scholarly journals Scalable convergent synthesis of therapeutic oligonucleotides

2021 ◽  
Author(s):  
Xianglin Shi ◽  
Xuan Zhou ◽  
Wuming Yan ◽  
William Kiesman ◽  
Yannick Fillon ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Liquid Phase ◽  
Fold Increase ◽  
Active Pharmaceutical Ingredient ◽  
Clinical Development ◽  
Full Length ◽  
Development Programs ◽  
Convergent Synthesis ◽  
Mrna Regulation ◽  
Batch Sizes

Abstract The recent explosive growth in the number of oligonucleotide clinical development programs and drug approvals underscores their ability to treat diseases via mRNA regulation. Currently, solid-supported synthesis is limited to ≤ 5 kg (~ 1 mole) batch sizes and the feasibility of liquid-phase syntheses to supply materials of sufficient purity and amount for clinical trials has not been proven. Herein we describe the first convergent synthesis of a full-length 18-mer mixed backbone (PO/PS) 2’-MOE gapmer oligonucleotide by the phosphoramidite approach suitable for use in clinical trials. Techniques described to control impurities during its synthesis can be implemented in common active pharmaceutical ingredient (API) manufacturing facilities and should enable a >10-fold increase in production batch scaling.

Pharmacokinetics of Full Length and Two-Domain Tissue Factor Pathway Inhibitor in Combination with Heparin in Rabbits

1993 ◽  
Vol 70 (03) ◽  
pp. 454-457 ◽  
Author(s):  
Claus Bregengaard ◽  
Ole Nordfang ◽  
Per Østergaard ◽  
Jens G L Petersen ◽  
Giorgio Meyn ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Anticoagulant Activity ◽  
Fold Increase ◽  
Volume Of Distribution ◽  
Full Length ◽  
Heparin Binding ◽  
Extrinsic Pathway ◽  
C Terminus ◽  
Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans, injection of heparin results in a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus.FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with and without simultaneous intravenous injections of low molecular weight heparin (450 anti-XaU/kg).Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found in the group receiving the two compounds simultaneously, suggesting that the releasable pool of FL-TFPI is removed very slowly in the absence of circulating heparin.

New Anti-VEGF Drugs in Ophthalmology

2020 ◽  
Vol 21 (12) ◽  
pp. 1194-1200
Author(s):  
Claudio Campa
Keyword(s):  
Clinical Trials ◽  
Delivery System ◽  
Clinical Development ◽  
Advanced Stage ◽  
Phase 3 ◽  
Anti Vegf

: This review focuses on 5 new anti-VEGF drugs in the advanced stage of clinical development (i.e., phase 3): conbercept, brolucizumab, port delivery system with ranibizumab, abicipar pegol and faricimab. : Results of clinical trials and the advantages of each drug compared to the available molecules are discussed in detail.

scholarly journals WEE1 Inhibitor: Clinical Development

2021 ◽  
Vol 23 (9) ◽  
Author(s):  
Anthony Kong ◽  
Hisham Mehanna
Keyword(s):  
Clinical Trials ◽  
Tp53 Mutation ◽  
Predictive Biomarker ◽  
Concurrent Chemotherapy ◽  
Clinical Development ◽  
Novel Agents ◽  
The Novel ◽  
Grade 3 ◽  
Chemotherapy Agents

Abstract Purpose of Review WEE1 inhibitor has been shown to potential chemotherapy or radiotherapy sensitivity in preclinical models, particularly in p53-mutated or deficient cancer cells although not exclusively. Here, we review the clinical development of WEE1 inhibitor in combination with chemotherapy or radiotherapy with concurrent chemotherapy as well as its combination with different novel agents. Recent Findings Although several clinical trials have shown that WEE1 inhibitor can be safely combined with different chemotherapy agents as well as radiotherapy with concurrent chemotherapy, its clinical development has been hampered by the higher rate of grade 3 toxicities when added to standard treatments. A few clinical trials had also been conducted to test WEE1 inhibitor using TP53 mutation as a predictive biomarker. However, TP53 mutation has not been shown to be the most reliable predictive biomarker and the benefit of adding WEE1 inhibitor to chemotherapy has been modest, even in TP53 biomarker-driven studies. Summary There are ongoing clinical trials testing WEE1 inhibitor with novel agents such as ATR and PAPR inhibitors as well as anti-PDL1 immunotherapy, which may better define the role of WEE1 inhibitor in the future if any of the novel treatment combination will show superior anti-tumor efficacy with a good safety profile compared to monotherapy and/or standard treatment.

scholarly journals The exosome journey: from biogenesis to uptake and intracellular signalling

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sonam Gurung ◽  
Dany Perocheau ◽  
Loukia Touramanidou ◽  
Julien Baruteau
Keyword(s):  
Clinical Trials ◽  
Plasma Membrane ◽  
Scientific Community ◽  
Cell Types ◽  
Clinical Applications ◽  
Clinical Development ◽  
Intracellular Signalling ◽  
Clinical Settings ◽  
Health And Disease ◽  
Adequate Definition

AbstractThe use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications.

