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Repros Therapeutics Inc. (Public, NASDAQ:RPRX)

Michael Scally MD

Michael Scally MD

Doctor of Medicine
Upcoming FDA Meeting to be Type C Meeting
http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=876703

THE WOODLANDS, Texas, Oct. 16, 2014 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today reported that its upcoming meeting with the FDA in the first half of November will be a Type C guidance meeting rather than a Type B Pre-NDA meeting. The Company received a communication from the FDA today indicating that based on its preliminary review of the Company's briefing document, there was not sufficient clinical information provided for the meeting to be a Type B Pre-NDA meeting.

While the Company does not know why the FDA believes the clinical information to not be sufficient, the Company notes that synopses for the one year DEXAsafety study and the Drug-Drug Interaction Study, which it believes may be significant to the FDA's review, were not available at the time the briefing document was submitted to the FDA.

The FDA indicated that it would like to proceed with the meeting as a Type C Guidance meeting, and that it will provide preliminary comments to the Company's questions prior to the meeting.

 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
[This is all RPRX has and Podolski will pump in every way possible to keep his paycheck coming.]

Repros plummets as the FDA deals a blow to its low-T hopes
http://www.fiercebiotech.com/story/repros-plummets-fda-deals-blow-its-low-t-hopes/2014-10-17

Repros said it doesn't know what led the FDA to change its mind on Androxal, but the agency's issue with the company's Phase III data are already well-established. Last year, Repros had to put off a planned mid-2014 filing for the drug when the agency called into question the company's chosen patient populations and endpoints in two late-stage trials. The parties eventually came to terms, with Repros amending its analysis, and the biotech believed it was finally on the path to Androxal's approval.

Things were looking up for Repros before its latest regulatory setback, as the company announced in August that Androxal beat out AbbVie's ($ABBV) top-selling AndroGel in boosting testosterone, one of two planned head-to-head studies. Furthermore, the company believed the FDA's recent scrutiny of testosterone-replacement therapies left Androxal, which isn't a form of testosterone, unscathed.

Repros hasn't given up hope for the oft-delayed treatment, pointing out that data packet under FDA consideration does not include results from a one-year safety or a drug-drug interaction trial, information the company believes may be significant to the agency's review.
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
[‪#‎RPRX‬] Results From Long-Term Study of Androxal(R) Exhibit Positive Safety Profile.
http://finance.yahoo.com/news/results-long-term-study-androxal-200100464.html

How is this good? What's the breakdown? And, looking further down, some were excluded for non-prescription testosterone use.

Interestingly, that make that conclusion based on the LH level, which is okay but how do they explain that to the FDA? One should recall their early studies where the FSH/LH were about 0!

IMO, the FDA is wise to PP*** and will question the data as they should. Hell, they admit the data is suspect. IMO, FAIL!

"The number of subjects enrolled into the study was 317, of which 220 (69%) completed the one year study."

"*The Company believes these subjects were using prohibited testosterone replacement based on no detectible [sic] LH, and when identified were terminated from the study." [Note: Table 2 - 16, 39, LOCF]

And, PP does the same old it's not what the PR says it's what it doesn't say.

***PP = Pump Podolski
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros Updates Androxal(R) Global Regulatory Status
http://finance.yahoo.com/news/repros-updates-androxal-r-global-211500532.html

On November 5, 2014, the Company received guidance from the FDA regarding its NDA submission for Androxal(R). During the second half of December the Company submitted a complete response to the guidance that the FDA provided. The Company believes it will have all documents to the contract organization assisting with the electronic filing of the NDA early in 2015 so that the dossier can be filed by the end of the first quarter 2015.

The Company had a follow-up discussion with the Agency regarding the Environmental Assessment requirements for the NDA. The FDA noted that commitment to perform the appropriate non-clinical experiments during the NDA review period would be considered sufficient for filing.

