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cmm3rd 11 posts  |  Last Activity: May 30, 2016 10:49 PM Member since: Jan 25, 2005
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  • cmm3rd cmm3rd May 30, 2016 10:49 PM Flag

    bob_hop
    My understanding is that Veltassa binds Na, so removes some of it similar to how it removes potassium, while ZS-9, which contains a substantial amount of Na, does not bind Na, so the net effect of taking ZS-9 on Na levels is to increase them. The mechanism might be more precisely said to be increased Na load rather than "retention.". That is rudimentary, just my opinion, and not a specific answer to your question.

    I do not routinely consider Seeking Alpha to be an authoritative source; however, there is an article devoted to this subject written by White Coat Mafia (who claims to be an MD) and published on SA on Nov. 12 or 13, 2015. The article was designated as an "Editor's Pick," fwiw.

    On Nov. 9, 2015, also on SA, Dr. Rodney Samaan (claims to be a preventive cardiologist) published an article discussing ZS-9 AE rates, and mentioning ZS-9's Na load. Unfortunately, he does not cite to a primary source for his data.

    These articles are found easily by searching on the SA site using either the author's pseudonym/name or the name Relypsa and then in the category "articles." I would recommend also that you read the comments to both articles; some of them are illuminating.

    The reliability of these two articles is not established. Both authors said they were long RLYP when publishing them. Each of us is left to judge what weight, if any, to give them.

  • Veltassa's NDA included in vitro binding data which led to BB DDI warning. Post approval, in vivo absorption data were done, with sNDA just submitted seeking to modify DDI warning/dosing separation.

    One would think AZN/ZS, knowing that, considered (perhaps after discussing same with FDA) how best to address potential DDI for ZS-9.

    Did they do in vitro binding studies similar to what RLYP did? Did they, after seeing what happened in Veltassa's case, judge in vitro binding studies as "no win" and instead do just in vivo absorption studies? Both?

    Could any of the above be the recently submitted data mentioned in AZN's PR?

  • cmm3rd cmm3rd May 28, 2016 2:18 PM Flag

    I did not look for (or stumble upon) the change in completion date, though have seen it discussed elsewhere. I agree that any such change also could imply something significant. What I find very remarkable is the deletion on 5/20/16 of the 200 patient, randomized, withdrawal sub-study. For reasons discussed above, that raises questions about safety.

    Assuming (as you note has been claimed) the data yet to be reviewed pertain only to manufacturing, AZN should have said so. Without speculating what that data pertain to, if AZN is confident that no additional data will be needed, but data recently submitted have yet to be reviewed, it would have been helpful to say both what the recently submitted data pertain to and something about why no additional data will be needed.

  • cmm3rd cmm3rd May 28, 2016 12:55 PM Flag

    We know ZS-9's side effects include increased sodium retention and thus exacerbation of edema and/or hypertension, conditions that already complicate management of a significant portion of hyperkalemic patients (who often are being treated for chronic kidney disease or sometimes congestive heart failure). With that in mind, two possible reasons this sub-study (n=200) was cancelled could include: (1) concern about either the number of subjects still in the study (original n=750) at 6 months or (2) the safety of those remaining at 6 months. If a significant number of subjects have had to withdraw from the study, or titrate downward the dosage of ZS-9 because of side effects (e.g., edema, hypertension), or if banning dose titration during the 28 day sub-study period (see above-quoted language) had proved to be impractical or unsafe (again, because of edema/htn issues), it might have been determined that the substudy could not be performed.

    Another unanswered question is what is the data that AZN “recently submitted” to FDA and that FDA has not yet analyzed (see AZN’s PR )? And, how can AZN say, without FDA having yet analyzed that data, that re-submission of the NDA will not require any additional data? If AZN is truly confident about that representation, they should be willing to explain why. Was it drug-drug interaction data, similar to either the in vitro, or more recently in vivo, data that Relypsa submitted (and, for the in vitro data in Relypsa’s case, which resulted in a controversial black box warning in the label that the recent in vivo data show was substantially unnecessary)? Or was it interim data from ZS005?

    There easily could be more to this CRL than what has been revealed, imo.

  • There may be more to the ZS-9 CRL than is obvious from AZN’s PR. According to clinicaltrials.gov website, archive section, for ZS-9’s 12 month maintenance clinical trial (ZS005, and which is shown to be no longer recruiting but still underway), on 5/20/16 the randomized withdrawal sub-study was deleted from the trial’s description. Here is what was deleted on 5/20, according to the website:

    "A subset of 200 subjects who have been well controlled on open label ZS for 6 months during the Maintenance Phase (defined as i STAT potassium values between 3.5 and 5.0 mmol/L, inclusive, at the Study Day 113, 141, and 176 visits during the Maintenance Phase) will be randomized at the Study Day 176 visit of the Maintenance Phase to immediately transition into the Randomized Withdrawal Study. Subjects will either continue on the same ZS dose they were receiving at the time of the Study Day 176 visit (n = 100) or receive placebo (n = 100) for an additional 28 days. Potassium (i STAT and central laboratory) will be measured during the Randomized Withdrawal Study at baseline, and on Study Days 4, 8, 12, 15, 18, 22, 25, and 29. No dose titration is allowed during the Randomized Withdrawal Study."

