Replies to post #7077 on Repros Therapeutics Inc (RPRX)

[y3maxx]

Mgmnt has been sitting on this info for how long now?

...Not very nice for legacy shareholders.

[hptaxis]

1500 Patients – NDA Submission

By RPRX statements, the total pooled patient count for NDA submission is 1500.




At least from the PR we now know they have less than 500 from all of their trials. It is to be noted that the data released is not for UF alone, but all patients. They are less than 1/3 to the patient exposures needed for the NDA. Their representation they are still on track for a 2010 NDA is bogus.

Their timeline is always being pushed back. Why not be honest about this and admit the filing will be delayed? Are we to believe that they will have an additional 1000 patient exposures within the next year?

The overall clinical development program for Proellex includes numerous pharmacokinetic, pharmacodynamic, Phase I, Phase II, and ongoing Phase III clinical trials. These studies used doses of Proellex ranging from 3 mg up to 200 mg daily. From completed studies as well as from an ongoing large open label trial, it has been determined that the drug appears to be well tolerated.

. . .

The following data were observed in 470 women treated with Proellex through June 2009 (n values may vary slightly due to randomization):

. . .

Additionally, Repros believes that any new studies required for the approval of the 12.5 mg dose will not adversely impact anticipated timing of NDAs for Proellex.

[DewDiligence]

From today’s PR:

The following data were observed in 470 women treated with Proellex through June 2009…

Note the deliberate wording—there is no assertion here that these 470 patients constitute all of the available data in the Proellex safety database. In other words, the data in the liver-tox table in today’s PR may have been cherry picked.

[hptaxis]

Uterine Fibroid Symptom Quality Of Life (UFSQOL)

Maybe now people will start to take a hard look at the other RPRX data. The LFTs was something that had to reveal. I am sure they delayed this information as long as possible. In the PR, RPRX makes claims about significant improvements in the “quality of life parameters.” They carefully do NOT state when these p values are obtained. Recall, the duration of treatment is four (4) months.

Completed studies at 25 and 12.5 mg doses have demonstrated statistically and clinically significant control of excessive menstrual bleeding and improvement in quality of life parameters. In a completed Phase II study, which included 127 women with uterine fibroids, doses of 25 and 12.5 mg were compared to placebo for a period of three months. Both the 25 and 12.5 mg doses showed statistically significant (p < 0.0001) improvements in three clinically relevant endpoints: hemoglobin level, menstrual bleeding scores and quality of life parameters.

What they do not state, these improvements were only found after three (3) months, not before. They discontinue the drug after month four (4). At most, the drug is helpful 50% of the time. Why do they discontinue the drug? The reason is unscheduled bleeding and emergency procedures, much more than LFT changes.





Also, the percent of women pain free is less than 50% for both 12.5 and 25 mg. Moreover, for the 12.5 mg treatment arm the percent is less than 30%.


Assuming no LFT changes, no unscheduled bleeding, and no emergency procedures, will the FDA approve a drug that is effective at most 50% of the time. After stopping the drug, there is the known concern for bleeding in the off-drug interval. Now, add back the known problems for unscheduled bleeding and emergency procedures, what is the chance for approval?

[hptaxis]

Benefit/Risk Profile Vs. Efficacy & Safety

The FDA does not do a benefit/risk analysis, but determines efficacy and safety. This might be just semantics for some, but this is a statutory requirement for the FDA. RPRX did not determine that LFT > 3X ULN was an unacceptable risk. This is a predetermined threshold for safety. LFT ULN is a well-described safety factor.

Repros believes that the decision to move forward with the 25 and 12.5 mg doses will improve the benefit/risk profile of Proellex.

“Drug development is a dynamic process, the aim of which is to try and bring to market a product with an optimal balance between benefits and risks that will address an unmet medical need in patients. Our decision to stop the 50 mg dose supports this concept, as well as demonstrates our commitment to safeguarding the well-being of the women participating in our clinical trials,” stated Dr. Paul Lammers, President of Repros Therapeutics.

Regardless of efficacy, other safety factors are unscheduled bleeding and procedures. These adverse events resulting from endometrial thickening. This is admitted to by RPRX.


In their own presentations, RPRX details these events to occur in relation to treatment duration or endometrial thickness. Both do not need to occur for these adverse events – only one is sufficient. What is more telling is that these adverse events occur after drug administration and they occur at each dose – 12.5, 25, and 50. This fits very well with the hysterectomies in the phase 2 Endometriosis trial. Not until there is an explanation for these procedures, I will assume the worst. This is more than a coincidence.


In RPRX presentation data (12.5 mg), the endometrial thickness at 120 days (4 months) was a median thickness of 17 mm. This is the median, not mean. Fifty percent of patients treated with 12.5 mg Proellex at 4 months have an endometrial thickness greater than ~17 mm. From the graph, an endometrial thickness ~18 mm demonstrates an increasing Maximum Bleeding Score. There will be a significant number of patients at 4 months with an endometrial thickness >18 mm. From Mutter's article, in both 12.5 and 25 treatment arms at least 15+% have a thickness over 20 mm.


In RPRX own words, “Prevention of normal endometrial shedding in premenopausal women treated with Proellex results in histological changes which may results in unscheduled bleeding.”


In case one did not read the above, RPRX repeats the warning that severe and unscheduled uterine bleeding occurred when the endometrial thickness exceeded 20 mm.


RPRX does admit facts. What RPRX does not do is to pull these know safety factors together and report them in a timely fashion. The LFTs are a start, now reveal the rest.

The PR admits dosing in 400+ patients. It is time they come out and categorically state that there was no (NONE) unscheduled bleeding or procedures. If there were any, admit them and let the chips fall.

They would rather have you know they are “safeguarding the well-being of the women participating in our clinical trials” by determining the benefit/risk. It is safety, not risk.

R.I.P.