Overall, the Company believes there are no refuse to file issues for its NDA.
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros Submits New Drug Application to FDA for Androxal (R)
http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=894079

THE WOODLANDS, Texas, Feb. 2, 2015 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today reported that it has electronically submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for Androxal®, the Company's lead product candidate. Androxal® is a single isomer of clomiphene citrate and an orally active proprietary small molecule compound. The Company is developing Androxal® for the treatment of secondary hypogonadism in overweight men wishing to restore normal testicular function. Men with secondary hypogonadism exhibit low testosterone levels due to under stimulated testes but they are generally fertile. Androxal® is designed to treat the underlying mechanism, insufficient stimulation of the testes by the pituitary, which causes secondary hypogonadism. Secondary hypogonadism due to being overweight or obese is the single greatest cause of hypogonadism in general.

The NDA for Androxal® includes a significant collection of data on safety and efficacy from over 20 studies. It is supported by four Phase 3 efficacy studies, two of which compared Androxal® to a leading FDA approved topical gel in addition to placebo. In the two active-comparative studies, Androxal® met the primary efficacy endpoints and demonstrated the reproducibility of the previous Phase 3 study results. Analyses found Androxal® to be superior to the topical gel in both co-primary endpoints: percent change from baseline in average sperm concentration and percent of subjects considered to be responders. A responder is defined as an individual achieving a 24 hour average testosterone in the normal range with associated average sperm concentration ≥ 10 million/mL. Androxal® exhibited no negative effects on sperm concentration compared to placebo but exhibited highly significant effects on normalizing testosterone levels compared to placebo control.

Androxal® is an investigational product and has not been determined safe or efficacious.

 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Enclomid and Topical Testosterone Elevate Testosterone in Hypogonadal Men but Enclomid Does Not Decrease Testes Size
https://endo.confex.com/endo/2015endo/webprogram/Paper21261.html

Introduction and Objective: It was our aim to evaluate oral enclomid (enclomiphene citrate or Androxal) as an alternative to a currently-available topical testosterone replacement therapy for men with secondary hypogonadism.

Methods:These trials (ZA-304 and ZA-305) were randomized, double blind, placebo- and active-control, multi-center phase III studies in 224 men between 25 and 60 years of age with secondary hypogonadism. Men received 12.5mg or 25mg of enclomid as a daily capsule and were provided with a placebo gel. Other men received AndroGel 1.6% and placebo capsules. Placebo men received placebo capsules and gels.

Results: Subjects needed to have initial testosterone (T) values below 300ng/dL at least twice. At End of Study (EOS), 16 weeks, there was a statistically significant rise in T in men receiving either enclomid or topical testosterone product into the normal range (see table). Placebo subjects did not change.

Enclomid did not decrease sperm counts unlike the topical gel. As we have seen before, enclomid increased LH and FSH while men in the topical arm showed decreases (not shown).

All men were similar at baseline in testes volume (p=0.94, ANOVA) by orchidometry. Men on topical testosterone demonstrated decreases in mean testicular volume (-0.86 cm3) in both studies and a significant decrease overall compared to the enclomid (p<0.05) or placebo (p<0.05).

Conclusions: Enclomid led to no deleterious effects on sperm counts or testes size by orchidometry. It also significantly increased total serum testosterone, LH and FSH which suggests that the drug normalized endogenous testosterone production through the hypothalamic-pituitary-testicular axis and supported the natural continuation of sperm number and testes volume.
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros Announces Acceptance for Filing of NDA
http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=904588

THE WOODLANDS, Texas, April 1, 2015 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that the New Drug Application (NDA) for its enclomiphene citrate product candidate, formerly known as Androxal®, has been accepted by the U.S. Food and Drug Administration (FDA), indicating that the application is sufficiently complete to permit a substantive review. This investigational product, which is the Company's lead product candidate, is a single isomer of clomiphene citrate and an orally active proprietary small molecule compound. The Company is developing this product candidate for the treatment of secondary hypogonadism in overweight men wishing to restore normal testicular function. Men with secondary hypogonadism exhibit low testosterone levels due to under stimulated testes but they are generally fertile. The Company's product candidate is designed to treat the underlying mechanism, insufficient stimulation of the testes by the pituitary, which causes secondary hypogonadism.
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros Receives Confirmation of Eligibility for Submission of a Centralized Marketing Authorization Application to the European Medicines Agency as a New Active Substance
http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=905062

