Ten patients with severe forms of the blood disorders sickle cell or beta thalassemia have all seen their condition improve after receiving an experimental treatment that genetically modified their cells, marking the latest step forward for a landmark technology known as CRISPR that won the Nobel Prize in Chemistry this year.
The results, showcased at a virtual meeting of the American Society of Hematology on Saturday, come from two pioneering early-stage trials of a treatment called CTX001 and developed by biotech partners CRISPR Therapeutics and Vertex.
In one study, seven beta thalassemia patients no longer needed blood transfusions for at least three months and as long as 20.5 months post-treatment. Those patients used a median of 15 infusions per year before receiving CTX001, according to a presentation of the results.
In the other trial, three sickle cell patients treated with CTX001 haven't experienced any instances of the excruciating pain episodes known as a vaso-occlusive crisis for at least three months and as long as about 17. Before joining the trial, they had a median of seven per year.
All 10 patients are also now producing "normal to near-normal" total levels of the oxygen-carrying protein hemoglobin, which is either missing or warped in people with severe beta thalassemia or sickle cell disease.
So far, the effects of treatment haven't diminished, the companies said, and results were consistent regardless of each patient's disease severity or underlying genetic characteristics. A report on the first two patients treated was published in the New England Journal of Medicine on Saturday.
"We have great hope that this can be a one-time treatment that's curative for life," said CRISPR Therapeutics CEO Sam Kulkarni, in an interview.
For many of the patients, results are still early, with follow-up for only three to six months. Whether the positive effects will wear off in some is uncertain, although the companies presented data to suggest benefit will be long-lasting.
Study participants will also continue to be watched for any safety problems. CRISPR and Vertex did report one serious side effect possibly related to CTX001, a case of a potentially life-threatening immune reaction known as hemophagocytic lymphohistiocytosis, which appeared associated with several other side effects.
The condition, which can occur following bone marrow transplants, resolved and Kulkarni said the patient is "doing fine."
"I would expect that it's unlikely that we see that [moving forward] or that it's related to the therapy," he contended. Most other adverse events were deemed mild to moderate and related to the chemotherapy regimen needed to prepare patients for treatment.
While CRISPR Therapeutics and Vertex are reporting data on 10 patients at ASH, nine others have now been treated with CTX001. The partner companies aim to seek approval once they've treated enough patients in the two ongoing studies, according to Kulkarni. The exact number needed to satisfy regulators is still being determined, but "we could make a strong case that we don't need a large number of patients" given the degree of benefit observed so far, he added.
Typically, new drugs require testing in hundreds or thousands of patients across several phases of study. With gene editing and gene therapy, however, the "effect size" of treatment can be quite large, and the biological rationale of treatment particularly clear, meaning companies can make a convincing case to regulators with far few patients treated.
The two gene therapies approved to date in the U.S., for example, were cleared following study in 41 and 36 patients, respectively.
Both of those treatments, called Luxturna and Zolgensma, use a different technology than CTX001, replacing rather than editing genes. The Food and Drug Administration hasn't yet specifically outlined the approval requirements for a CRISPR-based medicine, meaning CRISPR Therapeutics and Vertex are forging the path forward as they go.
CRISPR gene editing involves a two-part biological system that can delete or later DNA sequences with a precise cut. Its potential use as a medicine, diagnostic and drug discovery tool is enormous, and has led to the creation of a wave of new biotech companies. CRISPR Therapeutics, Editas Medicine and Intellia Therapeutics, for example, were each formed to advance CRISPR-based therapies.
In October, CRISPR Therapeutics co-founder Emmanuelle Charpentier and Intellia co-founder Jennifer Doudna were awarded a Nobel Prize for their work developing the gene editing method.
All three companies now have CRISPR-based therapies in human testing, but CTX001 is the first to produce results in a clinical trial.
Both beta thalassemia and sickle cell are caused by mutations in a gene that encodes for beta-globin, a protein that forms part of adult hemoglobin. With the gene damaged, individuals with either disease can't produce healthy hemoglobin, leading to anemia and a host of other health problems.
Many beta thalassemia patients depend on chronic blood transfusions, for example, but there are complications associated with that treatment, too. Sickle cell patients, meanwhile, have crescent-shaped blood cells that get lodged in blood vessels, triggering painful episodes that can require hospitalization.
The aim of CTX001 is to help patients make enough hemoglobin to free them from blood transfusions and pain crises. CTX001 consists of stem cells collected from a patient's bone marrow, which are then altered using CRISPR to encourage production of a form of hemoglobin that's present at birth but fades with age. The cells are then infused back into the body, where they take hold in the bone marrow and, in theory, churn out enough so-called fetal hemoglobin to change the course of the disease.
So far, that appears to be the case. Patients in both groups are producing meaningful levels of fetal hemoglobin, even in those individuals with genetic make-ups that make their disease more severe.
One patient with very severe beta thalassemia, for example, was producing 11.5 g/dL of hemoglobin — within the range of normal — as of a four-month follow-up evaluation conducted recently, said study investigator Haydar Frangoul, medical director of pediatric hematology and oncology at Sarah Cannon Research Institute, in a presentation.
CRISPR Therapeutics and Vertex's findings could put pressure on Bluebird bio, which won European approval for its gene therapy Zynteglo in beta thalassemia, but has hit multiple delays in the U.S. Bluebird's gene therapies have shown promise for both diseases, although the company has had to fine tune its approach in sickle cell. In beta thalassemia, Bluebird has the most data in patients with a less severe form.
The results also appear more varied from patient to patient. CRISPR Therapeutics and Vertex hope that gene editing may be more predictable and durable than gene replacement, but that hasn't been proven.
"I think gene editing will be looked at as a different class of medicines by regulators and by investigators," Kulkarni said.
Ned Pagliarulo contributed reporting.