Vertex, CRISPR Complete Rolling BLAs for Exa-Cel in Sickle Cell Disease and Transfusion-dependent Beta Thalassemia

Vertex Pharmaceuticals and CRISPR Therapeutics today announced that they had completed the rolling submission of their biologics license applications (BLAs) for the investigational therapy exagamglogene autotemcel (exa-cel; previously known as CTX001) for the treatment of sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT).¹ Both BLAs include additional requests for priority review—which would trim the FDA’s review time to 8 months, if granted.

The companies began the BLA submission process in November 2022,² and subsequently submitted marketing authorization applications for exa-cel to the European Medicines Agency and Medicines and Healthcare products Regulatory Agency in December 2022 and January 2023, respectively.¹ The investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy was granted priority medicines designation for both SCD and TDT in the European Union, and an innovation passport in the United Kingdom. In the United States, exa-cel has been granted regenerative medicine advanced therapy, fast track, orphan drug, and rare pediatric disease designations for both conditions.

Carmen Bozic, MD, executive vice president of Global Medicines Development and Medical Affairs, and the chief medical officer at Vertex Pharmaceuticals, said in a statement that the BLAs completion was an “historic milestone,” adding that, “We want to thank the clinical trial participants and the sickle cell and beta thalassemia communities, as well as the physicians, nurses, coordinators, caregivers and friends who support them.”¹

The BLAs are supported by data from 2 ongoing phase 3 clinical trials—CLIMB-111 (NCT03655678) in TDT and CLIMB-121 (NCT03745287) in SCD—as well as a long-term follow-up study—CLIMB-131 (NCT04208529)—that includes patients with both disorders. Data from the trials were presented at the American Society of Hematology (ASH) Annual Meeting and Exposition in December of 2022,^3,4 which detailed promising results for exa-cel.

“Within a decade, we have progressed from the discovery of the CRISPR platform to the first regulatory filings for a CRISPR-based therapy, which speaks to the transformative nature of CRISPR technology,” Phuong Khanh Morrow, MD, FACP, chief medical officer at CRISPR Therapeutics, said about the BLA submissions in a statement.¹

READ MORE: Lovo-cel BLA Submission Likely Delayed for Sickle Cell

All told, as of the February 2022 data cut in CLIMB-121, among patients with SCD aged 12 to 35 years, 31 individuals had been infused with exa-cell (mean follow-up, 9.6 months), of whom 19.4% (n = 6) were between 12 and 17 years old and 93.5% (n = 29) had the βs/βs genotype.3 In the 2 years prescreening, patients had experienced 3.9 severe vaso-occlusive crises (VOCs) per year (range, 2.0-9.5). At the time of the data cut after exa-cel infusion, though, all patients were VOC-free (follow-up range, 2.0-32.3 months post infusion).³

Additionally, the mean proportion of fetal hemoglobin (HbF) was greater than 20% by month 3, with mean total hemoglobin (Hb) levels exceeding 11 g/dL on and after the Month 3 time point. The median time from exa-cel infusion to last red blood cell (RBC) transfusion was 19 days (range, 11-52). All 11 patients with at least 12 months of follow-up after exa-cel infusion had maintained HbF levels above 20% while experiencing no VOCs. The mean proportion of edited BCL11A alleles in bone marrow CD34+ hematopoietic stem and progenitor cells (HSPCs) and peripheral blood mononuclear cells was 86.6% and 76.0%, respectively, at the 6-month mark. Notably, these proportions remained stable in every patient with at least 1 year of follow-up.³

At the same data cut time point in CLIMB-111, 44 individuals with TDT with a mean age of 21.3 years (range, 12-35) were infused with exa-cel (mean follow-up, 12.3 months) of whom 34.1% (n = 15) were aged between 12 and 17 years.4 Nearly 60% (n = 26; 59.1%) of patients had β0/β0 or a β0/β0‑like genotype, and in the 2-year period prior to screening, patients received 36.0 units (15.0–71.0) of RBCs per year.

Of those 44 individuals, 42 patients with TDT stopped RBC transfusion, with a median time since last transfusion of 9.0 months (range, 0.8-36.2). A total of 16 patients went at least 12 months since their last transfusion, and although 2 had not yet stopped transfusions, they had reductions of transfusion volume of 75% and 89%. By the third month, increases in HbF and mean total Hb levels (>9 g/dL) were met, with mean total Hb levels increasing to and maintained at levels greater than 11 g/dL from that point forward. The mean proportion of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells was 74.3% and 63.4%, respectively, at 6 months, which also remained stable in all patients with at least 1 year of follow-up.⁴

In CLIMB-121, there were no patients who had serious adverse events (AEs) considered related to exa-cel, and there were no deaths, discontinuations, or malignancies reported in either trial.^3,4 In CLIMB-111, though, 2 patients reported serious AEs considered treatment-related: 1 with concurrent events of headache, hemophagocytic lymphohistiocytosis, and acute respiratory distress syndrome, as well as idiopathic pneumonia syndrome considered related to both exa-cel and busulfan; and 1 patient with delayed neutrophil engraftment and thrombocytopenia considered related to both exa-cel and busulfan.⁴

REFERENCES
1. Vertex and CRISPR Therapeutics Complete Submission of Rolling Biologics License Applications (BLAs) to the US FDA for exa-cel for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Inc; CRISPR Therapeutics. April 3, 2023. Accessed April 3, 2023. https://www.businesswire.com/news/home/20230402005036/en/
2. Vertex and CRISPR Therapeutics Announce Global exa-cel Regulatory Submissions for Sickle Cell Disease and Beta Thalassemia in 2022. News release. Vertex Pharmaceuticals. September 27, 2022. Accessed April 3, 2023. https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-global-exa-cel
3.Frangoul H, Locatelli F, Bhatia M, et al. Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease. Presented at: 64th ASH Annual Meeting, December 10-13, 2022. Oral Abstract #12. https://ash.confex.com/ash/2022/webprogram/Paper162353.html
4. Locatelli F, Lang O, Li A, et al. Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia. Presented at: 64th ASH Annual Meeting, December 10-13, 2022. Oral Abstract #2137. https://ash.confex.com/ash/2022/webprogram/Paper166881.html