Repros Therapeutics, Inc. (RPRX)

[europtiger]

In average 0,435

[hiwatt1959]

Rprx had 90 days to answer day 120 questions, which was April 26. They asked for more time and were granted up to 90 more days. That puts final deadline no later than July 26. The whole time the approval clock is stop. Once answers are submitted, the clock starts again. If no outstanding issues
come up, a decision could occur 60 days latter. If additional issues come up, the clock stops again until issues are resolved. Once resolved, a decision occurs in 30 days

[damizo]

What does all of that mean in layman's term?

[hiwatt1959]

Page 28. http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2017/06/WC500229137.pdf

[damizo]

Do you have a link to all of this?

Any idea if additional info was submitted to FDA?

[hiwatt1959]

No need for urgency, stock is still 39 cents.
EU update.
Scope: Request by the applicant requesting an extension of clock stop to respond to Day
120 list of questions adopted on 26.01.2017.
Action: For adoption
The CHMP agreed to the request by the applicant for an extension to the clock stop to
respond to the Day 120 list of questions adopted on 26 January 2017.

[hiwatt1959]

The Company expects to submit the additional information and a proposed clinical protocol within a month. The Company intends to announce further information following receipt of additional guidance from the FDA.

A month would have been May 10th. So assuming FDA wants another 30 days to look everything over and respond, guidance could come around June 10th.

[damizo]

Do we know if they have submitted the updated data to the FDA yet?

[willlbone]

Delisting next.

[hiwatt1959]

No date or price on offering suggest they are waiting to hear from FDA on Proellex first. The NIH is also willing to wait.

As of May 2017, the Company had not yet met certain milestones under the license agreement. On May 11, 2017, after discussions with NIH, the Company received a letter from NIH stating that it remains NIH’s intention to re-establish meaningful development timelines with the Company once the Company has received further guidance from the Food and Drug Administration (the “FDA”) on the Company’s clinical path forward for Proellex®. NIH has indicated that it understands that the Company had a guidance meeting with the FDA and is waiting to hear back from the FDA once the agency consult with its internal liver experts. The NIH indicated that, consequently, the NIH does not consider the Company in breach of the license agreement at this time.

[Warrior198]

dilution coming...stick a fork in this company :(

[Brain Mills]

I hope you're correct and something positive happens.
Plus I'm sure the new President did not take the job for just a few weeks of pay. That would not look good on a resume

[hiwatt1959]

They should submit liver data this week and hopefully will get a decision by June 10th. Assuming a positive decision will boost stock price and allow them to sell the remainder ATM shares for another $6M. This should be enough cash to last into Q4 and the EU possible approval. Providing they execute on both drugs, another offering or partnership should follow. It's really cutting it close and that's why stock is priced at .86. I spoke with CFO last week and she wasn't in panic mode, so it kind of makes me wonder if a deal may be in the works after FDA rules on Proellex, IMO.

[Brain Mills]

What is the plan regarding cash? They had 3 million at end of 1Q and they have probably spent another $1.3 million in April so they're down to $1.7 million dollars leaving just enough for May. Will they see June???????????

[hiwatt1959]

New corporate presentation.
http://ir.reprosrx.com/secfiling.cfm?filingID=1144204-17-23802&CIK=897075

[damizo]

Dead Cat Bounce or does someone know something?

[damizo]

Nice bounce of those earlier week lows. When are we expecting answers from EMA regarding Enclomiphene?

[willlbone]

Sinking like a rock on small volume.

[hiwatt1959]

Below is trial design for Allergan P3 Pearl IV which was the same Venus 2 for Esmya. Clearly they are using an "off drug interval" in their 2 course line of treatment.
We believe that the intermittent 12-week ulipristal acetate daily dose regimens (the first course to be administered at the start of a menstrual cycle, and subsequent courses to commence at the start of the second menses after the previous course) fulfill most of these criteria, as evidenced by the low side effect burden and discontinuation rate, and the high compliance with treatment. Some patients did experience pain and excessive bleeding during off-treatment periods but generally not of the same magnitude as prior to treatment. Also there was no regrowth of fibroids observed during follow-up. Thus our results suggest that intermittent ulipristal acetate is a viable and attractive long-term medical management option for patients with symptomatic fibroids. Our data are also consistent with the results of an earlier study (26) reporting that up to four intermittent treatment courses of ulipristal acetate could be successively administered to control bleeding and shrink fibroids

[hiwatt1959]

We claim:

