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Repros Therapeutics Inc.

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November 12, 2015

Repros Therapeutics Completes Randomization of Phase 2b Study of Vaginal Proellex(R) in Women With Symptomatic Uterine Fibroid Bleeding

THE WOODLANDS, Texas, Nov. 12, 2015 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced it has completed randomization for its Phase 2b study of Proellex® in the treatment of women suffering with symptomatic uterine fibroids. The primary endpoint for the study is the incidence of amenorrhea induced by four months of treatment with two dose levels of Proellex® compared to placebo. In addition, subsequent to discussion with the FDA, Repros is collecting an assessment of blood loss by a validated alkaline hematin method at baseline and during off-drug intervals. At baseline menses women were required to exhibit > 80 ml of blood loss by that method to be enrolled.

In addition to blood loss, bulk symptoms associated with fibroids and treatment effects on uterine and fibroid size, determined by MRI, will also be assessed.

The Company expects to have topline results from the study of the subjects' first four-month course of treatment during the second quarter of 2016.

A sister study using low doses of oral Proellex® in similar women has completed screening and should be fully randomized before the end of January 2016. Correspondingly, the topline data from that study will be available later than the vaginal data.

In a publication in BMC Women's Health 2012; 12: 6, in a study of women age 15 - 49, across eight countries including the U.S., the self-reported incidence of uterine fibroids was 7% and 14.1% for women in their 30's and 40's, respectively. A U.S. study published in the American Journal of Obstetrics and Gynecology 2003 Jan; 188(1): 100-7, noted that by age 50, 70% of Caucasian and 80% of African American women have developed uterine fibroids before menopause. In the BMC article it was noted that in the U.S., a diagnosis of uterine fibroids is the leading indication resulting in hysterectomy. An effective therapeutic option for the treatment of fibroids is still a significant unmet medical need.
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Source: press release, 11/12/15. http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=942526

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December 29, 2014

Repros Initiates Two Phase 2B Uterine Fibroid Studies

Low dose oral Proellex® study in women with fibroids and heavy menstrual bleeding initiated

Vaginal administration of Proellex® in women with fibroids and heavy menstrual bleeding initiated

Company anticipates Type C meeting with FDA to discuss Phase 3 fibroid program and general NDA requirements around year end 2015

THE WOODLANDS, Texas, Dec. 29, 2014 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced it has initiated two Phase 2B efficacy studies of Proellex® in the treatment of uterine fibroids in women that experience heavy vaginal bleeding as a result of these benign tumors. The two studies both have the same FDA suggested endpoints but test two different routes of administration, oral and vaginal. The Company had previously tested both routes using similar doses and found that Proellex® exhibited significant effects on bleeding due to uterine fibroids with each route of administration.

In addition to significant effects on bleeding due to Proellex® administration, tumor size was significantly reduced. As a result of reduced tumor burden, bulk symptoms improved to the point where the majority of subjects reported to be symptom free using the Uterine Fibroid Symptom Quality of Life survey (UFSQoL). The UFSQoL is a validated survey that was used to approve uterine artery embolization and ultrasound focusing.

In earlier Phase 2 studies, both oral and vaginal administration of Proellex® stopped menses and hence, in this study, on recommendation from the FDA, Repros has chosen amenorrhea as the primary efficacy endpoint. The studies both have three double blind arms: placebo and Proellex® at 6 mg and 12 mg doses. The two studies are powered to achieve the desired impact on menstrual bleeding with only 15 subjects per arm. In addition to investigating the incidence of amenorrhea, actual menstrual blood loss will be estimated by the alkaline hematin method from used sanitary products.

The studies are designed to treat women for two 4-month dosing courses separated by an off drug interval to allow for menses. Following the second course, the FDA instructed the Company to follow the women for six additional menstrual events to investigate the duration of benefit.

