A single dose of CTX001, an experimental gene-editing cell therapy, rapidly increases the levels of hemoglobin and prevents vaso-occlusive crises (VOCs) for up to nearly two years in people with severe sickle cell disease (SCD), according to interim data from the Phase 1/2 CLIMB-SCD-121 clinical trial.

CRISPR Therapeutics and Vertex Pharmaceuticals are jointly developing CTX001 for the treatment of hemoglobin-associated diseases, including SCD and transfusion-dependent beta thalassemia (TDT).

These preliminary findings, along with positive interim results from the CLIMB-Thal-111 study (NCT03655678) testing the therapy in TDT patients, were presented at the European Hematology Association 2021 Virtual Congress, held June 9–17.

“We are excited about these results and look forward to additional longer-term data and to moving this investigational medicine forward for a larger population of patients with these two devastating diseases,” Samarth Kulkarni, PhD, CRISPR Therapeutics’ CEO, said in a press release.

Reshma Kewalramani, MD, Vertex’s president and CEO, said the data “add to the growing body of evidence that CTX001 may hold the promise for a one-time functional cure for sickle cell disease and beta thalassemia.”

“We are working with urgency to complete enrollment and look forward to finalizing regulatory discussions and moving towards filing,” Kewalramani added.

CTX001 uses the CRISPR-Cas9 gene-editing tool to modify a patient’s blood cell precursors so that they produce high levels of fetal hemoglobin in red blood cells. Fetal hemoglobin is a form of hemoglobin found in newborns that is more effective at transporting oxygen than its adult counterpart.

Originally discovered in bacteria as a defense mechanism, the CRISPR-Cas9 system allows researchers to edit parts of the genome — all genes that are present in our DNA — by adding, removing, or changing specific sections of a DNA sequence.

The modified cells are re-introduced back into the patient in the form of a stem cell transplant following myeloablative chemotherapy, a strategy that kills blood cell precursors in the bone marrow. This way, the stem cell transplant will have better chances of rebuilding healthy bone marrow.

By increasing the levels of fetal hemoglobin, CTX001 is expected to lower VOC frequency in people with SCD and the constant need for blood transfusions in TDT patients.

The Phase 1/2 CLIMB-SCD-121 study (NCT03745287) is assessing the two-year safety and effectiveness of a single administration of CTX001 in up to 45 people, ages 12–35, with severe SCD. Severe SCD patients are those who have experienced at least two severe VOCs per year in the two years prior to enrollment.

The trial is still recruiting patients across the U.S., Canada, and Europe. After completing the trial, participants will have the option to enter a long-term follow-up study called CLIMB-131 (NCT04208529).

Previous results from the first three participants with at least three months of follow-up post-dosing (range, three to 15 months) showed that CTX001 was generally safe and led to fast and sustained increases in total and fetal hemoglobin, while eliminating the occurrence of VOCs.

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In the e-poster, “CTX001 For Sickle Cell Disease: Safety and Efficacy Results From The Ongoing Climb Scd-121 Study Of Autologous Crispr-Cas9-Modified Cd34+ Hematopoietic Stem And Progenitor Cells,” researchers presented data from seven SCD patients who were followed for a minimum of three months, ranging from five to 22 months (nearly two years).

Data showed similar patterns of response in all seven patients and comparable to those previously reported. At last assessment, all remained VOC-free and showed clinically meaningful improvements in total hemoglobin, which rose from 11 to 15.9 grams per deciliter (g/dL), reaching the normal range, and in fetal hemoglobin, which rose from 39.6% to 49.6%.

In addition, bone marrow analysis of the four participants with at least six months of follow-up (two followed for one year) suggested that the therapy promotes durable effects.

CTX001’s safety profile was generally consistent with that associated with myeloablative chemotherapy followed by stem cell transplant. There were no CTX001-related serious adverse events, and most non-serious side effects were mild to moderate.

Similar positive, durable responses were reported for the 15 TDT patients with at least three months of follow-up after CTX001 dosing in the Phase 1/2 CLIMB-Thal-111 trial, whose design is very similar to CLIMB-SCD-121.

All 15 participants, followed for four to 26 months (a little more than two years), showed rapid and clinically meaningful improvements in total and fetal hemoglobin, and remained independent of blood transfusions.

These findings from a total of 22 patients “are impressive in both the consistency and durability of effect,” Kewalramani said.

“This approach uses CRISPR/Cas9 gene editing to enable the patient’s own cells to produce fetal hemoglobin, and to see results that demonstrate the potential for a treatment that may transform the lives of many patients is an exciting time for me and the team,” said Stephan Grupp, MD, section chief of cellular therapy and transplant of the oncology division at Children’s Hospital of Philadelphia in Pennsylvania.

CTX001 received orphan drug designation in both the U.S. and Europe, and fast track, rare pediatric disease, and regenerative medicine advanced therapy designations in the U.S. for SCD and TDT. It also recently was designated a priority medicine in Europe for both disorders. All these designations are meant to accelerate the therapy’s clinical development and regulatory review.





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