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Exelixis, Inc. Message Board

erniewerner 259 posts  |  Last Activity: 28 minutes ago Member since: Jan 18, 2000
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  • erniewerner by erniewerner May 20, 2016 9:59 PM Flag

    Wikipedia actually has a pretty good article in layman's terms. Cells have a mechanism to repair DNA damage referred to as mismatch repair. This mechanism is often disabled or damaged in cancer cells and when present is referred to as mismatch repair deficiency. It is especially common in colorectal cancer with a frequency of approx 85% and is also present in gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. CRC patients are normally tested for microsatellite instability, which indicates mismatch repair deficiency.

    PD1 testing in CRC has to date only been effective against mismatch repair deficient (also referred to as microsatellite unstable) disease. As Stephen pointed out, this is only a 15% subset of all CRC patients. This leaves a considerable unaddressed market for PD1 treatment in a major indication.

    As Stephen also pointed out, all we know is that 3 of 4 of the Cobi/Atezo responses were mismatch proficient. The data is very preliminary and will likely be updated at the meeting as the cutoff for the abstract was last October. If the overall 17% ORR holds up and there are no show stopping safety signals, I expect Roche to quickly define an indication and move into ph 3, with a flexible trial that might allow for an accelerated approval based on durable response rate with continued blinding to give a full approval based on OS.

    "If Cobi were expanded into another indication with a Roche drug, what would prevent them from further lowering the price of Cobi and raising the price of their wholly owned drug and sweeping more of the profit into their coffers?"

    Good question. I think they already screwed EXEL with the V/C price split. My guess is that they would use the same 1/3 vs 2/3 split for a C/A combo. CRC is big market and Roche has the opportunity to sew it up first. BMY and Merck appear to be concentrating on mismatch deficient disease so far. Even as the junior partner this would be big for EXEL.

  • erniewerner erniewerner May 20, 2016 7:41 PM Flag

    "One thing I need to point out, you missed the most important thing....."

    Thanks for pointing that out. This mismatch pair repair deficiency thing is a new wrinkle for me and I'm doing a self study crash course right now. I was also looking at the Nivo/Ipi results and that combination also seems more active in mismatch positive disease. I'm still looking and I'll have more to say later.

  • Abstract 3502

    "In preclinical models, targeted inhibition of MEK leads to upregulation of MHC I on tumor cells, induces intratumoral T-cell infiltration and enhances anti-PDL1 activity...... Results from the serial biopsy cohort showed enhanced PD-L1 upregulation, CD8 T-cell infiltration and MHC I expression on treatment, providing mechanistic rationale for the combination. "

    This abstract is good news on a few different levels. The combination is tolerable, shows efficacy in CRC, and confirms a preclinical scientific rationale that likely means the combination will be active in several tumor types.

    Atezo just received accelerated approval in 2nd line bladder cancer as monotherapy. It is their first U.S. approval so they are playing catchup against Nivo and Keytruda. It will be interesting to see if they move forward with any pivotal Cobi/Atezo trials. Took some profit today, but holding most of my position for higher prices.

  • Reply to

    Reiterates Buy..$8 price target

    by jhsudds May 19, 2016 8:04 PM
    erniewerner erniewerner May 20, 2016 3:10 PM Flag

    "Do the math."

    4000 X 7 (7 months per patient) X $10K (approx wholesale per month)= $280 mill. Not sure where $625 comes from?

  • Reply to

    clinical trial RCC

    by timesensitive May 7, 2016 5:46 AM
    erniewerner erniewerner May 19, 2016 1:26 PM Flag

    "A "sicker" real world population does outwardly suggest that there may be more patients that might be interested in Cabo, if only for Cabo's gaining rep as salvage treatment - perhaps immediately following exposure to Nivo...or sunitinib re challenge."

    I agree. It was good news that the scrips written so far indicate a similar duration of therapy to that seen on Meteor. Hopefully that holds up with wider adoption following the approval. I think real world oncs might keep their patients on med a bit longer than the trial criteria and office visits might be a bit less frequent. Whatever the reason it bodes well commercially.

    So far the abstracts have been pretty neutral. No surprises in either direction and the market seems to agree. Cobi/Atezo looks interesting in CRC, but the data was immature and it's also tough to get a read on the competing PD1's in the same space.

