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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. Both of these processes have their own sets of initiators or drivers. 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. 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, in addition to the initiating entities or drivers of these processes, and the ultimate therapeutic response.

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). 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 (a drug), interacting with a pharmacologic response element (e.g., a receptor or so-called drug target), 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 initiating entity or driver 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 identified using advanced bioinformatics and network-based approaches in disease initiation.

The culminating result of the interaction between these two processes, independent of the biologic level of the pivotal interaction, involves a clinical therapeutic response, determined by the clinical (pharmacologic) effect and the disease manifestation. While it is well recognized that there is a wide variability in the clinical therapeutic response of individual patients to a given approved drug (4,5), 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 relevant data and methods, and are likely to vary from one therapeutic class to another. A general commentary (6) 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 (6,7). 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

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).
Bjornsson TD (1996). A classification of drug action based on therapeutic effects. J. Clin. Pharmacol., 36:669-673.
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).
Rowland M, Tozer TN (2011). Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, Fourth edition, Lippincott Williams & Wilkins, Philadelphia (Chapter 12, Variability, pp. 333-356).
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.
Therapeutics Research Institute. Systems Therapeutics: Variabilities, May 2016. https://tri-institute.org/TyQij
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)

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).

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:

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.
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.
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”.
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

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.
Therapeutics Research Institute, Systems Therapeutics: A Diagram and Four Categories, April 2015, https://tri-institute.org/niDFW
Therapeutics Research Institute, Responder Rates and Therapeutic Response Variabilities, May 2015, https://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.

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

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.
Hernandez CJ, Keaveny TM: A biomechanical perspective on bone quality. Bone, 39:1173-1181, 2006.
Colman EG: The Food and Drug Administration’s osteoporosis guidance document: past, present, and future. Bone Miner. Res., 18:1125-1128, 2003.
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.

Snapshots from Progression of Modern Therapeutics

Background

The primary objective of the Progression of Modern Therapeutics project has been to provide visual illustrations of the significant differences in new drug approvals across the different therapeutic classes. The 2015 Report: Progression of Modern Therapeutics, issued in January 2016 (1), covered 40 therapeutic classes from 14 therapeutic categories. A following report, Great Variability in New Drug Approvals Among Pharmacologic Classes and Therapeutic Classes, posted in February 2016 (2), presented a further analysis of the significant variability in new drug approvals among the different therapeutic and pharmacologic classes. A secondary objective of this project is to provide support for the Therapeutic Response Characteristics project, which concerns therapeutic response to approved drugs.

The purpose of the present post, Snapshots from Progression of Modern Therapeutics, is to provide four snapshots of noteworthy patterns observed in new drug registration activities.

Methodology

The four snapshots presented are based on the data and graphs for the individual therapeutic classes covered in the 2015 Report. Following general inspection of the individual 40 graphs, looking for readily noticeable patterns involving two key pharmacologic classes within each therapeutic class, it was decided for the purposes of this post to focus on four patterns. Thus, each snapshot illustrates a specific pattern, observed for two pharmacologic classes for each of two therapeutic classes. The circles representing the individual approved new drugs of interest were copied from the original graphs, but for visual clarity, their names were not included. For consistency sake, the pharmacologic classes with first approvals are colored red, but those that follow are colored blue. Otherwise the framework is the same as that of the original graphs. The general methodology used in this project is described in the 2015 Report, including definitions of the timeframe for modern therapeutics and what approved new drugs are included; the snapshots were generated using Omnigraffle Pro (The Omni Group, Seattle).

Snapshots

Below are the four Snapshots from Progression of Modern Therapeutics (2015 Report), 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 approvals from older pharmacologic classes to newer pharmacologic classes. For a larger graph click here.

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 approvals for two dominant or somewhat similar pharmacologic classes or mechanisms of action. For a larger graph click here.

Snapshot #3: Two therapeutic classes showing an older dominant pharmacologic class and a new pharmacologic class with no overlaps in registration activities, i.e., HMG-CoA Reductase Inhibitors and PCSK9 Inhibitors for Dyslipidemia, and TNF Inhibitors and JAK Inhibitors for Rheumatoid Arthritis. Both examples show the introducion of new noteworthy pharmacologic classes or mechanisms of action following many drug approvals involving dominant pharmacologic classes. For a larger graph click here.

