CEimpact Podcast

Zilebesiran - A New Hypertension Treatment

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Injectable, long-acting therapy is a new frontier for hypertension management. Join host, Geoff Wall, as he evaluates zilebesiran, a hepatic angiotensinogen blocker for blood pressure control for up to six months.
 
The GameChanger
Zilebesiran blocks the final production of angiotensinogen at the hepatic level making it safer from a renal perspective than the ACEis or ARBs. A single subcutaneous injection provides therapy for up to six months.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension. N Engl J Med. 2023 Jul 20;389(3):228-238. doi: 10.1056/NEJMoa2208391. PMID: 37467498.
https://www.nejm.org/doi/full/10.1056/NEJMoa2208391
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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Describe the mechanism of action of Zilebesiran
2. Discuss possible advantages and disadvantages of this drug in the treatment of hypertension

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-323-H01-P
Initial release date: 10/16 /2023
Expiration date: 10/16/2024
Additional CPE details can be found here.


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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Hello and welcome to Game Changers clinical conversations. I am Jeff Wall, your host. I am a professor of pharmacy practice at Drake University. Welcome to Game Changers. Today we are going to talk about a new paper or new study that came out of the New England Journal of Medicine, talking about a brand new anti-advertisement. You may say to yourself, you know so what I mean. There is 8 million anti-advertisement on the market. Why would I really care about this one? I think it is less about the drug itself though it is actually pretty interesting and more about the way this anti-advertisement was developed and its mechanism of action, which is absolutely unique, and I think we will actually portend some of the new drugs we are going to see used in the future just because it is a novel way to approach drug development. But again, this is a new anti-advertisement.

Speaker 2:

Many of you out there I know treat hypertension on a daily basis and know that it is the single largest risk factor contributing to death and disability, adjusted years well, life years worldwide, resulting in 9.4 million deaths and the loss of 200 million healthy life years annually. And those numbers are kind of shocking because I mean when you say you know, wow, hypertension kills 10 million people globally a year. You think if that was anything else, if that was cancer or a new infectious disease, we would be throwing the kitchen sink at figuring out how to treat it and how to do a better job of doing it. I think because it is kind of a slow, creeping issue. I mean, again, very few people die because they have a high blood pressure for a day or a week or a month or a year. It takes time for that to happen and I think that kind of leads to some of the clinical inertia that you certainly see in many practices where you know, yeah, we'll put you on an advertensive and we get you down a little bit, that's great. But you know I'm not going to go, you know I'm not going to fall head over heels to make sure that you're at goal just because you know you may not take the medication or you might have some other problems and stuff like that. So again, it is worth noting that hypertension is one of the biggest risk factors for death in a worldwide and data from multiple sources suggest, especially in the United States that we have, you know, that we get less than 50% of patients to their goal of blood pressure and that's certainly something I've seen and, again, multiple studies have suggested that. So and I think it's you know, there's a number of factors involved with it. Again, I think clinical inertia plays a role.

Speaker 2:

I think changing targets makes things difficult for providers. Okay, so we're going for 140 over 90 now. We're going for 130 over 80 now. You know, you know what. You know which target am I am I using? You know, should I be targeting super low blood pressure levels in the very elderly? You know there's a lot of questions that I think we have some answers to but I think make it make it challenging for providers on a day to day basis to go okay, this is kind of the way I should be treating hypertension in most of my patients and, of course, probably the biggest issue is adherence.

Speaker 2:

You know it's very difficult to get patients to take medications for a disease they almost always don't have symptoms for. So you know they say to themselves well, I'm getting side effects from this and it's costing me money every month. Why should I take a drug for something that I can't feel that it's not causing any problems? So you know, we, we know that there's a, that it's it's common, it's a huge cause of more Nat mortality and morbidity and we don't do a good job of treating it. So in any disease state where that's going to come around, you have to think to yourself. You know, you know we should be looking for novel ways to treat it and the paper that we're going to discuss and we'll leave the link, as always in the show notes, you know notes that there's it's been over 15 years since a new I had to have a intensive has hit the U S market and the last one was Alice Skinran, which is a direct green rent inhibitor that nobody I know uses. I don't think I've ever seen a patient on it and that's because of it's very high side effect profile, including really high risk of some angioedema and stuff like that. So I mean the bottom line is is you know, yeah, alice Kiran came out but nobody uses it, and it's probably over 20, 25 years since a new mechanism of action drug hits hit the market. Yeah, as far as Bob's was concerned, alice has always used. This makes this talking about this drug kind of exciting.

