FDA approves alirocumab for lowering of LDL in certain patients

Christopher P. Cannon, MD

The population indicated for this drug is the group of people who were studied and who I think will benefit most from it: those with HeFH with very high cholesterol levels who have a desperate need to get their cholesterol down to where we’ve been able to get it for everyone else, and people with known CVD, who are at highest risk. The safety results have been very encouraging, and were likely why the drug received approval very quickly.

The language that FDA used, “in addition to diet and maximally tolerated statin therapy,” is very good in that it reminds everyone that those are the two foundations and is inclusive of the few people who can’t tolerate statins.

With IMPROVE-IT, we saw that going even lower with LDL levels than we used to did improve outcomes. It’s not yet proven that the lower LDLs achieved with this therapy will translate into lower rates of CV events, but I think it’s pretty likely.  In being able to get cholesterol levels down to low levels for the first time in some of these patients, we would expect many fewer of them to have MIs and strokes.

Focusing on exactly the people who are in the label will inform our prescribing pattern. Those with HeFH would be the first group to have this added to their usual multiple-drug therapy. Then, those who we’ve been following with CVD who still have very high LDL levels would be the other group to consider. The question is what hoops we have to jump through. I would anticipate that they would need to be on the maximally tolerated dosage of statin, likely plus ezetimibe (Zetia, Merck), and then still have an LDL higher than 70 mg/dL. Certainly, if it’s higher than 100 mg/dL, that’s an urgent need for those patients.

With any new therapy, we all have to learn who is a good patient for it. Now that we have a new therapy, it becomes more incumbent on us to make sure we are not overlooking FH amongst our many patients. This will help us focus on patients with very high cholesterol, and getting them and their families optimally treated. It will be exciting for me to re-look at all my patients now that we have multiple new treatments available for them. For example, it may prompt us to notice that a patient still has high LDL despite being on a moderate statin dose, and that we should try a higher dose of the statin. So the availability of this drug should have a broader impact than just on the patients who get it.

Seth S. Martin, MD

This is a revolutionary class of medications and getting to this point represents a remarkable triumph of science. How often do we see bench-to-bedside translation occur in just over a decade? This is an example of the research enterprise at its finest and the power of genetic medicine. Much of this story started with the discovery of individuals with genetic mutations in PCSK9. Those with loss-of-function mutations and very low LDL levels (even < 20 mg/dL) appear healthy and strongly protected from CVD.

I applaud the FDA's decision to make PCSK9 inhibitors available for clinical use. It's exciting that the time is here to move the discussion from meeting rooms to the clinic where informed clinicians and patients can discuss the available evidence in the context of the patient's individual case and decide if this is the next therapeutic option that makes the most sense. The patient populations that the FDA chose fit with what the advisory committee had said and what I expected.

At the Johns Hopkins University Lipid Clinic, part of our Ciccarone Center for the Prevention of Heart Disease, patients were coming in for months before the FDA decision asking about this new class of medications and whether it might be an option in their case. We could talk in theory then and now we can talk in more practical terms. We've seen that having this new option is giving patients a lot of hope, many with FH and very high CV risk. FH is more common than many may appreciate, present in one in every 200 to 500 people. We see patients who have tried all the different statins or other lipid-lowering medications, and have trouble tolerating them entirely or tolerating maximal doses, or simply don't achieve what we'd consider adequate LDL lowering. So it's easy to see why there is so much hope about the new medications and there is a strong need for them.

I'd encourage patients to talk with their health care providers about PCSK9 inhibitors. They may be a good candidate or the conversation itself may illuminate other non-PCSK9 inhibitor options to lower their future risk for MI or stroke. So what I'm expecting is that we may not only see a benefit from the availability of this new therapy, but also from the attention to it getting more patients talking with their clinicians about their CV risk. Those discussions may often bring up opportunities such as lifestyle habits (which are first and foremost), to add or maximize a statin, or to add ezetimibe.

Using a PCSK9 inhibitor is about more than just treating a number. It's about considering the overall CV risk status of the patient, looking at what's been done already, and in some cases treating a high-risk patient after shared decision-making with a new safe medication that substantially lowers a major causal factor in heart disease. It should be disclosed that the long-term outcome trials are ongoing, but the opportunity cost of waiting for those studies to finish is too much in some patients. The available evidence is already so strong.

Rita F. Redberg, MD, MSc

Right now, all we know about this drug is that it lowers LDL. Other drugs have been shown to lower LDL (torceptrapib, estrogen, to name a few) but have no benefit on outcomes. I think it is premature to approve this drug, when there are no outcomes data and thus, we do not know if it is good for patients or hurting them. Right now, it is treating a lab value, one we think is related to heart disease, but we are not sure as it is not always. I will not be prescribing it until we know the outcomes data and that it helps patients.

Nanette K. Wenger, MD, MACC, MACP, FAHA

Alirocumab is a very exciting drug, clinically and pathophysiologically. Both PCSK9 inhibitors [alirocumab and evolucumab] have begun to define for the clinical and research communities the safety of low LDL, which has always been questioned, even though the lack of safety has never been documented. I don’t believe anyone knew which populations the FDA was going to approve these drugs for. Both companies submitted a long list of indications based on the clinical trials in their New Drug Application packets.

Who is helped by this drug will depend in great part on the insurers and what they will cover. Both drugs are going to be costly and will likely be in the same price range. It will devolve to who from the indicated population is insured and what the insurers will approve. Alirocumab was not approved for statin-intolerant patients without heterozygous familial hypercholesterolemia or prior CVD. I’m not sure whether that will be the case for evolocumab; and even if it is approved for such patients, how statin intolerance would be defined is unclear.

I don’t expect alirocumab being approved before evolocumab will make much of a difference, because I expect the approval for the latter to come rapidly. But I do believe that there will have to be a great deal of education of the clinical community about both drugs, in part because these are injectable drugs and we don’t know how well injectable drugs for lipid lowering are going to be accepted [by patients].

Another question of interest is how this approach will be incorporated into the cholesterol guidelines, which no longer include LDL targets. It’s important to emphasize that in the guidelines, you anticipate with a high-potency statin a 50% reduction in LDL, and if you don’t achieve that, you can add another drug. With the FH patients and others with very high LDL, you may not get 50% reduction with a standard drug.

Part of provider education will involve the PCSK9 mode of action. In contrast to many biologicals with target receptors in many organ systems, PCSK9 receptors appear confined to the liver, likely explaining the apparent lack of significant adverse effects.

Daniel J. Rader, MD

The approved population is the one at highest need and is represented by the [patients] who were studied in the phase 3 program. Many of these patients cannot achieve desirable or optimal LDL levels with maximally tolerated existing therapies and will be greatly helped by PCSK9 inhibition with alirocumab in lowering their LDLs and (very likely) reducing their risk for recurrent [CV] events.

I expect to prescribe [alirocumab] for the patients it was approved for: CAD/vascular patients and familial hypercholesterolemia patients on maximally tolerated treatment with an LDL that is, in my opinion, higher than desirable for that patient.

In the short run, there is great pent-up demand and many of the eligible patients will be quickly prescribed alirocumab, but I don’t think alirocumab being approved first will have any long-term implications for how alirocumab and evolocumab are prescribed.