  • Reply to

    clinical trial RCC

    by timesensitive May 7, 2016 5:46 AM
    erniewerner erniewerner May 19, 2016 12:23 PM Flag

    "This is absolutely remarkable! To paraphrase (with my editorial comment in { } ) - clinical trials exclude the sickest people {purposely, so that the results look better than they will be in the real world}. There is no reason not to assume that the same is also true of CABO trials."

    The motive for carefully defining the inclusion and exclusion criteria for a pivotal trial is to maximize the likelihood of a successful outcome on the broadest possible user group. Sponsors want a drug approved and they also want an indication definition that includes as many patients as is possible. Every drug approval includes a defined indication. It is understood by all involved that patients presenting with more advanced or aggressive disease than the norm will statistically do worse their counterparts with a better prognosis. Cinical trials should be viewed as a scientific experiment to isolate an effect, they are not intended to perfectly mimick the real world. Clinicians and informed patients can compare their their status to that of the patients entering a trial. Drug labels include extensive data on patient characteristics and frequently have information on how different prognostic factors affect outcome.

    So I read this comment and I my first thought is "Well,duh!" It is the choice of the patient and clinician to use a drug when the patient does not meet the indication criteria or has a prognostic status at the lower end of the range allowed into a trial. Labelled trial results are not a promised outcome. They are a starting point for doctors and patients to make informed choices.

  • Reply to

    Look at CCXI flying !

    by biotechblood May 17, 2016 9:59 AM
    erniewerner erniewerner May 17, 2016 12:40 PM Flag

    "I hope you realise how stupid you ll be if ccxi sky rockets and you missed it !"

    I will cope with that disappointment if/when it occurs. In the meantime let's keep the EXEL mb about EXEL. Bought more at 5.31.

  • Reply to

    $6 is flashing!

    by godhairyballs May 16, 2016 8:38 AM
    erniewerner erniewerner May 16, 2016 11:17 AM Flag

    "Added at 5.46 and looking to add more."

    Nice pullback. More at $5.37. Still have more cash ready in case it keeps dropping.

  • Reply to

    $6 is flashing!

    by godhairyballs May 16, 2016 8:38 AM
    erniewerner erniewerner May 16, 2016 10:41 AM Flag

    "only 0.5% down after a huge rally last week..."

    Good point. Expect some backing and filling. Added at 5.46 and looking to add more. ASCO and 2nd q should be constructive for sp. Post ASCO for biotech in general is usually a tough period. We'll see. Looking for some clarity on future development plan for Cabo at the investor presentation at the end of ASCO.

  • Reply to

    comparing Cabozantinib and Lenvatinib

    by biotechblood May 14, 2016 6:45 AM
    erniewerner erniewerner May 15, 2016 7:56 PM Flag

    "And why do you think the NCCN voted the combo down, considering your early view that the data was strong enough for a possible approval? What did the KOL's from the NCCN not understand?"

    Good question and I think I have some good answers. First, I think both FDA and NCCN fully understood the issues, but I think they work off of differing priorities. FDA has to live within its legislatively defined guidelines and they make an effort to observe their own past precedent. All three of the relevant trials (Meteor, Nivo, L/E) ran simultaneously. FDA tries not to penalize a sponsor for events that occur subsequent to the initiation of a trial. That's the rationale for my pointing out that the measuring stick for L/E is Everolimus and not Cabo or Nivo. The NCCN guys view things from the perspective of a practicing oncologist rather than that of a regulatory agency and my impression is that they were considering why a clinician would want to prescribe L/E in an indication for which Nivo and Cabo are available with much less controversial data sets. FDA's view is that L/E meets approval criteria and the market can sort out where it should fall in the treatment algorithm. NCCN is taking the additional step and saying there are better alternatives. Now that the L/E approval has occurred, it will be interesting to see if or how NCCN adjusts its compendium to accommodate that approval.

    If L/E had read out before the Cabo or Nivo results were known, then I suspect L/E would have gotten a better reception from NCCN.

  • Reply to

    comparing Cabozantinib and Lenvatinib

    by biotechblood May 14, 2016 6:45 AM
    erniewerner erniewerner May 15, 2016 7:45 PM Flag

    "Any thoughts on the EMA following suit with an Lenva/Ever approval in RCC?"