THE WOODLANDS, Texas, April 6, 2015 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that the European Medicines Agency (EMA) has informed the Company, through Repros' wholly owned subsidiary, that its enclomiphene citrate capsules are eligible for submission for a centralized marketing authorization application (MAA) as a New Active Substance. Not all products are eligible for the centralized procedure and the Company was able to provide data to indicate significant differences between enclomiphene citrate and clomiphene. Assuming the MAA is successful, a centralized marketing authorization is valid in all European Union member states, as well as in the European Economic Area, a total of 31 countries. Granting New Active Substance status will allow an application to be made for a supplementary protection certificate which, if granted, can extend the exclusivity period of the product. Confirmation of eligibility for submission is not predictive of the EMA's ultimate approval of an MAA.
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros Announces November 30, 2015 PDUFA Goal Date for New Drug Application
http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=906763

THE WOODLANDS, Texas, April 15, 2015 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that the U.S. Food and Drug Administration (FDA) assigned a Prescription Drug User Fee Act (PDUFA) goal date of November 30, 2015, for substantive review of the Company's New Drug Application (NDA) for its enclomiphene citrate product candidate, formerly known as Androxal®. In addition, the FDA has informed the Company that the FDA is currently planning to hold an advisory committee meeting on the NDA during the review.
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
[RPRX] FDA Ad Com – The meeting will be held on November 3, 2015, from 8:30 a.m. to 5 p.m.

The committee will discuss new drug application (NDA) 207959, Enclomiphene citrate 12.5 milligram (mg) and 25 mg capsules, submitted by Repros Therapeutics, Inc., for the proposed treatment of secondary hypogonadism in fertile men (men with more than 15 million sperm/milliliter (ml)), younger than 60 years of age with a Body Mass Index (BMI) over 25 kilograms (kg)/meters squared (m2). https://s3.amazonaws.com/public-inspection.federalregister.gov/2015-20540.pdf

FDA intends to make background material available to the public no later than 2 business days before the meeting. If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting and the background material will be posted on FDA's Web site after the meeting. Background material is available at http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm.
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros Therapeutics Announces Cancellation of FDA Advisory Committee Meeting to Review Enclomiphene for the Treatment of Secondary Hypogonadism
http://ir.reprosrx.com/releasedetail.cfm?ReleaseID=939322

THE WOODLANDS, Texas, Oct. 29, 2015 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced that the Division of Bone, Reproductive and Urologic Products of the U.S. Food and Drug Administration (FDA) has cancelled the scheduled November 3, 2015 advisory committee to review the Company's New Drug Application (NDA) for its enclomiphene product candidate, formerly known as Androxal®, due to questions that arose late in the review regarding the bioanalytical method validation that could affect interpretability of certain pivotal study data.

The FDA has expressed its willingness to work with Repros to address these questions. The FDA accepted the NDA for review on April 1, 2015 and later assigned a Prescription Drug User Fee Act (PDUFA) goal date of November 30, 2015.

Conference Call Details:

Time: Thursday, October 29, 2015 - 3:30 PM Eastern
Participant Dial-In Number (Domestic): 888-225-7740; International: 303-223-2694
 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros tanks on another FDA hurdle for its 'low-T' treatment
http://www.fiercebiotech.com/story/repros-tanks-another-fda-hurdle-its-low-t-treatment/2015-10-30

Repros Therapeutics ($RPRX) is facing yet another setback for its long-delayed testosterone treatment as the FDA has backed out of a preapproval meeting and raised serious questions about the company's pivotal data.

The company was slated to go before an independent panel of FDA advisers next week to defend Androxal, a small-molecule treatment for low testosterone. But the agency has now canceled that meeting "due to questions that arose late in the review regarding the bioanalytical method validation that could affect interpretability of certain pivotal study data," Repros said.

