A company announcement of the first readout from a CRISPR–Cas9 therapy clinical trial suggests potentially curative responses in two patients with transfusion-dependent β-thalassemia and sickle cell disease, respectively.
The phase 1/2 results were made public on November 19 by CRISPR Therapeutics, located in Zug, Switzerland, and Vertex Pharmaceuticals. “It’s a magnificent moment for the field,” says Fyodor Urnov, a scientific director at the Innovative Genomics Institute at the University of California, Berkeley. Given the prevalence of β-thalassemia and sickle cell disease, it highlights the potential impact on public health for CRISPR technology, he adds.
Both patients were treated with CTX001, which entails harvesting their hematopoietic stem cells, engineering them ex vivo with CRISPR–Cas9 to boost the production of fetal hemoglobin, and then re-infusing the engineered cells. The CRISPR edit creates as deletion in BCL11A, which encodes a transcription factor that otherwise represses fetal hemoglobin synthesis. According to the companies’ release, CTX001 rendered the patient with β-thalassemia (who previously needed 16.5 transfusions a year) transfusion-free at 9 months after infusion, and the patient with sickle cell disease (who previously experienced 7 vaso-occlusive events a year) remained free of vaso-occlusive crises four months after infusion. Two serious adverse events occurred during treatment, a case of pneumonia and a liver complication related to the bisulfan conditioning treatment, but they were investigated and deemed unrelated to the CTX001 infusion.
Christopher Mason of the Department of Physiology and Biophysics at Weill Cornell Medicine, who has been tracking clinical trials using gene-editing therapy, says most CRISPR–Cas9-related trials are going after immuno-oncology applications (via chimeric antigen receptor (CAR)-T cell therapies). In this respect, Vertex’s pursuit of hemoglobinopathies with somatic CRISPR therapy is an outlier. Early results hold promise: in the patient with sickle cell disease, the total hemoglobin levels rose to 11.3 g dL–1 and fetal hemoglobin (HbF) level reached 46.6%; in the patient with β-thalassemia, total hemoglobin levels reached 11.9 g dL–1 and HbF was 10.1 g dL–1 — in both patients, well over the marks needed to show efficacy. These results have not as yet been published in a peer-reviewed journal.
Hemoglobinopathies, which include sickle cell disease and β-thalassemias, are inherited monogenic blood disorders caused by mutations in the β-globin gene, which produces one of the subunits of hemoglobin. The sickle cell mutation results in deformed red blood cells, which can obstruct small vessels, cause organ injury and pain crises. Companies are working to develop agents to both ease the symptoms and target — or even reverse — the disease-causing pathways.
CTX001 tackles the disease by boosting the production of HbF, a type of hemoglobin that is present at birth and is then replaced by the adult form. The approach, says Samarth Kulkarni, CEO of CRISPR Therapeutics, derived from the observation that individuals from several families with the β-thalassemia or sickle cell disease genotype remain asymptomatic because they have mutations that allow them to produce HbF even as adults. Urnov says CTX001 uses a similar strategy to one he developed as a team leader at Sangamo, which also targets BCL11A. Rather than CRISPR–Cas9, however, Sangamo uses zinc finger nuclease (ZFN) technology for gene editing of autologous hematopoietic stem cells. The latter company announced positive early data from a phase 1/2 trial of its therapy, ST-400, in β-thalassemia in April—but unlike in the CTX001 trial, the patients were not transfusion independent after treatment.
Both approaches to editing BCL11A “take the power off the brakes,” says Kulkarni, to allow the natural production of HbF. In β-thalassemia, Kulkarni adds the company had hoped to push total hemoglobin levels over 10 g dL–1 to allow sufficient oxygen transport, and at nine months after infusion, the patient with β-thalassemia had 10.1 g dL–1 of HbF and 11.9 g dL–1 of overall hemoglobin. Marina Cavazzana, a hematologist at the Necker Children’s Hospital and INSERM, Paris, France, calls the results “incredible” but says “if you’re thinking about possible secondary complications due to the CRIPSR–Cas9 procedures, probably we have to wait longer for follow-up.”
The limited release of data by CRISPR Therapeutics leaves a few important questions unanswered, according to Stefano Rivella, a pediatrician at the Children’s Hospital of Philadelphia. For one, it’s unclear whether more patients have so far been treated than the ones for whom data were released. If so, says Rivella, it may be because more time was needed to clarify the durability of the treatments.
A spokesperson for CRISPR Therapeutics says the companies are not planning to provide details on patient enrollment at each stage of the process, but that the trial has progressed and more patients have enrolled.
So far, Rivella remains unconvinced that the elevated HbF levels are solely from the treatment, as HbF levels often rise following bone marrow transplant. Because data for only a single patient with β-thalassemia were disclosed, Rivella says it’s unclear whether the therapy will be an optimal approach for different disease forms. In severe cases of β-thalassemia, where the body produces no normal adult hemoglobin, as with the patient in this trial, a gene replacement approach like CTX001 may prove to be one of the best, if the levels seen in this early readout prove stable over time. But in milder forms of the disease, where the body does produce some normal adult hemoglobin, a gene replacement could turn out to be less effective than a gene addition approach, which adds functional copies of a gene. “You’re not taking advantage of the hemoglobin made by the patient, like in non-beta 0 patients.”
Kulkarni says further data from the phase 1/2 trials will be made available at an undisclosed conference in 2020. In the meantime, enrollment continues in both the phase 1/2 CLIMB-Thal-111 β-thalassemia trial and the phase 1/2 CLIMB-SCD-121 sickle cell trial, which will follow up to 45 patients each for two years after infusion.
Beyond the encouraging outcome with CRISPR therapies, the outlook for patients with sickle-cell disease looks brighter, with different therapeutic options erupting onto the market. Within a week, the US Food and Drug Administration approved two new drugs. On November 15, Adakveo (crizanlizumab-tmca), a humanized IgG2-κ monoclonal antibody from Novartis, was given a green light. The antibody drug prevents vaso-occlusive crises by binding P-selectin, an adhesion molecule on blood vessel walls. The other US approval, on November 26, was for Oxbryta (voxelotor) from Global Blood Therapeutics. This once-daily pill addresses the root cause of the disease by retarding the hemoglobin polymerization that leads to misshapen erythrocytes, thereby preventing painful vaso-occlusive blockages that result. In June, the European Commission granted Bluebird Bio an approval for the potentially curative treatment Zynteglo, autologous CD34+ cells encoding the β-T87Q-globin gene, the first gene therapy approved for β-thalassemia.
Even if CTX001 does prove curative, it is still vital to explore other approaches, says Rivella, because gene editing won’t be the best option for all patients. CTX001 requires myoablative chemotherapy before infusion to prepare a niche in the bone marrow, and this carries its own set of risks, including infertility. Some patients will likely decide to take a drug first “and see if these companies come out with an additional approach that will prevent the loss of fertility.”
“I think there is room for any new approaches,” says Maria Domenica Cappellini, a clinician at the University of Milan and the Maggiore Policlinico Hospital, Milan. “We are starting to try to understand which kinds of patients will benefit from one treatment or the other.”
Costs will likely define the different agents’ accessibility and market uptake.