Systems Therapeutics: Diagram, Definitions and Illustrative Examples

Executive Summary

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed, consisting of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level. These different levels of interactions then determine four different systems therapeutics categories. Illustrative examples of these four different systems therapeutics categories are provided, as well as a glossary of the systems components. The systems therapeutics diagram further suggests that the wide interpatient variability in therapeutic response characteristics to approved drugs is contributed to by variabilities in both of these two processes. It is hoped that the systems therapeutics framework advanced here will promote discussions regarding the need for better understanding of the determinants of therapeutic response characteristics of modern therapeutics. 

Contents:

  • Executive Summary
  • Introduction
  • Systems Therapeutics Diagram
  • Systems Therapeutics Categories
  • Systems Therapeutics Illustrative Examples
  • Discussion
  • References
  • Glossary

Introduction

While a large number of new drugs have been approved by regulatory agencies over the past several decades, and we have witnessed significant scientific advances in molecular understanding of pharmacologic mechanisms and disease processes, there have only been sporadic efforts towards the construction of frameworks for understanding how pharmacologic and pathophysiologic processes interact to produce therapeutic effects. One noteworthy effort was presented by Grahame-Smith & Aronson in the Oxford Textbook of Clinical Pharmacology and Drug Therapy, which describes the chain of events linking the pharmacologic effects of drugs to their clinical effects, including several examples (1). An earlier effort by this author on classification of drug action based on therapeutic effects  was published in 1996 (2). More recent efforts have included a comprehensive white paper on quantitative and systems pharmacology by Sorger et al. of the QSP Workshop Group, including recommendations (3).

The purpose of this paper is to provide an updated summary of a systems therapeutics framework, depicting pharmacologic and pathophysiologic processes separately, thus enabling the presentation of the different biologic levels of interactions between these two processes. This paper summarizes and updates five previous iterations on the systems therapeutics framework posted on the Therapeutics Research Institute’s website, TRI-institute.org, between April 2015 and February 2018 (4,5,6,7,8). During this period, this has included an evolving construction of a systems therapeutics diagram, four systems therapeutics categories, relevant definitions, and illustrative examples of the different categories, as well as a discussion of variabilities in pharmacologic and pathophysiologic processes.

Systems Therapeutics Diagram

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response (see diagram below; click for a larger diagram).

The organizing principle underlying the systems therapeutics diagram presented above involves two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level. The systems components for pharmacologic processes start with a pharmacologic response element, followed by a pharmacologic mechanism, a pharmacologic response, and a clinical effect, whereas the systems components for pathophysiologic processes start with an etiologic causative factor, followed by a pathogenic pathway, a pathophysiologic process, and a disease manifestation. The four different biologic levels of interactions between these two processes then determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level), and Category IV (at the clinical level), as previously outlined (4). Brief descriptions of the individual systems therapeutics components are provided in the glossary below, including examples for each component.

Both of these two processes are initiated by their own sets of initiators or drivers, i.e., a pharmacologic agent and an intrinsic operator, for the pharmacologic and pathophysiologic processes, respectively. On the pharmacologic process side, a pharmacologic agent, interacting with a pharmacologic response element, and its concentration or exposure, is the fundamental driver of pharmacologic processes. On the pathophysiologic process side, a hypothetical intrinsic operator is proposed as an integral systems component interacting with and influencing an etiologic causative factor, and serving as a driver of pathophysiologic processes. This hypothetical intrinsic operator is intended to cover different biologic entities being identified using advanced bioinformatics and network-based approached, as previously discussed (5,6).

The culminating result of the interaction between these two processes, independent of the biologic level of interaction, involves a clinical therapeutic response. While it is well recognized that there is a wide variability in the clinical therapeutic response of individual patients to a given approved drug (9,10), it is less well recognized that both of these two processes, pharmacologic and pathophysiologic, have their inherent variabilities. This systems therapeutics construct thus further suggests that interpatient variabilities in both of these active processes contribute to and thus are co-determinants of the ultimate patient therapeutic response characteristics, including range and extent of response, response variability, and responder rate. Presently, however, the relative contributions of each of these process variabilities to the ultimate therapeutic response are typically unclear, most significantly due to limited availability of data and methods, and are likely to vary from one therapeutic class to another. A general commentary (5) discussed variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression).

Systems Therapeutics Categories

The systems therapeutics diagram presented here lends itself to determine four systems therapeutics categories, corresponding to the four different biologic levels of interactions between pharmacologic processes and pathophysiologic processes, as follows:

  • Category I – Molecular Level: Elements/Factors
  • Category II – Cellular Level: Mechanisms/Pathways
  • Category III – Tissue/Organ Level: Responses/Processes
  • Category IV – Clinical level: Effects/Manifestations

A further description of each of these systems therapeutics categories is provided below, including definitions and examples of pharmacologic classes and approved drugs for each.

Category I – Molecular Level: Elements/Factors

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves the primary corresponding molecular entities, the pharmacologic response element and the etiologic causative factor, respectively.

Examples of Molecular-based Therapy – These can involve replacement therapies (hormones, enzymes, proteins, genes) or genome-based therapies (interference with altered gene products):

  • Enzyme replacement therapy, e.g., Elaprase (idursulfase) for Hunter Syndrome
  • Protein replacement therapy, e.g., Recombinate (recombinant Factor VIII) for Hemophilia A
  • Potentiation of defective protein, e.g., Kalydeco (ivacaftor) for Cystic Fibrosis
  • Inhibition of abnormal enzyme, e.g., Gleevec (imatinib) for Chronic Myelogenous Leukemia (CML)

Category II – Cellular Level: Mechanisms/Pathways

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves a fundamental biochemical mechanism, related to the disease evolution, although not necessarily an etiologic pathway.

Examples of Metabolism-based Therapy – These can involve metabolism-based therapies (interference with a biochemical mechanism or a disease network-linked pathway):

  • HMG-CoA Reductase Inhibitors (statins), e.g., Lipitor (atorvastatin) for Hypercholesterolemia
  • TNF-a Inhibitors, e.g., Humira (adalimumab) for Rheumatoid Arthritis
  • Proton Pump Inhibitors, e.g., Nexium (esomeprazole) for Gastric Reflux & Ulcer Disease

Category III – Tissue/Organ Level: Responses/Processes

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves a modulation of a (normal) physiologic function, linked to the disease evolution, although not necessarily an etiologic pathway.

Examples of Function-based Therapy – These can involve function-based therapies (modulation of a (normal) physiologic function or activity):

  • Angiotensin II Blockers, e.g., Avapro (irbesartan) for Hypertension
  • PDE-5 Inhibitors, e.g., Cialis (tadalafil) for Male Erectile Dysfunction
  • Factor Xa Inhibitors, e.g., Eliquis (apixaban) for Thrombosis

Category IV – Clinical Level: Effects/Manifestations

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves an effect directed at clinical symptom(s) of a disease, but not directly its cause or etiology.

Examples of Symptom-based Therapy – These can involve symptom-based therapies (various symptomatic or palliative treatments):

  • Antipyretics, e.g., Tylenol (acetaminophen) for lowering high body temperature
  • Analgesics, e.g., Advil (ibuprofen) for Osteoarthritis 
  • Antitussives, e.g., Delsym (dextromethorphan) for cough suppression

Systems Therapeutics Illustrative Examples

Below are illustrative examples for each of the four systems therapeutics categories. The charts follows the design of the systems therapeutics diagram discussed above. The pivotal connection between pharmacologic and pathophysiologic processes represents the fundamental or primary interaction between these processes (represented by a fat arrow), thus determining the systems therapeutics category; these are followed by dependent or secondary connections to the right (represented by thin arrows). The descriptions for the individual systems components were generated from generally available textbooks of pharmacology, pathophysiology and medicine, and other sources, but with an emphasis on a separation of pharmacologic and pathophysiologic concepts and processes, culminating in a therapeutic response.

Illustrative Example for Category I:

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator for Cystic Fibrosis.
See diagram below; click for a larger diagram.

Illustrative Example for Category II:

Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD)
See diagram below; click for a larger diagram.

Illustrative Example for Category III:

Angiotensin-Converting Enzyme (ACE) Inhibitors for Hypertension
See diagram below; click for a larger diagram.

Illustrative Example for Category IV:

Non-Steroidal Anti-inflammatory Agents (NSAIDs) for Osteoarthritis
See diagram below; click for a larger diagram.

