Zuclomiphene citrate is a novel estrogen receptor agonist being developed for the treatment of hot flashes (aka vasomotor symptoms) caused by prostate cancer hormonal therapies in men with advanced prostate cancer.

hot flashes from a patient point of view

Hot Flashes During Prostate Cancer Treatment (ADT) – A Patient’s Perspective

Zuclomiphene: A potential treatment for men with hot flashes from prostate cancer treatment (ADT)

Zuclomiphene: A potential treatment for men with hot flashes from prostate cancer treatment (ADT)

Zuclomiphene citrate

VERU IS ENROLLING PATIENTS

To Ameliorate the Vasomotor Symptoms (Hot Flashes) Resulting from Androgen Deprivation Therapy in Men with Advanced Prostate Cancer

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Scientific Overview

Prostate cancer is the most common non-cutaneous cancer diagnosed in men with over 174,650 new cases expected in 2019 (American Cancer Society. Cancer Facts & Figures 2019). The estimated prevalence of prostate cancer is 2.35 million cases for which over one-third will have received androgen deprivation therapy (ADT). ADT-induced estrogen deficiency side effects can cause men to delay, pause and/or discontinue ADT, increases morbidity and mortality, and can significantly impact quality of life. ADT-induced side effects include hot flashes, bone loss and fractures, fatigue and libido, and adverse lipid and metabolic changes. Hot flashes, also known as vasomotor symptoms, are the most common and distressing side effect of hormonal therapies for the treatment of advanced prostate cancer. Hormone therapies include androgen deprivation therapies, like LUPRON DEPOT® (leuprolide acetate for depot suspension), for intramuscular use or ZOLADEX®(goserelin acetate implant), as well as the newer oral agents approved to treat castration resistant prostate cancer such as ZYTIGA® (abiraterone acetate) tablets and XTANDI® (enzalutamide) capsules.

Up to 80% of men on androgen deprivation therapy complain of hot flashes (vasomotor symptoms) (Frisk J, Maturitas 65:25-22, 2010). Hot flashes are defined as intense heat sensation, flushing and profuse sweating and chills as well as anxiety and palpitations. Although episodes of hot flashes occur repeatedly and last a few minutes, some may last up to 20 minutes and the sufferer may have to cease activities until hot flashes abates. Hot flashes associated with prostate cancer hormonal therapies tend to persist over time with consistent frequency and intensity throughout therapy. Up to 50% of men continue to report hot flashes after five years on prostate cancer hormonal therapy (Frisk J, Maturitas 65:25-22, 2010). Patients on prostate cancer hormonal therapy report significant effects on daily functioning and quality of life. Hot flashes are one of the main reasons for patients to be noncompliant with their prostate cancer hormonal therapy. As prostate cancer patients with advanced and metastatic disease are living longer as a result of more effective hormonal therapies, hot flashes have become an even bigger concern and impact on quality of life.

How does ADT cause hot flashes in men? In men, estrogen is derived from testosterone. ADT lowers testosterone to castrate levels resulting in low estrogen levels. Low estrogen levels appear to cause dysfunction of the hypothalamic thermoregulatory processes including alterations of neurotransmitters which causes the vasomotor symptoms perceived as hot flashes, or dysregulation of temperature. Hot flashes severity definition are as follows: Mild– sensation of heat without sweating; Moderate– sensation of heat with sweating, able to continue activity; and, Severe– sensation of heat with sweating, causing cessation of activity.

Hormonal and non-hormonal therapies have been used off-label to treat hot flashes in men on prostate cancer hormonal therapies. In general, off label hormonal agents intended to treat women especially estrogens and progestins have been shown to be effective in the scientific literature. However, generalized estrogen treatment is challenged by lack of consistent dosing, and side effects including gynecomastia (breast enlargement), mastodynia (painful breasts) and thromboembolic events including stroke. Non-hormonal agents that have been used off-label include anti-seizure agents and antidepressants, but that have their own unwanted bothersome side effects. Moreover, non-hormonal agents tend to be less efficacious than hormonal therapies for the treatment of hot flashes. There are no FDA-approved therapies for the indication to treat hot flashes caused by prostate cancer hormonal therapy in men with advanced prostate cancer.

Zuclomiphene citrate (cis-clomiphene;VERU-944) is an oral novel nonsteroidal estrogen receptor agonist. Clomiphene (CLOMID) contains two separate drugs (isomers): up to 70% is enclomiphene (an estrogen receptor antagonist and active ingredient) and 30-50% is zuclomiphene (an estrogen receptor agonist). Clomiphene (CLOMID) has been approved to treat female infertility since 1967.

Zuclomiphene citrate as a single drug has never been approved for any indication. We have evidence that as a component of clomiphene, zuclomiphene appears to be well-tolerated in 39 published studies in over 2,200 men with doses as high as 400 mg/day and up to three years of use. Zuclomiphene citrate, as a nonsteroidal estrogen receptor agonist, has the potential to be the first FDA approved product as an effective and well-tolerated treatment for hot flashes, a major side effect caused by hormonal therapies in men with advanced prostate cancer.

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Zuclomiphene citrate

Development Plan

As Zuclomiphene, comprises 30-50% of CLOMID (clomiphene citrate) which is approved for the treatment of ovulatory dysfunction in women desiring pregnancy, Veru will be able to reference the nonclinical and clinical safety information from both the listed drug labeling and the published literature under the 505(b)(2) regulatory pathway. Zuclomiphene, as a pure isomer, has never been FDA approved as such we will provide preclinical and clinical studies required for approval for hot flashes indication in men on hormone therapy for advanced prostate cancer. Veru held a Pre-IND meeting with the FDA, and the required development program has been discussed and confirmed with FDA. Veru entered into Phase 2 clinical development which is a randomized, dose-finding placebo controlled clinical trial and is intended to define the minimum effective dose of zuclomiphene in the treatment of hot flashes in men with advanced prostate cancer on androgen deprivation therapy. The study is testing 3 doses versus placebo enrolling approximately 90 subjects from 15 clinical centers in the United States. Top line clinical results are expected by the end of 2019.

Zuclomiphene citrate

Market

Hot flashes are the most common side effect of prostate cancer hormone therapy occurring in up to 80% of men, with about 30% having moderate to severe hot flashes. Approximately 600,000 men annually in the United States are on androgen deprivation therapy, abiraterone or enzalutamide for advanced prostate cancer. There are currently no FDA-approved therapies for hot flashes associated with prostate cancer hormonal therapies. Based on an independent market analysis sponsored by Veru, Veru estimates the US market potential for zuclomiphene citrate is over $600 million annually.