Vertex and CRISPR Therapeutics Report Positive Results from Pivotal Trials in TDT and SCD

Rare Daily Staff

Vertex Pharmaceuticals and CRISPR Therapeutics reported positive results from their pivotal trials for exagamglogene autotemcel in patients with transfusion-dependent beta thalassemia or severe sickle cell disease that met primary and key secondary endpoints at pre-specified interim analyses.

Sickle cell disease (SCD) is an inherited blood disorder caused by a mutation in the beta-globin gene that leads to polymerization of the sickle hemoglobin protein (HbS). In sickle cell disease, the red blood cells are misshapen in a sickle shape instead of a typical disc shape. The abnormal shape causes the red blood cells to have shortened lifespan and to block blood flow causing anemia, pain crises, organ failure, and early death. Higher levels of fetal hemoglobin (HbF) inhibit HbS polymerization, thus reducing the clinical manifestation of RBCs sickling.

Beta thalassemia is an inherited blood disorder caused by mutations that reduce or abrogate beta-globin gene expression. Insufficient beta-globin production leads to ineffective red blood cell production, chronic hemolytic anemia, the creation of blood cells outside of the bone marrow, and requirement for regular blood transfusion support in patients with transfusion-dependent beta thalassemia (TDT). TDT is the most severe form of beta thalassemia, and chronic red blood cell transfusions are complicated by iron overload leading to organ dysfunction and failure. Higher levels of HbF ameliorate anemia thereby reducing the need for regular red blood cell transfusions.

Exagamglogene autotemcel (exa-cel) is an experimental, autologous, ex vivo CRISPR/Cas9 gene-edited cell therapy that is being evaluated for patients with SCD or TDT, in which a patient’s own hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. The elevation of HbF by exa-cel has the potential to reduce or eliminate painful and debilitating vaso-occlusive crises for patients with SCD and alleviate transfusion requirements for patients with TDT.

Vertex and CRISPR Therapeutics entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. Exa-cel represents the first potential treatment to emerge from the joint research program. Under an amended collaboration agreement, Vertex now leads global development, manufacturing and commercialization of exa-cel and splits program costs and profits worldwide 60/40 with CRISPR Therapeutics.

Exa-cel has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration for both TDT and SCD. The FDA has accepted the Biologics License Applications (BLAs) for exa-cel.

In the European Union, exa-cel has been granted Orphan Drug designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency for both SCD and TDT. In the United Kingdom, exa-cel has also been granted an Innovation Passport under the Innovative Licensing and Access Pathway (ILAP) from the Medicines Healthcare products Regulatory Agency (MHRA).

The companies submitted applications for Marketing Authorization in Europe for exa-cel in December 2022 that were validated by the EMA and MHRA in January 2023.

“This analysis confirms the potential of exa-cel to render patients transfusion-independent or VOC-free, with significant improvement in their quality of life and physical performance,” said Franco Locatelli, professor of pediatrics at the Sapienza University of Rome, and director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. “This therapy offers the potential of a functional cure for patients with transfusion-dependent beta thalassemia or severe sickle cell disease along with a favorable safety profile.”

Both CLIMB-111 and CLIMB-121 met their primary endpoint and key secondary endpoint at the pre-specified interim analysis for each trial. These analyses evaluated the efficacy and safety of exa-cel in patients with TDT or SCD in the ongoing phase 3 trials as well as in the long-term follow up trial CLIMB-131. The data are from 83 patients (48 with TDT and 35 with SCD) dosed with exa-cel with follow-up up to 43.7 months. All patients treated with exa-cel demonstrated clinical benefit, and these data continue to demonstrate the potentially transformative profile of exa-cel.

Of the 48 patients with TDT who had received exa-cel at the time of the analysis, more than half (58.3 percent) have genotypes associated with severe disease, beta-zero/beta-zero or other beta-zero-like severe genotypes. At the time of the data cut, 27 TDT patients were evaluable for the primary and key secondary endpoint.

Some 24/27 (88.9 percent) achieved the primary endpoint of transfusion-independence for at least 12 consecutive months and the secondary endpoint of transfusion-independence for at least six consecutive months with a mean weighted hemoglobin of at least 9 g/dL. Mean duration of transfusion-independence was 20.5 months with a maximum of 40.7 months.

Of the three patients who did not achieve transfusion independence at 12 months, one patient has since stopped transfusions and has been transfusion-free for 2.9 months; the remaining two patients have had substantial reductions in transfusion volume from baseline.

Increases in total hemoglobin occurred early within the first few months and were maintained over time.

Of the 35 patients with SCD who had received exa-cel at the time of the analysis, 17 patients were evaluable for the primary and key secondary endpoint at the time of the data cut.

A total of 16/17 (94.1 percent) achieved the primary endpoint of freedom from vaso-occlusive crises for at least 12 consecutive months. The mean duration of vaso-occlusive crisis-free was 18.7 months, with a maximum of 36.5 months. All 17 achieved the key secondary endpoint of being free from hospitalizations related to vaso-occlusive crisis for at least 12 consecutive months.

The safety profile of exa-cel was generally consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. All patients engrafted neutrophils and platelets after exa-cel infusion.

As previously reported, two TDT patients had serious adverse events (considered related to exa-cel. One patient had three SAEs considered related to exa-cel: hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and headache, and one SAE of idiopathic pneumonia syndrome that was considered related to both exa-cel and busulfan. All four SAEs occurred in the context of HLH in the peri-engraftment period and have resolved. One patient had SAEs of delayed neutrophil engraftment and thrombocytopenia, both of which were considered related to exa-cel and busulfan, and both SAEs have resolved. Among the 35 patients with SCD, there were no SAEs considered related to exa-cel.

Also as previously reported, one adult patient with SCD developed pneumonia and respiratory failure following SARS-CoV-2 infection, resulting in death. The investigator assessed the events as not related to exa-cel. There were no other deaths or discontinuations, and there have been no malignancies in either study.