Clinical Trials of Novel Therapeutic Agents: Why did they fail?

Author(s):  
S. M. Opal
2005 ◽  
Vol 12 (2) ◽  
pp. 91-104 ◽  
Author(s):  
Wee Joo Chng ◽  
Lee Gong Lau ◽  
Noorainun Yusof ◽  
Benjamin M. F. Mow

Background: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. Methods: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. Results: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. Conclusions: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients.


2019 ◽  
Vol 25 (26) ◽  
pp. 2792-2807 ◽  
Author(s):  
Pobitra Borah ◽  
Satyendra Deka ◽  
Raghu Prasad Mailavaram ◽  
Pran Kishore Deb

Background: Adenosine mediates various physiological and pathological conditions by acting on its four P1 receptors (A1, A2A, A2B and A3 receptors). Omnipresence of P1 receptors and their activation, exert a wide range of biological activities. Thus, its modulation is implicated in various disorders like Parkinson’s disease, asthma, cardiovascular disorders, cancer etc. Hence these receptors have become an interesting target for the researchers to develop potential therapeutic agents. Number of molecules were designed and developed in the past few years and evaluated for their efficacy in various disease conditions. Objective: The main objective is to provide an overview of new chemical entities which have crossed preclinical studies and reached clinical trials stage following their current status and future prospective. Methods: In this review we discuss current status of the drug candidates which have undergone clinical trials and their prospects. Results: Many chemical entities targeting various subtypes of P1 receptors are patented; twenty of them have crossed preclinical studies and reached clinical trials stage. Two of them viz adenosine and regadenoson are approved by the Food and Drug Administration. Conclusion: This review is an attempt to highlight the current status, progress and probable future of P1 receptor ligands which are under clinical trials as promising novel therapeutic agents and the direction in which research should proceed with a view to come out with novel therapeutic agents.


2020 ◽  
Vol 3 (4) ◽  
pp. e203284 ◽  
Author(s):  
Audrey D. Zhang ◽  
Jeremy Puthumana ◽  
Nicholas S. Downing ◽  
Nilay D. Shah ◽  
Harlan M. Krumholz ◽  
...  

Critical Care ◽  
2019 ◽  
Vol 23 (1) ◽  
Author(s):  
Simon Lambden ◽  
Pierre Francois Laterre ◽  
Mitchell M. Levy ◽  
Bruno Francois

AbstractThe Sequential Organ Failure Assessment or SOFA score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose across a range of healthcare settings and environments.In recent years, the SOFA score has become extensively used in a range of other applications. A change in the SOFA score of 2 or more is now a defining characteristic of the sepsis syndrome, and the European Medicines Agency has accepted that a change in the SOFA score is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis. The requirement to detect modest serial changes in a patients’ SOFA score therefore means that increased clarity on how the score should be assessed in different circumstances is required.This review explores the development of the SOFA score, its applications and the challenges associated with measurement. In addition, it proposes guidance designed to facilitate the consistent and valid assessment of the score in multicentre sepsis trials involving novel therapeutic agents or interventions.ConclusionThe SOFA score is an increasingly important tool in defining both the clinical condition of the individual patient and the response to therapies in the context of clinical trials. Standardisation between different assessors in widespread centres is key to detecting response to treatment if the SOFA score is to be used as an outcome in sepsis clinical trials.


Thorax ◽  
2010 ◽  
Vol 65 (Suppl 4) ◽  
pp. A11-A11 ◽  
Author(s):  
E. W. F. W. Alton ◽  
C. Boyd ◽  
S. Cunningham ◽  
J. C. Davies ◽  
S. C. Hyde ◽  
...  

1996 ◽  
Vol 20 (4) ◽  
pp. 493-498 ◽  
Author(s):  
Arthur E. Baue ◽  
Rodney M. Durham ◽  
John E. Mazuski

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