Speaker 2:

Like alloskin rem, like ACE inhibitors, this drug does target the reninogen-tensin aldosterone system and that makes sense. I mean that we've always known that's a key regulator for blood pressure and that up-regulation increases blood pressure by basically constricting vascular beds and increasing vascular tone. But it also has effects on autosterone synthesis and fluid retention and things along those lines. But we've also known that even though we've had effective treatments targeting that pathway ACEs and ancient receptor blockers that over time there's doubt regulation of those receptors and there's always been some concern that these medications may lose their anti-abritance of potency over time. So while they're effective drugs and millions of patients are on them, there is some concern that over time they may lose their effectiveness and I think, especially in the elderly, the concerns about acute kidney injury and hyperkalemia and stuff like that do make them kind of tricky to use.

Speaker 2:

So even though this new drug targets the reninogen-tensin aldosterone system, it doesn't from a different angle and the way it does that is by basically a new approach to drug development called therapeutic gene silencing. And this is actually first discovered by two Nobel Prize-winning scientists who got the Nobel Prize for doing this, and they realized that this is an evolutionary-conserved endogenous pathway in which short strands of RNA, such as SiRNA, are responsible for some of the physiologic effects and if we can basically put some of these SiRNA strands it basically results in gene silencing. So whether that gene would normally produce a chemical that stimulates a receptor or even the receptor itself, that it would basically turn it off would basically turn off the development of that chemical, turn off the development of receptor development and placement. So basically a fascinating new target, because if we can do that we can target medications really kind of at the source and rather than trying to block receptors or block chemical production like interleukins and things like that, this really just basically tells the body stop producing angiotensin, to stop producing or up-regulating or down-regulating receptors. So it's again kind of a fascinating way to look at drug development.

Speaker 2:

And there is already a drug on the market that does this. Again, it's a drug that I have not seen clinically used but I know has been on the market for a couple years and that's inoclizarin, which is a drug that's for familial hypercholesterolemia, which is maybe probably the reasons I have not seen it, because this is the kind of drug that's used for patients, usually younger patients, who just have unbelievably high cholesterol and LDLs and stuff. So a fairly small percentage of patients, but it works. It was the first major drug on the market that basically inserts these SIRNA strands in the cause gene silencing and in this case, for hypercholesterolemia, it prevents the translation of PCSK9. So basically it's a PCSK9 inhibitor, but it's a PCSK9 inhibitor at the source, so it basically turns off the gene that causes the translation of PCSK9. So kind of fascinating and, I think, an interesting way to approach things. So the other interesting thing about these drugs is that at least currently, there won't be an oral version of them. They have to be administered subcutaneously because they just won't tolerate bioavailability. So that's the other thing that's kind of interesting. But the benefit of that is that these drugs may be, because they basically turn off the gene, they be incredibly long lasting, and I think that's the other issue is this may really help with adherence, because you have patients where you might be able to take one or two drugs every six months or a year or something like that and still have pretty good control, and that's kind of what this new medication shows. So again, this inclisirin is approved for hypercholesterolemia. Multiple studies have found that it actually does a very good job of knocking down a torocholesterolem LDL. But we're currently having in studies that, okay, that's terrific, but does it actually decrease heart outcomes like cardiovascular disease and stroke? And those studies are ongoing, as you might imagine. So that brings us to this brand new drug, zillabresian.

Speaker 2:

And this drug is interesting Again. It's an SIRNA drug that basically covalently links with the development of angiotensin II, but it actually does it in the liver, which is again completely different than ACEs or ARBs, which basically work in the kidney to block production of either ACEs or actually buying to the ARB receptor to keep those chemicals from working. So again, with this drug, it basically causes gene silencing of the production of angiotensin II, thereby reducing the production of it and then leading to crossing fingers a decrease in blood pressure, more importantly, a decrease in heart outcome. So again, kind of fascinating that. And instead of trying to block the receptor or block production of enzymes, this goes right to the heart of things and basically just says, hey, stop producing angiotensin II. So it's kind of interesting.