The Company plans to request a Type C meeting after all the subjects have experienced the menstrual event following the first course of treatment. An interim assessment of efficacy and safety is part of the analysis plan. Assuming enrollment proceeds according to plan, the Company believes it can schedule a Type C meeting with the FDA around year end 2015. The purpose of this meeting will be to discuss the overall FDA proposed size of the safety database required for an NDA.
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Source: press release, 12/29/14. http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=889055

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A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 6 and 12 mg Proellex® (Telapristone Acetate) Administered Vaginally in the Treatment of Premenopausal Women With Confirmed Symptomatic Uterine Fibroids
Estimated Enrollment: 45
Study Start Date: December 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. https://clinicaltrials.gov/ct2/show/NCT02323646?term=repros+pharmaceutic...

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Proellex Uterine FibroidsObstetrics and GynecologyUterine FibroidsProgesterone receptor antagonistProgesterone receptor

Mechanism of action: Proellex®, is an orally active, small molecule, selective blocker of the progesterone receptor that is being developed for the treatment of uterine fibroids and endometriosis.

Phase of Development: IIb

Event Type: Data: Phase IIb trial results

Dates: 2016-04-01 - 2016-06-30

Results:

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Repros Reports Topline Positive Clinical Data After Two 18 Week Courses of Proellex® Delivered Orally and Vaginally for the Treatment of Uterine Fibroids
Primary endpoint of induction of amenorrhea met for both pooled oral and vaginal delivery compared to placebo, p < 0.0001 and p=0.0071, respectively
Statistically significant reduction in fibroid size from baseline achieved by the combined active arms for the pooled oral dosage form compared to placebo, p=0.0004
Statistically significant improvement in Uterine Fibroid Symptom Severity Score (UFSQOL) achieved for the pooled oral dosage form compared to placebo, p=0.0211
On the basis of a comparison of oral and vaginal delivery systems, the Company will propose the oral route of administration for Phase 3 development
The Company plans to submit a request to the FDA before the end of 2016 to discuss the Phase 3 program
THE WOODLANDS, Texas, Nov. 14, 2016 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today reported the topline results for both its pooled oral and vaginal delivery Phase 2 studies in the treatment of uterine fibroids. Both studies enrolled women with confirmed fibroids by MRI at baseline and who were experiencing more than 80 mL of blood loss during menses as confirmed by alkaline hematin assessment. Proellex® at doses of both 6 and 12 mg, delivered by either route, substantially and significantly reduced excessive menstrual bleeding, the key symptom of uterine fibroids and the primary endpoint of the studies. The study of vaginal delivery enrolled 42 subjects and the oral delivery study's intent-to-treat population included 41 subjects.

Amenorrhea, cessation of menses, is known to occur when a sufficiently high plasma concentration of Proellex® is achieved. Subjects received 18 weeks of blinded treatment and were then withdrawn from the study medication to allow for menses. After menses occurred, a second 18 week course of treatment ensued. The study treatment assignments remained blinded to the subjects, physicians and those managing the study and data.

The incidence of amenorrhea in active treatment groups consistently showed a statistically significantly difference from the rate in placebo-treated subjects with both routes of administration. At the end of the second course of treatment (36 weeks total active treatment, or Last Observation Carried Forward, LOCF), 92.9% of oral Proellex®-treated subjects achieved amenorrhea, while only 50% of vaginally treated subjects stopped menses. The oral dosage form provided for consistent suppression of menses with evidence of a dose response. Furthermore, among those women who completed the second 18 week course of oral drug administration, 100% of the women at the 12 mg dose exhibited amenorrhea, whereas 88.9% of women on the 6 mg dose achieved amenorrhea.

Along with changes in menstrual patterns, fibroid size, measured by MRI, was reduced in volume. Fibroid volume decreased in the oral Proellex®-treated arms by a median of 42.0% (LOCF) and was statistically different from the change from baseline volume in the placebo subjects (0%, p = 0.0004). For women who completed the two 18 week courses of treatment, fibroid size reduction for the 12 mg oral and 6 mg oral doses was 58.2% and 32.9%, respectively, providing some evidence of a dose response effect.