1. A method for treating chronic estrogen-dependent hyperproliferation of uterine tissue according to an intermittent administration regimen comprising administering to a human female in need of such treatment a therapeutically effective amount of a selective progesterone receptor modulator (SPRM) selected from CDB-4124 (21-methoxy-17.alpha.-acetoxy-11.beta.-(4-N,N-dimethylaminophenyl)-19-nor- pregna-4,9-diene-3,20-dione) and 17.alpha.-acetoxy-11.beta.-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-d- iene-3,20-dione for an administration period during which the SPRM is administered daily consecutively over a period of from two to four months, then discontinuing said administration for a discontinuance period by means of a continual lack of treatment for a period of time sufficient for the female to undergo menstruation, said period of time being at least 32 days and equal to or less than the number of days during which the SPRM was previously administered, then administering a therapeutically effective amount of an SPRM daily consecutively over a period of from two to four months, then discontinuing said administration by means of continual lack of treatment for a period of time sufficient for the female to undergo menstruation, said period of time being at least 32 days and equal to or less than the number of days during which the compound was previously administered, and repeating this pattern of administration and discontinuance of administration for a sufficient duration to treat the chronic condition.

2. The method of claim 1, wherein the effective amount of SPRM is from 2 mg to 80 mg.

3. The method of claim 1, wherein the administration period is about three months.

4. The method of claim 3, wherein the administration period is about four months.

5. The method of claim 1, wherein the female is administered a progestin in an amount effective to induce menstruation during the discontinuance period.

6. The method of claim 5, wherein the female is administered a progestin selected from the group consisting of medroxyprogesterone, hydroxyprogesterone and progesterone.

7. The method of claim 1, wherein said compound is CDB-4124 (21-methoxy-17.alpha.-acetoxy-11.beta.-(4-N,N-dimethylaminophenyl)-19-nor- pregna-4,9-diene-3,20-dione).

8. The method of claim 7, wherein the administration period is about four months.

9. The method of claim 1, wherein the SPRM is 17.alpha.-acetoxy-11.beta.-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-d- ien-3,20-dione.

10. The method of claim 9, wherein the administration period is about three months.

[hiwatt1959]

Add Bayer to the sprm list that wants to long term treatment.

[hiwatt1959]

The FDA only allowed Allergan to do 2 rounds of treatment in Venus 2 if they had an off drug interval. The ODI allows a female to have a period and thus reduces endometrial thickness, which reduces the chances of cancer. If Allergan wishes to get Esmya approved for long term use, they may have to license Rprx's ODI patent.

[Warrior198]

are you saying allergan could be interested?

[hiwatt1959]

Note that Ulipristal Acetate is Allergan's SPRM.

Repros Announces the Issuance of New U.S. Patent Relating to Treatment Using Off Drug Intervals For Certain Uterine Conditions
THE WOODLANDS, Texas, April 17, 2017 (GLOBE NEWSWIRE) -- Repros Therapeutics Inc.® (Nasdaq:RPRX) today announced the issuance of a new patent, U.S. Patent number 9,616,074 (the ‘074 patent), that bolsters the Company's intellectual property relating to Proellex® (telapristone acetate). The ‘074 patent, which expires in 2027, relates to the use of Selective Progesterone Receptor Modulators (SPRM), in particular Telapristone Acetate (Proellex®) or Ulipristal Acetate, with an Off Drug Interval (ODI) for the treatment of estrogen-dependent hyperproliferative uterine conditions, such as uterine fibroids and endometriosis. Under the terms of the patent, ODI is defined as daily administration of the SPRM for a period of time, followed by an ODI sufficient for the patient to menstruate and then by another period of administration of the SPRM.

[TheSerb]

Wrong poster. Oops.

[hiwatt1959]

The Company believes the high concentrations of the active ingredient and its primary metabolite attained in first pass absorption and processing by the liver resulted in the delayed toxicity exhibited in roughly 3-4% of the women administered the 50 mg dose of the drug in Phase III studies. At 12.5 mg there were no adverse liver toxicity signals different than placebo. The maximum concentrations of parent and metabolite for the 12.5 mg dose were 25% of the 50 mg dose.

[Warrior198]

what do you mean by hint?

[TheSerb]

Hmm Interested on what's happening here......hint?

