Monthly Archives: August 2016

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

Background

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

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

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

Drug Approvals

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

Benign Prostatic Hyperplasia Graph copy

The new drug approvals are listed below:

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

Comments

A few noteworthy observations are in order:

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

References

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

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