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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)

Gout and Hyperuricemia: Reliance on Old Mechanisms

Introduction

Descriptions of gout, in its many clinical presentations, go back many centuries, e.g., in the Greek and Roman literature. Gout has been disproportionately represented in prominent authority figures, including members of the French, Spanish, and British aristocracy. In fact, gout has been called the “disease of kings”. It is of interest that the chemical identity of uric acid was first established as a constituent of a renal calculus in 1776 and in a tophus in 1797. Half a century later, the so-called “thread test”, a semiquantitative method for the measurement of uric acid, was described as a diagnostic test for gout and hyperuricemia (1).

Drug Approvals

There have been a total of 8 new molecule approvals for gout and hyperuricemia, in 4 pharmacologic classes. The first pharmacologic class, microtubule polymerization inhibitors (exact mechanism in gout still unknown), has only 1 drug, colchicine, which has been in clinical use for several decades as colchicine preparations, and for centuries as its precursor Colchicum extract. The next two pharmacologic classes, uricosuric agents, which inhibit proximal tubular reabsorption of uric acid, and xanthine oxidase inhibitors, which inhibit the conversion of uric acid from xanthine and hypoxanthine, had their beginnings with probenecid and allopurinol in 1951 and 1966, respectively. The most recent pharmacologic class involves urate oxidase or uricase, an enzyme that catalyzes the degradation of uric acid to a more soluble allantoin, with its first approval in 2002.

Refer to the accompanying chart below (click for a larger chart). In keeping with our convention, new formulations of approved drugs and new combinations of previously approved drugs are not included. The new molecule drug approvals are listed below:

Microtubule Polymerization Inhibitors: 1 new molecule; Colcrys (colchicine, 2009, official FDA approval of colchicine occurred as part of the 2006 FDA safety program on Unapproved Drug Initiative).
Uricosuric Agents: 3 new molecules; Benemid (probenecid, 1951), Anturane (sulfinpyrazone, 1953), and Zurampic (lesinurad, 2015).
Xanthine Oxidase Inhibitors: 2 new molecules; Zyloprim (allopurinol, 1966) and Uloric (febuxostat, 2009).
Uricase Preparations: 2 molecules; Elitek (rasburicase, recombinant uricase, 2002) and Krystexxa (pegloticase, pegylated uricase, 2010).

Comments

A few things stand out regarding gout and hyperuricemia therapeutics, as follows:

The long and remarkable history of the alkaloid colchicine, perhaps the oldest drug still used today, traces its start to ancient times, including the first description of Colchicum extract from the plant autumn crocus (Colchicum autumnale) as a treatment of gout in the first century AD. Colchicine was first isolated in 1820, and first synthesized in 1959. Benjamin Franklin, a gout sufferer, is said to have used Colchicum extract while serving as the Ambassador to France, and to have brought Colchicum plants to North America.
Numerous unapproved colchicine preparations had been in clinical use for several decades, until colchicine was officially approved by FDA in 2009, under the trade name Colcrys, as part of the 2006 FDA safety program on Unapproved Drug Initiative; shortly thereafter, all unapproved colchicine preparations were removed from the market.
The long hiatus in new drug approvals for gout and hyperuricemia since the approval of allopurinol in 1966 until the approval of the recombinant uricase preparation rasburicase (Elitek) in 2002 – almost 36 years; eigth years later a pegylated uricase preparation was approved.
The 2 other new drug approvals since 2009 involve the two other old pharmacologic classes, xanthine oxidase inhibitors and uricosuric agents, with the approvals of Uloric (febuxostat, 2009) and Zurampic (lesinurad, 2015), respectively.

Conclusions

Mechanistically, three of the four current pharmacologic classes for the treament of gout and hyperuricemia involve reducing uric acid levels, one class by reducing its production, i.e., xanthine oxidase inhibitors, which inhibit the conversion of uric acid from xanthine and hypoxanthine, and two classes by increasing its elimination, i.e., uricosuric agents by increasing the renal elimination of uric acid, and uricase preparations by increasing the conversion of uric acid to a more soluble and more readily eliminated allantoin. The fourth pharmacologic class represented by one drug, colchicine, works through multiple mechanisms of action affecting inflammatory processes, accounting for its efficacy in acute gout flare (2). Apart from possible new xanthine oxidase inhibitors and uricosuric agents, it would seem more plausible that new therapeutics for the treatment of acute gout would involve one or more of the anti-inflammatory mechanisms of colchicine.