[hiwatt1959]

The last time Rprx supplied additional data to FDA after they had changed meeting type from B to C (11-2014), the stock rallied $3 dollars a share, or at the time 50%. We rallied to $3.45 last year on Proellex V p2 data. A green light in the next month from FDA on P3 could get us back in $4 range. We could also in the next month see day 120 answers and restarting of EU clock, as well as conclusion of Enclomiphene p2b 15 month benefit study.

[hiwatt1959]

For Rprx not to pursue the vaginal Proellex that bypassed the liver altogether tells me they are confident in the safety of an oral solution. Additional data and protocol in next 30 days will clear any hurdles and concerns out of the way for big pharma. Toxicity only occurred at 50 mg and now it's current dosages are 6 mg and 12 mg. For the new CEO to commit to the job, after meeting with FDA is a positive. To here COB talk, they're looking forward to future growth.
"Larry is the right person to lead Repros forward as we advance our pipeline and move toward our next stage of growth," said Patrick Fourteau, Chairman of the Company's Board. "We are confident that Larry's fresh perspective, extensive experience and enthusiasm for Repros' future will be of great value as we face our near-term challenges and set a course for the longer term future."

[damizo]

What is your opinion of today's Proellex news?

[hiwatt1959]

When you look at the competition for Proellex, Abbvie-Allergan-Bayer, it's a David vs Goliath. It also shows big pharma realizes the potential for this billion dollar market.

Our main competitors for the treatment of uterine fibroids and endometriosis are GnRH agonists, especially Lupron®, the current therapeutic standard of care for uterine fibroids. Lupron® is marketed by AbbVie, which has far greater resources and marketing capabilities than we have. Recently AbbVie has licensed a Phase 3-ready molecule from Neurocrine Biosciences for the treatment of endometriosis. Gedeon Richter and Allergan have also entered into an exclusive license agreement to develop and market Esmya™ (an orally active selective progesterone receptor modulator) in the U.S, Canada and Europe. In addition, Bayer AG is also developing an oral selective progesterone receptor modulator, vilaprisan, which is anticipated to enter phase 3 clinical trials later this year. Surgical treatment of both uterine fibroids and endometriosis continues to compete with Proellex® by removing uterine fibroids and by removing misplaced tissue in women with endometriosis. We believe we can potentially compete with Lupron® and other GnRH agonists because we believe that Proellex® will not present the same side effect of a decrease in bone mineral density given its specific focus on progesterone inhibition, which differentiates it from GnRH agonists that create a low estrogen state. There are additional companies developing similar progesterone-blocking technology.

[hiwatt1959]

The easiest way is to go to www.ema.europa.eu and use their search at top of home page. The spell it a little different so you must use their spelling, enclomifene. Today there are 23 updates on the process. If you click sort by date it will give you the newest update first. They update every week.

[Warrior198]

Is there a place we can get an update as to whether or not repros had sent the answers to the questions back yet? From what i gather...the committee asked the list of questions on jan 23..so repros has till apr 23 or 90 days to get the answers back to them. The clock starts at that time and resumes as day 120, so by june 23 the chmp could recommend enclomifene to the EU and july 23 the EU could approve, and the public would know after anytime after july 23. However, if repros sent the answers to the questions back to the chmp earlier then the 90 day deadline or apr 23...then the amount of days earlier they sent the answers back would be deducted from the july 23 day i posted earlier. The math shows that we could get EU approval earliest may 23 and the latest would be end of october. My guess is we will hear in july

[damizo]

Thanks

[hiwatt1959]

By all appearances, Rprx is positioning itself for sale. Everybody is setting up to get paid. BODs all recently got 40K shares, CFO is getting 60K shares, Joe got $2.7M severance package, new CEO will get 50K shares with FDA green light for Proellex in April. Looks like they are not going to release enclomiphene P2b results until after May 15th, the 15 month completion date. If all goes well with EU, approval could come in Aug. With est. $4M cash after Q1, and est. $6M ATM shares left, funding should last into Q3. "If" big pharma comes in and takes both drugs to approval, it will be par for the course. It just goes to show how difficult it is for a small biotech to pull it off, NO mistakes. "If" all goes down with a buy out, the investors that profit will be longs that averaged down, or recent and new investors that bought in when share price was depressed.

