New Therapeutics in the Management of Sickle Cell Disease Are Providing Much Needed Additional Options for Patients

Pharmacy Times® interviewed Marilyn N. Bulloch, PharmD, BCPS, FCCM, SPP, on her presentation at the APhA 2023 Annual Meeting & Exposition titled “Taking the Sick Out of Sickle Cell Disease.”

Pharmacy Times: What are some of the new therapeutics that have become available for sickle cell disease in recent years?

Marilyn N. Bulloch, PharmD, BCPS, FCCM, SPP: We've had 3 new drugs come out. All of them have unique mechanisms. L glutamine [EnDari; Emmaus Medical] was the first to come out. It came out in 2017, and it's a powder. The nice thing about this is it can be given to kids as young as 5. Now, it’s exact mechanism isn’t well known. It may decrease the oxidative damage of sickled red blood cells by improving something called NAD, which is a common Redux cofactor. And in studies, it seems to improve hemoglobin, decrease pain crises, and decrease hospitalizations.

The other 2 both came out in 2019. So, the first was crizanlizumab [Adakveo; Novartis]. This is an IV monoclonal antibody that binds to P-Selectin, and it can be used in people over the age of 16. Now, this P-Selectin is on the surface of activated platelets and endothelial cells in the blood vessels. And by blocking it, the drug decreases the adhesion of the sickle cells, the platelets, and neutrophils. Now, this is, as I mentioned before, an IV infusion that's ultimately given about once a month, and it seems to decrease those pain crises, especially in people who have 5 to 10 or even more pain crises a year. And it also seems to be really effective in people who are already on hydroxyurea.

The newest kid on the block is voxelotor [Oxbryta; Pfizer]. This is approved for those aged 12 and older, and its big claim to fame is that it's the first hemoglobin oxygen affinity modulator. It has disease modifying, I want to say, potential by increasing hemoglobin levels and decreasing hemolysis. And by decreasing or inhibiting the polymerization of Hemoglobin S, it's supposed to prevent these vaso-occlusive or pain crises. In studies, it appears to improve hemoglobin and reduce hospitalizations, but the data only sort of suggests that it decreases vaso-occlusive crisis. It's not as definitive as with our other 2 options, and we really need more data.

Pharmacy Times: How have the availability of these new therapeutics impacted the management of sickle cell disease?

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Bulloch: The biggest thing that they do is they provide us new options for people who are not responding to hydroxyurea. I think that's the really important point. Our patients, at least in my area, are almost always still initiated on hydroxyurea first, but there is a small set of patients who just can't tolerate it because hydroxyurea decreases neutrophils and platelets, and their values just get too low. We also have a small group who their platelets and their neutrophils are fine, but they have so much nausea with hydroxyurea, that they can't and won’t take it. So, these are new options to help those patients.

There's another group that they can take hydroxyurea and they take it well—the way they're supposed to—it just isn't working for them, and they need an add-on therapy. And we haven't really had many add-on therapies before we had blood transfusions, stem cell transplants. These are the first new medication options we have to offer those patients.

Pharmacy Times: What are your recommendations for determining the ideal candidate for these new therapeutic options available?

Bulloch: I think the most important thing to remember is that all 3 drugs, in their studies, allowed patients taking stable doses of hydroxyurea to be enrolled, but we don't have any major studies indicating that any of these drugs are necessarily better than hydroxyurea. When taken correctly, hydroxyurea is a really effective drug. It decreases pain crises, hospitalizations. We know it helps mitigate or even prevent some of those sickle cell complications. It reduces blood transfusions. It’s even been shown to improve quality of life. So, this should be our go-to, first-line drug. I really don't see any other options taking the place of hydroxyurea as first-line for the average patient. But that's not to say they don't have a role.

All 3 of the drugs could be used as a second-line option when patients are not responding to hydroxyurea. I would say crizanlizumab is probably the better option for patients who were just experiencing a lot of pain crisis. Remember, in studies, it was very effective in those people who were experiencing 5 to 10 pain crises a year, though it could probably be extrapolated that if you were experiencing more than that, it would still work for you. Voxelotor and l glutamine could also be used in place of hydroxyurea and patients who can't tolerate it. We talked about that just a minute ago. I would say l glutamine seems to be the better choice, maybe, for patients with several pain crises per year, and may help with decreasing blood transfusions. That could be its role. The big difference so far between those 2 agents is that voxelotor has not been shown to decrease blood transfusions. But it does have sort of a unique benefit that l glutamine and crizanlizumab don’t have. Voxelotor does seem to maybe help heal leg ulcers that are known to occur in patients with sickle cell. So, if you had one of these patients who did seem to be more prone to these ulcers, this might be a good option for them.

Pharmacy Times: What is an example of an appropriate treatment plan for the management of vaso-occlusive crises?

Bulloch: We see patients admitted to our team in the hospital for pain from vaso-occlusive crisis regularly. I mean, we had some this week, for example. And many of the triggers for these pain crises are especially prominent this time of year: things like cold or windy weather—I mean, it's winter still in many places—higher air pressure, and infections. It is sort of that time of year where people are close together so infection tends to spread easily. All of those things can trigger a pain crisis. So can dehydration. I would say typically this, in the winter months, it's more associated with infection. People just don't feel good. They don't drink until they become dehydrated. Obviously, that becomes a different issue in the summer when it's hot and people aren't drinking enough. That can occur then, too.

I would say a big thing you want to keep in mind is that these patients are not opioid naïve. Pain crises in sickle cell began in infancy. And the first-line therapy is always going to be opioids. And chronically, some of these patients may never be pain-free, which I know is not what we’re used to in many of our other pain patients. So, the goal in crises is not to get them to be pain free, it’s to get them back to their baselines. And as I mentioned before, we're going to start with opioids in all settings, whether it's outpatient and you were trying to manage them at home, or we brought them into the hospital. But you can use acetaminophen or NSAIDs as good adjuvants. Now, you don't really want to use them alone, in most patients they’re not going to be effective enough, but they can be very good adjuvants to your opioids. And the patients are going to report that they have 10-out-of-10 pain, especially at the beginning of a crisis. You want to believe them. This is a legitimate type of pain. That sickling of the red blood cells, it hurts when it starts to stick to the blood vessels. So, you want to start, especially if they end up in the hospital, with an IV medication and then transition them back to their home regimen as the pain subsides.

And I'll tell you one thing that I've learned over the years, that is that some patients have enough pain crises that they know what works for them. And I think sometimes pharmacists or members of the healthcare team sort of get suspicious when patients come in and say, this is what works for me. But sickle cell patients are a little bit different. They legitimately have pain. They've gone through this enough—sometimes many, many episodes a year. They do know what works for them. And I have found it's just easier to make them part of the plan. In fact, a lot of patients are now starting to come in with documents from their outpatient sickle cell physician that actually has instructions on how to manage these vaso-occlusive crises. And following those care plans can actually get the patient back to their baseline quicker. They know what works for them, and I think that that's a new concept that we haven't necessarily thought of in the past, but it's been very helpful.