References

Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis Research & Therapy, 8(Suppl 1):S1, 2006.
Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clinical Therapeutics, 36 (10), 1465-1479, 2014.

Refer to Progression of Modern Therapeutics (2015 Report) available under Reports on this website, which includes the methodology used. Note the 2 uricase preparations have been added in this commentary.

Migraine Therapeutics: Slow Progress Towards Precision Medicine

Introduction

The ergot alkaloids ergotamine and dihydroergotamine were the first two agents used in the treatment of acute migraine. Ergotamine, which was first isolated from ergot by Stoll in Switzerland in 1918, was first used in the treatment of migraine by Maier, also in Switzerland, in 1925. Dihydroergotamine on the other hand was first introduced in 1943 (1). It is noted that the FDA approval dates for these two ergot alkaloids are not readily available. Subsequently, it wasn’t until the early 1990’s that a new pharmacologic class would be introduced for the treatment of acute migraine, the triptans.

In addition to drugs for the acute treatment of migraine, there have been approvals of new molecule treatments for the prevention of migraine, involving three pharmacologic classes. This has involved approvals in the late 1990’s and early 2000’s for antiepileptic agents, for botulinum toxin in 2010, and for beta adrenergic blockers; note that the FDA approval dates for the beta adrenergic blockers are not readily available.

Drug Approvals

There have been a total of 15 new molecule approvals for migraine therapeutics, in 5 broad pharmacologic classes. The first pharmacologic class, the ergot alkaloids, as been in use since the 1940’s, but the exact approval years for ergotamine and dihydroergotamine are not readily available, while the third drug in this class, Sansert (methysergide) was approved in 1962, but later withdrawn from the market due to toxicities. In keeping with our convention, included are approved new molecules for this indication, although they might have been previously approved for another indication, i.e., two antiepileptic drugs, two beta-adrenergic blockers, and one botulinum toxin. Note that all 5 of the approved drugs of these last three pharmacologic classes were for migraine prophylaxis. Refer to the accompanying chart below (click for a larger chart). The new molecule drug approvals are listed below:

Ergot Alkaloids: 3 new molecules; Ergotamine and Dihydroergotamine (FDA approval years not readily available) and Sansert (methysergide, 1962)
Triptans: 7 new molecules; Imitrex (sumatriptan, 1992), Zomig (zolmitriptan, 1997), Amerge (naratriptan, 1998), Maxalt (rizatriptan, 1998), Axert (almotriptan, 2001), Frova (frovatriptan, 2001), and Relpax (eletriptan, 2002).
Antiepileptic Agents: 2 new molecules; Depakote (divalproex, 1996) and Topamax (topiramate, 2004).
Beta Adrenergic Blockers: 2 new molecules; Inderal (propranolol) and Blocadren (timolol), (FDA approval years not readily available, but placed around 1985 as placeholders).
Botulinum Toxin: 1 new molecule; Botox (onabotulinumtoxin A, 2010).

Comments

The history of ergot alkaloids and their use in migraine represents one of the fascinating chapters in classic pharmacology. It is noteworthy, however, that after ergot alkaloids, there has only been one new pharmacologic class introduced for the treatment of migraine, the triptans. Below are a few general comments about the current status of migraine therapeutics:

There are two pharmacologic classes for migraine treatment, i.e., ergot alkaloids and triptans, and three pharmacologic classes for migraine prophylaxis, i.e., antiepileptic agents, beta adrenergic blockers, and botulinum toxin.
A new drug molecule for migraine treatment hasn’t been approved since 2002, a triptan, and a new drug molecule for migraine prophylaxis hasn’t been approved since 2010, a botulinum toxin.
It is noteworthy that there are few other therapeutic classes with more off-label uses than migraine, and these off-label drugs are frequently listed in recommended drugs for migraine. These unapproved drugs include tricyclic antidepressants, other beta adrenergic blockers, and other antiepileptic agents.
It is also noteworthy that anti-migraine drugs and treatments are not infrequently used in combination with other pharmacologic classes, such as antiemetics, NSAID’s, and caffeine.
These last two comments are likely related to the nature of migraine, its etiology and multifaceted pathophysiology and symptomatology.

