Type 1 diabetes prevention clinical trial simulator: Case reports of model-informed drug development tool.

Clinical trials seeking to delay or prevent the onset of type 1 diabetes (T1D) face a series of pragmatic challenges. Despite more than 100 years since the discovery of insulin, teplizumab remains the only FDA-approved therapy to delay progression from Stage 2 to Stage 3 T1D. To increase the efficiency of clinical trials seeking this goal, our project sought to inform T1D clinical trial designs by developing a disease progression model-based clinical trial simulation tool.

Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials.

Disease progression joint model predicts time to type 1 diabetes onset: Optimizing future type 1 diabetes prevention studies.

Clinical trials seeking type 1 diabetes prevention are challenging in terms of identifying patient populations likely to progress to type 1 diabetes within limited (i.e., short-term) trial durations.

Consortium-based approach to receiving an EMA qualification opinion on the use of islet autoantibodies as enrichment biomarkers in type 1 diabetes clinical studies.

The development of medical products that can delay or prevent progression to stage 3 type 1 diabetes faces many challenges. Of note, optimising patient selection for type 1 diabetes prevention clinical trials is hindered by significant patient heterogeneity and a lack of characterisation of the time-varying probability of progression to stage 3 type 1 diabetes in individuals positive for two or more islet autoantibodies. To meet these needs, the Critical Path Institute's Type 1 Diabetes Consortium was launched in 2017 as a pre-competitive public-private partnership between stakeholders from the pharmaceutical industry, patient advocacy groups, philanthropic organisations, clinical researchers, the National Institutes of Health and the Food and Drug Administration.

Leveraging Real-World Data for EMA Qualification of a Model-Based Biomarker Tool to Optimize Type-1 Diabetes Prevention Studies.

The development of therapies to prevent or delay the onset of type 1 diabetes (T1D) remains challenging, and there is a lack of qualified biomarkers to identify individuals at risk of developing T1D or to quantify the time-varying risk of conversion to a diagnosis of T1D. To address this drug development need, the T1D Consortium (i) acquired, remapped, integrated, and curated existing patient-level data from relevant observational studies, and (ii) used a model-based approach to evaluate the utility of islet autoantibodies (AAs) against insulin/proinsulin autoantibody, GAD65, IA-2, and ZnT8 as biomarkers to enrich subjects for T1D prevention. The aggregated dataset was used to construct an accelerated failure time model for predicting T1D diagnosis.

Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer.

Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns.

Effective Data Sharing as a Conduit for Advancing Medical Product Development.

Introduction: Patient-level data sharing has the potential to significantly impact the lives of patients by optimizing and improving the medical product development process. In the product development setting, successful data sharing is defined as data sharing that is actionable and facilitates decision making during the development and review of medical products. This often occurs through the creation of new product development tools or methodologies, such as novel clinical trial design and enrichment strategies, predictive pre-clinical and clinical models, clinical trial simulation tools, biomarkers, and clinical outcomes assessments, and more.

Use of biomarkers to improve immunosuppressive drug development and outcomes in renal organ transplantation: A meeting report.

On September 27-28, 2018 the Food and Drug Administration (FDA) and the Critical Path Institute's Transplant Therapeutics Consortium convened a public workshop titled "Evidence-Based Treatment Decisions in Transplantation: The Right Dose & Regimen for the Right Patient/Individualized Treatment." The workshop facilitated cooperative engagement of transplant community stakeholders, including pharmaceutical industry, academic researchers, clinicians, patients, and regulators to discuss methods to advance the development of novel immunosuppressive drugs for use in solid organ transplantation. Day 1 focused on the utility of biomarkers in drug development with considerations for seeking regulatory endorsement for use in clinical trials.

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies.

The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement.

The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools.

Chemoselective Preparation of Clickable Aryl Sulfonyl Fluoride Monomers: A Toolbox of Highly Functionalized Intermediates for Chemical Biology Probe Synthesis.

Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide-alkyne cycloaddition).

Tomato receptor FLAGELLIN-SENSING 3 binds flgII-28 and activates the plant immune system.

Plants and animals detect the presence of potential pathogens through the perception of conserved microbial patterns by cell surface receptors. Certain solanaceous plants, including tomato, potato and pepper, detect flgII-28, a region of bacterial flagellin that is distinct from that perceived by the well-characterized FLAGELLIN-SENSING 2 receptor. Here we identify and characterize the receptor responsible for this recognition in tomato, called FLAGELLIN-SENSING 3.

Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism.

Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism.

Identification of multiple salicylic acid-binding proteins using two high throughput screens.

Salicylic acid (SA) is an important hormone involved in many diverse plant processes, including floral induction, stomatal closure, seed germination, adventitious root initiation, and thermogenesis. It also plays critical functions during responses to abiotic and biotic stresses. The role(s) of SA in signaling disease resistance is by far the best studied process, although it is still only partially understood.

Interaction of structure-specific and promiscuous G-protein-coupled receptors mediates small-molecule signaling in Caenorhabditis elegans.

A chemically diverse family of small-molecule signals, the ascarosides, control developmental diapause (dauer), olfactory learning, and social behaviors of the nematode model organism, Caenorhabditis elegans. The ascarosides act upstream of conserved signaling pathways, including the insulin, TGF-β, serotonin, and guanylyl cyclase pathways; however, the sensory processes underlying ascaroside function are poorly understood. Because ascarosides often are multifunctional and show strongly synergistic effects, characterization of their receptors will be essential for understanding ascaroside biology and may provide insight into molecular mechanisms that produce synergistic outcomes in small-molecule sensing.

Synthesis of caeliferins, elicitors of plant immune responses: accessing lipophilic natural products via cross metathesis.

A cross metathesis (CM)-based synthesis of the caeliferins, a family of sulfooxy fatty acids that elicit plant immune responses, is reported. Unexpectedly, detailed NMR spectroscopic and mass spectrometric analyses of CM reaction mixtures revealed extensive isomerization and homologation of starting materials and products. It is shown that the degree of isomerization and homologation in CM strongly correlates with substrate chain length and lipophilicity.