Next we're going to talk about how potassium binders can enable renin-angiotensin-aldosterone system inhibition therapy in patients with heart failure. Here are my disclosures mostly reflecting leadership in clinical trials.

Let's first discuss some of the limitations of traditional approaches to treatment of hyperkalemia. As we all know, they have important limitations which is why novel potassium binders are really advanced in management of hyperkalemia. First is the low-potassium diet. While it can be effective in lowering potassium levels when strictly adhered to, we know that this diet is difficult to maintain in the long term. Because it also limits the types of foods that actually are healthy from a cardiovascular standpoint in large proportion of patients with hyperkalemia who have established cardiovascular disease, it may not be optimal for other reasons for patients to maintain it long term. There are both adherence issues and other aspects of cardiovascular disease risk and management that are important here. The second is loop diuretics which certainly can lower potassium levels. We also know that patients with heart failure including heart failure with reduced ejection fraction, while we want to have optimal dose of diuretics to effectively decongest the patient, we don't want to over their risk patients because that can actually fuel first activation of neurohormones which long term can be detrimental. The third is the option that we just talked about that has its own significant limitations. That's down-titration or discontinuation of RAASi treatment. It certainly will likely result in lower potassium levels but we know at least in observational studies that it's strongly associated with worse patient outcomes, including higher risk of mortality, and heart failure hospitalizations. Certainly, if we have alternate options, discontinuing or stopping potential life-saving treatment is not the best way to go forward. Finally, as a traditional potassium binder such as SPS or sodium polystyrene sulfonate, which can certainly be effective in acutely lowering potassium levels but for most patients it's not a viable option for chronic management of potassium and maintenance of normokalemia. Predominantly because of gastrointestinal side effects including constipation and diarrhea. It's also quite unpleasant for most patients to be taking this treatment long-term. If we actually look at the medium duration of treatment with SPS, we can see that it's about seven days and it's highly rare for patients to be able to maintain this treatment in long term.

In order to have an effective treatment option for lowering potassium levels without some of the limitations that we just talked about, there was a clear clinical need to develop potassium binders that are well-tolerated and highly effective in lowering potassium levels. That can be used for chronic maintenance of normokalemia. The good news is that we now have two of those novel potassium binders including sodium zirconium cyclosilicate or SZC which is an inorganic crystal, which is highly selective for potassium. Exchanges potassium for hydrogen and sodium, and patiromer which is the polymer that exchanges potassium for calcium.

Let's first review patiromer efficacy data. We now have several trials establishing patiromer efficacy for lowering potassium. First is the onset of action study that demonstrated that patiromer in patients with hyperkalemia can start lowering potassium within about four to seven hours. We know in these studies that were done longer term including OPAL-HK and AMETHYST that patiromer is also effective in lowering potassium levels and maintaining potassium levels on normal range over an extended time period. In OPAL-HK, patients with mild to moderate to severe hyperkalemia were treated with patiromer. As you can see here, patiromer lowered potassium levels in a normokalemic range in patients both with mild hyperkalemia and moderate to severe hyperkalemia and maintain potassium levels in normal range for four weeks.

In the AMETHYST study that was done with the intention of evaluating long-term effects again, in patients, predominantly with mild to moderate hyperkalemia potassium levels were effectively lowered to the normokalemia range and effectively maintained for one year. As can be expected, once the potassium binder in this case patiromer is discontinued at the end of the study, the potassium levels go back up and reach hyperkalemic range again, indicating that the majority of these patients require long-term treatment.

We also had the PEARL-HF study that was done several years ago now. That really for the first time tested the concept of using patiromer, as a novel potassium binder, can optimize the treatment of heart failure in those patients with established heart failure in this particular case looking at spironolactone dose. In this relatively small study of about 100 patients, those that were assigned to patiromer had a significantly greater likelihood of being able to be up-titrated to optimal spironolactone dose than those that were assigned to placebo.