What that boils down to, CEO Joseph Podolski told analysts on a conference call, is that the FDA has serious doubts about how Repros' chosen lab conducted testosterone tests in determining whether Androxal met its primary endpoint in Phase III. Podolski counters that the lab is CLIA-certified and ran its assays by the book.


Either way, investors seem to be running out of a patience with a drug program that has run for 13 years without an approval. Repros' shares fell more than 55% on the news as it became clear the FDA has no intention of approving Androxal by its previously stated Nov. 30 deadline.

The agency has "expressed its willingness to work with" the company on the issue, Repros said, but Podolski didn't say whether he expects to need to run another Phase III trial for the drug.

Androxal's latest setback follows years of fits and starts, clinical and regulatory. Repros has long struggled to convince the FDA that its drug works, repeatedly putting off filing Androxal for approval as the agency took issue with irregularities in its clinical data. Repros seemed to finally get on track in April when the agency accepted its application for review.

- read the statement


 
Michael Scally MD

Michael Scally MD

Doctor of Medicine
Repros Therapeutics stuck in neutral as FDA backpedals on advisory committee
http://www.bioworld.com/content/rep...k-neutral-fda-backpedals-advisory-committee-0

Repros Therapeutics Inc. should be preparing for an advisory committee meeting with a panel from the FDA's Division of Bone, Reproductive and Urologic Products, scheduled for Tuesday, to review the new drug application (NDA) for enclomiphene (formerly Androxal) to treat secondary hypogonadism (HG). Instead, late Thursday the company abruptly announced that the FDA canceled the meeting, sending its shares (NASDAQ:RPRX) plummeting 56 percent to close at $2.08. Shares eroded further on Friday, sinking to $1.62 before closing at $1.71 for a loss of 37 cents, or 17.8 percent.

What happens next for The Woodlands, Texas-based company isn't exactly clear. Joseph Podolski, president and CEO, acknowledged on a conference call that the FDA's qualms seem to go far beyond the purported concern that the bioanalytical methodology for testosterone measurements used by the company's CLIA-certified lab was not properly validated. The process was, in fact, very well validated, Podolski maintained, noting that the lab used a 510(k)-approved methodology, followed the manufacturer's instructions and ran samples in a timely fashion.

Instead, he called the FDA's stated reasoning "the tip of the iceberg."

In a long and winding explanation of the challenges now facing Repros, Podolski looked back to the September 2014 joint meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee as the primary culprit impeding a public discussion of enclomiphene. That panel first proposed changes in labels for testosterone replacement therapy (TRT) products, concluding 20-1 that such drugs should be used only in classic hypogonadism – low testosterone due to testicular or disease of the hypothalamic/pituitary glands – before voting 18-3 following a second day of discussion against approval of oral Rextoro (undecanoate) from Clarus Therapeutics Inc., of Northbrook, Ill. (See BioWorld Today, Sept. 19, 2014.)

Shares of Repros were dented following that adcom, but analysts split on the long-term implications of the panel's decisions on the company and its product – an estrogen receptor antagonist designed to treat the cause of secondary hypogonadism, which the company believes is a metabolic disorder due to inadequate pituitary hormones that is associated with overweight or obesity. Classic hypogonadism – low testosterone due to disease of the testicles or hypothalamic/pituitary glands – is a very different animal.

The two questions scheduled to be addressed at the Nov. 3 adcom, Podolski said, were whether the sponsor had studied the population intended to use the drug and whether the sponsor had identified a clinical benefit. Classic hypogonadism "would not include secondary hypogonadism as we define it," Podolski said.

No sponsor could sufficiently enroll patients to test any hormonal replacement product unless a significant number of patients "had an acquired disorder associated with them being overweight," he insisted. "That's a key consideration as we go forward and talk about hypogonadism in general."