Speaker 2:

So this study which was published in the Journal of Medicine is only a phase one study, which again, I think speaks to how even people at the high levels of medicine have said hey, this must be a. This has the potential to be a very, very important drug, because phase one studies usually don't get published in the Big Five Internal Medicine Journal, so that's kind of interesting. So, like all phase one studies, this was a tiny study, didn't have very many patients in it and it wasn't actually looking at efficacy though that was a secondary outcome. They were actually looking at safety and I think that's certainly reasonable. So this was a four part multi-center phase one study of Zillabesrian, which is designed to, again, primarily assess safety. It also looked at pharmacokinetic and pharmacodynamic characteristics, which they didn't actually report in the study. There was multiple parts to it and the parts we're gonna talk about are part A and part B and part E of this study and again, each one of these parts had a relatively low number of patients in them. But basically we're designed to look at safety of various dosing levels. It'll work its way into phase two studies as well, where you'll get more of a look at safety, at various dosing regimens, as well as efficacy.

Speaker 2:

But this really was just designed to say are we gonna see any weirdo side effects with this medication? So it was done in the United Kingdom and, because it was a phase one study, this is not going to be the population that you would probably see with hypertension. Commonly these were patients ages only 18 to 65. So patients over age 65 were excluded. So again, something we're gonna have to take a look at with future studies. They had to have a sitting systolic blood pressure of between 130 and 159, so they couldn't have sky high blood pressures. They could also be in with the diastolic of up to 100, but they excluded patients with secondary hypertension or super high mean diastolic blood pressures as well. So really this was a very controlled population of adults, but not people over 65. And their systolic had to be basically 130 to 160. So I mean so just kind of keep that in mind. They also excluded patients who basically had any other disease states, so diabetes, anything along those lines. They were excluded, as well as patients already taking drugs that effect. The Rhinocentrisen system were excluded. So again, a very, very narrow population. But the goal here really wasn't to say, hey, we should start using this in patients as just the starting steps of determining whether it should make it a phase three study.

Speaker 2:

So in part A, which is one of the studies we're gonna talk about, they took a look at several different dosing regimens, from 10 milligrams of Zillabestrian all the way to 800 milligrams. So a pretty wide dosing regimen there, and they did a two to one ratio compared to placebo. And so there was 12 patients in each of these dosing hordes, so 12 into 10 milligrams, 12 into 25 milligrams, et cetera. They were allowed to add on anti-eviruses of therapy at the discretion of the investigator at eight weeks for uncontrolled hypertension. Then in part B they did pretty much the same thing, but they divided patients into a low salt diet which they looked at actually 0.25 grams per day I don't know a single person in the United States who could adhere to a 0.25 gram per day sodium diet. So again, they must have some pretty motivated patients. And then a high salt diet which was six grams per day, essentially of sodium, and they were put on that in a run-in period for about three weeks before the study was started. And then they were put on a single high dose of Zillibestrian versus placebo just to see what a single dose would do in low salt diet patients versus high salt diet patients. And then finally, in phase E, they just looked at everybody, all comers who had more than a blood pressure of 120, getting a single dose of Zillibestrian. So I think part A is probably the most important one because it was a dose ranging study, especially when looking at safety, whereas part B and E we're really looking at. If we just give a single high dose, what is that going to do to patients? So kind of interesting in that.

Speaker 2:

So after they completed the study itself that ended at week 12, all patients were under new and extended safety follow-up period to see if they had any developing side effects or if, how long the effect of the drug would last. They were given guidance regarding to moderate their alcohol intake, to try and keep their sodium down, et cetera, et cetera. Anything that would any other drugs would affect blood pressure as well. The primary endpoint because this was a phase one study was just frequency of adverse effects. Again, the fact that this drug is essentially hepatically is where it's mech is of action, is in the liver. The theory is that you would have much less renal issues associated with this drug compared to ACEs and ARBs. Again, that kind of remains to be seen, but that was one of the things they wanted to look at. And secondary outpoints were again the changes in blood pressure at week six, eight, 12 and 24. And then they looked at that same issue in patients who were on the low and high salt diet as well, and then basically before and after co-administration of that single dose. So again, a single dose of subcutaneous drug was given and their conclusions, going into the study, was that it would probably last weeks.

Speaker 2:

So, and that's kind of what we'll take a look at here, they did extensive safety monitoring, as you might imagine adverse effects, laboratory assessments, vital signs, things along those lines. They did do pharmacokinetic and pharmacodynamic analysis, which I am not going to go into today because we just put everybody to sleep, unless you're a pharmacokinetics expert and listening to this just for fun. It was a descriptive study. You know only so many. You know they didn't do real inferential statistics because of the small numbers they wouldn't nearly have the power to show a statistical significant difference. They just wanted to take a look at total numbers, even though there was a placebo arm associated with that. So what do they find as far as safety? What do they find in this very, very tentative step as far as efficacy? We're going to talk about all that after. A word from our sponsor, ce Impact.