Snapshot #4: Two therapeutic classes showing two new pharmacologic classes with overlaps in registration activities, i.e., DPP-4 Inhibitors and SGLT2 Inhibitors for Type-2 Diabetes, and NS3 Protease Inhibitors and NS5B Polymerase Inhibitors for Hepatitis C. Both examples show the recent introduction of two new pharmacologic classes or mechanisms of action. For a larger graph click here.

Comments

This report has focused on illustrating specific patters in registration activities of modern therapeutics, showing that in addition to the wide variability in new drug approvals for the different therapeutic classes, there also are discernible patterns in registration activities across therapeutic classes. It is recognized that there may be different reasons behind such patterns, e.g., the number of new drugs already approved, technical feasibility of new pharmacologic targets, and commercial considerations. The registration activities patterns illustrated here were selected for their relative obviousness, but there are undoubtedly several other patterns in registration activities of modern therapeutics.

References

2015 Report: Progression of Modern Therapeutics. https://tri-institute.org/4mH3e. January 2016, or click on the report directly: Progression of Modern Therapeutics (2015 Report)
Great Variability in New Drug Approvals Among Pharmacologic Classes and Therapeutic Classes. https://tri-institute.org/tsv1K. February 2016.

Modern Insomnia Therapeutics: Not the Barbiturates or Anxiolytic Benzodiazepines of Yore

Introduction

Considering the different limitations and undesirable properties of earlier remedies used as hypnotics, such as alcohol, chloral hydrate, barbiturates and anxiolytic benzodiazepines, modern insomnia therapeutics clearly represent noteworthy improvements. In fact, the barbiturates, which were extensively used as hypnotics throughout the first half of the 20^th century, are no longer in clinical use for insomnia, and the anxiolytic benzodiazepines, which were extensively used off-label following their introduction in the 1960’s, have now been mostly replaced by better designed benzodiazepines and other modern insomnia therapeutics.

Drug Approvals

A total of 11 new drug molecules have been approved for insomnia since 1970, in 5 pharmacologic classes. The first pharmacologic class, benzodiazepines, has had 5 new drugs, starting with Dalmane in 1970, which had been preceded by a few anxiolytic benzodiazepines, e.g., Librium (chlordiazepoxide, 1960) and Valium (diazepam, 1963), which have been used off-label as hypnotics. The second pharmacologic class, non-benzodiazepines, has had 3 new drug approvals, starting with Ambien in 1992, while the last 3 pharmacologic classes have had 1 new drug approval each, i.e., the melatonin receptor agonist Rozerem in 2005, the tricyclic antidepressant Silenor in 2010, and the orexin receptor antagonists Belsomra in 2014.

Refer to the accompanying chart below (click for a larger graph). In keeping with our convention, neither new formulations of approved drugs nor new combinations of previously approved drugs in that therapeutic class are included. The new molecule drug approvals are listed below:

Benzodiazepines: 5 new molecules, over 20 years and 8 months; Dalmane (flurazepam, 1970), Restoril (temazepam, 1981), Halcion (triazolam, 1982), Doral (quazepam, 1985), and Prosom (estazolem, 1990).
Non-benzodiazepines: 3 new molecules, over 12 years; Ambien (zolpidem, 1992), Sonata (zaleplon, 1999), and Lunesta (eszopiclone, 2004)
Melatonin Receptor Agonists: 1 new molecule; Rozerem (ramelteon, 2005).
Tricyclic Antidepressants: 1 new molecule; Silenor (doxepin, 2010; originally approved as Sinequan for depression in 1969).
Orexin Receptor Antagonists: 1 new molecule; Belsomra (suvorexant, 2014).

Comments

A few noteworthy comments and observations about this therapeutic classes are as follows:

Excluding alcohol, opium, and bromide salts, the earliest hypnotics included chloral hydrate, which was introduced in the 1860s, and paraldehyde, which was introduced in the 1880s.
While barbiturates were extensively used as hypnotics throughout the first half of the 20^th century, e.g., phenobarbital, the only two barbiturates that have been approved as hypnotics are Butisol (butabarital, 1939) and Seconal (secobarbital, 1950); barbiturates are no longer in clinical use as hypnotics.
A few anxiolytic benzodiazepines, such as Librium (chlordiazepoxide, 1960), Valium (diazepam, 1963), and Ativan (lorazepam, 1977), have been used off-label as hypnotics. Dalmane (flurazepam, 1970), however, was the first benzodiazepine to be approved for insomnia.
Several sedating tricyclic antidepressants have also been used off-label as hypnotics, such as Elavil (amitriptyline, 1961), and Sinequan (doxepin, 1969). The only approved tricyclic antidepressant for insomina is Silenor (doxepin, 2010).