Discussion

The systems therapeutics diagram has been constructed with the goal of serving to facilitate better understanding and discussion of the different types of successful therapies involving approved drugs. Importantly, this framework shows the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a singular pharmacotherapeutic process, and thus illustrating at what biologic level the pharmacologic and pathophysiologic processes interact to result in a therapeutic response. The illustrative examples presented for the four different systems therapeutics categories offer descriptions of the two progressing processes in a storyboard-like fashion, highlighting at what biology level the pivotal interaction occurs between these two processes. 

In addition to the systems components for pharmacologic processes and pathophysiologic processes are the two initiators or drivers of these two processes, one actual (pharmacologic agent), the other hypothetical (intrinsic operator). The former driver is well recognized, including its concentration or exposure, while the rationale for the latter is based on recent bioinformatics and network-based approaches indicating that disease initiation can involve interactions between genetic and non-genetic components, although major research efforts are needed to elucidate the nature of these interactions (5,11). Also, one can speculate that the wide range in the age of disease onset for different diseases, from first year of life to late in life, does suggest unrecognized driving factors acting on an etiologic causative factor. At the present time, however, we are not aware of any current pharmacologic agent/mechanism interacting with such a hypothetical intrinsic operator (which when identified could be represented as systems therapeutics Category Zero). 

It is our hope that the systems therapeutics framework advanced here will help stimulate research towards better understanding of the relationships between the biologic levels of interactions between pharmacologic and pathophysiologic processes on one hand and the therapeutic response characteristics of modern therapeutics on the other. It has previously been noted that although this systems-based framework does not explicitly address interpatient variability in therapeutic response, this framework clearly suggests that variabilities in pharmacologic processes and pathophysiologic processes both contribute to the overall variability in therapeutic response. We further hope that this framework will stimulate research towards better qualitative and quantitative descriptions of the pharmacologic and pathophysiologic processes, including ways of defining the relative contributions of these two processes towards determining the overall therapeutic response characteristics.

References

  1. Grahame-Smith DG, Aronson JK (1992). Oxford Textbook of Clinical Pharmacology and Drug Therapy, Oxford University Press, Oxford (Chapter 5. The Therapeutic Process, pp. 55-66).
  2. Bjornsson TD (1996). A classification of drug action based on therapeutic effects. J. Clin. Pharmacol., 36:669-673.
  3. Sorger PK, Allerheiligen SRB, Abernethy DR, et al. (2011). Quantitative and systems pharmacology in the post-genomic era: New approaches to discovering drugs and understanding therapeutic mechanisms. An NIH white paper by the QSP workshop group. Bethesda: NIH (pp. 1-47).
  4. Therapeutics Research Institute. Systems Therapeutics: A Diagram and Four Categories, April 2015. http://tri-institute.org/niDFW
  5. Therapeutics Research Institute. Systems Therapeutics: Variabilities, May 2016. http://tri-institute.org/TyQij
  6. Therapeutics Research Institute. Systems Therapeutics: Updated Diagram, October 2016. http://tri-institute.org/S2j9D
  7. Therapeutics Research Institute. Systems Therapeutics: Where Pharmacologic and Pathophysiologic Processes Interact, February 2017. http://tri-institute.org/9sPlA
  8. Therapeutics Research Institute. Systems Therapeutics: Representative Illustrative Example for Category II. March 2018. http://tri-institute.org/nehUV
  9. Rowland M, Tozer TN (2011). Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, Fourth edition, Lippincott Williams & Wilkins, Philadelphia (Chapter 12, Variability, pp. 333-356).
  10. Eichler HG, Abadie E, Breckenridge A, Flamion B, Gustafsson LL, Leufkens H, Rowland M, Schneider CK, Bloechl-Daum B (2011). Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat. Rev. Drug Disc., 10:495-506.
  11. Barabasi AL, Gulbahce N, Loscalzo J (2011). Network medicine: a network-based approach to human disease. Nat. Rev. Genetics, 12:56-68

Glossary

Below is a glossary of the individual systems components for the pharmacologic and pathophysiologic processes represented in the systems therapeutics diagram presented above. Examples for each systems component are from among approved treatments and diseases that have previously been addressed in individual posts on the Therapeutics Research Institute’s website, TRI-institute.org.  

Pharmacologic Processes

Pharmacologic Agent 
A compound, could be a small molecule or a large bio-pharmaceutical, that initiates the pharmacologic process by interacting with a pharmacologic response element.

Examples:
   Nexium (esomeprazole), and
   Viagra (sildenafil)

Pharmacologic Response Element
A native biologic element, could be a receptor or an enzyme, with which a pharmacologic agent interacts (pharmacologic interaction). Commonly referred to as a pharmacologic target.

Examples:
   H+/K+ ATPase (proton pump); and
   cGMP-specific phosphodiesterase type 5 (PDE5).

Pharmacologic Mechanism
Molecular mechanism of action, typically involving a molecular pathway resulting in a biochemical reaction (signal transduction).

Examples:
   Inhibition of proton pump (for Acid Reflux and Ulcer Disease); and
   Inhibition of PDE5 (for Male Erectile Dysfunction).

Pharmacologic Response
Pharmacologic effect at the tissue/organ level mediated through a pharmacologic mechanism (pharmacodynamics).

Examples:
   Decreased gastric acid secretion resulting in decreased acidity (by proton pump inhibitor); and
   Smooth muscle relaxation in corpus cavernosum leading to increased blood flow (by PDE5 inhibitor).

Clinical Effect
A pharmacologic effect at the clinical level, which represents the pharmacologic basis for a therapeutic response (translation).

Examples:
   Decreased symptoms from gastric acidity (by proton pump inhibitor); and
   Increased erection (by PDE5 inhibitor).

Pathophysiologic Processes

Intrinsic Operator
A hypothetical entity interacting with and influencing an etiologic causative factor, serving as a driver of a pathophysiologic process. Could be genetic or non-genetic.

Examples:
   Currently typically not known 

Etiologic Causative Factor
A genetic or non-genetic factor, upon interaction with an intrinsic operator (disease preindication), determines a disease specific progression.

Examples:
   Dihydrotestosterone (DHT)-induced growth factors and their receptors (in Benign Prostatic Hyperplasia); and
   Post-menopausal and age-related osteoporosis is initiated by a developing imbalance between net bone formation and resorption (in Osteoporosis).

Pathogenic Pathway
Molecular pathogenic pathway mediating ongoing disease progression (disease initiation).

Examples:
   DHT-induced growth factors stimulate proliferation of stromal cells (in Benign Prostatic Hyperplasia); and
   The normally regulated bone remodeling process is modulated by numerous systemic factors (in Osteoporosis)

Pathophysiologic Process
Ongoing pathophysiologic process (pathogenesis).

Examples:
   Formation of  discrete hyperplastic nodules in periurethral region (in Benign Prostatic Hyperplasia); and
   Gradual and continuing loss of bone mineral density, decreased bone quality, with increased risk of fracture (in Osteoporosis)

Disease Manifestation
Development of characteristic clinical signs and symptoms associated with a given disease (progression), typically independent of a specific etiologic causative factor.

Examples:
   Lower urinary tract symptoms (in Benign Prostatic Hyperplasia); and
   Loss of bone mineral density and risk of bone fracture (in Osteoporosis).

Therapeutic Response
Therapeutic benefit of a drug on which approval is based, showing a beneficial change in specific objective and/or subjective measures of a disease.

Examples:
   Symptom relief and mucosal healing (e.g., after proton pump nhibitors in Acid Reflux and Ulcer Disease)
   Improved erection (e.g., after PDE5 inhibitors in Male Erectile Dysfunction)
   Decreased urinary frequency (e.g., after 5-alpha reductase inhibitors in Benign Prostatic Hyperplasia)
   Decreased bone fractures (e.g., after bisphosphonates in Osteoporosis)

Systems Therapeutics: Representative Illustrative Example for Category II

Introduction

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed (1), consisting of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and the clinical level, culminating in a therapeutic response. The interactions at these different biologic levels then determine the four different systems therapeutics categories, Categories I – IV. The above referenced summary only named therapeutic class examples for each of the four systems therapeutics categories, but did not include representative illustrative examples for each of these categories.