The Uterine Fibroid Symptom Quality of Life Survey (UFSQOL) was utilized in this study. The UFSQOL assesses distress from both bleeding and the bulk symptoms of uterine fibroids. Bulk symptoms include distress associated with pelvic pressure, frequent urination and fatigue. Proellex®-treated subjects experienced a LOCF median 70.9% improvement while placebo-treated subjects reported a 37.5% improvement (p = 0.0211).

The drug was generally well tolerated.

Joseph Podolski, President and CEO of Repros, commented, "We believe the benefit:risk profile of Proellex® could afford a significant advantage over GnRH agonists and antagonists in the treatment of uterine fibroids. The longer treatment period and apparent improvement in efficacy based on the incidence of amenorrhea compared to other selective progesterone antagonists is also encouraging."

The Company plans to request, before the end of this year, a meeting with the FDA to discuss Phase 3 development of the oral dosage form.
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Source: press release, 11/14/16. http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=999335

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Repros Reports Positive Clinical Data for Vaginal Proellex® in Women With Severe Menstrual Bleeding Due to Uterine Fibroids
Primary endpoint of induction of amenorrhea met for both vaginal doses compared to placebo, p < 0.0011
Proellex®-treated subjects reported a median 100% reduction in diary reports of menstrual bleeding product usage (PBAC)
Statistically significant reduction in fibroid size from baseline achieved for the combined active arms compared to increase in fibroid volume in placebo arm, p=0.0437
Low dose oral data from a comparable study to be reported in Q2 2016

THE WOODLANDS, Texas, April 12, 2016 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today reported that vaginal administration of Proellex ® at doses of both 6 and 12 mg achieved significant reduction in excessive menstrual bleeding, the key symptom of uterine fibroids.

Normal menstrual blood loss in a menstrual cycle is approximately 35 mL. Woman experiencing blood loss of > 80 mL are considered to suffer from menorrhagia or excessive menstrual bleeding. In this small Phase 2b study, 13, 15 and 14 women with confirmed uterine fibroids were enrolled in the 6mg, 12mg and placebo arms, respectively. At baseline, the mean amount of blood lost for one menstrual cycle was 255 mL, 274 mL and 238 mL for each arm, respectively. The blood loss ranged from a low of 94 mL to a high of 654 mL. The most severe menstrual bleeding at baseline was observed in the 12 mg group. Blood loss was determined by collecting all sanitary products used from an individual and then an alkaline hematin assay was performed to estimate the actual amount of blood collected in the pads.

When a sufficient concentration of Proellex® is achieved in circulation, amenorrhea (cessation of menses) is achieved. Just over half, 52%, of Proellex®-treated subjects became amenorrheic with no evidence of a dose effect. All subjects treated with Placebo continued to menstruate throughout the 18 week dosing period. The p-value for this comparison is 0.0011. Bleeding diaries consistently report a statistically significant difference in the number of days of bleeding and bleeding intensity between those treated with Proellex® and Placebo.

Bleeding was also evaluated by PBAC (Pictorial Blood Assessment Chart). Subjects tallied sanitary product usage and stain size as guided by the chart. Proellex®-treated subjects reported a median 100% reduction in PBAC scores while Placebo-treated subjects reported a 25.4% reduction, further supporting the treatment affect associated with bleeding (p=0.0033).

Along with changes in menstrual patterns, fibroids measured by MRI were reduced in volume in the Proellex®-treated arms by 18% while the Placebo group showed continued increase in size, p= 0.0437.

The drug was generally well tolerated. Women in the drug arms continued to exhibit levels of estradiol consistent with bone preservation.

After the first 18 week treatment period, the women were withdrawn from drug to allow for menses. The women in the study are currently being treated with the second course of treatment for another 18 weeks. The study treatment assignment remains blinded to the subjects, physicians and those managing the study and data. The results of the second course of treatment should be reported within the next 5 months.

The Company believes Proellex® represents a significant advantage over GnRH agonists and antagonists in the treatment of uterine fibroids. Once both the vaginal and oral studies complete both 18 week courses of treatment the Company plans to request an end of Phase 2 meeting with the FDA to jointly discuss plans for Phase 3.
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Source: press release, 4/12/16. http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=964736

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