Replies to post #167187 on Biotech Values

[projectchris]

We'll have to wait and see if BioinvestorX was correct that COMET-1 placebo arm would mimick Zytiga/Xtandi post-chemo trial post progression survival - my guess right now is COMET-1 placebo arm mOS will be less than what he suggested:

I'm guessing BiotechinvestorX is assuming patients will not be on drug for the same length of time in the commercial world vs clinical trial experience. Zytiga patients in the post docetaxel trial were on drug past radiologic progression and had a median OS of 7 months post Zytiga withdrawal. That means Zytiga patients were taken drug 2-3 months post radiologic progression. I believe patients were withdrawn from drug upon PSA progression.

We'll have to wait and see if BioinvestorX was correct that COMET-1 placebo arm would mimick Zytiga/Xtandi post-chemo trial post progression survival - my guess right now is COMET-1 placebo arm mOS will be less than what he suggested:

I agree and think the COMET 1 trial assumptions that assume 7 month median OS are conservative. Especially in light of the fact that patients will not be dosed on placebo immediately following Zytiga withdrawal.

Link to my thoughts on COMET 1 trial.--link to discussion thread here, you may need to sign into Motley Fool account but it is free.

http://boards.fool.com/on-os-30764730.aspx?sort=whole#30766894

Do you think the survival issue is stacked against ExEL in their study designs?

The trial has 90% power to detect a 25% reduction in the risk of death (HR = 0.75). The final analysis will be event driven, with 578 events required. A single interim analysis is planned after 387 events. The secondary endpoint is bone scan response as assessed by an independent radiology facility (IRF).

It appears they need a 25% reduction in the risk of death at at 578 events. If Cabozantinib doesn't show a 25% reduction in risk of death at 578 events, is it really worth being on the market anyway? Jevtana had a 30% reduction in risk for death in post docetaxel setting for comparison. Jevtana will be the primary competition here.

How does Ernie handicap the probabilities of OS success? Gut feeling or is there other data to base this on?

Ernie hasn't shown his work to make his conclusion. Very hard to analytically come to definitive conclusion with so much missing information. The biggest known negative issue I have mentioned is that 26% of the patients didn't go on to receive Abiraterone,Jevtana, or Enzalutamide.---Ernie stated his disappointment that OS was not broken down specifically by prior therapy, and Ernie has been critically vocal about the subset of patients that didn't go on to get treated with abiraterone in NRE trial.


Your 3 month estimate seems consistent with other trials of other agents such as Provenge. Is that how you are guesstimating potential OS or using another metric?

I did my best to give a guesstimate with imperfect information we have on hand. Probably in your words--"gut feeling"

I'll touch on how I handicap the known factors.

I keep the 7 month placebo estimation for COMET 1 static, and adjust known factors to adjust the 10.8 month survival in NRE and extrapolate to COMET1. First, I assume that 74% of the patients who went on to receive post docetaxel treatment would have an estimated 7 month survival regardless of whether that treatment was Abiraterone or some other treatment. I assume the 24% of patients that didn't go on to receive treatment after docetaxel to have an 11 month survival based on Abiraterone placebo arm in COUGAR 301 trial.(estimation of survival in NRE trial without Cabo treatment) I took a full 2 months off the Cabo NRE OS arm to account for this.(your probably thinking my adjustment here should be on COMET 1 placebo estimation, but for simplicity accounted on Cabo arm) Next, I assume that the Cabo treated patients in post docetaxel(24% of patients) are more progressive than patients in COUGAR 301 trial. I add 1 month onto NRE OS to account for this.

Rough estimate on known factors I mention in above 10.8-2+1=9.8
9.8-7= 2.8 month Cabo OS advantage

Cabo NRE characteristics
meetinglibrary.asco.org/content/118040-132
Cabo NRE press release
http://www.exelixis.com/investors-media/press-releases

Abiraterone study patient characteristics and misc.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/20237...

Jevtana patient characteristics and misc.
http://www.jevtana.com/hcp/tropic-study/patient-characterist...


Now obviously I am missing a lot of information to give a credible guess, but again I am doing the best I can with the information I have. Let me just go through some of the other known details of importance.

I extrapolate entire study characteristics into the 24% of patients in NRE that did not go on to receive post docetaxel treatment in Cabo NRE trial.
1. 100% of NRE had bone metastasis vs 90% Abiraterone Cougar trial vs 80% in Jevtana trial= sicker population in Cabo NRE

2. 100% of NRE were considered progressive by Recist/bone scan vs 70% in Abiraterone COUGAR trial= sicker population in Cabo NRE(The 30% of Abiraterone population that had PSA only progression had a 4 month OS advantage vs RECIST/Bone scan and or PSA progresson, so this one appears fairly significant much like the 26% of patients in NRE that didn't receive treatment post docetaxel)

3. 47% of NRE had symptomatic >4 BPI score vs 45% Abi COUGAR= push

4. 31% NRE had visceral disease vs 30% Abi COUGAR= push

5. 30% of Abi COUGAR had 2 chemotherapy treatments--I suspect most of the 30% went on to have 2 separate docetaxel treatments, and a small amount of this population had paclitaxel and other unidentified taxane. The NRE didn't specify, but I would hazard to guess that the NRE patients didn't get 2 chemotherapy lines= sicker population Abiraterone

Now some of my known unknowns

1.Tinker mentioned the 60 mg dose may be more tolerable and affect Cabo treated OS in a positive way. I suspect it will

2. No gleason scores in NRE to compare

3. No study entry post last docetaxel dose in NRE to compare

4. No ECOG scores in NRE

5. unknown unknowns


Now obviously Cabo would compete well with main competitor JEVTANA if COMET 1 demonstrates stat sig OS due to 1. Cabozantinib unique bone effect 2. pain palliation from Cabo.

Jevtana pain palliation vs mixantrone was approx. 34% vs 17%


I'll stop here for now. I sure wrote a lot for a guesstimate. Anyways, hope you found something useful out of that.