The purpose of this post is to provide an illustrative example for one of the systems therapeutics categories, Category II, where the pivotal interaction between the pharmacologic and pathophysiologic processes involves a fundamental biochemical mechanism at the cellular level, related to the disease evolution, although not necessarily an etiologic pathway. The illustrative example chosen for Category II involves Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD). Future communications will provide illustrative examples for the other systems therapeutics categories.

Illustrative Example for Category II

The chart below (click for a larger view) illustrates the individual systems components for pharmacologic and pathophysiologic processes for Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD), culminating in a therapeutic response.

This chart follows the design of the systems therapeutics diagram previously referenced (1), which includes definitions of the individual systems therapeutics categories and a glossary of the individual systems components. The chart was developed using OmniGraffle (The Omni Group, Seattle, WA). The bold connection between pharmacologic and pathophysiologic processes represents the pivotal interaction between these processes, which here is at the cellular level (Category II). The descriptions for the individual systems components were generated from generally available textbooks of pharmacology, pathophysiology and medicine, and other sources, but with an emphasis on a separation of pharmacologic and pathophysiologic concepts and processes, culminating in a therapeutic response.

Comments

The systems therapeutics framework referenced above (1), including a diagram, four categories, definitions and a glossary, was constructed with the goal of serving to facilitate discussion and understanding of the different types of FDA approved drugs. Importantly, this framework attempts to illustrate the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a singular pharmacotherapeutic process, in contrast to previously published attempts, thus enabling highlighting at what level the pharmacologic process engages with the pathophysiologic process. It has previously been noted that this systems-based framework does not explicitly address interpatient variability in therapeutic response, although this framework clearly suggests that variabilities in pharmacologic processes and pathophysiologic processes both contribute to the overall variability in therapeutic response. A general commentary on variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression) has been previously published (2).

The chart presented in this publication has provided a representative illustrative example for one of the four systems therapeutics categories (Category II). It is hoped that this illustration will serve as a useful example of how the systems therapeutics framework can provide a framework for facilitating discussions concerning various aspects of different therapeutics, as well as suggesting areas in need of future research and better understanding.

References

  1. Systems Therapeutics: Where Pharmacologic and Pathophysiologic Processes Interact. Therapeutics Research Institute, February 2017.
    This post summarizes the systems therapeutics framework, including the systems therapeutics diagram, its four categories, related definitions, as well as a glossary. Note the example presented above for Category II was initially named as Category III.
  2. Systems Therapeutics: Variabilities. Therapeutics Research Institute, May 2016. 
    This post discusses variability in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression). Note the systems therapeutics diagram in this post represents an earlier version of the diagram. 

 

 

 

 

Infographics of Modern Therapeutics

Introduction

The purpose of this report is to provide highlights from two posts involving infographics of modern therapeutics, since these posts were originally only listed under their months of posting, but not indicating their titles. These were as follows:

The graphs in these two posts are in addition to extensive infographics on the progression of 40 therapeutic classes, across 14 therapeutic categories, included in Progression of Modern Therapeutics, issued January 2016, and in a more extended reporting on 16 therapeutic classes, summarized in List of 16 Posts on Individual Therapeutic Classesissued January 2018.

Methodology

The data used in both of these two above referenced posts are originally from Progression of Modern Therapeutics, which covers 40 therapeutic classes from 14 therapeutic categories, and which includes a detailed description of the methodology and definitions used in this project. Note the following definitions used throughout:

  • Modern therapeutics – refers to those new drug approvals belonging to a given pharmacologic class that were first approved in the 1970’s to 1980’s timeframe and going forward, as further defined in Progression of Modern Therapeutics.
  • Pharmacologic class – refers typically to a biologic target-based or mechanism of action-related classification, but in some instances involves a chemical classification, or a mix of the two.
  • Therapeutic class – refers to new drug approvals for a given disease or indication, independent of pharmacologic class.
  • Therapeutic category – refers to approved therapeutics in a given anatomical organ or system.
  • Length of registration interest – refers to the time interval between the dates of the first and the latest new drug approval within a given pharmacologic class.

Number of Pharmacologic Classes per Therapeutic Classes

The number of pharmacologic classes per individual therapeutic classes for new drug approvals is shown in the graph below, in a descending order, for 38 of the 40 therapeutic classes covered in Progression of Modern Therapeutics. 

Click here for a larger graph. Note the wide range in the number of pharmacologic classes per therapeutic classes, ranging from 11 and 9 for Type-2 Diabetes and Multiple Sclerosis, respectively, and 8 each for Rheumatoid Arthritis and Melanoma, to 1 each for Idiopathic Thrombocytopenic Purpura and Systemic Lupus Erythematosus, and several therapeutic classes with 2 each, including Alzheimer’s Disease and Schizophrenia. Note that the mean and median for the number of pharmacologic classes per individual therapeutic classes (N=38) are 4.3 and 4.0, respectively.

New Drug Approvals per Therapeutic Classes

The number of new drug approvals for 38 of the 40 therapeutic classes covered in Progression of Modern Therapeutics is shown in the graph below, in descending order. 

Click here for a larger graph. Note the wide variability in the number of new drug approvals for the different therapeutic classes, ranging from 44 for Hypertension, 28 for HIV-1/AIDS, 27 for Type-2 Diabetes and 23 for Schizophrenia, to 1 for Systemic Lupus Erythematosus, 2 each for Idiopathic Thrombocytopenic Purpura and Idiopathic Pulmonary Fibrosis (both orphan indications) and 3 for Fibromyalgia. Note that the mean and median for the number of new drug approvals per individual therapeutic classes (N=38) are 11.5 and 9.5, respectively.

Selected Snapshots from Noteworthy Patterns in Registration Avivities

Below are two selected snapshots based on data in Progression of Modern Therapeutics, each illustrating a specific pattern in registration activities of modern therapeutics:

Snapshot #1: Two therapeutic classes showing two key pharmacologic classes with no overlaps in registration activities, i.e., H2 Receptor Antagonists and Proton Pump Inhibitors for Acid Reflux and Ulcer Disease, and Benzodiazepines and Non-benzodiazepines for Insomnia. Both examples show an abrupt switch in new drug introductions from older pharmacologic classes to newer pharmacologic classes. For a larger graph click here.

no overlap

Snapshot #2: Two therapeutic classes showing two key pharmacologic classes with overlaps in registration activities, i.e., Corticosteroids and Beta-2 Adrenergic Agonists for Asthma, and SSRI’s and SNRI’s for Depression. Both examples show concurrent new drug introductions for two dominant or somewhat similar pharmacologic classes or mechanisms of action. For a larger graph click here.

overlap

Length of Registration Interest

Perusal of the graphs for 40 therapeutic classes in Progression of Modern Therapeutics also illustrates a wide variability in the length of registration interest, i.e., the time interval between the dates of the first and the latest new drug approval within a given pharmacologic class (shown on the right hand side of the graphs). Of the more than 180 pharmacologic classes covered, it is if interest to note that 16 classes have lengths of registration interest longer than 25 years, e.g., Beta-Blockers for Hypertension (40.1 decimal years) and Typical and Atypical Antipsychotics for Schizophrenia (26.9 and 25.9 decimal years, respectively), and that lengths between 10 and 20 years are quite common for established pharmacologic classes, e.g., TNF Inhibitors for Rheumatoid Arthritis (10.5 decimal years) and PDE-5 Inhibitors for Erectile Dysfunction (14.1 decimal years).

Comments

The infographics of modern therapeutics presented in this report involve examples from two previous posts, but are highlighted here, since the original posts were only listed under their months of posting (February 2016 and June 2016), but not indicating their titles. 

The graphs and texts illustrate wide variability in new drug approvals among the different pharmacologic classes and therapeutic classes. This involves both the number of pharmacologic classes per individual therapeutic classes, and the number of new drug approvals per individual therapeutic classes. For example, the number of pharmacologic classes per individual therapeutic classes ranged from 11 (Type-2 Diabetes) to 1 (Systemic Lupus Erythematosus), and the number of new drug approvals per individual therapeutic classes ranged from 44 (Hypertension) to 1 (Systemic Lupus Erythematosus). Also noteworthy is that 16 pharmacologic classes of the more than 180 covered have lengths of registration interest longer than a quarter of a century; also note the most common interval of lengths of registration interest is 10-20 years (31 pharmacologic classes), for lengths longer than 5 years.

Note these graphs only involve new drug approvals, and do not include generics, new formulations, or new trademarks of previously approved chemical entities. Also note these graphs and texts are based on data available in early 2016; there may have been a few new drug approvals in some of the covered therapeutic classes since then, but not so much as to alter the key conclusions presented.

