6292, from in vitro quantification of CD25 and RG6292 pharmacology using human tissues to in vivo assessment of PK/PD/safety relationships in cynomolgus monkeys as non‐human primate species (NHP). Fundamental knowledge on CD25 and Treg biology in healthy and diseased tissues across NHP and human highlighted the commonalities between these species in regard to the target biology and demonstrated the conservation of RG6292 properties between NHP and human. The integration of in vitro and in vivo PK/PD/safety data from these species enabled the identification of human relevant safety risks, the selection of the most appropriate safe starting dose and the projection of the pharmacologically‐relevant dose range. The first clinical data obtained for RG6292 in patients verified the appropriateness of the described approaches as well as validated the full clinical relevance of the projected safety, PK, and PD profiles from animal to man. This work shows how the integration of mechanistic non‐clinical data increases the predictive value for human, allowing efficient transition of drug candidates and optimizations of early clinical investigations. [ABSTRACT FROM AUTHOR]

Vismodegib (Erivedge; Roche), a Hedgehog pathway inhibitor (HPI), is indicated for the treatment of symptomatic metastatic basal cell carcinoma (BCC) and locally advanced BCC inappropriate for surgery or radiotherapy. Due to the known risk of HPI teratogenicity, the Erivedge Pregnancy Prevention Program (PPP) was introduced at approval (2013) as part of the EU Risk Management Plan. Structured, quantitative Web-based surveys were conducted in 2015 (Wave 1), 2016 (Wave 2), and 2017/2018 (Wave 3) among prescribing oncologists and dermato-oncologists in Austria, France, Germany, Hungary, and the United Kingdom to assess the effectiveness of the Erivedge PPP. Overall, 95%, 87%, and 91% of respondents in Waves 3 (N = 181), 2 (N = 214), and 1 (N = 207), respectively, were vismodegib prescribers. The surveys consistently showed a high awareness about the risk of teratogenicity associated with vismodegib (98%, Wave 3; 95%, Wave 2) and that a high proportion of prescribing physicians took appropriate precautions to minimize this risk (95%, Wave 3; 92%, Wave 2; 88%, Wave 1). Physicians were also highly aware of the Erivedge PPP (70%, Wave 3; 67%, Wave 2; 71%, Wave 1). Survey data suggest that the risk of teratogenicity with vismodegib has been effectively communicated to the prescribing community. [ABSTRACT FROM AUTHOR]

Purpose: Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi., Experimental Design: The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi., Results: Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples., Conclusions: The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation., (©2021 American Association for Cancer Research.)

Background: Voriconazole for the treatment of invasive aspergillosis (IA) shows superior clinical outcome and tolerability compared to conventional amphotericin B. However, the latter is often used as initial treatment due to lower drug acquisition costs. Therefore we performed a cost-effectiveness analysis., Methods: A decision analytic model was designed to compare the cost-effectiveness of a regimen of voriconazole followed by conventional amphotericin B to a regimen of conventional amphotericin B followed by voriconazole. Patients initiated on treatment either completed initial therapy or switched to second line therapy due to toxicity or non-response. Probability of a switch was based on clinical trial data and local rates of renal toxicity. Resource use in the hospital was taken from the Global Comparative Aspergillosis (GCA) study. Costs were based on local drug acquisition costs, local cost estimates for hospitalisation and adjusted additional costs of amphotericin B-induced acute renal failure from the literature. Effectiveness was defined as survival at 12 weeks from the GCA study. An incremental cost-effectiveness ratio was estimated as the incremental cost per life saved comparing voriconazole to conventional amphotericin B., Results: Based on this model, initial therapy of IA with voriconazole reduced total costs when compared to initial therapy with conventional amphotericin B (CHF 37 878/patient vs CHF 49 861/patient) and resulted in better survival at 12 weeks, making it the dominant treatment in terms of incremental cost-effectiveness. Results were most sensitive to alternative assumptions of the incidence of acute renal failure, but cost savings were sustained for voriconazole over a wide range of values., Conclusion: Considering that initial therapy with voriconazole is both cost-saving and results in better clinical outcomes, voriconazole is the dominant cost-effective option for initial therapy of IA, despite very low drug acquisition costs of conventional amphotericin B.