[hiwatt1959]

Scan down to 3.3.4. They are in stop clock period. Once answers are given clock will restart for 60 days. If no issues arise, approval could follow in 30 days.
http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2017/03/WC500224116.pdf

[Warrior198]

Actually after a closer look i think they are sitting in the "Clock Stop" period while responding to the list of questions the CHMP gave them to answer...usually this period is 3 months long and repros should have sent the answers to their questions by april 23rd. The the clock starts again from day 121 thru day 180 or day 210. If all goes well we could have a response in august or september

http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/10/WC500004235.pdf

[Warrior198]

Im not an expert on the EU approval process but from what i understand, the EU accepted repros' submission of enclomifene on october 5th, the 120 day period ended and the CHMP had made either a favorable or unfavorable opinion of enclomifene on january 23rd and forwarded that recommendation to the EU commission. I read that now the second phase, which is the decision making process by the EU commission has begun..am I reading correctly that now that they have received the recommendation from the CHMP they will have 60 days to either approve or reject enclomifene for marketing in the european union?

[damizo]

Do you have a link for this?

[hiwatt1959]

EU update on Enclomiphene.

3.3.4. - enclomifene - EMEA/H/C/004198
treatment of hypogonadotrophic hypogonadism
Scope: Day 120 list of questions
Action: For adoption
The Committee discussed the issues identified in this application.
The Committee adopted the CHMP recommendation and scientific discussion together with
the list of questions.

[hiwatt1959]

Full transcript of Dec adcom on secondary hypogonadism now up on FDA website.

[hiwatt1959]

Esmya, length of treatment 12 weeks, Proellex 18 weeks.
Annual US sales for Esmya are projected from $286M to $1B, depending on competition and label restrictions. If Proellex proves to be 50% more effective and length of treatment is 50% longer, it stands to reason Proellex could capture more than 50% of that market, even with Esmya's first mover advantage. Even if sales are just $500M and if Proellex could capture $300M and a company's value is >5 times revenue, that puts value of Proellex at a possible $1.5B upon approval. With just 25M shares, that's a value of $60 per share. Question is, how much could Rprx bring on the open market for P2 data and FDA P3 guidance for Proellex and Androxal, because they don't have the cash to get both drugs to approval.



Allergan’s uterine fibroids prospect, Esmya, has racked up more data that’ll support the FDA filing it expects to make later this year. But the med will still face some market hurdles that could thwart the major sales potential its maker expects.

Tuesday, the Dublin pharma and partner Gedeon Richter rolled out phase 3 results showing their candidate had topped placebo at staving off uterine bleeding. The data follow up on earlier phase 3 results that dropped last May and make Esmya the first oral uterine fibroids therapy to prove safe and effective two U.S. pivotal studies, Allergan said.

Now, the companies are turning their attention to an FDA filing set to drop in the second half of this year. But the way Barclays analyst Doug Tsao sees it, thanks to “potential labeling limitations” and the “competitive landscape,” the relative market size for Esmya “remains uncertain,” he wrote in a Tuesday note to clients.

Uterine fibroids are the most common benign tumors in women of childbearing age, he noted, amounting to “an incremental 600,000 hysterectomies per year.” AbbVie’s Lupron is also an option for patients, though the “pseudo-menopausal” state it brings on comes along with “burdensome” side effects and symptoms.

Still, the FDA could restrict Esmya’s patient population only to those women eligible for surgery, and it also still unclear whether regulators will restrict dosing of the once-daily treatment to two cycles—both of which could limit the U.S. potential that Allergan pegs between $500 million and $1 billion.

Analysts are less optimistic, Tsao wrote, citing a $286 million peak sales consensus estimate from First Order Analytics. And that’s in part because AbbVie and partner Neurocrine have a competitor on the rise in elagolix, which is currently in phase 3.

Regardless, an FDA green light for Esmya would be a win for Allergan, whose buyer Watson has been here with the med before. The company went after a U.S. approval for Esyma in 2013, but it withdrew a phase 3 study before completion. Allergan replaced the study with the two current phase 3 studies after negotiations with the FDA.

That’s not to say Allergan hasn't already profited stateside off the compound. The company marketed Esmya’s active ingredient as contraception pill Ella in the U.S. before selling those rights to HRA Pharma.