It is tempting to speculate what might be the reasons underlying such wide variabilities in the number of pharmacologic classes per therapeutic classes, in the total number of new drug approvals per therapeutic classes, and in the relatively long periods of registration interest for numerous pharmacologic classes, but that will be left to another time. Public discussion on these important topics, however, is very important, since at a high level, these are likely to relate to how society in general – including the academic research community, the regulatory agencies, the pharmaceutical R&D community, and patient and disease organizations – attempt to address varying degrees of scientific knowledge about disease etiology and pathophysiology, levels of research funding, commercial assessment, and different levels of unmet medical need. 

List of 16 Posts on Progression of Individual Therapeutic Classes

Introduction

Of the 40 therapeutic classes (across 14 therapeutic categories) that have examined Progression of Modern Therapeutics (last report issued in early 2016, under Reports) a more extended reporting has been made on a total of 16 therapeutic classes, under Posts. The majority of these posts involved the following subtitles: Background, Drug Approvals, Comments, and References (as appropriate), as exemplified by the post on Benign Prostatic Hyperplasia (BPH: Relying on Mechanisms First Approved a Quarter of a Century Ago, August 2016, click here), in addition to a timeline chart illustrating the individual approved drugs and their mechanisms of action.

Since these posts on individual therapeutic classes were only listed under their months of posting, the purpose of this reporting is to summarize 16 of these therapeutic classes under their therapeutic categories, including the titles of these posts.

Cardiovascular Therapeutics
Hypertension Progression of Modern Antihypertensive Therapeutics: An Example of a Mature Therapeutic Class. (December 2014) Click here.
Dyslipidemia Lipid Lowering Drugs: Steady Progress Over Half a Century. (September 2015) Click here.

Hematologic Therapeutics
Thrombosis Progression of Modern Antithrombotic Drugs: What’s Next? (January 2015) Click here.

Gastroenterologic Therapeutics
Acid Reflux and Ulcer Disease Progression of Acid Reflux and Ulcer Disease Therapeutics. (October 2014) Click here.
Irritable Bowel Syndrome IBS: Underlying Mechanism(s) Not Established but Six New Drug Approvals Since 2000. (September 2016) Click here.

Endocrinologic Therapeutics
Type-2 Diabetes Progression of Modern Therapeutics for Type-2 Diabetes. (November 2014) Click here.
Obesity Weight Reduction Drugs: Slow Progression and Innovation. (March 2015) Click here.
Osteoporosis Osteoporosis: Better Drugs and Better Scientific Understanding Needed. (July 2016) Click here.

Psychopharmacologic Therapeutics
Schizophrenia and Depression Slow Progress in Psychopharmacologic Therapeutics. (September 2014) Click here.
Attention Deficit Hyperactivity DisordeADHD Therapeutics: Slow and Limited Progress. (November 2015) Click here.
Insomnia Modern Insomnia Therapeutics: Not the Barbiturates or Anxiolytic Benzodiazepines of Yore. (April 2016) Click here.

Neurologic Therapeutics
Alzheimer’s Disease Alzheimer’s Disease: Many Years to Go. (June 2015) Click here.
Migraine Migraine Therapeutics: Slow Progress Towards Precision Medicine. (December 2015) Click here.

Rheumatologic Therapeutics
Rheumatoid Arthritis Progression of Modern Therapeutics for Rheumatoid Arthritis. (October 2015) Click here.
Gout and Hyperuricemia Gout and Hyperuricemia: Reliance on Old Mechanisms. (March 2016) Click here.

Genitourinary Therapeutics
Benign Prostatic Hyperplasia BPH: Relying on Mechanisms First Approved a Quarter of a Century Ago. (August 2016) Click here.

Systems Therapeutics: Where Pharmacologic and Pathophysiologic Processes Interact

Executive Summary

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed, consisting of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level; these different levels then determine four different systems therapeutics categories. Both of these two processes are initiated by their own sets of initiators or drivers, i.e., a pharmacologic agent and an intrinsic operator, for the pharmacologic and pathophysiologic processes, respectively. The systems therapeutics framework further suggests that the wide variability in therapeutic response characteristics to approved drugs is contributed to by variabilities in both of these two processes. Examples are provided for each of the four systems therapeutics categories, and a glossary is provided for the individual systems components.

Contents:

  • Executive Summary
  • Introduction
  • Systems Therapeutics Diagram
  • Systems Therapeutics Categories
  • Discussion
  • References
  • Glossary

Introduction

While a large number of new drugs have been approved by regulatory agencies over the past several decades, and we have witnessed significant scientific advances in molecular understanding of pharmacologic mechanisms and disease processes, there have only been sporadic efforts towards the construction of frameworks for understanding how pharmacologic and pathophysiologic processes interact to produce therapeutic effects. One noteworthy effort was presented by Grahame-Smith & Aronson in the Oxford Textbook of Clinical Pharmacology and Drug Therapy, which describes the chain of events linking the pharmacologic effects of drugs to their clinical effects, including several examples (1). An earlier effort by this author on drug classification of drug action based on therapeutic effects  was published in 1996 (2). More recent efforts have included a comprehensive white paper on quantitative and systems pharmacology by Sorger et al. of the QSP Workshop Group, including recommendations (3).

The purpose of this paper is to present a systems therapeutics framework, depicting pharmacologic and pathophysiologic processes separately, thus enabling the illustration of the different biologic levels of interactions between these two processes, and including definitions and examples. We hope this framework will be useful when examining the different types of therapeutic effects and discussing sources of variabilities in therapeutic effects. This paper on systems therapeutics summarizes and updates three previous iterations on a systems therapeutics framework posted on the Therapeutics Research Institute’s website, between April 2015 and October 2016 (4,5,6).

Systems Therapeutics Diagram

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce in a clinical therapeutic response (see diagram below; click for a larger diagram).

The systems therapeutics diagram presented above consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level. The systems components for pharmacologic processes start with a pharmacologic response element, followed by a pharmacologic mechanism, a pharmacologic response, and a clinical effect, whereas the systems components for pathophysiologic processes start with an etiologic causative factor, followed by a pathogenic pathway, a pathophysiologic process, and a disease manifestation. The four different biologic levels of interactions between these two processes then determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level), and Category IV (at the clinical level), as previously outlined (4).

Both of these two processes are initiated by their own sets of initiators or drivers, i.e., a pharmacologic agent and an intrinsic operator, for the pharmacologic and pathophysiologic processes, respectively. On the pharmacologic processes side, a pharmacologic agent, interacting with a pharmacologic response element, and its concentration or exposure, is an undisputed fundamental driver of pharmacologic processes. On the pathophysiologic processes side, a hypothetical intrinsic operator is proposed as an integral systems component interacting with and influencing an etiologic causative factor, and serving as a driver of pathophysiologic processes. This hypothetical intrinsic operator is intended to cover different biologic entities being identified using advanced bioinformatics and network-based approached, as previously presented (5,6).

The culminating result of the interaction between these two activated processes, independent of the biologic levels of interactions, involves a clinical therapeutic response. While it is well recognized that there is a wide variability in the clinical therapeutic response of individual patients to a given approved drug (7,8), it is less well recognized that both of these two processes, pharmacologic and pathophysiologic, have their inherent variabilities. This systems therapeutics construct thus further suggests that inter-patient variabilities in both of these active processes contribute to and thus are co-determinants of the ultimate patient therapeutic response characteristics, including range and extent of response, response variability, and responder rate. Presently, however, the relative contributions of each of these process variabilities to the ultimate therapeutic response are typically unclear, most significantly due to limited availability of data and methods, and are likely to vary from one therapeutic class to another. A general commentary on variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression) was previously provided (5).

Brief descriptions of the different systems therapeutics components are provided in the glossary below, including examples for each component.

Systems Therapeutics Categories

The systems therapeutics diagram presented here lends itself to determine four systems therapeutics categories, corresponding to the four different biologic levels of interactions between pharmacologic processes and pathophysiologic processes, as follows:

  • Category I – Molecular Level: Elements/Factors
  • Category II – Cellular Level: Mechanisms/Pathways
  • Category III – Tissue/Organ Level: Responses/Processes
  • Category IV – Clinical level: Effects/Manifestations

A further description of each of these systems therapeutics categories is provided below, including definitions and examples of pharmacologic classes and approved drugs for each.

