Matthew M. Heeney, MD, reviews the mechanism of action and the safety and efficacy data of FDA-approved therapies for the management of sickle cell disease.
Biree Andemariam, MD: Matt, very briefly, give us an overview of the drugs Nirmish was just alluding to: hydroxyurea, l-glutamine, crizanlizumab, and voxelotor. Those are the drugs we have that are FDA approved. What are their mechanisms of action? What are their therapeutic targets? What do we know about efficacy and safety? Give us a quick overview of where they are.
Matthew M. Heeney, MD: Hydroxyurea is a repurposed medication that was noted to increase fetal hemoglobin in patients initially without sickle cell disease but then with sickle cell disease. We know from epidemiologic studies that higher fetal hemoglobin leads to better overall outcomes, including survival. This was an attempt to induce fetal hemoglobin, and it does so quite effectively, particularly in children when started early but also in adults. It has been shown over the previous 40 years to improve overall mortality. It’s the backbone of our care and the mainstay of our care.
The other major potential benefit of hydroxyurea is that it’s myelosuppressive. Patients with sickle cell disease who have the highest white blood cell counts tend to do the worst. If we can suppress their white blood cell count by increasing the dose to a maximally tolerated dose, to induce a mild myelosuppression, this could also provide a secondary benefit to the drug. There are other theoretical benefits with hydroxyurea, but those 2 are the main ones: the induction of fetal hemoglobin and the reduction of neutrophils and white blood cells.
L-glutamine is very attractive in some respects because it’s clearly nontoxic. This is a food additive or an amino acid supplement that’s used in a number of foodstuffs. But it also has potential antioxidant capabilities and has been shown in a clinical trial to reduce complications of sickle cell disease, particularly vaso-occlusive crises and acute chest syndrome. It requires 2 large glasses of fluid a day to mix this powder with it. Some patients have found that challenging, but it’s a potential intervention that some may find helpful.
Crizanlizumab is a humanized monoclonal antibody targeting P-selectin, which is an intercellular adhesion molecule found on a number of blood cells and vascular endothelial cells and its binding partner P-selectin ligand. This is an attempt to interfere with some of the cell-cell interactions, which are increased in the vaso-occlusive event. The activated endothelial cells will bind white blood cells more avidly, white blood cells will bind sickled red blood cells, and platelets also have P-selectin ligand on their surface. This is a potential way of decreasing the stickiness of all the cellular components that are potentially involved in vaso-occlusion. Their pivotal phase 2 clinical trial showed a reduction in vaso-occlusive … events when crizanlizumab was prescribed preventively. They reduced them by almost half.
Finally, voxelotor is a small molecule that was engineered as an allosteric modifier of hemoglobin. In doing so, it changes the shape of the sickle hemoglobin to increase its oxygen affinity. This is an attempt to increase hemoglobin in patients with sickle cell disease. In a pivotal trial, two-thirds of patients who took the drug had an increase of 1 g/dL in their hemoglobin. The FDA approved it as a surrogate marker for overall mortality, given that epidemiologic studies have shown that higher hemoglobin and sickle hemoglobin will result in improved mortality. Those are the 4 FDA-approved medications. They may have slightly different indications. Most of us would agree that the backbone of this is hydroxyurea and potentially other medications, depending on the exact phenotype of the patient.
Transcript Edited for Clarity