Conclusions

Until the 1970s, there had not been much progression in insomnia therapeutics for approximately a century, although different remedies were available, mostly used off-label. Since the early 1980s, there have been noteworthy improvements in this therapeutic class, with the approvals of a total of 8 new benzodiazepines and non-benzodiazepines, as well as the introduction of 2 new pharmacologic classes, a melatonin receptor agonist and a orexin receptor antagonist.

Refer to page 29 of Progression of Modern Therapeutics (2015 Report) available under Reports on this website; this report also includes a description of the methodology used.

Great Variability in New Drug Approvals Among Pharmacologic Classes and Therapeutic Classes

Introduction

The objective of the present report is to examine and illustrate the significant variability in new drug approvals among different therapeutic classes, principally by focusing of the number of pharmacologic classes per therapeutic classes, and the number of new drug approvals per therapeutic classes. The data used are from the 2015 Report on the Progression of Modern Therapeutics, available on this website under Reports, which covers 40 therapeutic classes from 14 therapeutic categories, and includes a description of the methodology used.

At the outset, definitions of a few terms used here are in order, as follows:

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 (2015 Report).
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 in a given disease or indication, independent of pharmacologic class.
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 therapeutic classes is shown in the graph below, in a descending order, for 38 of the 40 therapeutic classes covered in the Progression of Modern Therapeutics (2015 Report). For the purposes of the present analyses, the following two therapeutic classes were not included, i.e., Pediatric Acute Lymphoblastic Leukemia and Malaria, since these contained a significant proportion of older drugs.

Click here for a larger graph. Note the wide range 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. The mean and median values were 4.3 and 4, respectively.

Modern Therapeutics New Drug Approvals per Therapeutic Classes

Below are shown the total number of new drug approvals for 38 of the 40 therapeutic classes covered in the Progression of Modern Therapeutics (2015 Report). Click here for a larger graph. Note the 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. The mean and median values were 11.5 and 9.5, respectively.

Summary Data

Below is summary data used in the two graphs above, specifically, the number of pharmacologic classes per therapeutic classes, along with the range of new drug approvals for those pharmacologic classes, the total number of new drug approvals for that therapeutic class, and the mean and median length of registration interest in the pharmacologic classes within each therapeutic class (counted in decimal years). Pharmacologic classes with only 1 new drug approval and those with <1 year of length of registration interest are not included; the number of pharmacologic classes averaged for each therapeutic class is shown in parenthesis. The data is from the 2015 Report.

Cardiovascular Therapeutics

Hypertension: 6 pharmacologic classes, with 1 to 14 new drug approvals each, totaling 44, with mean and median length of registration interest of 19.5 and 15.1 decimal years, respectively (N=5).
Dyslipidemia: 7 pharmacologic classes, with 1 to 8 new drug approvals each, totaling 19, with mean and median length of registration interest of 25.1 and 26.7 decimal years, respectively (N=3).

Hematologic Therapeutics

Thrombosis: 4 pharmacologic classes, with 1 to 5 new drug approvals each, totaling 14, with mean and median length of registration interest of 10.9 and 8.7 decimal years, respectively (N=3).
Thrombolysis: 3 pharmacologic classes, with 1 to 3 new drug approvals each, totaling 6, with mean and median length of registration interest of 12.3 and 12.3 decimal years, respectively (N=2).
Idiopathic Thrombocytopenic Purpura: 1 pharmacologic class, with 2 new drug approvals, totaling 2, length of registration interest not calculated.

Gastroenterologic Therapeutics

Acid Reflux & Ulcer Disease: 3 pharmacologic classes, with 2 to 5 new drug approvals each, totaling 11, with mean and median length of registration interest of 9.7 and 10.7 decimal years, respectively (N=3).
Inflammatory Bowel Diseases: 2 pharmacologic classes, with 2 and 4 new drug approvals each, totaling 6, with mean and median length of registration interest of 10.5 and 10.5 decimal years, respectively (N=2).
Irritable Bowel Syndrome: 6 pharmacologic classes, with 1 new drug approval each, totaling 6, length of registration interest not calculated.
Prevention of Nauseas & Vomiting Associated with Cancer Chemotherapy: 2 pharmacologic classes, with 3 and 4 new drug approvals each, totaling 7, with mean and median length of registration interest of 12.5 and 12.5 decimal years, respectively (N=2).

