Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.

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.

Tuberculosis (TB) is the leading cause of mortality due to a single infectious agent. The currently used combination drug regimens produce cure rates that exceed 95%, given good patient adherence during the multiple months treatment period. However the recent surge in HIV infections and the synergy between HIV and TB as well as the emergence of resistance resulted in an unforeseen increase in the number of TB cases, including multi-drug resistant (MDR) and extensively-drug resistant (XDR) forms of TB. Consequently, there is an urgent need to develop novel, fast acting antituberculosis drugs with high potency that can provide treatment options for all forms of TB. It is well known that the current TB drugs exhibit differences in their in vivo activity profile and these differences are largely determined by their pharmacodynamics (PD), i.e. intrinsic antibacterial activity, biopharmaceutical properties such as solubility and permeability, and pharmacokinetic (PK) properties such as drug exposure, tissue distribution, and protein binding. An understanding of the relationships among these properties is considered key for a rational use of antituberculosis therapeutics. The current review provides a comprehensive summary of physicochemical/biopharmaceutical, PK, and PD properties of currently used antituberculosis drugs and novel agents under development. Also, a brief review of PK/PD parameters of current TB drugs is given and properties of a desirable TB drug target and drug molecule are outlined. The information provided herewith may be useful in the optimization of biopharmaceutical and PK/PD characteristics in the development of novel TB therapeutics and in the design of optimal treatment regimens.

Prolonged time delay in response to drug action is a common feature of hematological responses to pharmacotherapy such as erythropoiesis. The objective of this study was to compare the performance of two competing modeling approaches for delayed drug effects, mechanistic cell life span models, and semi-mechanistic cell transit models. The comparison was performed with an experimental dataset from multiple dose administrations of an erythropoietin mimetic to Cynomolgus monkeys. Comparative performance measures include visual predictive checks, goodness-of-fit plots, model estimation time, estimation status, and estimation error. The analysis revealed that both models resulted in a similarly good description of the erythropoietic drug effect, with precision and bias of the model-based predictions of red blood cell counts of less than 11%. The cell transit model needed slightly longer time to converge compared to the cell life span model. The system and drug effect parameters were similar in both models indicating that the models can be interchangeably used to describe the current data. Thus, model selection would be dependent on the purpose of the modeling exercise, the available data, and the time allocated for model development.

Tislelizumab, an anti‐programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first‐in‐human, dose‐finding BGB‐A317‐001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5–10 mg/kg every 2 weeks (q2w), 2–5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune‐mediated AEs, and infusion‐related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure–response (E–R) analyses by logistic regression using data from study BGB‐A317‐001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018–2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E–R relationship. Overall, the totality of data, including efficacy, safety, and E–R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.

Purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates hepatic LDL receptors, playing a key role in cholesterol metabolism. Gain of function genetic mutations cause autosomal dominant hypercholesterolaemia, while nonsense mutations lower LDL-c and the risk of coronary events. RG7652 (MPSK3169A) is a fully human IgG1 monoclonal antibody (mAb) directed against PCSK9. This first-in-human study evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy in healthy individuals with elevated LDL-c. Methods: This Phase I study tested single and multiple doses of RG7652 and placebo given subcutaneously to 80 healthy volunteers with elevated serum LDL-c concentrations. Subjects entered six ascending, single-dose (SD) and four multiple-dose (MD) cohorts allocated 6 active:2 placebo. Two MD cohorts included atorvastatin therapy (40 mg daily) prior to administration of study drug. Following cohort safety reviews, escalation to the next higher dose cohort continued. The primary efficacy endpoint was change in LDL-c 2 weeks after final dose of study drug, with safety follow-up occurring during Weeks 8-16. Results: Eighty subjects (mean age 45 years, range 19-64; 48% male) with mean LDL-c of 162 mg/dL (4.2 mmol/L) were randomised. RG7652 reduced mean LDL-c by as much as 90 mg/dL (60%) from baseline, with a dose-dependent effect that appeared to saturate at the highest doses. The average reduction in LDL-c at Day 15 in SD and Day 36 in MD was >40 mg/dL in all cohorts other than the lowest dose. RG7652 had similar LDL-c lowering effects and kinetics when added to atorvastatin. No dose-limiting safety effects were identified and no subjects discontinued study drug for adverse events (AEs). Thirty-seven AEs, all mild, were attributed to study drug: 27 in 14 RG7652 subjects; 10 in 6 placebo subjects. Conclusions: The anti-PCSK9 mAb, RG7652, safely decreased LDL-c in healthy volunteers with elevated LDL-c as monotherapy and in combination with atorvastatin. The results support further testing of RG7652 in dyslipidaemic patients.