I was quite excited to see the development of novel agents to help us manage hyperkalemia in our kidney patients in place of kayexalate, which is extremely unpleasant for patients, is associated with diarrhea and have reported severe side effects such as intestinal necrosis. As previously reviewed, recent trials were published on two major drugs: Patiromer (Veltassa) and ZS9.Patiromer is a polymer that binds K in exchange for calcium (NEJM 2015). FDA recently approved this agent for treatment of chronic hyperkalemia (not acute) though it included a black box stating that patiromer can significantly affect the absorption of many orally administered medications and therefore it should be taken 6 hours apart from any other medication (a significant limitation). This decision by the FDA was based on some in vitro data (could not find the actual data on the recent papers) so it is unclear which drugs may significantly be affected if taken in close proximity. The company is now performing a number of studies to elucidate that. Currently, Patiromer is available to patients but it is only dispensed in subspecialty pharmacies and most hospitals don’t have this medication on formulary yet, in part related to the cost of $30 per pill. The main side effects reported with Patiromer were hypomagnesemia and constipation. Duration of trials were up to 52 weeks.
ZS9 is a crystalline compound of zirconium silicate that exchanges Na+/H+ for K+. Based on its mechanism of action, patients will have about 300mg of extra Na+ intake per day (Kayexalate has the same issue). The main side effect of ZS9 was edema (~7%). Duration of trial with ZS-9 was only 4 weeks. FDA has not approved ZS9 yet but it is likely that once approved, it will be the leading drug in the market, especially if the black box from FDA remains for patiromer.
These first trials excluded patients on dialysis and patients with potassium greater than 6.5 mmol/L. Let us know if you have used Patiromer in the real world so that we can start gaining more knowledge outside of a controlled clinical trial.
Figure from Nephcure.org
Thanks for the update on HK treatments. I have a couple questions after reading your blog. First, you noted that the trial data for ZS-9 is limited to a 1-month study. Do you suppose the FDA will approve ZS-9 for the chronic setting based on 1-month data or are the 52-week maintenance phase trial data going to be required by the FDA prior to potential approval?
ReplyDeleteSecond, are there specific superior efficacy/safety data with ZS-9 that you don't see in patiromer's trials that lead you to believe ZS-9 will be the market leader? I'm assuming you believe the benefits/safety profile with ZS-9 will translate well going forward into the current 52-week maintenance study. Otherwise, it seems to me that there is really little to reference when comparing ZS-9 to patiromer in a chronic setting - one data set is associated with a 4-week study (ZS-9) and the other is for a 52 week study (patiromer).
Third, the interim safety results for ZS-9's ongoing maintenance trial show some hypertensive adverse events (7% or so reaching a 180/105 threshold with fewer than 10% of trial participants reaching 52 weeks) in addition to numerous other adverse events. Do you think we could be looking at some hypertensive adverse events related to the long term use of a sodium exchange binder?
Thanks, I look forward to your perspective.