Podolski credited the FDA with wanting to "back away from a circus" in the context of an adcom to focus on a broader discussion about the appropriate population to treat for hypogonadism. Still, Podolski said, a decision to cancel the adcom and reevaluate the treatment standard "should have been five months ago."

The FDA accepted the enclomiphene NDA for review on April 1, later assigning a PDUFA date of Nov. 30, which Podolski said will clearly not be met. (See BioWorld Today, April 3, 2015.)

The FDA delivered its decision to cancel the adcom verbally, he added. Repros quickly appealed through the FDA ombudsman, but to no avail.

"We've been at this since 2002," Podolski said. "It's not been a trivial exercise. But we think, given the FDA's willingness to talk to us, that we can work with them in a collegial fashion. In the final analysis, this makes for better development of a medicine that's clearly needed in a majority of men with low testosterone."

SECONDARY HYPOGONADISM 'A REVERSIBLE DISORDER'

Podolski was in no mood for a friendly chat with analysts, interrupting their questions and wandering through long soliloquies about the Repros drug, the nuances of the indication and the FDA's changing stance on TRT. He insisted that enclomiphene is a differentiated candidate that is designed to boost testosterone levels in men temporarily at the same time that they participate in a program of diet and exercise to lower their weight.

"The main cause for secondary hypogonadism is a metabolic disorder, and those are the men we seek to treat," he said. "We think that population has a reversible disorder."

In February 2014, the FDA seemed to accept the company's contention that enclomiphene was a different type of TRT product, indicating that new safety tests would not be needed before Repros submitted the NDA. (See BioWorld Today, Feb. 10. 2014.)

But later in the year, the FDA threw a curve ball to the company when it switched the pre-NDA meeting from a type B to a less-routine type C session, citing insufficient clinical information in briefing documents submitted by Repros for enclomiphene. (See BioWorld Today, Oct. 20, 2014.)

A month later, Repros said the FDA re-confirmed during the meeting that it was generally satisfied with the NDA package and would not seek additional trials. (See BioWorld Today, Nov. 10, 2014.)

The next step for Repros is to meet with the FDA, but no timetable has been set for that discussion. Podolski predicted that Repros might have a year's worth of work with the FDA, potentially including additional studies, before the agency is ready to review enclomiphene. Long term, the delay will result in better treatment by differentiating between the two groups of men with hypogonadism, he insisted.

"It's important to me that we keep our relationships with the FDA good and that we develop our drugs in a fashion that is meaningful from the standpoint of the men who are seeking treatment today," he said. "We will investigate all options for shareholder value improvement, and we'll see how that turns out as we move forward."

Repros remains on track to submit its marketing authorization application for enclomiphene to the EMA, likely around the beginning of the second quarter of 2016, and "I don't think [the FDA's action] will affect that," Podolski said.

The company's Proellex (telapristone acetate) program is advancing, with a phase II study in uterine fibroids nearly fully enrolled.

"Since we're not moving into launch mode, our cash is in pretty good position," Podolski added. "We can certainly get through next year and deep into the following year."

Repros reported cash and equivalents of $32.2 million as of June 30, although Podolski said the current amount is closer to $25 million.

Laidlaw & Co. analyst Yale Jen placed much of the blame on the FDA, noting that the agency "did not even offer an opportunity" for Repros to present its case.

"We continue to view Androxal as an effective and better HG treatment," Jen wrote in a company update. "The FDA, in our opinion, should develop workable guidelines for medically managing the dominant majority of 'non-classic' HG patients."

That said, "Due to great uncertainty for the clinical path forward, we have removed the value of Androxal in second HG in the U.S. from our model until greater visibility is available," Jen added.

Brean Capital LLC analyst Jonathan Aschoff, however, dubbed enclomiphene an asset with "too little clarity" and "too many issues." He downgraded the stock to hold from buy and noted that the clock continues to tick on the company's lead program.

"Enclomiphene largely defines Repros' prospects and valuation," Aschoff wrote. "With the patent regarding enclomiphene expiring in 2021, even with an extension, the duration of market exclusivity will remain a concern."
 
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