Replies to post #7094 on Repros Therapeutics Inc (RPRX)

[hptaxis]

LFT: Tip Of the Iceberg

The post was not about LFTs, but about the safety issues of unscheduled bleeding and procedures. The LFTs are but the tip of the iceberg. Further, >3X ULN is not a benefit/risk analysis to be done by RPRX. This is a safety factor that is not changeable or to be taken relative to any efficacy measure.

As in your prior post (that you deleted), you read differently than the original document. “Nice Try Though.”

"LFT ULN is a well-described safety factor"

Yes it is. Take Lipitor for example. On Lipitor's label it speaks about cases of patients being over 3x ULN. Ranges of APPROVED DOSES range from approximately <1% to 3%. In my opinion, Repros believes that efficacy is equivalent for all 3 doses so why create noise/distractions to dampen the efficacy signal by taking a dose forward that is ~4% when the other 2 doses are below 1%.
The only "beef" that anyone could have that I can see is POSSIBLY that a more rigorous look at the data could have teased this out after phase 2 data (phase 2 is done in part to chose phase 3 dose).

It was not a decision of RPRX to continue the trials at 50 mg unless they wished to waste more resources. At a level >3X ULN, in a significant percent, the trials had to stop. The FDA would need to look no further than this to deny approval regardless of efficacy.

The actual wording of the Lipitor label (with link) follows. The label clearly states that LFT >3X ULN need to be discontinued (stopped – halted). RPRX LFT data stated it was >3X ULN, not below 3X ULN. A big difference. Far from reaching close to 5% with Proellex, the percent is 0.2%-0.6% for doses below the highest, which is 2.3% (80 mg).

Liver Dysfunction

HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.

. . .

It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (eg, semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with atorvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.

https://www.pfizerpro.com/sites/ppro/pages/product_info/lipitor_pi_warnings.aspx