CRISPR-Driven Treatment Proves “Transformative” for Patients With Sickle Cell Disease, Beta Thalassemia

This article has been updated.

For the patients with beta thalassemia, the blood transfusions have stopped. For those with sickle cell disease (SCD), the painful episodes that landed them in the hospital over and over again have ceased, a change that treating physicians call “transformative.”

Reports of 10 patients treated with therapy using CRISPR gene-editing—the same technology that won the 2020 Nobel Prize in chemistry—headlined Sunday’s plenary session at the 62nd meeting of the American Society of Hematology (ASH).¹ Results also appeared in The New England Journal of Medicine (NEJM).²

The technique calls for targeting BCL11A, which interferes with the production of fetal hemoglobin; if BCL11A could silenced by an infusion of modified CD34+ homeopathic stem and progenitor cells, the patient could produce fetal hemoglobin, and the debilitating conditions of both blood disorders would be held in check.

And so far, as presented by Haydar Frangoul, MD, a pediatric hematologist and medical oncologist of Tristar Medical Group in Nashville, Tennessee, the approach looks like a home run. While the number of patients is still small and the follow-up is comparatively short—the longest duration Frangoul reported is 21.5 months—all signs point to that elusive word: cure.

“For patients with beta thalassemia, they have been transfusion independent, and for patients with sickle cell disease, they have been vaso-occlusive crisis–free,” Frangoul said. Both fetal hemoglobin and total hemoglobin levels rose early after treatment have been maintained, and the safety profile matches that of patients who have received autologous bone marrow transplants.

The news has been anticipated for a year, since the first glimmers of the treatment were reported last year at ASH. One of Frangoul’s patients was profiled on National Public Radio. The FDA has approved disease-modifying therapies for both conditions recently, and transplants are increasingly common. But graft-versus-host disease remains a major challenge, and for older patients, a sibling donor may not be available.

"Allogeneic bone marrow transplantation can cure both [transfusion-dependent β-thalassemia] and SCD, but less than 20% of eligible patients have a related human leukocyte antigen–matched
donor," the authors wrote in NEJM.

CDC estimates that SCD affects 1 out of every 100,000 Americans and occurs in about 1 of every 365 births among Blacks, and 1 of every 16,300 births among Hispanics. The life-changing nature of what Frangoul called a “functional cure” for SCD and beta thalassemia, a related condition, cannot be overstated. A 2019 paper in Hematology found that 64% of adults and 43% of children with SCD had been admitted to the hospital within the past year, with uncontrolled pain being the most common reason. The coronavirus disease 2019 (COVID-19) pandemic has hit patients with SCD hard, with a separate paper at this year’s ASH meeting reporting that even higher shares of patients with SCD and COVID-19 being hospitalized.

A new approach. The treatment presented Sunday at ASH, which is currently named CTX001, is being developed by Vertex Pharmaceuticals and CRISPR Therapeutics; the trials, called CLIMB-THAL-111 and CLIMB-SCD-121, are phase 1/2 single-arm, open-label studies that will enroll 45 patients each, aged 12 to 35 years.

CLIMB-THAL-111 is measuring the share of patients able to achieve a sustained reduction of infusions of at least 50% for at least 6 months, starting 3 months after infusion. CLIMB-SCD-121 is measuring the share of patients with fetal hemoglobin ≥ 20% sustained for at least 3 months, starting 6 months after infusion.

For those with SCD, targeting BCL11A appears “particularly advantageous," according to a separate group of authors from Dana-Farber/Boston Children's Cancer Cancer and Blood Disorders Center, who also published results in NEJM.³ According to those authors, when BCL11A is suppressed, the rise in fetal hemoglobin is accompanied by a drop in sickle hemoglobin; even small changes here have major effects on the process that alters red blood cells, creating the misshapen “sickle” effect that causes these cells to clog blood vessels and restrict oxygen flow.

CLIMB-THAL-111. Frangoul reported on the 7 patients in the beta thalassemia trial. In CLIMB-THAL-111, fetal hemoglobin accounted for about half of total hemoglobin on average by the 2-month mark (5.1 Hb g/dL out of 10.5 Hb g/dL) and had reached 12.1 Hb g/dL fetal hemoglobin out of 12.4 Hb g/dL total hemoglobin by the 12-month mark.

No patient needed a transfusion after the 2-month mark, and the first enrolled patient in the study has not had a transfusion in 22 months, after previously receiving 34 units of red blood cells a year.

CLIMB-SCD-121. Frangoul reported the data on the 3 patients individually; each has seen gradual improvement in fetal hemoglobin levels, with the longest infused patient going from 9% fetal hemoglobin prior to infusion to 43% in 15 months post-infusion.

In both trials, measures of the BCL11A gene editing in patients bone marrow are holding at the 6-month, and for those who have reached the mark, at 12 months.

Adverse events (AEs). Two patients experienced a total of 5 serious AEs related to busulfan, febrile neutropenia, and colitis, which have resolved. Four serious AEs were reported not related to any drug. Seven non-serious AEs were reported. Most AEs emerged within the first 60 days. One long-term consequence is not known: whether women who receive this treatment will be able to become pregnant, given the production of fetal hemoglobin.

Frangoul was asked if the CRISPR technology resulted in an off-target edits; he said this was examined in the NEJM paper and none were found. “We are tracking patients with sequential marrows to evaluate for any long-term genetic abnormalities,” he said. “We have not seen any yet.”

Perhaps the most important outcome was not measured: one questioner asked what it’s been like for patients when a life with chronic illness changes for the better?

Frangoul brightened with the report from a physician who has treated many sickle cell patients. “This has been transformative to their life. It really changed them to the better,” he said. “I cannot tell you how grateful that patients are and how well they feel.”

References

1. Frangoul H, Bobruff Y, Cappellini MD, et al. Safety and efficacy of CTX001 in patients with transfusion-dependent β-thalassemia and sickle cell disease: early results from the CLIMB THAL-111 and CLIMB SCD-121 studies of autologous CRISPR-CAS9–modified CD34+ hematopoietic stem and progenitor cells. Presented at the 62nd American Society of Hematology Annual Meeting and Exposition, Virtual; December 5-8, 2020; Abstract 4.

2. Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-Thalassemia. N Engl J Med. Published online December 5, 2020. DOI: 10.1056/NEJMoa2031054

3. Esrick EB, Lehmann LE, Biffi A. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. Published online December 5, 2020. doi:10.1056/NEJMoa2029392