[hiwatt1959]

Allergan released final P3 results for Esmya, the Proellex SPRM competitor. No SAEs and meet endpoints. When you compare the data, two things become apparent. Proellex appears to be 50% more effective and length of treatment is 50% longer.
Percentage of women that stopped bleeding
Proellex-6mg 88% 12mg 94%
Esmya --5mg 48% 10mg 57%

Quality of life percentage improvement
Proellex---70%
Esmya------56%

The study included 432 U.S. patients with 162 and 157 patients randomized to ulipristal acetate 5 and 10 mg respectively, and 113 to placebo. The average age of patients enrolled was 41 years and 67 percent of enrolled patients were Black/African Americans. The study met all the co-primary and secondary endpoints with both ulipristal treatment arms achieving statistically significant results over placebo (p<0.0001). The co-primary efficacy endpoints were percentage of patients with absence of uterine bleeding and time to absence of uterine bleeding on treatment during Treatment Course One (12-week duration). Significantly more patients in the 10 mg group (54.8%) and the 5 mg group (42.0%) achieved absence of bleeding compared to placebo (0%).

The secondary efficacy endpoints were the percentage of patients with absence of uterine bleeding from Day 11 to end of the first treatment course; the percentage of patients with absence of uterine bleeding after the second treatment course; time to absence of uterine bleeding on treatment during treatment course two; and the change from baseline in the UFS-QOL revised Activities subscale at the end of the first treatment course.

More patients in the 10 mg group (55.4%) and the 5 mg group (34.6%) achieved absence of bleeding within 10 days after treatment initiation in Treatment Course One compared to placebo (0.0%). Significantly more patients in the 10 mg group (57.3%) and the 5 mg group (40.5%) achieved absence of bleeding compared to placebo (8.0%) in Treatment Course Two. The improvement from baseline in the UFS-QOL revised activities subscale was significantly greater in the 10 mg group (56.7%) and the 5 mg group (48.3%) compared to placebo (13.0%).

The UFS-QOL is a validated fibroid-specific symptom and health-related quality of life instrument. This questionnaire is an established instrument to assess disease impact on the well-being of women with uterine fibroids.

"It is indeed very encouraging that we have another successful phase III study conducted in patients with uterine fibroid symptoms, which shows that ulipristal acetate could bring promising treatment for women suffering from this condition," added Dr István Greiner, Research Director of Gedeon Richter Plc. "We remain committed to the development of female healthcare products aiming towards the improvement of the quality of life of women in all age groups."

The most common adverse events (≥5%) on ulipristal acetate treatment were hot flush, headache, fatigue, and nausea in the combined period of Treatment Course One and first off-treatment interval. The most common adverse event (≥ 5%) on ulipristal acetate treatment was headache in the combined period of Treatment Course Two and second off-treatment interval.

[hiwatt1959]

Institutional holdings up to 28.2% from a low of 24% a few months back. Two years ago, holdings were as high as 80%. Board of directors loaded up on 200K shares this week. This thing is getting ready to pop. EU news and Androxal P2B year long study results due out very soon.

[hiwatt1959]

A new study from Boston University Medical Center has found that long-term therapy to treat low testosterone in men may also lower the risk of cardiovascular disease.

Testosterone is the male sex hormone responsible for the development of male reproductive tissues, sex drive and sex-specific characteristics like increased muscle mass and body hair growth. Testosterone also contributes to overall health and can prevent bone loss or osteoporosis.

Men with testosterone deficiency, also known as hypogonadism, are often treated with testosterone therapy.

Researchers at the Boston University schools of Medicine and Public Health created a registry to examine the long-term effectiveness and safety of testosterone therapy, or TTH, in men.

The study followed 656 men age 60 and older with low testosterone for eight years, with 360 men receiving testosterone therapy and 296 not receiving testosterone therapy.

Results showed there were only two deaths in the group that received treatment and the deaths were not cardiovascular related. There were 21 deaths in the non-treatment control group, and 19 were cardiovascular-related deaths. In the non-treatment control group, there were 26 non-fatal mycardial infarctions and 30 non-fatal strokes, but none in the treatment group.

"The low CV [cardiovascular] events observed in the T-group compared to the untreated [control] group strongly suggests that TTH is protective," Abdulmaged M. Traish, Ph.D., professor of biochemistry and urology at BUSM and corresponding author of the study, said in a press release. "We believe that the protective effect of T on the CV system provides clinicians with the opportunity to utilize this approach for secondary prevention for hypogonadal men with a history of CV events."

The study was published in the Journal of Cardiovascular Pharmacology and Therapeutics.

[hiwatt1959]

New younger CEO announced, Larry Dillaha, age 52, EU day 120 update due, Androxal P2B results due end of Feb, FDA summary of Dec adcom on secondary hypogonadism out any day now, FDA guidance on Proellex P3 due in April, rally overdue.

[guest613]

We are primed!

[lecorb]

Thank's for the info.! ??
??

[lecorb]

THAK´S