Category I – Molecular Level: Elements/Factors

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves the primary corresponding molecular entities, the pharmacologic agent (or the pharmacologic response element) and the etiologic causative factor, respectively.

Examples – These can involve replacement therapies (hormones, enzymes, proteins, genes) or genome-based therapies (interference with altered gene products), resulting in a therapeutic effect:

Molecular-based Therapy

  • Enzyme replacement therapy, e.g., Elaprase (idursulfase) for Hunter Syndrome
  • Protein replacement therapy, e.g., Recombinate (recombinant Factor VIII) for Hemophilia A
  • Potentiation of defective protein, e.g., Kalydeco (ivacaftor) for Cystic Fibrosis
  • Inhibition of abnormal enzyme, e.g., Gleevec (imatinib) for Chronic Myelogenous Leukemia (CML)

Category II – Cellular Level: Mechanisms/Pathways

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves a fundamental biochemical mechanism, related to the disease evolution, although not necessarily an etiologic pathway.

Examples – These can involve metabolism-based therapies (interference with a biochemical mechanism or a disease network-linked pathway), resulting in a therapeutic effect:

Metabolism-based Therapy

  • HMG-CoA Reductase Inhibitors (statins), e.g., Lipitor (atorvastatin) for Hypercholesterolemia
  • Modulation of glucose metabolism (biguanides), e.g., Glucophage (metformin) for Type-2 Diabetes
  • TNF-a Inhibitors, e.g., Humira (adalimumab) for Rheumatoid Arthritis
  • Inhibition of microtubule polymerization, e.g., Colcrys (colchicine) for Gout

Category III – Tissue/Organ Level: Responses/Processes

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves a modulation of a (normal) physiologic function, linked to the disease evolution, although not necessarily an etiologic pathway.

Examples – These can involve function-based therapies (modulation of a (normal) physiologic function or activity), resulting in a therapeutic effect:

Function-based Therapy

  • Angiotensin II Blockers, e.g., Avapro (irbesartan) for Hypertension
  • PDE-5 Inhibitors, e.g., Cialis (tadalafil) for Male Erectile Dysfunction
  • Proton Pump Inhibitors, e.g., Nexium (esomeprazole) for Gastric Reflux & Ulcer Disease
  • Factor Xa Inhibitors, e.g., Eliquis (apixaban) for Thrombosis

Category IV – Clinical Level: Effects/Manifestations

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves an effect directed at clinical symptom(s) of a disease, but not directly its cause or etiology.

Examples – These can involve symptom-based therapies (various symptomatic or palliative treatments), resulting in a clinical therapeutic effect

Symptom-based Therapy

  • Antipyretics, e.g., Tylenol (acetaminophen) for lowering high body temperature
  • Analgesics, e.g., Advil (ibuprofen) for Ostoearthritis
  • Antihistamines, e.g., Allegra (fexofenadine) for allergic symptoms
  • Antitussives, e.g., Delsym (dextromethorphan) for cough suppression

Discussion

The systems therapeutics framework presented here has been constructed with the goal of serving to facilitate understanding and discussion of the different types of successful therapies involving approved drugs. Importantly, this framework shows the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a singular pharmacotherapeutic process, and thus illustrating at what biologic level the pharmacologic process engages with the pathophysiologic process.

The systems therapeutics diagram consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, thus determining four different systems therapeutic categories. The two initiators or drivers of these two processes are also depicted, one actual (pharmacologic agent), the other hypothetical (intrinsic operator). Our rationale for the latter is based on recent bioinformatics and network-based approaches indicating that disease initiation can involve interactions between genetic and non-genetic components, although major research efforts are needed to elucidate the nature of these interactions.

The examples provided here for the different systems therapeutic categories above, as well as those provided for the individual systems components under the glossary below, are being put forward to illustrate application of the systems therapeutics framework, recognizing that some of the examples still remain provisional, pending more detailed understanding and knowledge about the mechanisms involved. Furthermore, we hope improved infographics approaches to better illustrate the proposed systems therapeutics approach will make it more useful and insightful.

It is our hope that the systems therapeutics framework presented here will help stimulate work towards better understanding of the relationships between the biologic levels of interactions between pharmacologic and pathophysiologic processes on one hand and the therapeutic response characteristics of approved drugs on the other. We also hope that this framework will stimulate research towards better qualitative and quantitative descriptions of the pharmacologic and pathophysiologic processes, including ways of defining the relative contributions of these two processes towards determining the overall therapeutic response characteristics.

References

  1. Grahame-Smith DG, Aronson JK (1992). Oxford Textbook of Clinical Pharmacology and Drug Therapy, Oxford University Press, Oxford (Chapter 5. The Therapeutic Process, pp. 55-66).
  2. Bjornsson TD (1996). A classification of drug action based on therapeutic effects. J. Clin. Pharmacol., 36:669-673.
  3. Sorger PK, Allerheiligen SRB, Abernethy DR, et al. (2011). Quantitative and systems pharmacology in the post-genomic era: New approaches to discovering drugs and understanding therapeutic mechanisms. An NIH white paper by the QSP workshop group. Bethesda: NIH (pp. 1-47).
  4. Therapeutics Research Institute. Systems Therapeutics: A Diagram and Four Categories, April 2015. http://tri-institute.org/niDFW
  5. Therapeutics Research Institute. Systems Therapeutics: Variabilities, May 2016. http://tri-institute.org/TyQij
  6. Therapeutics Research Institute. Systems Therapeutics: Updated Diagram, October 2016. http://tri-institute.org/S2j9D
  7. Rowland M, Tozer TN (2011). Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, Fourth edition, Lippincott Williams & Wilkins, Philadelphia (Chapter 12, Variability, pp. 333-356).
  8. Eichler HG, Abadie E, Breckenridge A, Flamion B, Gustafsson LL, Leufkens H, Rowland M, Schneider CK, Bloechl-Daum B (2011). Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat. Rev. Drug Disc., 10:495-506.

Glossary

Note the examples chosen below are from among approved treatments and diseases that have been addressed in individual posts on the Therapeutics Research Institute’s website, TRI-institute.org, either in individual posts or annual reports. At this time, separate examples (high-level) are provided for pharmacologic processes and pathophysiologic processes for individual systems components. 

Pharmacologic Processes

Pharmacologic Agent 
A compound, could be a small molecule or a large bio-pharmaceutical, that initiates the pharmacologic process by interacting with a pharmacologic response element. Examples:

  • Nexium (esomeprazole), and
  • Viagra (sildenafil)

Pharmacologic Response Element
A native biologic element, could be a receptor or an enzyme, with which a pharmacologic agent interacts (pharmacologic interaction). Commonly referred to as a pharmacologic target. Examples:

  • H+/K+ ATPase or proton pump; and
  • cGMP-specific phosphodiesterase type 5 or PDE5.

Pharmacologic Mechanism
Molecular mechanism of action, typically involving a molecular pathway resulting in a biochemical reaction (signal transduction). Examples:

  • Inhibition of proton pump (for Acid Reflux and Ulcer Disease); and
  • Inhibition of PDE5 (for Male Erectile Dysfunction).

Pharmacologic Response
Pharmacologic effect at the tissue/organ level mediated through a pharmacologic mechanism (pharmacodynamics). Examples:

  • Decreased gastric acid secretion resulting in decreased acidity (by proton pump inhibitor); and
  • Smooth muscle relaxation in corpus cavernosum leading to increased blood flow (by PDE5 inhibitor).

Clinical Effect
A pharmacologic effect at the clinical level, which is the basis for a therapeutic effect (translation). Examples:

    • Decreased symptoms from gastric acidity (by proton pump inhibitor); and
  • Increased erection (by PDE5 inhibitor).

Pathophysiologic Processes

Intrinsic Operator
A hypothetical entity interacting with and influencing an etiologic causative factor, serving as a driver of a pathophysiologic process. Could be genetic or non-genetic.

Etiologic Causative Factor
A genetic or non-genetic factor, upon interaction with an intrinsic operator (disease preindication), determines a disease specific progression. Examples:

  • Dihydrotestosterone (DHT)-induced growth factors and their receptors (in Benign Prostatic Hyperplasia, BPH); and
  • Post-menopausal and age-related osteoporosis is initiated by a developing imbalance between net bone formation and resorption (in Osteoporosis).

