Q: What is erectile dysfunction and what causes it?
A: Erectile dysfunction (ED) is the inability to achieve and sustain an erection suitable for sexual intercourse, and it is considered abnormal at any age. Erectile dysfunction may have a psychological basis (e.g. depression or anxiety) or be caused by physical changes (e.g. atherosclerosis, diabetes, or spinal cord injury). (1,2)
The National Institutes of Health estimates that ED affects as many as 30 million men in the US. Incidence increases with age; about 4 percent of men in their 50’s and nearly 17 percent of men in their 60’s experience a total inability to achieve an erection. The incidence jumps to 47 percent for men older than 75. (3,4)
According to Drs. Allard and Guiliano(5), urologists specialized in central nervous system (CNS)-based ED treatment, dopamine, one of the major neurotransmitters in the brain, plays a central role in sexual motivation and penile erection. Another neurotransmitter, serotonin, also influences the CNS control of human sexual behavior. These neurotransmitters form “brain circuits,” such as dopaminergic mesocortical and mesolimbic pathways that have a broad effect on the brain, including the hypothalamus and descending neuronal projections. The neuronal innervations from the brain form “nuclei” in the sacral sections of spinal cord, which are crossings between CNS inputs that relay emotional information and ascending routes from touch receptors of genitalia. This circle of central and peripheral nerves consists of the parasympathetic nervous system and can control human sexual performance.
Rexahn is developing a drug called Zoraxel™ as a treatment for ED. Zoraxel™ is a clinical stage drug for sexual dysfunction that directly modulates the sexual activity regions in the brain, enhancing the action of serotonin and dopamine, and three phases of male sexual activity: arousal, erection, and release. Zoraxel™ may be the first ED therapeutic to affect all three of these phases.
Q: What are pharmacological treatment options for ED?
A: Typically, the first line of treatment for ED is Viagra®, Cialis®, or Levitra®. These drugs act by blocking an enzyme phosphodiesterase (PDE)-5, which increases blood flow to the peripheral organ.(6) While these drugs are popular, a subset of patients does not respond to these drugs. Rexahn believes that a drug like Zoraxel™, with its demonstrated ability to enhance serotonin and dopamine, which directly modulates the sexual activity regions in the brain, could address the underlying condition of the disorder, unlike the PDE-5 drugs, and could establish a new standard of care for ED.
Q: What are drawbacks of existing ED drugs?
A: According to the drug labels of ED drugs, side effects associated with PDE-5 inhibitors include heart attack, headache, flushing, sudden loss of hearing, or changes in vision. In addition, over 30% of patients are known to be refractory to the PDE-5 inhibitors.(7)
Q: What differentiates Zoraxel™ from other ED drugs and how does it benefit the patients?
A: Unlike PDE-5 inhibitors targeting peripheral blood flow, Zoraxel™ works to boost sexual function by directly affecting the brain circuit. Zoraxel™ enhances the action of serotonin and dopamine in the brain, which play key roles in three phases of male sexual activity: arousal, erection, and release. Preclinical studies suggest Zoraxel™ increases dopamine and serotonin levels in nucleus accumbens, a brain region that influences the parasympathetic nervous system which, in turn, controls penile erection.
Because Zoraxel™ may have the potential to reinforce the parasympathetic tone toward the genitalia by modulating either the autonomic spinal cord nuclei controlling penile smooth muscle or parts of the brain projecting to the region, it may offer important treatment benefits for patients with “psychogenic” ED.
Q: What have clinical studies shown so far?
A: Rexahn has completed a Zoraxel™ Phase IIa proof-of-concept clinical trial to identify clinically relevant dose levels and quality of life measures of ED patients. Using the International Index of Erectile Function – erectile function (IIEF-EF) as an endpoint, the randomized, double-blind, placebo-controlled, dose-exploring Phase IIa study demonstrated that treatment with 15mg of Zoraxel™ improved subjects’ IIEF-EF scores by 6.5, a value obtained from the changes off the baseline between scores of 15 mg of Zoraxel™ and the placebo group. The Phase IIa clinical study also showed Zoraxel™ to be well-tolerated and without any serious side effects common to PDE-5 inhibitors.
To examine the clinical relevance of Zoraxel™ as an erectile dysfunction drug, effect size analysis has been conducted. Effect size (ES) is a data analysis index developed by Dr. Jacob Cohen of New York University and is derived from the improvement in IIEF mean score for the treatment group minus the improvement in IIEF mean score of the placebo group over the treatment period, divided by the standard deviation of the entire sample at baseline.(8) This method has been successfully adopted to prove clinical relevance of clinical data, and an ES value greater than 0.80 indicates “a considerable change.”(9) The ES for IIEF-EF and IIEF-intercourse satisfaction indices of Zoraxel™ (2.59 and 0.88, respectively) were larger than 0.80, suggesting a meaningful improvement of sexual experiences in Zoraxel™-treated patients.
In addition, because Zoraxel™ acts on the central nervous system, unlike PDE-5 inhibitors, Zoraxel™ may be effective for ED patients who are refractory to these treatments. With its unique CNS-based mechanism, pro-erectile function and minimal side-effects, Zoraxel™ has the potential to be an important new therapy for ED patients.
1. K. Wylie, Adv. Psychosom. Med. 29, 33 (2008).
2. S. Carrier, Can. J. Urol. 10 Suppl 1, 12 (2003).
3. NIH, JAMA 270, 83 (1993)
4. C. Saigal, Arch. Intern. Med. 166, 207 (2006)
5. J. Allard, Curr Urol Rep. 6, 488 (2001)
6. I. Eardley et al., J. Sex Med. 7, 524 (2010).
7. A. Nehra, Mayo Clin. Proc. 84, 139 (2009).
8. J. Cohen, Psychological Bulletin. 112, 155, (1992)
9. A. Ponizovsky, Int J Environ Res Public Health, 6, 2510, (2009).
