Ask the Experts

  1. David McHale
  2. General Nephrology Questions
  3. Tuesday, 19 April 2016
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If you have the time, I would be very very interested and grateful to hear your take on Veltassa and your own experience with it, (if you have had any) now that it has arrived on the market. Data does seem to indicate that it has a better safety profile than it's counterpart ZS-9 in a number of ways. ZS-9's heavy sodium load has been shown to be capable of leading to some considerable adverse effects, including most prominently the danger of hypertension in CKD patients. Further, the sodium component, alongside the heavy fluid intake required (240ml water per dose) in patients already with potential fluid overload issues sounds worrisome. Besides these potentially mortal effects, observed peripheral edema is concomitant of the issues noted above and I was idly wondering how much patient comfort comes into consideration when choosing between courses of treatment.

The issue of hypertension is perhaps the most striking when I compare both treatment's safety profiles. From what I have read, Veltassa may even provide a lowering of a patient's blood pressure. I could not find data on this, but came across a podcast involving Relypsa's CMO who indicated their findings on this will be published around the start of May. Very exciting stuff. This would be in stark contrast to ZS-9's long-term study (ZS005) which - though still underway - can be used to project a hypertension level of around 15% of prospective patients using interim data. This higher BP can be related to the impact of the sodium load being released and then absorbed by the body I would initially assume. Recent studies also indicate sodium's detrimental effect on the progression of those with CKD, besides the aforementioned issues with patient's blood pressure. For reference, every 5g dose of ZS-9 contains 400mg of salt, upto a maximum of 1200mg of salt for the maximum 15g dose. Perhaps What's most striking about this however is that ZS Pharma's hypertension threshold was 180/105mmHg in this trial! Surely if it were lower we would of seen many more cases emerge? Also, as far as I can tell, patients did not received renin-angiotension-aldosterone system inhibitors, which was specified as being included in Veltassa's Phase 3 trial. Given their importance this worries me even more if they were not used.

Having said all of this, ZS-9 does seem to have a more rapid onset of action in correcting levels of potassium. This seems the only saving grace that I can see for this drug in comparison to Veltassa, but I am no professional and would welcome knowledge and corrections to the contrary!
Sooo... taking into consideration all of this - as well as your own intimate knowledge with treating patients with CKD - what is your own perception and professional opinion on ZS-9's sodium issues and its general safety profile in comparison to Veltassa? Do you perhaps know what the wider perception of both drugs in the nephrologist field is, and how they would be used in a medical setting? Could you imagine ZS-9 still having a place in the clinic for acute cases - i.e, emergency cases where a rapid onset of action is required of which Veltassa could not provide? If there is anything else you'd like to talk about in respect to these two treatments or CKD please feel free! I would find anything you could tell me on the subject more interesting than I probably should... haha.

Some relevant information on both the ZS004 trial study and ZS005 trial study, respectively:

http://twitlonger.com/show/n_1snv8ib

http://infinata.com/biopharma-solution/by-product/biopharm-insight/proprietary-intelligence/78-biopharma-solution/759-biopharm-insight-exclusive-news-zs-pharma.html

http://sciencedaily.com/releases/2015/09/150918080614.htm High dietary sodium, potassium may worsen chronic kidney disease

Thanks a lot Jordan, any professional opinion and insight you can provide on this matter would be greatly appreciated

David
Responses (6)
Accepted Answer Pending Moderation
Hi there,

It's always difficult to compare two drugs head-to-head unless they are studied head-to-head in the same patients under the same conditions.

Having said this, the rapid onset of ZS-9 would indeed be a theoretical advantage if using in acute settings. In the short term as well, hypertension would be less of a a concern if only limiting the drug to acute settings. If using it longer-term settings, hypertension could be a concern. But if mild, could also be easily managed and there may be considerable advantage to keeping patients on ACE or ARB long term under the protection from hyperkalemia offered by such a drug. All these issues require further study.

Regarding Veltassa, given slower onset but better hypertension profile, it might be better suited to long-term management - though drug-drug interactions need to be better understood with this drug (and perhaps ZS-9 as well).

As an aside, these drugs are not available in Canada and so my own opinion is based on reading of the literature only.

Dr. Jordan Weinstein
  1. more than a month ago
  2. General Nephrology Questions
  3. # 1
Accepted Answer Pending Moderation
I figured as much, but it was good to hear a professional opinion, thanks Jordan

David
  1. more than a month ago
  2. General Nephrology Questions
  3. # 2
Accepted Answer Pending Moderation
Glad I could help.

Jordan
  1. more than a month ago
  2. General Nephrology Questions
  3. # 3
Accepted Answer Pending Moderation
Yo Jordan

Just in case you are interested here are the abstracts of the studies Relypsa hopes to present at the National Kidney Convention next week. I figured that you may find them interesting - especially the potential use of Veltassa in patients on hemodialysis from its binding of phosphate. Though the level of calcium absorption may be a worry, the Chief Medical Officer of Relypsa indicated in this podcast that the level of Ca absorption per day is 50-70mg a day, less than a glass of milk! (http://www.rsnhope.org/kidneytalk-podcast/show-index/potassium-problems-new-hope/) Contained also below is the study abstract indicating Veltassa's positive effect in lowering blood pressure that I mentioned before.

https://twitter.com/amylucio2009/status/723249668226985986

Furthermore, the links that follow are a forward article in the AJKD indicating a potential case of drug to drug interaction in the use of ZS9 and Yarrow towards the end result of causing acute interstitial nephritis in a patient. Patient number was only 1 so more research is required here, but I found it of particular interest given that ZS9 had also been previously observed to cause acute interstitial nephritis in dogs in a study a while ago, of which I have also attached below the AJKD article abstract.

http://www.ajkd.org/article/s0272-6386%2816%2900560-6/abstract
http://www.google.com/patents/wo2012109590a9?cl=en
^
"Microscopically, minimal to mild focal and/or multifocal inflammation was observed in the kidneys of treated animals but not in Control animals. The lesions had similar incidence and severity at 650 and 1300 mg/kg and were less frequent and severe at 325 mg/kg. In some dogs the inflammation was unilateral rather than bilateral and in some cases was associated with inflammation in the urinaiy bladder and origin of the ureter. Taken together these observations suggest that factors other than direct renal injury, such as alterations in urine composition of ZS- 9-treated dogs may have resulted in increased susceptibility to subclinical urinary tract infections, even though no microorganisms were observed in these tissues. In recovery animals the inflammation was completely resolved in females and partly resolved in males suggesting that whatever the cause of the inflammation it was reversible following cessation of dosing. The increased incidence of mixed leukocyte inflammation observed in Beagle dogs treated with ZS-9 is summarized below. "
^
http://patentimages.storage.googleapis.com/wo2012109590a9/imgf000032_0001.png

Good luck in the future Dr. Weinstein! I hope you find what information I have rustled up useful and interesting.

David
  1. more than a month ago
  2. General Nephrology Questions
  3. # 4
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