Nine months after receiving an infusion of gene-edited stem cells, a patient in a closely followed clinical study is free from the blood transfusions necessary for those who live with severe beta-thalassemia, an inherited disease caused by defective red blood cells.
Another patient has not suffered a painful sickle cell crisis in the four months since receiving the same gene-editing therapy in a separate trial for the related blood condition.
The results, unveiled Tuesday by partners CRISPR Therapeutics and Vertex, offer an initial glimpse at the potential for CRISPR-based gene editing to change the course of hereditary disorders like sickle cell and beta-thalassemia.
"This is a very important landmark, not just for us as a company but for the field," said CRISPR CEO Samarth Kulkarni in an interview.
The two patients are the first to be treated in the companies' Phase 1/2 trials, which are the furthest along among drugmaker-led efforts to translate the breakthrough science into medicines and, possibly, genetic cures.
Only so much can be drawn from their experience, and side effects remain a concern in a field that's advanced rapidly from laboratory and animal testing into humans. Fuller data will also be needed to assess if patients improve over time, and remain transfusion- or crisis-free.
But Vertex and CRISPR Therapeutics report that their therapy, dubbed CTX001, appears to have accomplished what it was designed to do. Both patients achieved levels of hemoglobin — the oxygen-carrying protein rendered dysfunctional by sickle cell disease and beta-thalassemia — that approach what's considered normal, or at least mildly anemic.
Tuesday's disclosure was highly anticipated, both for its implications for gene-editing therapies and as the first clinical update from CRISPR Therapeutics, a Switzerland-headquartered biotech that went public in the U.S. three years ago.
Progress from CRISPR's pipeline also comes as Vertex, which inked a research deal with the smaller drugmaker in 2015, expands beyond the cystic fibrosis research for which it's known. Bets in newer technologies like CRISPR and cell therapy look to play a part in that plan.
CTX001 is built from stem or progenitor cells extracted from each patient scheduled to be treated. Those cells are then genetically modified outside the body using CRISPR-cas9 technology to spur production of a type of hemoglobin that's present at birth but normally replaced shortly thereafter.
Put simpler, CRISPR and Vertex hope to recreate a condition known as hereditary persistence of fetal hemoglobin, substituting the usually short-lived fetal hemoglobin for the mutant beta-globin found in sickle cell and beta-thalassemia patients.
In the first patient with beta-thalassemia, total hemoglobin reached 11.9 grams per deciliter, of which 10.1 was classified as fetal, at nine months post treatment. According to the World Health Organization, mild anemia is classified as over 11 g/dL and normal as over 13 g/dL.
Prior to enrolling in the study, the individual needed more than one blood transfusion per month. After nine months following treatment without a single transfusion, CRISPR and Vertex said the patient is now transfusion independent.
The sickle cell patient, whose medical journey has been chronicled by NPR, achieved 11.3 g/dL of hemogobin — 47% fetal — at four months. While she experienced seven vaso-occlusive crises annually in the two years prior to treatment, the individual has yet to have one of the characteristic pain crises since CTX001 infusion.
"The ratio [between sickling, anti-sickling cells] is what matters in sickle cell to prevent sickle cell formation," said CRISPR's Kulkarni, noting that the study's main goal is the proportion of patients whose levels of fetal hemoglobin surpass 20%.
Both patients experienced serious side effects, albeit ones judged by investigators to be unrelated to treatment.
The first experienced pneumonia in the presence of neutropenia and veno-occlusive liver disease that was linked to the chemotherapy pre-conditioning given before infusion of the gene-edited stem cells. The other reported sepsis occurring alongside neutropenia, gallstones and abdominal pain.
All events resolved, Vertex and CRISPR said.
Both the beta-thalassemia and sickle cell studies began last fall and are each set to enroll as many as 45 patients across sites in the U.S., Canada and Europe.
Enrollment and treatment have proceeded slowly, allowing for the companies to carefully monitor patient safety. The Food and Drug Administration, which previously placed a since-lifted clinical hold on CTX001 in sickle cell disease, has also taken a cautious view of gene-editing therapies.
Once CRISPR and Vertex treat two patients in each study, they anticipate moving more quickly. Further data will be presented at a medical meeting next year, Kulkarni said.
Sickle cell and beta-thalassemia are caused by mutations in the beta-globin gene, leading to the characteristic sickled red blood cells in the former condition and dysfunctional cells in the latter. Anemia, or the resulting insufficient oxygen levels in the blood, can cause organ damage and shorten patients' lifespans.
Both are well understood genetic diseases and now a common target for drugmakers hoping to apply advances in gene replacement and gene editing medicine. Biotech developer Bluebird bio, for example, recently won approval in Europe for the gene therapy Zynteglo to treat transfusion-dependent beta-thalassemia, and it hopes to soon expand into sickle cell as well.
Besides Vertex and CRISPR, other drugmakers are advancing CRISPR-based medicines. Editas Medicine, which licenses its intellectual property from a rival academic camp to CRISPR Therapeutics, plans to treat the first patient in a study of its gene-editing candidate for a rare eye disease early next year. A third company, Intellia Therapeutics, is further behind.
Gene editing efforts in academia are progressing, too. Researchers from the University of Pennsylvania recently reported initial findings from the first attempt in the U.S. to use CRISPR gene editing to treat cancer, while in China scientists have moved quickly ahead with testing CRISPR in humans.