Now, we have a much larger trial that was just recently completed and published called the DIAMOND. The DIAMOND study randomized more than 800, nearly 900 patients that either had hyperkalemia at baseline or were considered to be at high risk for hyperkalemia. Those patients were initiated on patiromer even in open-label phase during which ACE inhibitor, ARB, ARNI treatment was to be optimized, and patients were also to be initiated and optimized on MRAs. Those that were successfully optimized with well-maintained potassium levels were then randomized through a randomized withdrawal mechanism, to either continue on patiromer or to be switched to placebo. This trial was initially designed as an outcome trial, but was heavily impacted by COVID-19. The impact was really a double whammy. The recruitment itself was slower than expected due to COVID-19. Also, the event rates were significantly lower than expected, likely also the consequence of COVID-19 pandemic. As a result of that, there was a protocol amendment and the primary endpoint was changed from this being an outcome trial, to the primary endpoint being potassium-based. Let's take a look at the results of the study. The primary endpoint was again between group difference in potassium levels at the end of study, which was 0.1 mEq/L lower with patiromer as compared with placebo, with a highly significant p-value of 0.001. You can say it's statistically significantly, but the difference between the groups is quite modest. It is modest of just 0.1 mEq/L. However, it's important to keep in mind that patients could be down-titrated or discontinued on their RAASi treatment. After randomization, The physicians, of course, or clinicians taking care of patients didn't know who is on patiromer and who is on placebo, but because the potassium levels were higher in the placebo group, they were more likely to have their RAASi treatment down-titrated or discontinued. In a way, that artificially depressed the difference between the two treatment groups when it comes to potassium levels. What I think it's actually a more meaningful endpoint is the secondary endpoint that was time-to-first hyperkalemia event. That was defined as an event with a potassium level of greater than 5.5 mEq/L. I think there are two important lessons to learn from this slide. First, is that in the placebo group, that you can see depicted here in gray, majority of patients actually were free of hyperkalemic events. What that means is that they were able to be successfully maintained on their RAASi treatment even while being on placebo without developing hyperkalemia. What that tells you is that in part there is a lot of clinical inertia in many patients that are not on appropriate, or optimal RAASi treatment including use of MRAs, can be successfully up-titrated and maintained even without the need for a potassium binder. The lesson number two is that patiromer was highly effective in reducing the risk of first hyperkalemia event by about 37% with a concentration of 0.63 that was highly statistically significant. In addition, there was also a significant reduction in the time-to-first MRA dose down-titration. What that means effectively is that patients treated with patiromer were more likely to be maintained on optimal MRA therapy than those assigned to placebo. Again, there was a 38% relative risk reduction in that endpoint and there was also a significant reduction in the total number of investigated endpoint of hyperkalemia events.

I think the lessons from DIAMOND trial is that large proportion of patients that are currently not receiving optimal RAASi can be up-titrated and optimized. Some of them will require or may require a potassium binder, and certainly use of potassium binders in the high-risk population can effectively reduce the risk of subsequent hyperkalemia. Here are some additional endpoints in the DIAMOND trial and I specifically highlighted some of the cardiovascular outcome data. It's very important to keep in mind as it can clearly be seen here when you just look at the sheer number of events that while this was initially designed as an outcome trial, the number of outcome events was very small and it's really not meaningful here. There are no real conclusions that can be drawn from outcome data because the number of events is so small.