Pulmonary Therapeutics

Asthma: 7 pharmacologic classes, with 1 to 6 new drug approvals each, totaling 18, with mean and median length of registration interest of 18.1 and 19.8 decimal years, respectively (N=4).
Chronic Obstructive Pulmonary Disease: 3 pharmacologic classes, with 1 to 9 new drug approvals each, totaling 14, with mean and median length of registration interest of 30.1 and 30.1 decimal years, respectively (N=2).
Pulmonary Arterial Hypertension: 4 pharmacologic classes, with 1 to 4 new drug approvals each, totaling 10, with mean and median length of registration interest of 12.0 and 11.8 decimal years, respectively (N=3).
Idiopathic Pulmonary Fibrosis: 2 pharmacologic classes, with 1 new drug approval each, totaling 2, length of registration interest not calculated.
Cystic Fibrosis: 3 pharmacologic classes, with 1 to 3 new drug approvals each, totaling 6, with length of registration interest of 3.4 decimal years (N=1).

Endocrinologic Therapeutics

Type-2 Diabetes: 11 pharmacologic classes, with 1 to 5 new drug approvals each, totaling 27, with mean and median length of registration interest of 8.7 and 3.0 decimal years, respectively (N=7).
Obesity: 7 pharmacologic classes, with 1 new drug approval each, totaling 7, length of registration interest not calculated.
Osteoporosis: 5 pharmacologic classes, with 1 to 4 new drug approvals each, totaling 9, with mean and median length of registration interest of 14.3 and 14.3 decimal years, respectively (N=2).

Psychopharmacologic Therapeutics

Depression: 4 pharmacologic classes, with 3 to 8 new drug approvals each, totaling 22, with mean and median length of registration interest of 18.7 and 19.6 decimal years, respectively (N=4).
Schizophrenia: 2 pharmacologic classes, with 11 and 12 new drug approvals each, totaling 23, with mean and median length of registration interest of 26.4 and 26.4 decimal years, respectively (N=2).
Attention Deficit Hyperactivity Disorder: 4 pharmacologic classes, with 1 to 2 new drug approvals each, totaling 7, length of registration interest not calculated. Note enantiomers and prodrugs are not included.
Insomnia: 5 pharmacologic classes, with 1 to 5 new drug approvals each, totaling 11, with mean and median length of registration interest of 16.3 and 16.3 decimal years, respectively (N=2).

Neurologic Therapeutics

Alzheimer’s Disease: 2 pharmacologic classes, with 1 and 4 new drug approvals each, totaling 5, with length of registration interest of 7.4 decimal years (N=1).
Parkinson’s Disease: 5 pharmacologic classes, with 1 to 6 new drug approvals each, totaling 14, with mean and median length of registration interest of 9.6 and 8.5 decimal years, respectively (N=4).
Multiple Sclerosis: 9 pharmacologic classes, with 1 to 5 new drug approvals each, totaling 13, with length of registration interest of 21.1 decimal years (N=1).
Migraine: 5 pharmacologic classes, with 1 to 7 new drug approvals each, totaling 15, with mean and median length of registration interest of 9 decimal years, respectively (N=2). Note values for two pharmacologic classes not readily available, and thus not included.

Rheumatologic Therapeutics

Rheumatoid Arthritis: 8 pharmacologic classes, with 1 to 5 new drug approvals each, totaling 13, with mean and median length of registration interest of 9.3 and 9.3 decimal years, respectively (N=2).
Systemic Lupus Erythematosus: 1 pharmacologic classes, with 1 new drug approval, totaling 1, length of registration not calculated.
Gout and Hyperuricemia: 3 pharmacologic classes, with 1 to 3 new drug approvals each, totaling 6, with mean and median length of registration interest of 53.5 and 53.5 decimal years, respectively (N=2).
Fibromyalgia: 2 pharmacologic classes, with 1 and 2 new drug approvals each, totaling 3, length of registration interest not calculated.

Genitourinary Therapeutics

Urinary Incontinence: 3 pharmacologic classes, with 1 to 6 new drug approvals each, totaling 8, with length of registration interest of 33.6 decimal years (N=1).
Erectile Dysfunction: 2 pharmacologic classes, with 1 and 4 new drug approvals each, totaling 5, with length of registration interest of 14.1 decimal years (N=1).
Benign Prostatic Hyperplasia: 3 pharmacologic classes, with 1 to 4 new drug approvals each, totaling 7, with mean and median length of registration interest of 15.3 and 15.3, decimal years, respectively (N=2).

Dermatologic Therapeutics

Plaque Psoriasis: 5 pharmacologic classes, with 1 to 3 new drug approvals each, totaling 7, with length of registration interest of 3.7 decimal years (N=1).

