This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr Michelle O’Donoghue, reporting for Medscape. I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.
Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve.
Stephen J. Nicholls, MBBS, PhD: Thanks for having me.
O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.
Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?
Pelacarsen, an ASO
Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.
We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.
O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there?
Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies.
We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before.
We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful.
The siRNAs
O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3 testing, albeit we haven’t seen yet the phase 2 results.
What is your sense of lepodisiran and its efficacy?
Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect.
I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future.
Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.
O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year.
Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration.
That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients.
O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.
What’s your sense of that?
Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.
The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice.
O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients.
Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin.
Muvalaplin, an Oral Small Molecule
Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them.
Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.
Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now.
O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.
Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.
O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it?
Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all.
O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment.
Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.
I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news.
The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work.
O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.
Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.
I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.
It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively.
O’Donoghue: Thanks again for taking the time. This was a very helpful discussion. Signing off for Medscape, this is Dr Michelle O’Donoghue.
Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates.
COMMENTARY
Drugs to Target Lp(a): What’s Coming
DISCLOSURES
| December 13, 2024This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr Michelle O’Donoghue, reporting for Medscape. I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.
Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve.
Stephen J. Nicholls, MBBS, PhD: Thanks for having me.
O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.
Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?
Pelacarsen, an ASO
Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.
We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.
O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there?
Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies.
We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before.
We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful.
The siRNAs
O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3 testing, albeit we haven’t seen yet the phase 2 results.
What is your sense of lepodisiran and its efficacy?
Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect.
I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future.
Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.
O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year.
Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration.
That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients.
O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.
What’s your sense of that?
Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.
The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice.
O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients.
Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin.
Muvalaplin, an Oral Small Molecule
Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them.
Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.
Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now.
O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.
Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.
O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it?
Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all.
O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment.
Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.
I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news.
The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work.
O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.
Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.
I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.
It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively.
O’Donoghue: Thanks again for taking the time. This was a very helpful discussion. Signing off for Medscape, this is Dr Michelle O’Donoghue.
Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
TOP PICKS FOR YOU