Conclusions

Migraine is a multifaceted, episodic CNS disorder, with complex symptomatology and a genetic component. Previously, it was thought to be related to vascular dysfunction, but more recently, it is thought to include cortical spreading depression. At the very least, the efficacy of disparate pharmacologic classes would attest to complex etiology and pathophysiology. Clearly, there is a great need for detailed understanding of the precise biologic mechanisms underlying the pathophysiology of migraine, including the different components of its symptomatology. As has previously been discussed, progress in other CNS therapeutic classes has been slow – Schizophrenia and Depression (2), Attention Deficit Hyperacticity Disorder (3) – suggesting a need for more basic research to identify new precision medicine-based therapeutic options for these – and other – CNS disorders.

References

Tfelt-Hansen PC, Koehler PJ. History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward. Cephalalgia, 28(8):877-886, 2008.
TRI-instirute,org: Slow Progress in Psychopharmacologic Therapeutics, Sep 2014, https://tri-institute.org/?p=184.
TRI-institute.org: ADHD Therapeutics: Slow and Limited Progress, Nov 2015, https://tri-institute.org/?p=742.

Refer to Progression of Modern Therapeutics (2014 Report) available under Reports on this website, which includes the methodology used.

Alzheimer’s Disease: Many Years To Go

Background

On 3 November 1906, Dr. Alois Alzheimer, a German psychiatrist, described together the clinical symptoms of presenile dementia and the pathologic findings of amyloid plaques and neurofibrillary tangles, based on clinical records and autopsy of patient Auguste D. Four years later, in 1910, Dr. Emil Kraepelin, an influential German psychiatrist, coined the name “Alzheimer’s Disease” for this disease, in the eighth edition of his textbook “Psychiatrie”. It wasn’t until 9 September 1993, however, or 86 years and 10 months following Dr. Alzheimer’s initial presentation, that the first drug specifically targeting symptoms of Alzheimer’s Disease was approved, the acetylcholinesterase inhibitor Cognex (tacrine).

Drug Approvals

There have been a total of six drugs approved for the treatment of Alzheimer’s Disease, not including new formulations of previously approved drugs (click on Alzheimer’s Disease). The pharmacologic classes of the approved drugs for the treatment of patients with different stages of dementia of the Alzheimer’s type are only two, acetylcholinesterase inhibitors and NMDA antagonists:

Acetylcholinesterase Inhibitors: 4 NME’s, i.e., Cognex (tacrine); Aricept (donepezil), Exelon (rivastigmine), and Razadyne (galantamine); registration interest spans 7 years and 5 months, from 1993 to 2001. Note that the first of these drugs, Cognex (tacrine), has been discontinued.
NMDA Antagonists: 1 NME, i.e., Namenda (mematine); approval in 2003.
Combination products: 1 non-NME, i.e., Namzaric (donepezil + memantine); approval in 2014. Note that this it not an NME, since both active components had been previously approved.

It should be noted that Hydergine (ergoloid mesylates), first approved on 18 January 1953, has been used in the past for treating patients with dementia or ‘age-related’ cognitive symptoms, although it has not been approved for the treatment of symptoms of Alzheimer’s Disease.

Therapeutic Activity

All three current acetylcholinesterase inhibitors (Aricept, Exelon, Razadyne) are approved for the treatment of mild to moderate dementia of the Alzheimer’s type, and one (Aricept) is also approved for the treatment of moderate to severe dementia of the Alzheimer’s type. The other two approved drugs (Namenda, Namzaric) are approved for the treatment of moderate to severe dementia of the Alzheimer’s type. The registration (Phase III) trials for these agents have used similar assessment scales, i.e., ADAS-cog (the cognitive subscale of the Alzheimer’s Disease Assessment Scale) and CIBIC-plus (Clinician’s Interview-Based Impression of Change with caregiver information) for mild to moderate, and ADCS-ADL (Alzheimer’s Disease Cooperative Study – Activities of Daily Living) and SIB (Severe Impairment Battery) for moderate to severe. In general, the therapeutic effects of these agents were modest, and both the active treatments and the placebo treatments showed a wide range of responses, but the active treatments were more likely to show the greater improvements.

Comments

Two issues are worth commenting on in the context of approved treatments for Alzheimer’s Disease. First, the most recent approval (Namzaric) involves a combination product of two previously approved drugs. Considering the current development challenges in this area (many failed development programs and failed mechanisms of action), the high unmet medical need, and that the effects of the approved drugs are not considered to significantly affect disease progression, although delaying cognitive decline, one wonders what other chronic diseases, where there has been limited development progress, might be ripe for new combination products of previously approved drugs. For example, for obesity, where there has been a paucity of new therapeutic approaches and high unmet medical need, two of the four drug approvals since 1999 (Contrave, Qsyma), have involved combination products of previously approved drugs (1). A systematic and comprehensive review of other therapeutic classes will undoubtedly identify several other diseases where similar situations exist, including for other Psychopharmacologic and Neurologic Therapeutics.