Speaker 1:

Are you a pharmacist by design? Since we hold a vital position on the health care team, it is our responsibility to advance our knowledge and skills so we can provide the best possible care to our patients. Being a pharmacist by design means striving to be the best version of ourselves, not just as professionals, but as individuals dedicated to improving patient outcomes. Learn more about pharmacists by design at cempackcom. Join us and begin your journey to being the best version of your pharmacist self.

Speaker 2:

So we're talking about this new drug, Zillibeserian, in a phase one study for hypertension just recently published in the Wingland Journal of.

Speaker 2:

Medicine In this study, from May 30th 2019 through January 26th 2022, they had a total of 107 patients enrolled and, again, not for high numbers, because this is a phase one study, and most of them were in the Part A group because, though that was the different dose ranging study, in total they had 56 patients that signed Zillibeserian versus 28 versus placebo. They had 12 patients in the low high salt diet part of the study and 16 patients in the patients who got a single high dose of it stuff like that. If you take a look at pooled baseline characteristics, the mean age was 53. Again, considering that they blocked people from being age 65 in the study, 62% of the patients were men. What I think is a very good thing is that 25% of patients were black. Again, we know that black patients tend to have more resistant hypertension and, unfortunately, have worse outcomes with hypertension compared to other populations, so I'm glad they were able to at least get at least a decent number. I think 24 hour means to stop blood pressure across all groups was about 140. And that was true regarding different characteristics of the study and the different types of patients they had in it, and then that was really it, because again, they had such stringent inclusion, exclusion criteria, they really couldn't go much beyond that.

Speaker 2:

As far as taking a look at baseline characteristics as far as adverse effects and again there's no statistics here but if they took a look at any adverse effect across part A, which again I think is the highest number, they actually found that 86% of patients in the placebo arm versus 75% of patients in the Zillibeserian arm complained of a side effect. As far as serious side effects, which they had specific definitions for, the percentages were virtually identical and that's true for any adverse effect or any serious adverse effect. Nobody died. But I mean, again with these small numbers, I'm not surprised by that. As far as what the side effects were, headache was actually reported, the most interestingly, more in the placebo arm than in the Zillibeserian arm and, as you might imagine, the biggest side effect was injection site reactions which they described as just swelling and pain, which occurred in 9% of patients in the Zillibeserian arm compared to nobody in the placebo arm. Not surprising.

Speaker 2:

There Any other adverse effects of interest. They did not see any changes in levels of potassium or their electrolytes. They didn't see any renal adverse effects, but again a fairly small number. A little bit of a signal of concern was that across the board they did have one patient who had LFT abnormalities. Lte's rose greater than three times the level of normal in this Zillibeserian arm compared to placebo. Again, that may not seem like a lot but again, when you only have 56 patients in the study that is kind of a signal of concern and I'm sure we'll be looked at in phase two and further studies.

Speaker 2:

But on the whole, the primary outcome in the study, noting safety, really the only at all common side effect was injections at reactions, which again, not that surprising in this. So then again we go into efficacy and again worth noting that this is the study is not designed to look to look very comprehensively not only at blood pressure but at heart outcomes. But it does give us some interesting results in that after a single dose of this medication, at doses of the Zillibeserian of more than 200 milligrams and so they remember they the max was 800, but when they started to see doses at 200 milligrams, after a single dose, they actually found a significant decrease of over 10 milligrams millimeters of mercury in systolic blood pressure and greater than five millimeters of mercury in diastolic blood pressure at the Zillibeserian 200 milligram dose. And when they took a look at week 24, the observed change, especially in the higher doses above 200 milligrams, was this decrease in stalled blood pressure of 22 and a decrease in diastolic blood pressure of 10. So again, you know, fairly effective and this was particularly true in the highest doses of 800 milligrams of Zillibeserian, and almost nobody in that study had to receive any additional anti-advertisement therapy to keep their blood pressure in control.