Clinical Trials and Machine Learning: Regulatory Approach Review

2021 ◽  
Vol 16 ◽  
Author(s):  
Diego Alejandro Dri ◽  
Maurizio Massella ◽  
Donatella Gramaglia ◽  
Carlotta Marianecci ◽  
Sandra Petraglia
Keyword(s):  
Artificial Intelligence ◽  
Machine Learning ◽  
Clinical Trials ◽  
Patient Safety ◽  
Drug Discovery ◽  
Clinical Applications ◽  
Clinical Development ◽  
Regulatory Approach ◽  
National Competent Authorities ◽  
Review Current

: Machine Learning, a fast-growing technology, is an application of Artificial Intelligence that has significantly contributed to drug discovery and clinical development. In the last few years, the number of clinical applications based on Machine Learning has constantly been growing. Moreover, it is now also impacting National Competent Authorities during the assessment of most recently submitted Clinical Trials that are designed, managed, or generating data deriving from the use of Machine Learning or Artificial Intelligence technologies. We review current information available on the regulatory approach to Clinical Trials and Machine Learning. We also provide inputs for further reasoning and potential indications, including six actionable proposals for regulators to proactively drive the upcoming evolution of Clinical Trials within a strong regulatory framework, focusing on patient safety, health protection, and fostering immediate access to effective treatments.

Regulatory and Technical Challenges in Incorporating Surrogate Tissue Profiling Strategies into Clinical Development Programs

2005 ◽  
pp. 249-261
Author(s):  
William Trepicchio ◽  
Monica Cahilly ◽  
Lisa Speicher ◽  
Judith Oestreicher ◽  
Michael Burczynski ◽  
...  
Keyword(s):  
Clinical Development ◽  
Development Programs ◽  
Tissue Profiling ◽  
Surrogate Tissue ◽  
Technical Challenges

scholarly journals Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design

US Neurology ◽  
2018 ◽  
Vol 14 (1) ◽  
pp. 47 ◽  
Author(s):  
Said R Beydoun ◽  
Jeffrey Rosenfeld
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Trial Design ◽  
Development Program ◽  
Clinical Trial Design ◽  
Clinical Development ◽  
Disease Heterogeneity ◽  
Clinical Development Program ◽  
Lateral Sclerosis

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

scholarly journals Elevated Serum Sorbitol and not Fructose in Type 2 Diabetic Patients

2010 ◽  
Vol 5 ◽  
pp. BMI.S4530 ◽  
Author(s):  
Gregory M. Preston ◽  
Roberto A. Calle
Keyword(s):  
Elevated Serum ◽  
Fold Increase ◽  
Clinical Development ◽  
Gas Chromatography Mass Spectrometry ◽  
Diabetic Patients ◽  
Dose Selection ◽  
Type 2 Diabetic Patients ◽  
Early Proof ◽  
Proof Of Mechanism

Reductions in fasting serum fructose or erythrocyte sorbitol have been proposed as markers for early proof of mechanism in clinical development of aldose reductase (AR) inhibitors. However fructose is significantly impacted by meals and evaluation of erythrocyte sorbitol poses technical challenges. To more accurately assess the performance of these markers in biological samples, a gas chromatography-mass spectrometry assay was modified and validated. Serum was collected on three consecutive days from 13 healthy volunteers (HV) and 14 patients with type 2 diabetes mellitus (T2DM), and assayed for sorbitol and fructose using this assay. Serum fructose and sorbitol were relatively constant across the three days. Fasting fructose levels were comparable between the two groups (T2DM: 1.48 ± 0.49 mg/L; HV: 1.39 ± 0.38 mg/L, mean ± standard deviation, P = 0.61), but fasting sorbitol levels were significantly higher in diabetics (T2DM: 0.280 ± 0.163 mg/L; HV: 0.164 ± 0.044 mg/L, P = 0.02). Feeding resulted in a 5–6 fold increase in serum fructose levels, but only a 5%-10% increase in sorbitol. Only sorbitol remained significantly elevated pre- and post feeding in T2DM patients relative to HV. These data suggest that serum sorbitol may be a robust proof of mechanism biomarker and facilitate dose selection for clinical development of AR inhibitors.

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