Second, if recent history of progression of modern therapeutics is any guide, it is not unlikely that will take many years until there are next generation(s) of new NME drug approvals for Alzheimer’s Disease, including more than one per each new pharmacologic class. We note that the average number of pharmacologic classes per therapeutic class for 25 therapeutic classes that have been looked at is 4 (ranging from 1 to 10), and that the number of new NME drug approvals per pharmacologic class ranges widely, from 1 to 14 (2). We also note that the length of registration interest, defined here as the length of time from the first approval to the latest approval within a give pharmacologic class, has varied tremendously, ranging from a year or two to over 40 years (2). Thus, based on recent NME approval history of 25 therapeutic classes, and assuming there are one or more new breakthrough pharmacologic classes in the pipeline, and assuming more than one new NME drug approval per pharmacologic class, unfortunately, it is likely to take many years until we have a markedly different therapeutic choices for Alzheimer’s Disease. One hopes meaningful progress will have occurred before the 120th anniversary of Dr. Alois Alzheimer’s initial presentation.

References

Weight Reduction Drugs: Slow Progression and Innovation (https://tri-institute.org/?p=394).
Progression of Modern Therapeutics (2014 version), pages 33-35 (Progression of Modern Therapeutics (2014 Report))

Refer to page 23 of Progression of Modern Therapeutics (2014 Report) available under Reports on this website; this Report also includes the methodology used.

Responder Rates and Therapeutic Response Variabilities

Background

While it’s generally recognized that individual patients respond differently to approved drugs, this topic has received limited public comments by developers and regulators. A single publication from 2001 lists approved drugs across thirteen therapeutic classes, reporting that the patient responder rate ranged from 25 to 80%, averaging about 50% across these therapies (1). The therapeutic classes examined involved drugs for Alzheimer’s disease, analgesics (Cox-2 inhibitors), asthma, cardiac arrhythmias, depression (SSRIs), type-2 diabetes, hepatitis C virus, urinary incontinence, migraine, oncology, osteoporosis, rheumatoid arthritis, and schizophrenia (click on Table 1). Only the percentage of the trial populations characterized as responders was reported for each therapeutic class, but neither the inter-patient variability in therapeutic response nor which or how many drugs were evaluated for each class. The responder qualifications were based on regulatory requirements for approval for each class, and the responder rates were based on information provided in the approved product labels (2); thus, a responder rate as used here is a regulatory construct. There doesn’t appear to have been any update or followup on this topic since that publication. It is noteworthy in this regard that since the time of the above-mentioned publication, a total of 386 new drugs or NMEs (between years 2001 and 2014, inclusive) have been approved by the FDA (3), including those with novel mechanisms of action, new platforms, new indications, suggesting that some of the reported therapeutic class-based responder rates may have changed and new ones added. It is also worth noting that the above-mentioned publication has often been quoted to promote personalized medicine (4,5), based in part on the unmet medical need of the non-responders.

Publicly Available Database on Therapeutic Response Characteristics

Considering the significance of therapeutic response characteristics, including responder rates, of approved drugs or therapeutic classes, it’s all the more surprising how limited data is readily available on this topic, i.e., information that’s presented in a uniform and easily understood format. Given the current situation and the desire for a comprehensive, publicly available database on therapeutic response characteristics of approved drugs, before there can be meaningful progress on this front, there are a few significant methodological and procedural issues that need to be considered and resolved.

First, clinical trials data – The most comprehensive clinical trials data for approved drugs, including clinical study reports with complete data tables, listings and figures, involve the registration submission dossiers from individual pharmaceutical sponsors. Considering that these documents are proprietary, the most obvious sources of patient response and efficacy information would be the regulatory authorities that review and approve new drug applications or marketing authorizations, as well as the respective product labels. For US approvals, this involves the review summaries by the FDA medical and other reviewers (formerly called Summary Basis for Approval), containing the different regulatory reviews supporting approval and the product label (6). Similar information is available for European approvals, in a slightly different format (7). While both of these public sources contain huge amounts of data, the information of interest does not appear to be specifically highlighted, or at least not developed into a readily digestible uniform format. Also, when using such clinical trials data for the task at hand, there are different aspects that may need to be considered for a given therapeutic class, e.g., changes in regulatory requirements, changes in clinical practice, data from post-approval clinical trials, dose-response relationships, number of approved doses, and risk-benefit considerations. These considerations require the development of a review protocol, with details commensurate with the intended level of assessment granularity.