Pathogenic Pathway
Molecular pathogenic pathway mediating ongoing disease progression (disease initiation). Examples:

  • DHT-induced growth factors stimulate proliferation of stromal cells (in BPH); and
  • The normally regulated bone remodeling process is modulated by numerous systemic factors (in Osteoporosis)

Pathophysiologic Process
Ongoing pathophysiologic process (pathogenesis). Examples:

  • Formation of  discrete hyperplastic nodules in periurethral region (in BPH); and
  • Gradual and continuing loss of bone mineral density, decreased bone quality, with increased risk of fracture (in Osteoporosis)

Disease Manifestation
Development of characteristic clinical signs and symptoms associated with a given disease (progression), typically independent of a specific etiologic causative factor. Examples:

  • Lower urinary tract symptoms (in BPH); and
  • Loss of bone mineral density and bone fracture (in Osteoporosis).

Therapeutic Response
Therapeutic benefit of a drug on which approval is based, showing a beneficial change in specific objective and/or subjective measures of a disease.

2016 Update on Current Projects

Introduction

The Therapeutics Research Institute, a 501(c)(3) nonprofit corporation located in Saint Davids Pennsylvania, was initiated in August 2012 to examine and report on various aspects of modern therapeutics. Its website, TRI-institute.org, which contains all its reports and commentaries, became operational in August 2014.

Objectives

The objectives of the Therapeutics Research Institute (TRI-institute), which are listed at TRI-institute.org/Organization, are:

  1. To conduct scientific assessments of characteristics of drug treatments of human diseases based on available information and relevant frameworks;
  2. To analyze and report such findings by indications and therapeutic areas, pharmacological mechanisms, types of endpoints, and disease types;
  3. To co-sponsor seminars, particularly in the Greater Philadelphia region, directed at the pharmaceutical startup community, exploring lessons from the findings; and
  4. To engage in other activities related to the objectives of the corporation, that will further its mission.

Current Projects

High-level outlines of the three current projects, Progression of Modern Therapeutics, Characteristics of Therapeutic Response, and Systems Therapeutics, are shown on the graph below (click here for a larger graph).

current-projects-november-2016

Update on Current Projects

A summary Update on Current Projects, for the three current projects, are shown on the graph below (click here for a larger graph). The dates of individual reports and posts (month, year) are also shown, except those for the 17 commentaries on individual therapeutic classes.

update-on-current-projects-november-2016

Examples from Recent Work

Below are three examples from recent work, i.e., from one of the 17 commentaries on individual therapeutic classes, from an analysis of the number pf pharmacologic classes per therapeutic classes and the number of approved new molecules per pharmacologic classes, and on an updated diagram on systems therapeutis.

New Drug Molecules for Osteoporosis

Osteoporosis Graph

Above is a chart from one of the 17 posted commentaries on individual therapeutic classes, which had originally been included in Progression of Modern Therapeutics (2015 Report), this one on approved modern therapeutics for osteoporosis, from Osteoporosis: Better Drugs and Better Scientific Understanding Needed (July 2016). These commentaries have included, to name a few, Irritable Bowel Syndrome (September 2016), Benign Prostatic Hyperplasia (August 2016), Migraine (December 2015), Rheumatoid Arthritis (October 2015) and Lipid Lowering Drugs (September 2015).

Regarding osteoporosis, since 1984, a total of 9 new drug molecules have been approved for osteoporosis, in 5 pharmacologic classes. The 1995 approval of Fosamax (alendronate), the first of 4 approved bisphosphonates, represented an important milestone for this therapeutic class. The other 4 pharmacologic classes involve the SERM’s (Selective Estrogen Receptor Modulators), calcitonins, parathyroid analogs, and RANK (Receptor Activator of Nuclear factor Kappa-B) ligand. It was also commented on concerns about bone quality and the effects current osteoporosis drugs may have on bone quality, and that a new FDA draft guidance called for additional long-term nonclinical pharmacology studies (bone quality studies) to support new osteoporosis drug development.

Number of Pharmacologic Classes per Therapeutic Classes

The above chart shows the number of modern therapeutics’ pharmacologic classes per 38 of the 40 therapeutic classes covered in Progression of Modern Therapeutics (2015 Report), from Great Variability in New Drug Approvals Among Pharmacologic Classes and Therapeutic Classes (February 2016). This graph illustrates the significant variability in the number of pharmacologic classes per therapeutic classes, ranging from as high as 11 for Type-2 Diabetes to 1 for Systemic Lupus Erythematosus and Idiopathic Thrombocytopenic Purpura. Note the mean and median values for the number of pharmacologic classes per therapeutic classes were 4.3 and 4, respectively. The same commentary also showed a wide range in the total number of new drug approvals for these therapeutic classes, ranging from 44 for Hypertension to 1 for Systemic Lupus Erythematosus; note he mean and median values for the number of new drug approvals for these therapeutic classes were 11.5 and 9.5, respectively.

Systems Therapeutics

systems-therapeutics-sep-2016

Above is the recently updated systems therapeutics diagram, from Systems Therapeutics: Updated Diagram (October 2016). The systems therapeutics diagram consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different levels of interaction between these processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level. Where these pivotal interactions occur for individual pharmacologic classes determine the four systems therapeutics categories. These two processes are initiated by an interaction between a pharmacologic agent and a pharmacologic response element on one hand and a hypothetical intrinsic operator and an etiologic causative factor on the other, and then culminate in a therapeutic response. Each of these two processes, pharmacologic and pathophysiologic processes, have their inherent variabilities; this construct further suggests that in addition to pharmacologic processes, pathophysiologic processes also contribute to ultimate patient therapeutic response characteristics.

Ongoing and Future Directions

Progress to-date has focused on generating work on each of the three initial projects, and uploading these to the TRI-institute.org website. Work on the Characteristics of Therapeutic Response project has been hampered by the challenges in identifying appropriate publicly available databases and the best reporting formats. The most recent efforts have focused on the Systems Therapeutics project, including the recently updated diagram, and current and future efforts will include additional work in this area, e.g., examples and exhibits, as well as strengthening collaborative outreach.

Systems Therapeutics: Updated Diagram

Background

Two reports have been posted on Systems Therapeutics on this website, first, “Systems Therapeutics: A Diagram and Four Categories” in April 2015 (1), and second, “Systems Therapeutics: Variabilities” in May 2016 (2). The purpose of the underlying systems therapeutics diagram is to provide a high-level framework to facilitate discussions on how pharmacologic processes and pathophysiologic processes interact to produce a therapeutic response.

In essence, the systems therapeutics diagram consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, each starting at the molecular level, through the cellular and tissue/organ levels, and finally the clinical level, culminating in therapeutic response. The pivotal interactions between the pharmacologic and pathophysiologic processes, at each of the four biologic levels, determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level), and Category IV (at the clinical level), as was outlined in the May 2015 post. In addition, each of these two processes, pharmacologic and pathophysiologic processes, have their inherent variabilities, as was outlined in the May 2016 post, which also suggested that variability on the pathophysiologic process side might be an important determinant of patient therapeutic response characteristics, including response variability and responder rate, in addition to variability on the pharmacologic process side, although it is unclear where the source of such variability might reside, including potentially at different levels.

Updated Diagram

The current report presents an updated systems therapeutics diagram, see below (click here for a larger graph), that includes the following modifications of the diagram presented in the May 2016 post:

systems-therapeutics-sep-2016

  • On the pharmacologic processes side, the following systems components have changed names: “Pharmacologic Agent” has replaced “Drug” and “Drug Concentration”, and “Pharmacologic Response Element” has replaced “Pharmacologic Target”. The rationale is to use more neutral and descriptive terms, with an emphasis on an agent acting on an element in a pharmacologic pathway, resulting in a response. Here, the pharmacologic agent, and its concentration or exposure, is the undisputed fundamental driver of pharmacologic processes, including interpatient variability. Another change involves adding at the clinical level “Clinical Effect” as the last systems component on the pharmacologic processes side, corresponding to “Disease Manifestation” on the pathophysiologic processes side. The descriptors for the transitions from one systems component to another on the pharmacologic processes side, e., signal transduction, pharmacodynamics and translation, remain unchanged.
  • On the pathophysiologic processes side, the following systems components have changed names: “Intrinsic Operator” has replaced “Environmental” and “Factor”, and “Etiologic Causative Factor” has replaced “Etiologic Factor”. The main rationale is to simplify and depict similarly the initial events of both pharmacologic and pathophysiologic processes, with an emphasis on an etiologic factor in a disease network being driven by a hypothetical operator, eventually leading to manifestation of a disease. It is noted that this construct, incorporating a hypothetical systems component at the beginning of pathophysiologic processes, is intended in part to lump together different entities thought to influence “Etiologic Causative Factor” (as addressed in the May 2016 post, including etiome and network medicine), and in part to serve as a hypothetical driver of pathophysiologic processes, including interpatient variability. Whether this simple hypothesis survives the test of time is obviously unclear, but for now this “Intrinsic Operator” serves a role as an integral systems component. The descriptors for the transitions from one system component to another on the pathophysiologic process side, e., disease initiation, pathogenesis and progression, remain unchanged.