Speaker 2:

They did do 24 ambulatory blood pressure monitoring and what they found was actually pretty encouraging in that they found over the full 24 hour period through week 24, there was good blood pressure control, you know, around the 24 hours every day through week 24. And again found complete control over again week 24. And then when they took a look at low versus is high salt patients, this is probably not a big surprise. Patients in a low salt dialet tended to have a more profound decrease in blood pressure compared to those who are in a high salt diet. The numbers were similar but the low salt diet found about a decrease in 18 millimeters of mercury and stock blood pressure and eight diastolic, and the numbers weren't as high in the high salt group. So, like many other antiripotensives, there seems to be a correlation between trying to keep your dietary sodium down and effectiveness of your antiripotensives. So to kind of summarize basically, a single subcutaneous dose of this drug through week 24 maintain significant blood pressure decreases kind of across the board at doses above 200 milligrams, and particularly notable in patients who received 800 milligrams of the zillabrestrian, and especially if they were able to maintain a low salt diet.

Speaker 2:

So again, I think this really opens up a lot of very interesting avenues, I think, for studies and for the possibility of using a medication that may provide significant long-term effectiveness and after about daily pill burden and things along those lines. So the authors note that what they found was that there was dose related increases, decreases in blood pressure and decreases in serum angiotensinogen and angiotensin levels. They found that this decrease was sustained up to week 24. They noted that this seemed to be pretty well tolerated, that again, transient injection site reactions, no hypotension, no hyperkalemia, no worse than your renal function was noted. But again, the study wasn't long enough or big enough to really show that. So this is pretty interesting and it also notes that Aldosterone escape, which has been one of the things that's been suggested to happen with ACEs and ARBs, that they start to lose effectiveness over time did not seem to happen here. So that's kind of interesting and the thought that this is utilized apatically and not renaly. The authors note that this may actually be an advantage from a safety perspective as well.

Speaker 2:

So again, phase one study, just really kind of tantalizing possibility of what may occur here in the future. I guess it'll be at least several, two, three years before the drug is in the hands of prescribers ready to go, and I have no doubt it'll be unbelievably expensive, because all new drugs are. But I think that especially if they find that the medication has effectiveness in a wide swath of patients, if it decreases hard outcomes, and I think that especially in patients where adherence may be an issue or patients with resistant hypertension, I think you've got a nice new medication here that someone were to get two shots a year or maybe even one shot a year. Again, the study only came out to 24 weeks and they didn't go longer than that. Who knows, maybe it has effectiveness long beyond that. The ability to improve adherence with one shot every six months or one shot a year of this medication to decrease high blood pressure is very interesting. And as long as at week 24 or beyond they don't see something. You should sure hate for someone to develop LFT abnormalities and say, well, I don't know when the drug is gonna wear off, so here we go, we'll just have to kind of watch you. So I mean drugs with really long half lives. There's always kind of a double-edged sword there, but it'd be very interesting to see where this kind of ends up. So, based who studies are underway. It'll be interesting to see if it makes it all the way to market. I've learned the hard way over the years to not try to guess whether a drug that looks good in early phase studies will actually make it to market. I've been wrong several times on that score, and so I'm just suffice it to say this is tantalizing for a number of reasons, and we'll see if it actually does anything.

Speaker 2:

I think as importantly, this gene silencing effect has the ability to treat all sorts of different diseases, because really, when you think about it, so many of the targets we offer for drugs is either receptor antagonism or agonism or decreasing endogenous cytokines or other chemicals that are leading to adverse effects. And so if you have the possibility to gene silence a variety of other diseases, could you gene silence the ability, the production of uric acid crystals. Could you gene so no gout. Could you gene silence the basal constrictor effect in the brain of the CGRP? So you could basically have a long-term migraine prophylaxis once a year or something along those lines, and that's just stuff kind of up the top of my head. I mean, you could take a look at some of the more more difficult to treat diseases, like some of the autoimmune diseases, some of things like multiple sclerosis and stuff like that. There's lots of potential applications. So it'll be very interesting to see in the next few years if gene silence becomes one of the dominant ways to come up with new medications on the market.

Speaker 2:

So stay tuned. That's it for this week of Game Changers. Hope you like what you heard. Also a shameless plug which I made last week as well. Many of you know I produce electronic music, mostly house music, under the name Profit of Jupiter. I was fortunate to have a new single released by Electronic Eagle, eden Records, electronic Eden, excuse me, and I'm on all platforms Spotify, soundcloud, et cetera, et cetera. So take a listen. Hope you like what you hear. We will see you next week, but remember until then, time flies. I don't know where it's going, but the most important day is today. We will see you next week.

Speaker 1:

Jen here. Be sure to check out our education at cempackcom. You'll find it to be your one stop shop for all the CE resources you need. Become a pharmacist by design member today to access it all for free, including CE for this podcast. Thanks for listening. We'll talk to you next week on Game Changers Clinical Conversations.