    Theoretically, ever since the ICH (international conference on harmonization) accords were adopted, the major regulatory agencies all have the same drug approval criteria. Yet, as we know, FDA and EMA occasionally disagree on approvals. The perception is that EMA is slightly more permissive, yet FDA approved the T/D combination in melanoma about 2 years ahead of the EMA and now they approved L/E first based on the controversial ph 2 study. My guess is that EMA will follow suit and approve L/E, but my conviction level is more like 60/40 than 90/10.

    Here are my reasons for expecting the approval and some may seem a bit subtle. First, the trial fully met the prospectively defined PFS criteria and some protocol patchwork was done to provide supplemental OS data even though the label is ambiguous in this regard. The drug had breakthrough status so the lines of communication were open between FDA and Eisai. The NCCN vote was a clear negative, but then FDA did not schedule an ODAC to give them the political cover to say "No." Most telling for me was that Eisai never started a phase 3 confirmation study. This told me that they expected a full approval and I believe their confidence in this regard was from FDA assurances that a ph 3 would not be required. Granted, there is some guesswork in this, but I connected the dots and it's what I came up with.

  • Reply to

    comparing Cabozantinib and Lenvatinib

    by biotechblood May 14, 2016 6:45 AM
    erniewerner erniewerner May 15, 2016 6:12 PM Flag

    "Too bad the pretreated Opdvio population didn't have 50 patients in Cabo arm."

    The reference here is the phenomenal HR=.22 enjoyed by this small subgroup. Perhaps Dr. Apolo's results will satisfy some of the questions in this regard. We'll see sooner or later.

  • Reply to

    comparing Cabozantinib and Lenvatinib

    by biotechblood May 14, 2016 6:45 AM
    erniewerner erniewerner May 15, 2016 6:06 PM Flag

    "I really think FDA at minimum should have required a post approval sequential L than E study to answer this question."

    The sequential vs parallel question is totally valid and in my mind a more valid concern than trial size or parsing the rectitude of post hoc analyses. It's a can of worms that FDA has largely avoided. On the flip side, there is a logic to making each step in the algorithm as effective as possible and anticipating that additional therapies with different MoA's will compensate for any missteps in this regard.

  • Reply to

    What causes the decent gain recently

    by james_mattack May 15, 2016 11:37 AM
    erniewerner erniewerner May 15, 2016 5:55 PM Flag

    "Come in peace? That's what the macrocephalic aliens said in Mars Attacks.."

    I guess that happened before they had the audacity to turn Carrie into a chimeric Chihuahua.

  • Reply to

    comparing Cabozantinib and Lenvatinib

    by biotechblood May 14, 2016 6:45 AM
    erniewerner erniewerner May 15, 2016 5:46 PM Flag

    "If I understand your logic correctly - would you expect a successful supplemental filing to be made based on non-inferior CABOSUN results?"

    No, and not for the reason you think. Non-inferior has a specific meaning to the FDA and the criteria to meet noninferiority is a statistical test that proves the tested drug retains a high percentage of the control's superiority margin with a high degree of confidence. Proof of noninferiority requires very large sample sizes.

    "If not, how positive would you expect those results need be to create the basis for a successful filing in frontline RCC?"

    CaboSun has a statistical action plan included in the protocol. Most likely (but we don't know for certain), for PFS, it requires P less than or equal to .05 based on a Log rank or Cox regression test. Successfully passing that test would be the requisite criteria to demonstrate superiority based on PFS. FDA would then likely look at OS to confirm that even though Cabo confers a PFS advantage it does not result in an OS disadvantage. This is the same scenario used for Cabo approval in MTC.

    Recognize though, that approval criteria generally gets more rigorous as one ascends the treatment algorithm from salvage to frontline. Also as the art advances, indications that previously required only ORR and/or PFS endpoints to merit approval can evolve to require the higher standard of proof that an OS endpoint confers. I'm not saying this will or will not happen, but it is circumstance that applies in a general sense to all oncology indications.

  • Reply to

    comparing Cabozantinib and Lenvatinib

    by biotechblood May 14, 2016 6:45 AM
    erniewerner erniewerner May 15, 2016 11:38 AM Flag

    "I'm actually a bit alarmed by the L/E approval, for all the reasons I've suggested and more...
    Just when you think you've got a handle on the overture of conservatism practiced by the FDA - they grant approval in a crowding indication based upon data from a 50+ patient cohort! when the competition only just recently proved out in very much larger trials."

