Advances in the Treatment of Sickle Cell Anemia - Episode 11
Ify Osunkwo, MD, MPH: That segues into the next section where we’re talking about recently approved treatment for sickle cell disease. We are in a good place this year. We’ve had 2 drugs approved by the FDA for sickle cell disease, and we’re very excited about that. The first one is crizanlizumab and the second one is voxelotor. I want to start with Matt first and then Julie chiming in. There’s a lot of buzz during the ASH [American Society of Hematology] symposium in 2019 about the results of the studies that led to the approval of crizanlizumab. First starting with Julie, tell us what crizanlizumab is, how it works. Then I’ll have Matt talk about some of the abstracts that are going to be presented at ASH.
Julie Kanter, MD: First you have to learn to say crizanlizumab.
Ify Osunkwo, MD, MPH: Ten times backwards.
Julie Kanter, MD: Crizanlizumab is also known as Adakveo, now that it’s FDA approved. Adakveo is a P-selectin inhibitor. Selectins are actually all through the blood vessels and on several other cell types like platelets and white cells, specifically leukocytes. What they do is act as hooks or sticky proteins that attach cells to the inside of the blood vessel. Of course, when you’re bleeding you want those cells to stick so that you can stop bleeding. The specific one that this drug targets is called P-selectin. It’s on both platelets as well as on the inside of the endothelium, or the inside of the blood vessel. By decreasing the stickiness or blocking that P-selectin, it allows the blood to flow more easily, so that even if the cell is sickled it can still flow without occluding or stopping that blood flow.
Ify Osunkwo, MD, MPH: Kind of like greasing a tube, like Jiffy Lube.
Julie Kanter, MD: Exactly. It helps the blood flow and prevents the blood from sticking. That’s how it works, and what we’ve seen over time in many different places, is in sickle mice with P-selectin, if you inhibited the P-selectin, they didn’t have any vaso-occlusive events. They developed this medication and tested it initially in the SUSTAIN study. It was published a few years ago and presented at ASH 2018. In the SUSTAIN study, it was a randomized double-blind placebo-controlled study in which individuals were randomized to receive either a higher dose or a lower dose of crizanlizumab or placebo. We found that in the higher dose group, crisis was reduced by almost 50%, 47%, so fairly dramatic.
Ify Osunkwo, MD, MPH: That’s amazing.
Julie Kanter, MD: In some more recent studies where we looked at the PK [pharmacokinetics] and PD [pharmacodynamics], we looked how well the drug lasts in the body. We were able to see great successes, which led to the approval.
Ify Osunkwo, MD, MPH: It’s not just in SS [hemoglobin genotype] patients, it’s not just in S-beta zero thalassemia patients, it was effective in all genotypes.
Julie Kanter, MD: It was the first study that’s been approved for all genotypes and for ages 16 and up. It was effective across the board as to not just in different genotypes, but if patients were already on hydroxyurea and they still had breakthrough pain crisis, it still reduced that pain. We saw a 30% decrease even in patients already on hydroxyurea.
Ify Osunkwo, MD, MPH: Matt, can you talk about the safety profile of this new drug, Adakveo, for sickle cell disease? What have we noticed in terms of specific organs and how it has either helped or not helped specific complications of sickle cell disease?
Matthew Heeney, MD: Presenting abstracts here at ASH are quite interesting. They’re trying to build on some of the outcomes from the SUSTAIN trial where they show a reduction in vaso-occlusive crises. One of the abstracts here is actually looking at the decreased rate of hospitalization. It wasn’t statistically significant, however it was certainly favorable in terms of reducing hospitalizations themselves. The safety profile, also a group abstract here looking at not only the SUSTAIN data but a subsequent open-label trial in adults looking at a slightly different formulation of the monoclonal antibody. This seemed to mimic the overall generally good safety and low rate of adverse events in patients. It’s like many biologics. It’s quite well tolerated from that point of view and is administered like many biologics, monthly.
In terms of other trials, the sponsors have come now to look at potentially specific organs. One of the abstracts here is looking at priapism. Priapism is one of the complications in sickle cell that does not have very good therapeutic options, and so it’s exciting that this is potentially a new therapeutic intervention for that complication. They’re also looking at the chronic renal failure or the progression of renal disease, which is a well-known early indicator of morbidity and mortality in adults. It’s exciting to see them not only moving from vaso-occlusive events, but also into these chronic organ damage or complications that don’t typically have good therapeutic options.
Ify Osunkwo, MD, MPH: Because patients actually die from renal failure. There’s significant morbidity from having priapism and erectile dysfunction. Can you speak about the SPARTAN study, and specifically there was a study looking at priapism. What are the inclusion criteria? What are they looking for? We really want to let the community know that if you have patients with sickle cell disease who have recurrent episodes of priapism, there is a study open to try to see if this medicine will help reduce their priapic events.
Matthew Heeney, MD: Obviously you must be a boy, or a male. Anybody with post-pubertal age who’s had an incidence of priapism. The trial itself is broken up into a prescreening, screening, treatment phase, and then post-treatment phase. During the pre-screening phase, it’s almost a 4-month period, the patient has to have had 4 priapism episodes. If they graduate from that into the screening episodes, for 3 months they have to have at least 3 episodes of priapism during that screening. Then they go into a year’s worth of therapy if they make it through those hurdles and then a post-treatment phase. These are patients who clearly have to have priapism on average at least once a month to be able to qualify during that pre-screening and screening phase.
Ify Osunkwo, MD, MPH: We thought that we were not going to find that many patients, but when we began to look at our practice, easily we found 10 patients who, oh wow, we’re just not asking the right questions, kind of speaking to what you were saying. If you ask, you’re going to find out the information.
Transcript edited for clarity.