Let's now pivot and talk about the efficacy data from sodium zirconium cyclosilicate trials. The one trial that I'm going to highlight first is HARMONIZE trial that was one of the pivotal registration studies for indication for SZC as a novel treatment for hyperkalemia. In the HARMONIZE trial patients with hyperkalemia, they could have mild, moderate to severe hyperkalemia initially entered open-label phase in which they were treated with SZC 10 grams three times a day. Those that achieved normokalemia at the end of the open-label phase subsequently were randomized to three different doses of SZC or to placebo and treated for four weeks. During the trial, patients on RAASi were not allowed to titrate or discontinue RAASi treatment. Let's first talk about open-label phase, where you can see that almost immediately within one hour, there was a statistically significant reduction in potassium levels of 0.2 mEq/L. Potassium levels continued to decline, achieving about 1.1 mEq/L reduction at 48 hours. The overwhelming majority of patients were normokalemic at the end of the open-label run-in phase. It's important to keep in mind that these results were highly consistent across different subgroups, including those with CKD, heart failure, diabetes, or taking RAASi. The results were also consistent in patients with mild, moderate, or severe hyperkalemia, even including those patients who had potassium levels at entry more than 6 mEq/L. What happened after the open-label phase in a randomized phase of the study, as you can appreciate here, SZC effectively maintained normokalemia where patients assigned to placebo had returned to hyperkalemic range. It was also a long-term extension of the HARMONIZE trial that looked at treatment for close to one year. Again, the same story we see that potassium levels are maintained in the normal range but after stopping the medication, go back in a hyperkalemic range indicating need for long-term treatment. This was also further investigated with sodium zirconium cyclosilicate in a study called 005. Where in the open-label single-arm design, patients with hyperkalemia received treatment with SZC that was titrated depending on potassium levels as one would in a clinical practice. What we see here is once again, SZC was effective in lowering potassium levels from baseline about 5.6 milliequivalents per liter to the normokalemic range and maintained potassium levels in the normal range for up to one year. After treatment was discontinued as we've seen before, potassium levels return to close to hyperkalemic range indicating need for long-term therapy.

What about looking at SZC as potential enablement strategy to optimize and maintain optimal RAASi. That's actually being actively investigated in the REALIZE-K trial. This is a phase four double-blind placebo-controlled randomized withdrawal trial evaluating effectiveness and safety of SZC in the management of hyperkalemia and patients with heart failure and reduced ejection fraction. The patient population in this trial are those with heart failure and EF less than or equal to 40% receiving ACE inhibitor or ARB or ARNI and those that either aren't receiving currently an MRA or only can tolerate low-dose MRA. Those who need to be on other GDMT including a beta blocker. There are two cohorts in the study. Either those with baseline hyperkalemia or those that are considered to be at higher risk for developing hyperkalemia. Patients initially enter open-label run-in phase where depending on the cohort, they either get started on SZC upfront while the MRA is being optimized. Or if they don't have hyperkalemia at baseline, they get optimized on MRAs and get started on SZC once hyperkalemia develops. Once they're optimized on spironolactone therapy if they also have normokalemia at the end of run-in phase, the patients are randomized to the continuing current dose of SZC or being withdrawn to placebo. The primary endpoint of the trial is a classic endpoint for RAASi enablement. That's proportion of patients who are optimized on spironolactone and free for hyperkalemia or in other words, have potassium in the normokalemic range. Do not require rescue therapy for hyperkalemia during the treatment phase. The trial is currently ongoing, and we believe that it will significantly contribute to the evidence base for looking at novel potassium binders as enablement strategy for optimizing goal-directed medical therapy in HFrEF.

In summary, what we've heard so far is the prevalence of hyperkalemia continues to be higher and will continue to increase. It's particularly a problem in patients with heart failure and reduced ejection fraction because it's a key limiting step in optimizing RAASi. The typical clinical decision-making that we see today is to down-titrate to stop RAASi despite their benefits, and we know that at least in observation studies, it is associated with poor patient outcomes. It also is resulting in marked underuse of GDMT in patients with HFrEF especially when it comes to MRAs. Novel potassium binders may change this treatment paradigm in favor of optimizing the use and dose of RAASi including MRAs because it really offers us an alternative therapeutic option to simple down-titration or discontinuation of therapy. The guidelines as you will hear shortly from Clara have acknowledged novel potassium binders as potential treatment option, but to date, have not yet strongly endorsed the use. In part because there is a need for additional data generation. That data is, in fact, being generated and we're doing additional trials looking at the use of potassium binders as RAASi-enablement strategy. This will likely further advance the adoption in future clinical practice. With that, I will close. Thank you very much for your attention.

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