Benefits of PCSK9 Inhibitors

In this segment, experts Cheryl Allen, BS Pharm, MBA; Bryan Bray, PharmD, CPP; Jeffrey Dunn, PharmD, MBA; Jennifer Reiter, PharmD, BCPS, BCACP, BCADM; and Peter L. Salgo, MD, outline the benefits of using PCSK9 inhibitors to treat hypercholesterolemia.

Peter L. Salgo, MD: What type of benefits do the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors offer on top of what a statin typically does?

Jeffrey Dunn, PharmD, MBA: Aside from low-density lipoprotein (LDL), the biggest is reduction in myocardial infarctions (MI) and stroke—the reduction in events.

Peter L. Salgo, MD: What about the side effect profile?

Bryan Bray, PharmD, CPP: From an efficacy standpoint, it’s just what you said—in those patients that have ACSVD (atherosclerotic cardiovascular disease) that are uncontrolled, it gives us that added benefit of being able to reduce that LDL further. It gives us an option for that patient that truly can’t tolerate a statin to lower their LDL. So, I think the efficacy of lowering the LDL is a benefit in the right patient (not for everyone). From a side effect profile, I think there’s just tolerability issues around injection site reactions. From a safety standpoint, they appear to be safe.

Jeffrey Dunn, PharmD, MBA: That’s interesting. Both of those comments leads me to an important point. You mentioned the rate of denials. The biggest challenge for us, is most of our requests for these drugs are in patients who are not on a statin. I think that makes sense. If you’ve had rhabdomyolysis or something, or you can’t take a statin, then you need another alternative. I get that. But 99% of the patients in the trials were on a statin, and so, all we’re asking is that a member stays on a statin. Whether you’re moving from a high potency statin to some other statin, we want them on a statin because we don’t know. We understand, totally, that we’re going to see a significant LDL reduction with these drugs. That’s proven, right? But we don’t know outcomes. We don’t know if there’s going to be a reduction in events if you’re using this without a statin.

Peter L. Salgo, MD: It’s worth noting that some of the effects of statins are not just on LDLs.

Jeffrey Dunn, PharmD, MBA: Right.

Peter L. Salgo, MD: The statins actually improve compliance and they decrease inflammatory responses, independent of the LDL cholesterol. So, I guess that’s what you’re saying?

Jeffrey Dunn, PharmD, MBA: But it kind of ties in with who the appropriate patient is, the budget impact, and how much we’re spending. Our willingness to pay is evidence-based. So, that’s one question, I think, that has to be answered. What is the reduction in events with these drugs not on a statin? That’s a completely different population.

Bryan Bray, PharmD, CPP: The conundrum is getting patients onto a statin. We talked about this in the very beginning, so we’ve kind of come full circle. That’s the conundrum. I think we need to treat patients with high intensity statins, first. It’s just getting those patients on it.

Peter L. Salgo, MD: If a patient’s not on a statin because of statin intolerance, that’s not the same. You’re not talking about that, are you?

Jeffrey Dunn, PharmD, MBA: If it’s true statin intolerance, more than likely, these drugs will be approved. It’s the “not-clear-statin-intolerance” and the fact that they haven’t tried a statin in 5 years or 10 years, or whatever else is going on. I see a lot of it.

Peter L. Salgo, MD: Now, you were worried about central nervous system (CNS) effects. People are worried about brain effects because part of what’s going on, the myelination process in the brain, depends on cholesterol. The concern was LDL cholesterols of 30 mg/dL may impair cerebral function. Was that a red herring—not happening or what?

Bryan Bray, PharmD, CPP: It didn’t happen in the 2-year study. Now, there’s an extension going with that study to see if there’s any long-term effects on it, so we’ll study it a little bit longer to see. I think that question still has to be answered. I think there’s still a population of providers that are still concerned about that particular side effect. But at least in that 2-year study, we haven’t seen it. And we haven’t seen it in either of the drugs.

Peter L. Salgo, MD: It’s worth noting, also, that statins do have CNS side effects.

Bryan Bray, PharmD, CPP: They do.

Peter L. Salgo, MD: A fair number of folks, in addition to rhabdomyolysis, and the muscle pain, or renal failure, a fair number of folks discuss more subtle CNS changes, right?

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: And those are considered to be reversible when the drug is stopped. I think what we’d be more concerned about is something a little more permanent if we’re looking at long-term effects of having low LDL which, as Bryan mentioned, we haven’t seen yet. Even in older studies where they’ve looked at LDL levels less than 40 mg/dL, we haven’t seen that. So, that would be the major concern.

Peter L. Salgo, MD: Do these drugs cross the blood-brain barrier?

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: My guess is going to be no, due to the size of monoclonal antibodies, but I guess I don’t know the answer for sure.

