CTX001 Found to be Safe and Effective in First Tested Patient with Severe Sickle Cell Disease, Preliminary Data Suggest

CTX001 Found to be Safe and Effective in First Tested Patient with Severe Sickle Cell Disease, Preliminary Data Suggest

CTX001 safely and effectively increased the levels of fetal hemoglobin and prevented vaso-occlusive crises in the first severe sickle cell disease (SCD) patient receiving the therapy, according to preliminary data from a Phase 1/2 clinical trial.

CTX001 is a CRISPR-based gene editing therapy developed by CRISPR Therapeutics and Vertex Pharmaceuticals as a potential treatment for hemoglobin-associated diseases, including SCD and beta-thalassemia.

It uses the CRISPR-Cas9 gene editing system to genetically modify a patient’s hematopoietic (bone marrow) stem cells to produce high levels of fetal hemoglobin in red blood cells, which are then delivered back to the patient as part of a stem cell transplant.

The CRISPR-Cas9 system, which is similar to the editing system used by bacteria as a defense mechanism, allows researchers to edit parts of the genome by adding, removing, or changing specific sections of DNA.

Fetal hemoglobin, the main form of oxygen-carrying hemoglobin in the human fetus and newborn, largely disappears between six months to one year after birth, being replaced by its adult form.

Since the adult form is the one containing the defective component of hemoglobin in people with SCD and beta-thalassemia, an artificial increase of fetal hemoglobin has the potential to compensate for the defective hemoglobin produced by these patients and reduce or prevent their symptoms.

The open-label, multi-center Phase 1/2 CLIMB-SCD-121 study (NCT03745287) is currently evaluating the safety and effectiveness of a single administration of CTX001 in people ages 18 to 35 with severe SCD.

The trial, which is expected to enroll up to 45 people, is still recruiting at 12 clinical sites in the United States, Canada, and Europe. Participants will be followed for approximately two years after treatment, and have the opportunity to enter a long-term follow-up study.

Before receiving CTX001, participants will undergo myeloablative chemotherapy, a strategy that kills cells in the bone marrow, thereby lowering the number of blood-forming cells. This way, the stem cell transplant will have more chances to rebuild a healthy bone marrow.

Researchers will first determine when the transplanted modified cells begin to produce mature blood cells in the patients, a process known as engraftment. After confirmation of engraftment, safety and effectiveness will be assessed as part of the trial’s primary and secondary goals.

One primary goal is to assess the proportion of people with an increase of at least 20% in the production of fetal hemoglobin, starting six months after CTX001 treatment. This increase must be sustained for more than three months at the time of analysis.

Among secondary goals is determining whether CTX001 reduces the annualized rate of vaso-occlusive crises.

In February, CRISPR Therapeutics and Vertex announced the enrollment of the first patient in the CLIMB-SCD-121 study, who was recruited in the U.S. and received CTX001 in mid-2019.

Now, the companies have shared the preliminary four-month data of this patient, a 33-year-old woman who had experienced seven vaso-occlusive crises per year — the annualized rate of the two years before her enrollment in the trial.

Results showed that she had a confirmed engraftment 30 days after receiving CTX001 treatment. Four months after treatment, no vaso-occlusive crises were reported and she had stopped blood transfusion treatments.

After four months, her total hemoglobin levels were 11.3 g/dL, fetal hemoglobin levels had increased from 9.1% to 46.6%, and the percentage of fetal hemoglobin-producing red blood cells had increased from 33.9% to 94.7%.

CTX001’s early safety profile was consistent with that previously reported for myeloablative chemotherapy followed by stem cell transplant. The woman experienced three serious adverse events, all of them resolved and considered to be unrelated to treatment.

Positive preliminary data were also announced for the first patient with beta-thalassemia receiving CTX001 in the Phase 1/2  CLIMB-Thal-111 study (NCT03655678).

“We are very encouraged by these preliminary data … [which] support our belief in the potential of our therapies to have meaningful benefit for patients following a one-time intervention,” Samarth Kulkarni, PhD, CRISPR Therapeutics’ CEO, said in a press release.

A webcast and presentation about these preliminary results are available on the company’s website.

“The data … 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,” said Jeffrey Leiden, MD, PhD, Vertex’s chairman, president, and CEO.

Leiden added that the trial is still in its early phase and that he looks forward to its final results.

Early this year, CTX001 received fast track status for the treatment of sickle cell disease by the U.S. Food and Drug Administration, which is expected to accelerate CTX001’s development and regulatory approval process.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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