Comments

The systems therapeutics diagram, first introduced in the April 2015 post (1) has been modified twice, first in the May 2016 post (2), and now in the present report. Both modification have principally involved the system components at the beginning of the pharmacologic and pathophysiologic processes, how they are depicted and named.

This updated framework, highlighting how these parallel processes – pharmacologic and pathophysiologic – contribute to patient therapeutic response characteristics, also helps focus on areas where future basic research efforts are sorely needed, such as initiating disease process mechanisms and variability in disease process drivers.

It is our hope that those interested in this general subject will find the updated systems therapeutics diagram useful as an aid in thinking about the various determinants, known and unknown, of patient therapeutic response to approved drugs, while recognizing our limited understanding in this area at this time.

References

  1. Therapeutics Research Institute: Systems Therapeutics: A Diagram and Four Categories, May 2015. http://tri-institute.org/niDFW
  2. Therapeutics Research Institute: Systems Therapeutics: Variabilities, May 2016. http://tri-institute.org/TyQij

 

IBS: Underlying Mechanism(s) Not Established but Six New Drug Approvals Since 2000

Background

Irritable Bowel Syndrome (IBS), not to be confused with Inflammatory Bowel Disease (IBD), represents a group of symptoms characterized by abdominal pain and discomfort and changes in bowel movement patterns. There are two key types of IBS, depending on the predominant changes in stool consistency, i.e., IBS with constipation, or IBS-C; and IBS with diarrhea, or IBS-D. In addition, there are two other types of IBS, i.e., mixed IBS, or IBS-M; and unsubtyped IBS, or IBS-U.

IBS is a functional gastrointestinal disorder, without any evidence of underlying large intestinal damage, including no radiologic or endoscopic abnormalities. The cause(s) and pathogenesis of IBS have not been established, although clearly there is an interplay between various facors and abnormal GI motility. Recent meta-analyses have reported an average prevalence of about 11% worldwide, with some differences by regions. It can occur both in women and men, but is reported more frequently in women.

Drug Approvals

Since 2000, there have been a total of 6 drug approvals for IBS — 3 for IBS-C predominant and 3 for IBS-D predominant. Refer to the accompanying chart below (click here for a larger graph).

The new drug approvals are listed below separately for IBS-D predominant and IBS-C predominant, based on the most recent product labels as listed on Drugs@FDA:

Approvals for IBS-D predominant:

  • Serotonin 5-HT3 Receptor Antagonist: Lotronex (alosetron, 2000), for IBS-D predominant, indicated for women only.
  • mu-Opioid Receptor Antagonist: Viberzi (eluxadoline, 2015), indicated for both women and men.
  • Rifamycin Antibacterial: Xifaxan (rifaximin, 2015), indicated for both women and men. Also approved for traveler’s diarrhea and hepatic encephalopathy.

Approvals for IBS-C predominant:

  • Serotonin 5-HT4 Receptor Agonist: Zelnorm (tegaserod, 2002), for IBS-C predominant, was indicated for women only. Was also approved for chronic idiopathic constipation. Zelnorm was withdrawn from the market in 2007 due to increased risk of heart attacks and strokes.
  • Prostaglandin E-1 Metabolite Analog: Amitiza (lubiprostone), indicated for women only. Also approved for chronic idiopathic constipation and opiod-induced constipation.
  • Guanylate Cyclase-C Receptor Agonist: Linzess (linaclotide, 2012), indicated for both women and men. Also approved for chronic idiopathic constipation.

Comments

A few general comments are in order:

  1. The approved treatments for IBS todate are symptomatic, aimed at relieving the abdominal pain and discomfort and the abnormal patterns of bowel movement.
  2. Treatments approved between 2000 and 2010 were based on single-item patient-reported rating of overall change in condition as the primary efficacy endpoint, involving questions regarding adequate or satisfactory relief and subject global assessment of relief (Table 1, in reference 1).
  3. A recently issued Guidance for Industry (1), in recognition of the limitations of single-item patient-reported rating of overall change, outlines the development of a multi-item patient-reported outcome (PRO) measures as primary endpoints for IBS clinical trials. It is emphasized that the recommendations contained therein, regarding primary endpoints, trial design, patient entry criteria and responder definitions, are provisional, considering the time-consuming task of developing the most appropriate PRO instruments and the need for continued efforts to develop more effective therapies for IBS.
  4. The current lack of an understanding of the cause(s) and pathogenesis of IBS is clearly hampering the development of new and more effective drugs for IBS. It is noted that the average patient responder rates for the more recently approved IBS drugs is generally approximately within the second quartile of responder rates (25% to 50%, but with a few endpoints lower and higher), with significant placebo response (2). There is therefore a significant need for more fundamental research on the cause(s) of IBS to guide new drug discovery and development efforts.
  5. To this date, no reliable biomarker for IBS has been identified. Thus, this is another area of needed fundamental research to facilitate future drug development for IBS.

References

  1. Guidance for Industry. Irritable Bowel Syndrome – Clinical Evaluation of Drugs for Treatment. FDA, May 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM205269.pdf
  2. Most recent product labels, as listed for the individual drugs on Drugs@FDA, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, accessed in August 31, 2016.

Refer to page 16 of Progression of Modern Therapeutics (2015 Report) available under Reports on this website; this report also includes the methodology used.

BPH: Relying on Mechanisms First Approved a Quarter of a Century Ago

Background

Benign Prostatic Hyperplasia (BPH, also called prostatism) is the most common benign prostatic disease in men over 50 years of age.(1) The general symptomatology is also referred to as LUTS (Lower Urinary Tract Symptoms), of which BPH is the most common cause in men. Its pathology is characterized by hyperplasia of prostatic stromal and epithelial cells, forming discrete nodules in the periurethral region of the prostate. BPH represents a significant medical problem in men older than 50 years of age having moderate to severe symptoms. Epidemiological studies estimate that 50% of men have histological BPH by age 60; the prevalence increases to 90% in men over 85.

Although the ultimate cause of BPH is not known, it is thought to be driven by dihydrotestosterone (DHT)-induced growth factors. DHT is the main prostate androgen, which is formed from testosterone, through the action of type 2 5-alpha reductase in stromal and epithelial prostate cells. The interaction of DHT with the nuclear androgen receptor (AR) stimulates the transcription of androgen-dependent genes, which include several growth factors and their receptors, most importantly members of the FGF family and TGF-beta. DHT-induced growth factors act by increasing the proliferation of stromal cells and decreasing the death of epithelial cells.

The two key pharmacologic classes for BPH act by inhibiting the formation of DHT via inhibition of 5-alpha reductase and by decreasing prostate smooth muscle tone via inhibition of alpha-1 adrenergic receptors.

Drug Approvals

Since the late 1980’s, a total of 8 new drug molecules have been approved for BPH, in 3 pharmacologic classes, i.e., alpha-1 adrenergic antagonists, 5-alpha-reductase inhibitors, and phosphodiesterase-5 inhibitors. In keeping with our convention, new formulations and new combinations of previously approved drugs are not included. Refer to the accompanying chart below (click here for a larger graph).

Benign Prostatic Hyperplasia Graph copy

The new drug approvals are listed below:

  • Alpha-1 Adrenergic Antagonists: 5 new molecules; Hytrin (terazosin, 1987); Cardura (doxazosin, 1990); Flomax (tamsulosin, 1997); Uroxatral (alfuzosin, 2003); and Rapaflo (silodosin, 2008). Regulatory interest spans 21 years and 2 months, from 1987 to 2008. Note one combination product, Jalyn (dutasteride + tamsulosin, 2010), is not included since it contains two previously approved drugs for the same indication.
  • 5-Alpha-Reductase Inhibitors: 2 new molecules; Proscar (finasteride, 1992); and Avodart (dutasteride, 2001). Regulatory interest spans 9 years and 5 months, from 1992 to 2001.
  • Phosphodiesterase-5 Inhibitors: 1 new molecule; Cialis (tadalafin, 2011).

