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The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case‐by‐case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence‐based approach to optimize oncology drug dosing regimens effectively. [ABSTRACT FROM AUTHOR]

A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision‐making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow‐up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program. [ABSTRACT FROM AUTHOR]

Approved and emerging siRNA therapeutics are primarily designed for targeted delivery to liver where the therapeutic gene silencing effects occurs. Impairment of hepatic/renal function and its impact on siRNA pharmacokinetics/pharmacodynamics (PKs/PDs) are yet to be mechanistically evaluated to describe the unanticipated clinical observations for this novel modality. We developed pathophysiologically relevant models for organ impairment within a physiologically‐based PK‐PD (PBPK‐PD) modeling framework focusing on modality‐specific mechanistic factors to evaluate impact on siRNA PKs and PDs. PBPK‐PD models for two US Food and Drug Administration (FDA) approved siRNAs inclisiran and vutrisiran were developed as case studies leveraging available tissue‐specific data and translated to humans. Key determinants of the clinical PK and PD of N‐acetylgalactosamine conjugated siRNAs (GalNAc‐siRNAs) with varying sequences were also identified to inform effective clinical translation strategies for emerging GalNAc‐siRNA candidates. A 30–70% reduction in hepatic asialoglycoprotein receptors concentrations still allowed for sufficient amount of free cytoplasmic siRNA for RISC‐loading to produce PD effects comparable in extent and duration to normal liver function. This included severe hepatic impairment for which no clinical data are available. Inclusion of other modality agnostic physiological changes relevant to organ impairment did not alter the findings. Changes in renal physiologies, including changes in GFR across various degrees of impairment, well predicted minimal changes in PD for inclisiran and vutrisiran. This work provides a quantitative mechanistic framework and insights on modality‐specific factors that drive clinical translation and patient/disease‐related factors that impact specific dosing considerations and clinical outcomes to help accelerate the optimal development of siRNA therapeutics. [ABSTRACT FROM AUTHOR]

Bispecific T cell engagers (Bi‐TCEs) have revolutionized the treatment of oncology indications across both liquid and solid tumors. Bi‐TCEs are rapidly evolving from conventional intravenous (i.v.) to more convenient subcutaneous (s.c.) administrations and extending beyond adults to also benefit pediatric patients. Leveraging clinical development experience across three generations of Bi‐TCE molecules across both liquid and solid tumor indications from i.v./s.c. dosing in adults and pediatric subjects, we developed a mechanistic‐physiologically‐based pharmacokinetic (PBPK) platform model for Bi‐TCEs. The model utilizes a full PBPK model framework and was successfully validated for PK predictions following i.v. and s.c. dosing across both liquid and solid tumor space in adults for eight Bi‐TCEs. After refinement to incorporate physiological ontogeny, the model was successfully validated to predict pediatric PKs in 1 month – < 2 years, 2–11 years, and 12–17 years old subjects following i.v. dosing. Following s.c. dosing in pediatric subjects, the model predicted similar bioavailability, however, a shorter time to maximum concentration (Tmax) for the three age groups compared with adults. The model was also applied to guide the dosing strategy for first generation of Bi‐TCEs for organ impairment, specifically renal impairment, and was able to accurately predict the impact of renal impairment on PK for these relatively small‐size Bi‐TCEs. This work highlights a novel mechanistic platform model for accurately predicting the PK in adult and pediatric patients across liquid and solid tumor indications from i.v./s.c. dosing and can be used to guide optimal dose and dosing regimen selection and accelerating the clinical development for Bi‐TCEs. [ABSTRACT FROM AUTHOR]

With the promise of a potentially single‐dose curative regimen, CAR‐T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies with 6 approved products in the USA. However, there are no approved CAR‐T cell therapies for solid tumors. Herein, we report the clinical pharmacology profile of AMG 119, the first CAR‐T cell therapy targeting delta‐like ligand 3 (DLL3), in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC). AMG 119 demonstrated robust cellular expansion with long‐lasting cell persistence and a favorable exposure–response relationship. AMG 119 has been demonstrated to be clinically safe and well tolerated at the doses tested, with no dose‐limiting toxicities (DLTs) reported. This is the first publication of the clinical pharmacology profile of a CAR‐T cell therapy in SCLC, with encouraging cellular kinetics data supporting the potential for CAR‐T cell therapy in solid tumor space. [ABSTRACT FROM AUTHOR]

CAR‐T therapies have shown remarkable efficacy against hematological malignancies in the clinic over the last decade and new studies indicate that progress is being made to use these novel therapies to target solid tumors as well as treat autoimmune disease. Innovation in the field, including TCR‐T, allogeneic or "off the shelf" CAR‐T, and autoantigen/armored CAR‐Ts are likely to increase the efficacy and applications of these therapies. The unique aspects of these cell‐based therapeutics; patient‐derived cells, intracellular expression, in vivo expansion, and phenotypic changes provide unique bioanalytical challenges to develop pharmacokinetic and immunogenicity assessments. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Translational and ADME Sciences Leadership Group (TALG) has brought together a group of industry experts to discuss and consider these challenges. In this white paper, we present the IQ consortium perspective on the best practices and considerations for bioanalytical and immunogenicity aspects toward the optimal development of CAR‐T and TCR‐T cell therapies. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) represent a rapidly evolving area of drug development and hold significant promise. To date, nine ADCs have been approved by the US Food and Drug Administration (FDA). These conjugates combine the target specificity of monoclonal antibodies with the anticancer activity of small‐molecule therapeutics (also referred to as payload). Due to the complex structure, three analytes, namely ADC conjugate, total antibody, and unconjugated payload, are typically quantified during drug development; however, the benefits of measuring all three analytes at later stages of clinical development are not clear. The cytotoxic payloads, upon release from the ADC, are considered to behave like small molecules. Given the relatively high potency and low systemic exposure of cytotoxic payloads, drug–drug interaction (DDI) considerations for ADCs might be different from traditional small molecule therapeutics. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) convened an ADC working group to create an IQ ADC database that includes 26 ADCs with six unique payloads. The analysis of the ADC data in the IQ database, as well as nine approved ADCs, supports the strategy of pharmacokinetic characterization of all three analytes in early‐phase development and progressively minimizing the number of analytes to be measured in the late‐phase studies. The systemic concentrations of unconjugated payload are usually too low to serve as a DDI perpetrator; however, the potential for unconjugated payloads as a victim still exists. A data‐driven and risk‐based decision tree was developed to guide the assessment of a circulating payload as a victim of DDI. [ABSTRACT FROM AUTHOR]

The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid [...]

The predictive performance of physiologically‐based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design. [ABSTRACT FROM AUTHOR]