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Data revealed on novel CRISPR/Cas9 gene-editing therapy for first two severe haemoglobinopathy patients

pharmafile | November 19, 2019 | News story | Manufacturing and Production, Research and Development | Vertex, crispr, pharma

Vertex and CRISPR Therapeutics have unveiled the first interim Phase 1/2 data demonstrating the safety and efficacy of the investigational CRISPR/Cas9 gene-editing therapy CTX001. The data concerns the treatment of the first two patients with severe haemoglobinopathies.

The first patient, who has transfusion-dependent beta thalassemia (TDT), received transfusion in the first quarter of this year, generating nine months of follow-up data on the therapy. The individual has the β0/IVS-I-110 genotype and required an annualised rate of 16.5 transfusions per year.

The findings revealed that the patient achieved neutrophil engraftment within 33 days of transfusion and platelet engraftment within 37 days. During examination, two serious adverse events were recorded: pneumonia in the presence of neutropenia and veno-occlusive liver disease attributed to busulfan conditioning. Both conditions were ultimately resolved, and neither was considered to be related to the CTX001 therapy according to the principal investigator.

By the end of the nine months, the patient was transfusion independent, and their total haemoglobin levels were recorded as 11.9g/dL and 10.1g/dL foetal haemoglobin, with 99.8% F-cells (erythrocytes expressing foetal haemoglobin)

The second patient, who has severe sickle cell disease (SCD), received transfusion in mid-2019, providing four months of follow-up data. They experienced a total of seven vaso-occlusive crises (VOCs) per year before enrolment

The patient was shown to achieve neutrophil and platelet engraftment within 30 days of transfusion. Three serious adverse events occurred: sepsis in the presence of neutropenia, cholelithiasis, and abdominal pain. Again, all three were resolved, and none were linked to the transfusion. At the end of the four months of recorded data, the patient was free of VOCs with haemoglobin levels of 11.3g/dL, 46.6% foetal haemoglobin, and 94.7% F-cells.

Both studies aim to enrol up to 45 participants between 18 and 35 at six sites across Europe, the US and Canada in TDT and SCD, and will be continued until two years of data have been harvested.

“We are very encouraged by these preliminary data, the first such data to be reported for patients with beta thalassemia and sickle cell disease treated with our CRISPR/Cas9 edited autologous hematopoietic stem cell candidate, CTX001,” explained Dr Samarth Kulkarni, Chief Executive Officer of CRISPR Therapeutics. “These data support our belief in the potential of our therapies to have meaningful benefit for patients following a one-time intervention. We continue to enrol these studies as we drive forward to develop CRISPR/Cas9 therapies as a new class of transformative medicines to treat serious diseases.”

Dr Jeffrey Leiden, Chairman, President and Chief Executive Officer of Vertex, also commented: “The data we announced today are remarkable and demonstrate that CTX001 has the potential to be a curative CRISPR/Cas9-based gene-editing therapy for people with sickle cell disease and beta thalassemia. While the data are exciting, we are still in the early phase of this clinical programme. We look forward to continuing to work with physicians, patients, caregivers and families over the coming months and years to bring forward the best possible therapy for these two serious diseases and to continue to accelerate our gene-editing programs for other serious diseases such as Duchenne muscular dystrophy and myotonic dystrophy type 1.”

Matt Fellows