Comments

A few noteworthy observations are in order:

  1. The first-in-class approvals within the two key pharmacologic classes, alpha-1 adrenergic blockers and 5-alpha reductase inhibitors occurred approximately a quarter of a century ago, in 1987 and 1992, respectively.
  2. Recently approved drugs for signs and symptoms of BPH have used the International Prostate Symptom Score (IPSS), a questionnaire involving 7 questions concerning the severity of irritative and obstructive symptoms (using a scale of 0-5 for each: incomplete emptying, frequency, intermittency, urgancy, weak stream, straining, nocturia) and 1 quality of life question, as the primary endpoint, and maximum urinary flow rate (Qmax) as a secondary endpoint. Note the IPSS is very similar to the American Urologic Association Symptom Index (AUASI), which has also be used in registration trials.
  3. Based on our recently proposed systems therapeutics framework (2), the alpha-1 adrenergic blockers would belong to Category III, defined as, “the pivotal interaction between pharmacologic processes and pathophysiologic processes involves a modulation of a normal physiologic function, linked to the disease evolution, although not necessarily an etiologic pathway”, whereas the 5-alpha reductase inhibitors would belong to Category II, defined as, “the pivotal interaction between pharmacologic processes and pathophysiologic processes involves a fundamental biochemical mechanism, related to the disease evolution, although not necessarily an etiologic pathway”.
  4. While the registration trials for these agents showed a statistical significance compared with placebo, unfortunately, an overall quantitative assessment of their therapeutic response characteristics, such as patient responder rates and response distribution and variability, is not possible at this time. This is because of the lack of well-defined and easily understood publicly available databases on therapeutic response characteristics. Such future informative therapeutics databases will be important for assessing the gaps in the ultimate utility of modern therapeutics.(3)

References

  1. Epstein JI, Lotan TL: The Lower Urinary Tract and Male Genital System, Chapter 21, in: Kumar V, Abbas AK, Aster JC, Robbins and Cotran Pathologic Basis of Disease, Ninth Edition, Elsevier, Philadelphia, 2015, section on Benign Prostatic Hyperplasia, pp. 982-983.
  2. Therapeutics Research Institute, Systems Therapeutics: A Diagram and Four Categories, April 2015, http://tri-institute.org/niDFW
  3. Therapeutics Research Institute, Responder Rates and Therapeutic Response Variabilities, May 2015, http://tri-institute.org/6p79Y

Refer to page 40 of Progression of Modern Therapeutics (2015 Report) available under Reports on this website; this report also includes the methodology used.

 

Osteoporosis: Better Drugs and Better Scientific Understanding Needed

Background

Osteoporosis is characterized by a decrease in bone mass and density, resulting in a predisposition to fractures, typically in vertebrae, hips, or wrists. It is particularly common in postmenopausal women, and its prevalence increases with age, hence the two key forms of the disease, i.e., postmenopausal (also called Type I) and age-related (also called Type II or senile) osteoporosis. Drugs for osteoporosis are aimed at preventing fractures due to reduced bone mass.

While the adult skeleton may appear static, an estimated 10% of the skeleton is replaced annually through a tightly regulated remodeling process, representing a balance between net bone formation and resorption, and modulated by numerous systemic factors (1). Peak bone mass is achieved during young adulthood, but once reached, there is a gradual age-related bone loss, which may average about 0.7% per year. In postmenopausal women, there is an accelerated phase of bone loss superimposed on this pattern. Radiographically, bone loss of more than 2.5 standard deviations below mean peak bone mineral density (BMD) in young adults is considered osteoporosis, whereas bone loss of 1 to 2.5 standard deviations below that mean is considered osteopenia. Since osteoporosis cannot be reliably detected in plain radiographs until 30% to 40% of the bone mass is lost, it is difficult to screen for osteoporosis in asymptomatic individuals. Best diagnostic tests of bone mineral density involve specialized radiographic imaging techniques, such as dual-energy x-ray absorptiometry or bone densitometry, also called DXA or DEXA, which measures an individual’s spine, hip or total body bone density to help gauge fracture risk, and quantitative computed tomography.

Drug Approvals

Since 1984, a total of 9 new drug molecules have been approved for osteoporosis, in 5 pharmacologic classes. Before that time, drugs for this therapeutic class had mainly involved estrogens, with or without progestins, and calcium and vitamin D. The 1995 approval of Fosamax (alendronate), the first of 4 approved biphosphonates, represented an important milestone for this therapeutic class; this pharmacologic class has since remained the dominant class. The other 4 pharmacologic classes involve the SERM’s (Selective Estrogen Receptor Modulators), calcitonins, parathyroid analogs, and the RANK ligands (Receptor Activator of Nuclear factor Kappa-B Ligand).

For new drug molecule approvals for osteoporosis, refer to the accompanying chart below (click here for a larger graph). In keeping with our convention, new formulations of previously approved drugs are not included.

Osteoporosis Graph

The new drug molecule approvals are listed below:

  • Calcitonins: 1 new molecule; Calcimar (calcitonin salmon, 1984, discontinued). More recent formulations are Miacalcin (1986) and Fortical (recombinant, 2005).
  • Biphosphonates: 4 new molecules; Fosamax (alendronate, 1995); Actonel (risedronate, 2000); Boniva (ibandronate, 2003); and Reclast (zoledronic acid, 2008). Registration interest spans 12 years and 8 months, from 1995 to 2008.
  • SERM’s: 2 new molecules; Evista (raloxifene, 1997); and Duavee (bazedoxifene and conjugated estrogens, 2013). Registration interest spans 15 years and 10 months, between 1997 and 2013.
  • Parathyroid Analogs: 1 new molecule; Forteo (teriparatide, 2002).
  • RANK Ligands: 1 new molecule; Prolia (denosumab, 2010).

Comments

Osteoporosis is an important public health issue, with its clinical consequences being fractures; signs and symptoms of hip fractures include pain, reduced mobility and disability, whereas those of vertebral fractures include back pain, loss of height and deformity. The treatment benefits of agents directed against osteoporosis thus involve assessments of the reduction in fractures compared with placebo, in addition to biomarker and radiographic measurements. In general, these effects have been considered relatively modest. Of note is that drugs within a given pharmacologic class have their separate benefit-risk considerations, including adverse effect profiles. A few general comments on the current status of modern osteoporosis therapeutics are as follows:

  • No new drug mechanism of action introduced since 2010, since the apporval of the RANK ligand Prolia (denosumab).
  • There are concerns about bone quality and the effects current osteoporosis drugs may have on bone quality. Although bone quality is a somewhat vague term, it generally refers to the effects of skeletal factors that contribute to bone strength, but are not accounted for by measures of bone mass or quantity (2).
  • Official FDA guidelines for the clinical evaluation of drugs used for the treatment of osteoporosis have continued to evolve over time (3). In general, these guidelines have involved evolving emphasis on prevention of fractures vs. radiographic measurements. It has also become apparent that our understanding of the relationship beteeen bone mass measures and risk of fractures is incomplete, and that a better scientific understanding of these relationships is needed.
  • A recent draft guidance from FDA (4) calls for additional long-term nonclinical pharmacology studies (bone quality studies) to support new osteoporosis drug development, due to concerns about long-term adverse effects of pharmacologic intervention on bone quality.

References

  1. Horvai A: Bones, Joints, and Soft Tissue Tumors, Chapter 26, in: Kumar V, Abbas AK, Aster JC, Robbins and Cotran Pathologic Basis of Disease, Ninth Edition, Elsevier, Philadelphia, 2015, pp. 1179-1227.
  2. Hernandez CJ, Keaveny TM: A biomechanical perspective on bone quality. Bone, 39:1173-1181, 2006.
  3. Colman EG: The Food and Drug Administration’s osteoporosis guidance document: past, present, and future. Bone Miner. Res., 18:1125-1128, 2003.
  4. FDA Draft Guidance: Osteoporosis: Nonclinical Evaluation of Drugs Intended for Treatment. Guidance for Industry. June 2016. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm506366.pdf

Refer to page 25 of Progression of Modern Therapeutics (2015 Report) available under Reports on this website; this report also includes the methodology used.