Role of Crizanlizumab and Voxelotor in SCD
EP: 1.Sickle Cell Disease QoL and Life Expectancy
EP: 2.Sickle Cell Disease Prevalence and Pathophysiology
EP: 3.Complications of Sickle Cell Disease
EP: 4.How COVID-19 Has Impacted Patients With SCD
EP: 5.Mechanism of Action of Hydroxyurea
EP: 6.The Role of L-Glutamine in Treating SCD
EP: 7.Indications and Adverse Effects of Blood Transfusions
EP: 8.Patients Considered for HSCT
EP: 9.Role of Crizanlizumab and Voxelotor in SCD
EP: 10.Gene Therapy Strategies for Sickle Cell Disease
EP: 11.Promising Developments for Gene Therapy
EP: 12.Importance of Communication Between Patients and Physicians
EP: 13.Gene Therapy Toxicities and Management
EP: 14.The Cost of Gene Therapy Versus Alternatives
EP: 15.Potential for Cure with Gene Therapy and Final Thoughts
Biree Andemariam, MD: 2019 was a big year. Julie, discuss the recently approved crizanlizumab and its ability to reduce painful crisis frequency in adults with sickle cell disease.
Julie Kanter, MD: Crizanlizumab is an IgG P-selectin inhibitor. That means it targets P-selectin, which is like a hook on the inside of the blood vessel and on platelets that actually make the platelets, the white cells, and even the sickle cells stick to the inside of the blood vessel. By inhibiting that, first in mice and then in humans, you could significantly decrease vaso-occlusion. The sustained study showed us that the use of 5 mg/kg of crizanlizumab could decrease crises by 43% and increase the time to first crisis by 4 months. That’s 4 times the amount compared with placebo, so we have really amazing outcomes.
There were a few adverse events. We saw a slight increase in headaches and some muscular and joint pain. Some of that joint pain was during infusion but seemed to be mitigated by slowing down the infusion or using Benadryl. We’re using clinical practice, and we’re pretty excited.
Biree Andemariam, MD: It’s an infusion, which is different from everything we’ve talked about so far. Has anybody seen problems getting crizanlizumab into patients? We all know that a lot of patients can have trouble with IV [intravenous] access.
Julie Kanter, MD: We’ve had great success. We have about 50 patients getting the drug here at UAB [the University of Alabama at Birmingham], and we’ve had people really excited about it. Some people who are already on hydroxyurea didn’t want another pill. Some patients don’t want to take any more medicines but are willing to do an infusion every month. We haven’t really seen an increase except for a couple of patients needing ports. Otherwise, we’ve been able to do IV access.
Biree Andemariam, MD: Elliott, what is the mechanism of voxelotor, which was also approved in 2019 for individuals with sickle cell disease?
Elliott Vichinsky, MD: I’m 1 of the investigators with this drug. What excited me about this drug initially is particularly that pain wasn’t the primary aim of the FDA approval. Pain is a good binary thing to determine sickle cell, but a large percentage of organ failure and progression injury occurs in sickle cell patients with low pain rates.
Ideally, we need to look at drugs that change the biology of sickling. While pain is a good measurement of some things, it’s not a measurement of other things. I think this is the first time the FDA approved the drug for a different indication, which was to raise the hemoglobin of healthy cells.
The primary indication was to correct the anemia in sickle cell disease. There has been 40 years of work to try to do that with a drug like this, from urea to cyanate and others. The basic concept is that if you can change the oxygen affinity within the cell and more oxygen is held in a cell, then the cell will be less likely to sickle and these rods won’t be formed. We know that hemoglobin F increases the oxygen affinity. That’s why the fetus gets oxygen off the mother’s red cells. We know that there are other kind of drugs that tried to do that, but they could not do that at a therapeutic level.
Trials were undertaken with this drug after much work and previous work by looking at HMF [hydroxymethylfurfural]. The drug was found, first in vitro, to remarkably improve the red cell rheology of the cell and the rate of polymerization. It had secondary adverse effects, such as membrane deformability and red cell survival. As the clinical trials started in phase 2 and 3, they did demonstrate a remarkable improvement in the hemoglobin. It was associated not with an erythropoietin drive but actually a decrease in hemolysis. LDH [lactate dehydrogenase], bilirubin, erythropoietin levels, and other markers went down, which were related to hemolysis—which in itself is problematic. The study was reported at the 24-week period and showed a rather significant improvement in the hemoglobin, and then at 72 weeks. The bottom line is that the drug can effectively elevate the hemoglobin.
The overall group largely had a hemoglobin increase of greater than 1 g/dL. The majority of patients were reaching a hemoglobin of 10 g/dL. I was always worried that if the hemoglobin went up too high, they would have increased pain. However, the recent data in a post hoc analysis showed that the higher the hemoglobin, the lower the pain rates. To me, that seemed to be because the cells were making healthy cells. That also correlated with the amount of drug availability. In essence, there were patients with hemoglobin at 12 or 13 g/dL who had the lowest pain rate.
I see this as a drug that may slow down end-organ disease. Hopefully, we’ll be able to show benefit in improving oxygenation of tissues beyond. I do believe it will improve quality of life, in the sense of energy and cognitive function, and it may have some benefit in decreasing pain. There it is already shown, but it adds to our armamentarium. So far, it’s a very safe drug. There’s been no evidence of any problems with oxygen delivery. We’re going to learn a lot more about the drug, and it should be considered in anemic patients who need to have a higher hemoglobin. It would be very helpful.
Biree Andemariam, MD: Michael, we have 2 new drugs that have been out since 2019 that are potentially disease modifying. How do you anticipate that individuals are or will be using crizanlizumab and voxelotor either singly or in combination with or without hydroxyurea? There are a lot of questions.
Michael DeBaun, MD, MPH: There are a tremendous number of questions. This is where the federal government leadership from the NIH [National Institutes of Health] and the NHLBI [National Heart, Lung, and Blood Institute] should step up. Right now, the hematologist, regardless of whether they’re providing medical care for children and adults with sickle cell disease, are in a quandary. We all believe that hydroxyurea should be a mainstay for hemoglobin SS or sickle beta-0 thalassemia. But then after you start with that drug, you have 3 other FDA-approved drugs that can be added to the treatment regimen. What’s the right combination, and what’s the indication to initiate the right combination?
As we have seen in antihypertensive therapy, and as we have seen in treatment for cystic fibrosis and cancer, rarely do you have a disease without some level of control trial looking at multimodal therapy to address optimal benefit and minimize the risk. I see this as a window of opportunity for NHLBI leadership to work with the 3 companies that recently had FDA-approved drugs, plus hydroxyurea, to design a trial that will answer these questions: What is the optimal approach for the management of this patient population? For which indications would we prefer to use combination A vs combination B?
Biree Andemariam, MD: There are lots of questions, and we need grant funding on a large scale to help us answer these questions.
Transcript Edited for Clarity