    Why was this part of ZS005 abandoned at this point in the trial? Not to accelerate completion, so, why? (con'd below)

  • On 5/20, the randomized withdrawal sub-study was deleted from the ZS005 description. On 5/23, MS upgraded RLYP. Mere coincidence? Here is what was deleted from the ZS005 study on 5/20:

    "A subset of 200 subjects who have been well controlled on open label ZS for 6 months during the Maintenance Phase (defined as i STAT potassium values between 3.5 and 5.0 mmol/L, inclusive, at the Study Day 113, 141, and 176 visits during the Maintenance Phase) will be randomized at the Study Day 176 visit of the Maintenance Phase to immediately transition into the Randomized Withdrawal Study. Subjects will either continue on the same ZS dose they were receiving at the time of the Study Day 176 visit (n = 100) or receive placebo (n = 100) for an additional 28 days. Potassium (i STAT and central laboratory) will be measured during the Randomized Withdrawal Study at baseline, and on Study Days 4, 8, 12, 15, 18, 22, 25, and 29. No dose titration is allowed during the Randomized Withdrawal Study."

    Two possible reasons this substudy (n=200) was cancelled could be concern about the number of subjects still in the study (original n=750) at 6 months or the safety of those remaining at 6 months . If a lot of subjects withdrew because of long term issues (e.g., edema, hypertension), or if banning dose titration during the 28 day substudy period was deemed impractical or unsafe (again, because of edema/htn issues), it might have been determined that the substudy could not be performed.

    So what did Berens/MS know on 5/23 when he issued his revised rating on RLYP?

  • Reply to

    ZS-005 Long term study was revised on 5/20/16

    by cmm3rd May 23, 2016 3:45 PM
    cmm3rd cmm3rd May 23, 2016 4:41 PM Flag

    Only the latter sentence, beginning with the phrase "In addition ..." was deleted. The first sentence was retained. Again, the withdrawal study (only) is what was deleted. Imo, this raises many questions.

  • Per Clinical Trials.gov Archive site (use link at ZS-005 study site on Clinical Trials .gov site "Change history" line to get there), the following language was deleted from the trial description: "The Open-Label Maintenance Study contains an Acute Phase, in which subjects will be dosed with ZS 10 g three times daily (tid) for 24 to 72 hours, followed by a long-term Maintenance Phase. In addition, a subset of subjects (n = 200) who are well controlled (defined as i STAT potassium values between 3.5 and 5.0 mmol/L, inclusive, at the Study Day 113, 141, and 176 visits during the Maintenance Phase) after 6 months of treatment in the Maintenance Phase will enter the 28-day Randomized Withdrawal Study."

    Inotherwords, this randomized withdrawal study of 200 patients "who are well-controlled" (as defined) after 6 months of treatment" is not being done.

    Anyone want to guess why and the implications?

  • Reply to

    05/06/2016 SCRIPTS

    by keystone.investments May 13, 2016 8:36 AM
    cmm3rd cmm3rd May 13, 2016 9:31 AM Flag

    Vascepa's absolute numbers, and market share numbers, were all time highs. From ihub:

    Scripts Update - ATH Across the Board - Week Ending 06/05

    V
    TRx: 15,853 {vs 15,068; +5.21%} Sector +1.84% ATH
    NRx: 6,378 {vs 5,958; +7.05%} Sector +1.58% ATH
    Ref: 9,475 {vs 9,110; +4.01%} Sector +2.00% ATH

    L
    TRx: 2,610 {vs 2,680; -2.61%}
    NRx: 888 {vs 916; -3.06%}

    GenL
    TRx: 62,059 {vs 61,319; +1.21%}
    NRx: 22,823 {vs 22,747; +0.33%}

    V TRx Market Share: 19.69% vs 19.06% ATH
    V NRx Market Share: 21.20% vs 20.11% ATH
    V Ref Market Share: 18.79% vs 18.42% ATH

  • Reply to

    Interesting, Rob Cos...

    by seneca700 May 11, 2016 1:17 PM
    cmm3rd cmm3rd May 11, 2016 3:45 PM Flag

    I can assure you that Rob has not lost interest in CRMD. He is devoting his primary attention to ZIOP because he thinks it more likely that news that will move ZIOP will hit before news that moves CRMD will hit.

  • cmm3rd cmm3rd Apr 17, 2016 2:49 PM Flag

    The language in the 8K describing the 706 outpatient prescriptions in March that were covered and dispensed includes the words "Retail TRx." And, unlike the 1,277 March number for the starter kits, the words "new patients" do not appear.

    Doesn't TRx necessarily include any refills? Wouldn't some patients who (after using their starter kit supply) filled (their first) retail prescription for 30 packets (for once daily use) in late January or in February be expected to refill in March? The VeltassaKonnect form does facilitate dispensing either a 30 day or 90 day supply (though in my opinion its wording is confusing).

    Still, I am encouraged that March (706) covered and dispensed prescriptions were double those of February (350), but if the above is true, it appears that some of the March covered and dispensed prescriptions would be refills.

    Also encouraging is the large increase (1,277 vs. 812) in new patients who started Veltassa using a starter kit in March. Hopefully that will translate to a significant increase in (first) covered and dispensed prescriptions in April. And hopefully April will see a still greater increase in new patients starting Veltassa with starter kits, which would continue the trend in covered and dispensed prescriptions going forward.

    Note that the starter kit consists of an initial 15 day supply and a second 15 day supply to be used while the patients "await their final insurance coverage determination." (See VeltassaKonnect enrollment form)

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