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Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
FROM EHA 2023