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Fedovapagon for Nocturia

Fedovapagon (VA106483) is a novel small molecule drug candidate discovered by Vantia and currently in pivotal clinical trials for the treatment of nocturia, a common condition that causes sufferers to wake frequently during the night in order to urinate. Vantia has chosen to focus initially on males with BPH. Nocturia is a common condition in the BPH population and is commonly the reason that men with this condition seek medical attention. However, medications prescribed to treat the symptoms of BPH are rarely effective in treating the nocturia, and whilst other BPH symptoms may improve, the symptom that led to the presentation at the doctor’s office i.e. nocturia, often remains unresolved.

Fedovapagon is an antidiuretic that acts directly in the collecting ducts of the kidney by binding to, and activating, vasopressin V2 receptors. Activation of the V2 receptors causes the kidneys to reabsorb water from urine as it passes towards the bladder. If fedovapagon is dosed before going to bed the result is less urine produced overnight. Men with nocturia commonly produce large volumes of urine at night and it is hypothesised that this leads to multiple trips to the bathroom to empty their bladder. It is hoped that producing less urine overnight will reduce the number of trips to the bathroom and, in turn, increase sleep time.

Fedovapagon has been extensively studied in clinical trials and data, presented at the American Urological Association meeting in 2010, demonstrated a dose-dependent reduction in nighttime urine volumes. Importantly, this effect was reliable on repeated dosing. More recently, data presented in San Diego at the 2012 American Urological Association meeting, showed that fedovapagon effectively reduced nighttime urine production from the first night of dosing and that there was no effect following cessation of dosing.

Vantia has recently completed a pivotal clinical trial investigating the effect of fedovapagon as a new treatment for nocturia in men with BPH. The EQUINOC trial was a randomized, double-blind, placebo controlled efficacy study in the USA ( identifier: NCT01656239) and enrolled 432 BPH patients with BPH and nocturia. Patients were randomised to receive fedovapagon or placebo orally each evening over a 12-week treatment period.

The trial showed a statistically significant effect of treatment on both co-primary endpoints, demonstrating a reduction in nocturnal voids (waking and urinating: p<0.001) and improved quality of life through a patient reported outcome score, NocTIMe® (p=0.034). The clinical significance of treatment was supported by statistically significant results for other endpoints including time to first void (p<0.001), nights when patients have 0 or 1 voids (p<0.006) and patients who reduce their voids by 50% (p<0.001). The benefit of treatment was further endorsed by significant treatment effect on independent endpoints including patient reported voiding in the International Prostate Symptom Score (IPSS) and Nocturia Quality of Life (NQoL).

Fedovapagon was generally well tolerated which, in combination with the efficacy endpoints, strengthens the potential for it to be a safe and effective treatment for nocturia in men with BPH. A second pivotal Phase III study based on the same endpoints and population will now be conducted with the goal of providing further data required to support regulatory filings for marketing approval in the US and Europe.

Market Opportunity

Nocturia is defined as the complaint that the individual has to wake at night one or more times to void. It is a common condition affecting all ages but increases in frequency with age such that >70% of the general population over the age of 60 years suffer from the condition. Whilst waking once a night has limited impact on most patients a frequency of two voids per night or more represents a significant burden to sufferers. Multiple studies have shown a link between nocturia and negative impact on outcomes such as quality of life, depression and night-time falls. Not surprisingly, these result in significant negative effects on daytime activity and work productivity and result in a significant economic burden to society estimated in multiple billions of dollars per year.

Current nocturia treatment options are limited for men with BPH. Whilst most patients are advised to limit evening fluid intake this approach is of limited value and whilst pharmacological treatments, such as alpha blockers are administered, they have limited, if any, efficacy and no regulatory approval for the treatment of nocturia. The peptide drug, desmopressin, is used for the treatment of nocturia in some parts of the world but has shown a risk for hyponatremia, especially in elderly patients. As a result there is a significant population of patients seeking alternative treatments.