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Statistical Approaches in the Development of Digital Therapeutics
Published in Oleksandr Sverdlov, Joris van Dam, Digital Therapeutics, 2023
Oleksandr Sverdlov, Yevgen Ryeznik, Sergei Leonov, Valerii Fedorov
Developing a new drug/treatment involves drug discovery (screening multiple candidate compounds and identifying several lead ones to progress further in development), pre-clinical development (chemistry, manufacturing and controls, and animal studies), followed by clinical development. The latter part is split into four phases. Phase I includes studies in humans to establish the compound's safety, tolerability, and pharmacokinetics and to identify doses/dose ranges suitable for testing in subsequent studies. Phase II includes studies in the target patient population to establish proof-of-concept (does the drug work as intended?), determine the therapeutic dose range, and select doses/regimens to be tested in large confirmatory trials. Phase III includes randomized controlled trials (RCTs) to test/confirm the pre-specified clinical research hypotheses. Evidence from phase III RCTs forms the basis for regulatory submission and drug approval. Phase IV includes post-marketing studies of long-term safety and optimization of drug use in subpopulations.
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the preclinical development phase, other biomarkers provide information on safety (i.e., risk-benefit-ratio) and efficacy in animal models. These so-called “safety biomarkers” help to establish the toxicities for a particular agent along with confirmatory data on its mechanism of action and the maximum-tolerated dose (MTD). Furthermore, correlation of these biomarkers with PK/PD data allows the refinement of dosage regimens and may provide useful information for the optimization of formulations. Importantly, the biomarkers used and studied at this stage of the development cycle may identify those that will ultimately be used in the clinic. Furthermore, the assay techniques developed at this stage to identify the presence and level of biomarkers (e.g., based on DNA sequencing, immunohistochemistry, mass spectrometry, etc.) may inform the development of Companion Diagnostic Kits that will be used both in clinical trials and after regulatory approval to identify patients suitable for treatment with the agent.
Background and Motivation
Published in Arkadiy Pitman, Oleksandr Sverdlov, L. Bruce Pearce, Mathematical and Statistical Skills in the Biopharmaceutical Industry, 2019
Arkadiy Pitman, Oleksandr Sverdlov, L. Bruce Pearce
Once the lead compound has been identified, it is progressed through various stages of development, which can be broadly categorized as pre-clinical development, early clinical development (phase I and phase IIa), and full clinical development (phase IIb and phase III). In the pre-clinical development, the objectives are: 1) to manufacture a drug product that is high quality and has acceptable bioavailability of the active ingredient to exert its therapeutic effect; and 2) to study drug efficacy, safety, and pharmacokinetics in animals and in laboratory settings.
Tackling the tumor microenvironment – how can complex tumor models in vitro aid oncology drug development?
Published in Expert Opinion on Drug Discovery, 2023
Megan C. Cox, Rita Mendes, Kathleen N. Halwachs, Giacomo Domenici, Catarina Brito, Erwin R. Boghaert
Cancer is a major therapeutic challenge with an estimated worldwide incidence of 19.3 × 106 new cases in 2020 [1] and a mortality of approximately 107 individuals per year. Pharmaceutical cancer therapy has evolved from cytotoxic cancer drugs to targeted therapy with small molecule inhibitors and biotherapeutics. Recently, immune and gene therapy became available [2]. Despite advances in therapy options and improved understanding of the pathophysiology of cancer, the estimated success rate of clinical trials for novel cancer drugs is 3.4% [3]. The capacity of the traditional preclinical development cascade to predict clinical efficacy has therefore been questioned [4]. Response to cancer therapy is not only dependent on the response of isolated cancer cells but is also determined by the millieu in which the cancer cell resides (tumor microenviroment, [TME] [5]). Therapeutic response also changes during progression because cancer evolution generates intrapatient and intratumoral heterogeneity of histological tumor composition [6]. Hence, a predictive preclinical model must not only mimic the ‘organotypic’ configuration [7] but also reflect the evolution of the disease. Because cancer progression may take several years, even the most advanced complex preclinical cancer models reflect limited aspects of the disease. We will review benefits and shortcomings of existing complex in vitro models for drug testing and suggest design improvements to address discovery and development needs.
The triple function of the capsaicin-sensitive sensory neurons: In memoriam János Szolcsányi
Published in Temperature, 2023
Erika Pintér, Zsuzsanna Helyes, Éva Szőke, Kata Bölcskei, Angéla Kecskés, Gábor Pethő
We provided strong proof of concept evidence that SOM exerts potent analgesic and anti-inflammatory actions via SST4 located both in the periphery and the central nervous system. Therefore, SST4 agonists are promising novel drug candidates for neuropathic pain and neurogenic inflammation but rational drug design has not been possible due to the lack of knowledge about the 3-dimensional structure of SST4. We modeled the SST4 structure, described its agonist binding properties, and characterized the binding of novel small molecule SST4 agonists using an in-silico platform and SOM displacement in the competitive binding assay on SST4-expressing cells. We defined high- and low-affinity binding pockets of SST4 for our ligands, binding of the highest affinity compounds were similar to that of the reference ligand J-2156. Strong G protein activation was shown with the highest potency of 10 nM EC50 value and highest efficacy of 342%. Oral administration of 100 μg/kg of several compounds significantly inhibited acute neurogenic plasma protein extravasation in the paw skin and diminished sciatic nerve ligation-induced neuropathic hyperalgesia [43–45]. Lead selection and optimization processes are currently ongoing to determine the most appropriate drug candidate for preclinical development.
Development pathways for subcutaneous formulations of biologics versus biosimilar development
Published in Expert Review of Precision Medicine and Drug Development, 2022
Artem Zharkov, Bettina Barton, Dominik Heinzmann, Georgios Bakalos, Thomas Schreitmüller
Therefore, a biosimilarity assessment typically includes all of the following: head-to-head comparative analytical, pre-clinical, and clinical evaluation (Table 1) [39,40]. Pre-clinical development of a biosimilar comprises extensive analytical and functional studies as well as limited assessments in animals [18,19]. Clinical trials are specifically designed as a final comparative evaluation step and aim to resolve residual uncertainties that remain following pre-clinical development, regarding the similarity of the proposed biosimilar with the reference product. The study population and selected endpoint(s) need to be adequately sensitive to detect potential differences in efficacy, safety, or immunogenicity between the biosimilar and originator. Development programs for the recently approved biosimilars of MabThera and Herceptin included large Phase 3 studies randomizing up to 827 patients [41,42].