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FDA approves first new drug for sickle cell in nearly 20 years
A second drug is approved for this rare, serious, and potentially fatal disorder.
CONCORD, N.C. – Approved treatments for sickle cell disease have been extremely limited, but there are several therapies in the research pipeline that use new pathways to target the disease.
“We do have much better understanding of the pathophysiology, which is getting us a few more targets to aim at,” Julie Kanter, MD, director of sickle cell research at the Medical University of South Carolina, Charleston, said at Sickle Cell Disease Symposium held by Carolinas Health Care System. These targets include influencing how cells interact with the vascular endothelium, inhibiting platelets, and preventing cell sickling and inflammation.
Dr. Julie Kanter
“I’m waiting to see who’s willing to take it just because it is a lot of powder that the patient has to mix and drink twice a day, but it does look promising to reduce inflammation,” Dr. Kanter said.
SCD pipeline
Deeper in the sickle cell pipeline is a class of antisickling agents known as hemoglobin modifiers. “We’re tying to change the way hemoglobin binds to oxygen, and if we can keep hemoglobin binding to oxygen longer, it actually decreases the risk of hemoglobin sickling and polymerizing in the cell,” Dr. Kanter explained.
One hemoglobin modifier is voxelotor (previously called GBT440), a once-daily oral agent that Global Blood Therapeutics has in development.
Another category of antisickling agents that researchers are looking at is anti-inflammatory moderators, Dr. Kanter said. These include nitric oxide donors like sildenafil, which did not “quite work” in SCD, and arginine and glutamine, which increase the amount of nitric oxide once in the body “and hopefully reduce the risk of sickling,” she said. “If we can improve inflammation, we might be able to improve the risk of crisis.”
Cell adhesion modifiers are a drug class that aims to prevent cells from binding to each other. These include platelet inhibitors and endothelial blockers. “There are several antiplatelet agents that are approved really for stroke prevention or heart attack prevention, and we’re trying to see if we can repurpose these in sickle cell disease in a specific pathway that allows the platelet to stick to the endothelium, but if we only inhibit one pathway it should not increase the risk of bleeding,” Dr. Kanter said.
One platelet inhibition pathway that researchers are focused on is the P2Y12 adenosine diphosphate blockade, which the platelet inhibitor prasugrel (Effient) acts on. A 2016 study of this pathway in SCD “wasn’t successful,” Dr. Kanter said, “but it had some interesting results” – namely that the drug may be most effective in adolescents (N Engl J Med. 2016 Feb 18;374[7]:625-35).
Selectin-blocking medications are a drug class that act on white blood cell adhesion to, and movement through, the endothelium, Dr. Kanter said. “Neutrophils can instigate a sickle cell crisis, so if we can interrupt some of this rolling or sticking, could we decrease the risk of a sickle cell crisis?” The drug GMI-1070 is currently being studied in a phase III trial and so far has shown “a significant decrease in the amount of opioids used by those individuals who received the study drug,” she said.
Crizanlizumab (also known as SelG1) is a humanized monoclonal antibody with an affinity to P-selectin and is the subject of the phase II SUSTAIN trial, which included a cohort that also was taking hydroxyurea. Treatment with high-dose crizanlizumab resulted in an annual rate of sickle cell–related pain crises that was more than 45% lower than with placebo (N Engl J Med. 2017 Feb 2;376[5]:429-39).
Stem cell transplants
Besides drugs, stem cell transplants to treat SCD have advanced in recent years to the point where cure rates are exceeding 90%, Dr. Kanter noted. “However, the real issue with stem cells is that patients still don’t have enough donors,” she said.
SCD is also potentially amenable to gene therapy, Dr. Kanter said, noting that SCD gene therapy trials in progress are looking at harvesting patients’ own bone marrow, using the lentivirus viral vector, inserting a gene to increase production of nonsickle hemoglobin, and using myeloablative chemotherapy to remove old marrow and replace it with new, manipulated bone marrow.
Several programs are investigating using a gene editing technique, known as CRISPR/Cas9, to alter the BCL11A gene to maintain fetal hemoglobin production.
“We all make fetal hemoglobin at birth, and then over 6 months to 1 year of life, our bodies convert fetal hemoglobin to adult hemoglobin,” she said. “In sickle cell disease, it converts to sickle hemoglobin. What if we could prevent that conversion and keep the fetal hemoglobin turned on?” That could potentially eradicate the complications of SCD starting at an early age, Dr. Kanter said.
Dr. Kanter, who has been involved in several of the SCD trials, reported relationships with Pfizer, AstraZeneca, Bluebird Bio, Global Blood Therapeutics, Novartis, Guidepoint, GLG, ApoPharma, and Purdue Pharma.