Category Archives: Modern Therapeutics

Progression of Modern Therapeutics project

Infographics of Modern Therapeutics

Introduction

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

Great Variability in New Drug Approvals Among Pharmacologic Classes and Therapeutic Classes, posted February 2016, and
Snapshots from Progression of Modern Therapeutics, posted June 2016.

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

Methodology

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

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

Number of Pharmacologic Classes per Therapeutic Classes

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

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

New Drug Approvals per Therapeutic Classes

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

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

Selected Snapshots from Noteworthy Patterns in Registration Avivities

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

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

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

Length of Registration Interest

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

Comments

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

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

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

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

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

Background

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

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

Drug Approvals

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

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

Approvals for IBS-D predominant:

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

Approvals for IBS-C predominant:

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

Comments

A few general comments are in order:

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

References

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

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

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

Background

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

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

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

Drug Approvals

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

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.

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.

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.

2015 Report: Progression of Modern Therapeutics

The 2015 Report of Progression of Modern Therapeutics provides graphs of new drug approvals for 40 therapeutic classes from 40 therapeutic categories. These include the 25 therapeutic classes that were in the 2014 Report, any updates on these, and 15 new ones, including irritable bowel syndrome, HIV-1/AIDS, hepatitis C, malaria, melanoma, pediatric acute lymphoblastic leukemia. Click here for the 2015 Report on this website.

Comments

As with most projects there are sometimes unexpected issues that come up from time to time, and this project is no different. We will comment on three such issues at this time:

Missing approved new drugs. Since the approach used for what new drug approvals to include involves a therapeutic class centered approach rather than an NME centered approach, it is possible there may be missing drug approvals, since these may involve secondary indications of NME’s or subsequent approvals of the same compound, and would thus not be included in FDA’s annual NME listings. Any such omissions will be corrected as appropriate.

Missing approval dates. For several older drugs, the exact initial approval date may not be listed in the Drugs@FDA database, or other readily available databases. In such cases, a footnote is added to that effect on the graphs for individual therapeutic classes, e.g., pediatric acute lymphoblastic leukemia and migraine; other examples would include tuberculosis.

Off-label use. For some diseases there is considerable off-label use, and a number of drug information websites may include such use, without necessarily distinguishing between FDA approved drugs and off-label use, e.g., migraine. Such examples of clinical use are typically not included on the graphs.

Random Observations and Comparisons

A perusal of this 2015 Report suggests a few lessons learned, including the following random observations and comparisons:

Note significant recent advances in new drug approvals for hepatitis C, melanoma, cystic fibrosis, idiopathic pulmonary fibrosis, and irritable bowel syndrome, to name just a few.
Note recent introductions of new pharmacologic classes or mechanisms of action for type-2 diabetes, dyslipidemia, multiple sclerosis, pulmonary arterial hypertension, and rheumatoid arthritis, to name just a few.
Note no new introductions of new pharmacologic classes for depression (MAO inhibitors, tricyclics, SSRI’s/SNRI’s) and schizophrenia (typical and atypical antipsychotics) since the late 1980’s.
Contrast melanoma with 8 new drug approvals since 2010 with childhood acute lymphocytic leukemia with most drugs from the 1950’s, 1960’s and 1970’s.
Contrast plaque psoriasis with 7 new drug approvals with systemic lupus erythematous with 1 new drug approval since 2000.
What do thrombolysis and acid reflux/gastric ulcer have in common? No new drug approvals since 2000/2001.

The two prior annual update reports (2013 Report and 2014 Report) contained different summary graphics, which are not included in the 2015 Report; these will be addressed in future posts.

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.