    I can explain some of the rationale behind the decision. Eisai's trial compared L/E to Ever, not Cabo or Nivo. When Eisai started their trial the SOC for 2nd line RCC was Ever and the criteria for approval was statsig PFS. That could change now because both Cabo and Nivo have demonstrated statsig OS, but that was not the measuring stick for L/E. The trial size, 3 arms with 50 in each arm, is more concern from a safety profile perspective than from an efficacy viewpoint. Is a 50 patient sample size in a nearly always fatal disease large enough to characterize the safety profile for the drug? Past practice for FDA very much says that it is, plus this is a supplemental for both L and E, so each drug has been vetted individually. From an efficacy perspective, a sponsor assumes greater risk with a smaller trial, but the results of the statistical test are no less valid. A p value is a probability. As an example, a 1000 patient trial and a 100 patient trial both achieve an identical p value of .01. The probability of a false positive for each is 1%. The larger trial will have narrower confidence intervals around its HR and medians, but a p value endpoint is designed to answer a binary yes/no question.

  • Reply to

    lenvatinib/everolimus combo approved

    by rad.onco May 13, 2016 5:05 PM
    erniewerner erniewerner May 14, 2016 11:04 AM Flag

    "Would that indicate the combo would not be approved for use in 3rd line....after 2nd line Nivo?"

    The label merely reflects the preconditions the trial imposed for enrolment. Don't get caught up with the notion that clinicians and insurers are required to follow the label literally. Treatment algorithms are frequently adjusted to accommodate new treatments.

    We've already discussed the L&E data at length. It will have some impact on Cabo, but not much. The majority of KOL's appear to be more comfortable with Cabo vs L&E and at present Cabo has a price advantage. Ever is a Novartis drug and L is an Eisai drug. They do not have a formal collaboration in place to market the combination, so end users will presumably have to pay full price for both dugs. That could change. They could package, market and price the combination specifically for RCC to make it more competitive. We'll see. I'm not surprised by the approval.

    The label for L&E is interesting. The KM curve for OS is included, but no claim of extended survival is supported or denied. No OS p value is included either. Technically the approval is based on the predefined PFS endpoint achieving significance. PFS has been a recognized approvable outcome for 2nd line RCC.

  • Reply to

    Bank of America presentation remark

    by hbomb57108 May 10, 2016 5:55 PM
    erniewerner erniewerner May 10, 2016 9:49 PM Flag

    "At 25 min and 15 seconds into the presentation Morrisey seems encouraged by Cobi + Atezo combination."

    At the very least it sounded as if he had seen the abstract Roche will be presenting at ASCO. Abstracts are released May 18, 5pm. He mentioned data for colorectal cancer. That's good. Roche appears to be aiming at NSCLC and Trip neg BC with Atezo/Avastin and CRC with Atezo/Cobi. None of these are in phase 3 yet, but you have to know the PD1 combinations are coming soon. Cobi is at best a breakeven proposition unless Roche moves it into another indication and CRC would be a big boost to the Cobi partnership.

  • Reply to

    $12 is fair but $20 is wanted ...

    by godhairyballs May 10, 2016 10:35 AM
    erniewerner erniewerner May 10, 2016 12:11 PM Flag

    "One concern I have always had is the convertible notes and the fact that the price has to be over $6.90 (I think, correct me if wrong) for a certain amount of time in order to buy back the notes..."

    That is a precondition to call them early, otherwise they just continue to maturity in 2019. If the share price is less than $5.31 the notes will be redeemed for cash. If the share price is in excess of $5.31, expect the holders to convert and take stock.

  • Reply to

    CABOSUN

    by rad.onco May 9, 2016 3:01 PM
    erniewerner erniewerner May 9, 2016 4:28 PM Flag

    Hey Duck, I think Gisela is hedging a bit on that 1st half prediction for CaboSun. You are right, she has been saying 1st half all along until the April 30 CC and she said:

    "The primary endpoint is progression free survival and the study achieved at the target enrollment of 150 patients in March of 2015. Given the study is conducted independently by a cooperative group, we don't have the exact details on timing of data availability but are expecting results with study in 2016 time frame based upon the historical duration for PFS in this setting."

    I'm guessing that by now the study has the requisite # of progression events to trigger the analysis, but I would also guess that there is not the same sense of urgency to finish the analysis and publish the result that would exist if EXEL were sponsoring the study.

EXEL
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