Peter L. Salgo, MD: But, again, the statins apparently do, whereas these may not.

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: And I don’t think we’re concerned about the drug itself causing neurocognitive defects. It’s the profound LDL lowering causing it.

Peter L. Salgo, MD: So, the safety profile here is rational on these new drugs? Let’s take a look at some of the research you’ve been talking about. There was the New England Journal of Medicine article about FOURIER. What do these outcome research studies with PCSK9 inhibition really show? What is the research supporting here?

Jeffrey Dunn, PharmD, MBA: A significant reduction in LDL, and a reduction in stroke and MI on top of a statin—so, good data.

Bryan Bray, PharmD, CPP: In patients with an LDL already at goal, because the average starting LDL in that study was 92 mg/dL.

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: Yes.

Peter L. Salgo, MD: That’s something we didn’t hear before. That’s important, and that’s what you were alluding to—patients already on statin therapy. We presume they’re on statin therapy because their LDLs were high. So, if somebody walked into your office with an LDL of 90 mg/dL, you wouldn’t necessarily go ahead and give them a statin? These are folks where you’ve been driving the statin down already. And then, as I understand it, on top of that, you’re telling me they gave the new drugs and drove it down further, and they had a decrease in stroke and MI.

Jeffrey Dunn, PharmD, MBA: That’s the issue. We know we’re going to get an LDL reduction with these drugs. We don’t know if we’re going to get a reduction in events without the statin.

Peter L. Salgo, MD: Okay. That study’s yet to be done? Is anybody willing to do that? Is that an ethical study?

Jeffrey Dunn, PharmD, MBA: I think they’re (both manufacturers) looking into patients not on statins.

Peter L. Salgo, MD: And presumably, that they would be patients who couldn’t tolerate statins to start with.

Jeffrey Dunn, PharmD, MBA: Yes, and that changes the criteria. If these drugs were priced like a branded statin, or something different, then we would not be doing this. It’s the cost of medication that is requiring us to manage the way we are. And the other downstream impact of that (because of the trends that I mentioned earlier), with these escalating costs, and specialty drugs, and budget impact to employers, is really not having money to pay for medications potentially moving forward, and some of the few mechanisms we have in place to manage this that affect the member. So, it’s more use of closed formularies, more coinsurance, and higher deductibles. And that’s another barrier with these drugs. Even if a patient is appropriate for these drugs, now we have other factors that we have to take into play to make sure that they’re compliant on these drugs. We’ve talked about compliance with the other drugs, but now you talk about a high out-of-pocket, an injection, and a number of other things. Once we identify the patient, we have to do a lot of work to make sure that these patients are staying on these drugs.

Peter L. Salgo, MD: But I heard something buried in that answer that I want to ask everybody else about. You said that if these drugs were priced the way branded statins are priced, we wouldn’t be having this conversation. And the conversation is entirely about on-label use in compliance with research. Did you mean to imply that if this drug was cheaper, you would approve it more for off-label use, or not in compliance with this research?

Jeffrey Dunn, PharmD, MBA: I do, because we would probably not be using prior authorizations the same way we are now.

Peter L. Salgo, MD: There you go. So that’s what happened with statins, right? And doctors started prescribing them because they worked, even though the research took a while to catch up. Should price be the driver on that?

Jeffrey Dunn, PharmD, MBA: Cost, efficacy, and value should be the driver of that.

Cheryl Allen, BS Pharm, MBA: Exactly. I think one of the tough things, also, that Jeff mentioned, was passing the cost on to the patient. There’s a higher out-of-pocket cost to patients for higher cost therapies, and it’s a challenge for patients. We talked about why patients are not seeking treatment. There’s abandonment on prescriptions, particularly in patients who are comorbid. They probably have 3 to 5 other prescriptions that they’re taking.

Peter L. Salgo, MD: But these are expensive drugs. On the other hand, what we did (as the medical community, and I, and payers) with that was, as the statins came down in price, we recognized that a lot more people could benefit from them. That was indicated in the original literature, so we just expanded it. At first, statins were just for high-risk patients who were diabetic hypertensive smokers. Now, everybody gets them as long as their cholesterols are too high. So, is it just the money that’s driving this, really? Is that right?

Bryan Bray, PharmD, CPP: The problem we’ve got in medicine is the silo effect. The costs associated with drug costs is in 1 silo, and the overall healthcare cost is in another silo, and they often don’t communicate. In a lot of situations, there’s data out there to prove that if you, perhaps, spend more money on medications, you could save more money in the overall healthcare system by rationally managing those medications. I think it comes down to just choosing that right patient and rationally managing that right medication to be appropriate.

Jeffrey Dunn, PharmD, MBA: It’s the appropriate patient, but I also think it’s completely unfair to say we just focus on clinical and ignore cost. Both of those have to be addressed.