Ophthalmologic Therapeutics

Glaucoma: 4 pharmacologic classes, with 2 to 5 new drug approvals each, totaling 14, with mean and median length of registration interest of 11.9 and 13.9 decimal years, respectively (N=4).
Age-related Macular Degeneration: 2 pharmacologic classes, with 1 and 3 new drug approvals each, totaling 4, with length of registration interest of 6.9 decimal years (N=1).

Antiviral Therapeutics

HIV-1/AIDS: 6 pharmacologic classes, with 1 to 10 new drug approvals each, totaling 28, with mean and median length of registration interest of 10.7 and 11.1 decimal years, respectively (N=4).
Hepatitis C: 5 pharmacologic classes, with 1 to 4 new drug approvals each, totaling 13, with mean and median length of registration interest of 4.8 and 2.1 decimal years, respectively (N=4).

Oncologic Therapeutics

Melanoma: 8 pharmacologic classes, with 1 to 2 new drug approvals each, totaling 11, with mean and median length of registration interest of 2.1 and 2.1 decimal years, respectively (N=2).

Comments

A few high-level comments are listed below:

Pharmacologic Classes – Note the wide variability 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 pharmacologic classes per therapeutic classes (N=38) are 4.3 and 4, respectively.

Therapeutic Classes – Note the wide variability in the total 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 total number of new drug approvals per therapeutic class (N=38) are 11.5 and 9.5, respectively.

Speculations – It is tempting to speculate what might be the reasons underlying such wide variabilities in the number of pharmacologic classes per therapeutic classes as well as in the total number of new drug approvals per therapeutic classes, but that will be left to another time. Public discussion on this important topic, however, is very important, since at a high level, these are likely to relate to how society attempts 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.

Length of Registration Interest – The length of registration interest across the different therapeutic classes (based on those with >2 pharmacologic classes) varied greatly, with median values higher than 20 decimal years for Schizophrenia (26.4), Dyslipidemia (26.7), Chronic Obstructive Pulmonary Disease (30.1) and Gout and Hyperuricemia (53.5). This parameter is of interest since sometimes it can be an indication of a need for better treatment and new biologic targets.

Classifications – It is noted that the pharmacologic classifications for modern therapeutics typically involve biologic target-based or mechanism of action-related classifications, but in some instances these involve chemical classifications, e.g., for Malaria and Pediatric Acute Lymphoblastic Leukemia (both of which were not included in the present analyses), or a mix of the two, e.g., for Migraine and Attention Deficit Hyperactivity Disorder. Going forward, it is desirable to have uniform biologically based approaches for pharmacologic classifications.

Modern Therapeutics vs. Older Drugs – The project on Progression of Modern Therapeutics, as the name implies, addresses modern therapeutic, as defined above. Thus, it is recognized that older drugs, typically those introduced before the 1970’s, which are not included in this project although still in active clinical use, could influence the key parameters under study if included in these analyses, i.e., the number of pharmacologic classes per therapeutic classes, and the total number of drug approvals per therapeutic classes.

Conclusion

The present assessment of modern therapeutics has illustrated wide variability in the number of pharmacologic classes per 38 therapeutic classes. These ranged from 11 for Type-2 Diabetes to 1 for Systemic Lupus Erythematosus, with a median of 4. Similar wide variability was also evident for the number of new drug approvals for each of these 38 therapeutic classes. These ranged from 44 for Hypertension to 1 for Systemic Lupus Erythematosus, with a median of 9.5.

It is noted that although the separation between older drugs and modern therapeutics is somewhat arbitrary, over these past four decades or so there have been impressive advances in new drug introductions, including numerous new pharmacologic classes that have changed and are changing the treatment and outcome of a number of diseases, e.g., Hypertension, Dyslipidemia, Acid Reflux and Ulcer Disease, Inflammatory Bowel Diseases, Type-2 Diabetes, Multiple Sclerosis, Rheumatoid Arthritis, Melanoma, Hepatitis C and HIV-1/AIDS, to name just a few. It is also noted that to date the project on the Progression of Modern Therapeutics has only covered two Oncologic Therapeutics diseases, i.e., Melanoma and Pediatric Acute Lymphoblastic Leukemia, but this particular therapeutic category has witnessed significant progress over the past few decades. Therefore, considering these recent therapeutic advances across a great number of diseases one can only remain highly optimistic about the future of drug discovery and development, and the introduction of novel new drugs.