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Subject:  Re: Fuma--TCDA update Date:  9/2/2020  4:42 PM
Author:  Fuma102 Number:  25404 of 25643

So I'm going to post a bunch of stuff this afternoon on my holdings. Let's start here.

Basically, the investor powerpoint in August is a good starting point:

“According to the CRL, the FDA is seeking additional data beyond the TRCA-301 and TRCA-301E trials regarding the magnitude and durability of the treatment effect of veverimer on the surrogate marker of serum bicarbonate and the applicability of the treatment effect to the  population. FDA also expressed concern as to whether the demonstrated effect size would be reasonably likely to predict clinical benefit. There were no safety, clinical pharmacology/biopharmaceutics, CMC or non-clinical issues identified in the CRL.”

In English:
The FDA is not convinced that serum bicarb levels are an applicable surrogate marker, and they question if a treating bicarb levels help. Now, normally I would agree, and say surrogate markers can in fact be a smoke screen, except that there already multiple studies showing bicarb levels correlate to progression of chronic kidney disease (read: dialysis).
… and from international guidelines: “Serum bicarbonate concentrations less than 22 mmol/L are associated with risk of CKD (chronic kidney disease) progression and increased risk of death.... We suggest that in people with CKD and serum bicarbonate concentrations <22 mmol/L treatment with oral bicarbonate supplementation be given to maintain serum bicarbonate within the normal range, unless contraindicated”

It does get interesting when you did a bit deeper as there was one study in which, “Our results suggest that at least for patients aged 60 and over with CKD GFR categories 4 and 5, 1.5 to 3 g per day of oral bicarbonate does not produce any health benefits and may be associated with net harms.” .... which would be totally fine, except there are multiple other studies showing benefit.

Now, good science would say, "well, does an improvement of serum bicarb **with tricida's drug** correlate with improved patient outcomes?" - these sort of questions are RARELY asked, and often why I scream into the vortex and often crap all over most biotech companies. So what has TCDA done?

TRCA101 – 2 week P1/2 trial randomized, double blind placebo controlled, 135 patients
TRCA301- 12 weeks, P3, 217 patients (serum bicarb as endpoint)
TRCA301E – 40 weeks, P3 trial, 196 subjects.

301 showed better quality of life, better exercise tolerance, 65% reduction in a composite outcome of death, renal replacement therapy or >50% drop in renal function.

Now, typically I would crap all over a composite outcome (this is what statins did, and its **MUCH** less than a 65% reduction in their composite outcomes!) - but going from 12% to 4% PLUS patient centered outcome improvements is a pretty air-tight case. The only complaint would be number of patients included (500 or so patients all in all). To be clear the FDA has accepted much, much, MUCH less.

So they asked for more data. and TCDA had *already* started their large trial, Valor CKD, with 1600 patients, looking at a primary outcome of delay to dialysis. Randomized double blind placebo controlled trial. ValorCKD was planned on being a post-marketing study. Its been ongoing since 2018, ETA for completion Q4 2022. Protocol specifies an interim analysis when at least half the planned number of primary endpoint events have been accrued -- I suspect an update in 2021, and perhaps resubmission at that time.

I can not stress enough, this is what good science looks like, and good results. TCDA has enough cash to last through mid 2022, $437m.

This is frustrating, especially when there is more bs medicine out there with much less rigorous evaluation. TCDA is dead money until the Valor CKD study. BUT, this is still a 2b or more per year drug, for a company with a 560m market cap and good leadership.

I have plenty of shares, and as a rule try to avoid adding to my losers; but I still like TCDA even though this hurts a bit.
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