Second, definitions and methodology – Patients with varying degrees of a desired pharmacologic or therapeutic response have been referred to clinically by different terms, which have often been poorly and inconsistently defined. This refers typically to patients on both ends of the response distribution curve, e.g., non-responders, poor responders and treatment resistant patients on one end, and good responders, super-responders and treatment sensitive patients on the other end. This calls for unambiguous definitions of the different terms used for therapeutic response characteristics. Also, for greater utility, should other definitions than those based on regulatory approval requirements for responders be considered? It would seem desirable that a consistent format be developed and adopted for presenting therapeutic response characteristics of approved drugs, somewhat analogous to the development of data standards for clinical trials data, including the actual response or efficacy endpoint values, and the outlier response groups, both the top and bottom values. Then there are the issues of how to address drugs within the same pharmacologic class, individually or as a group, and whether the approved NME involved is a single drug or a combination product or therapy, e.g., on top of standard of care? It is suggested that to arrive at innovative and informative designs for characterizing therapeutic response data will require inputs from the relevant academic, industry and regulatory communities.

Third, implementation approach – As has been addressed above, preliminary work is needed on what clinical trials data to use, although the FDA medical and statistical reviewers summaries sound like a good starting place, and on definitions and methodology, including infographics designs, and what therapeutic classes to start with. It is noted that our organization’s project on “Progression of Modern Therapeutics” was initiated in part to help guide this project on “Therapeutic Response Characteristics”, including what pharmacologic and therapeutic classes first to consider for this project. Clearly, considering the many issues and complexities involved in both the needed preliminary work and the subsequent work on the therapeutic response characteristics database, this is a long-term project that will require well coordinated partnerships among the relevant academic, industry and regulatory communities.

Benefits of a Publicly Available Database

There are many benefits and opportunities to the medical and scientific communities associated with having a comprehensive, publicly available database on key therapeutic performance measures of approved drugs within their therapeutic classes, including actual responses, responder rates, and response outliers, in an easily understood and consistent manner. These include the following:

Raising widespread awareness, among patients, prescribers, payors, researchers, developers large and small, regulators, and disease organizations regarding differing therapeutic response characteristics among approved drugs by indications and therapeutic areas;
Highlighting unmet medical need due to therapeutic inadequacy for a disease or indication based on high rates of poor responders to approved drugs and related healthcare implications;
Providing an evidence-based foundation for future knowledge-base explorations, e.g., combining such a database with biologic, pharmacologic, disease and genomic databases;
Catalyzing interest in the development of companion diagnostics and clinically applicable tests to monitor treatment effects to avoid continuing treatment in those not responding (but still at risk of experiencing adverse effects);
Allowing explorations across different therapeutic classes, e.g., comparing response characteristics of small molecules vs. biological drugs, and comparing response characteristics based on surrogate vs. clinical endpoints; and finally,
Addressing various questions and hypotheses relating to systems therapeutics, e.g., how similar are response characteristics for different pharmacologic classes for given therapeutic classes?

Conclusions

The case has been presented for the development of a publicly available database on therapeutic response characteristics of approved drugs, presented in a consistent and easily understood format. We believe that this important topic has not been given the attention it deserves. We further believe there are numerous benefits and opportunities deriving from such a database, not the least of which is catalyzing activities on precision medicine and regulatory science. Obviously, an undertaking of this magnitude will require a significant effort involving the participation and partnerships with the relevant academic, industry and regulatory communities.

References

Spear, B.B., Heath-Chiozzi, M., Huff, J. Clinical applications of pharmacogenetics. TRENDS Mol. Med., 7, 201-204 (2001).
Physicians Desk Reference (printed version, 54th edition, 2000), now available online at http://www.pdr.net.
FDA’s New Molecular Entity (NME) Drug and New Biologic Approvals, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ucm373420.htm
Personalized Medicine Coalition. The Case for Personalized Medicine, 4th Edition, 2014, accessible at http://www.PersonalizedMedicineCoalition.org
Aspinall, M.G., Hamermesh, R.G. Realizing the promise of personalized medicine. Harvard Business Review, 85(10), 108-117 (2007).
Food and Drug Administration’s Drugs@FDA, http://www.accessdata.fda.gov/scripts/cder/drugsatfda
European Medicines Agency’s European Public Assessment Reports (EPAR), http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125