Date: 2017-12-11
Type of
information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting in Orlando
Company: bluebird bio (USA - MA)
Product: LentiGlobin® BB305 (autologous CD34+ haematopoietic stem cells transduced with lentiviral vector encoding the human beta A-T87Q-globin gene)
Action
mechanism:
- gene therapy/stem cell therapy. LentiGlobin BB305 Drug Product consists of autologous CD34+ hematopoietic stem cells transduced with lentiviral vector LentiGlobin BB305 encoding the human Beta A-T87Q-globin gene and suspended in cryopreservative solution.
Disease: beta-thalassemia, sickle cell disease
Therapeutic
area: Hematologic diseases - Genetic diseases - Rare diseases
Country: France
Trial
details:
- The HGB-205 Study is planned to enroll 7 patients with beta thalassemia major or sickle cell disease at a single site in Paris, France. The phase 1/2 study is designed to evaluate the safety and efficacy of LentiGlobin drug product in the treatment of subjects with beta-thalassemia major and severe sickle cell disease. The study is designed to enroll up to seven subjects. Subjects will be followed to evaluate safety and transfusion requirements post-transplant. In sickle cell disease patients only, efficacy will also be measured based on the number of vaso-occlusive crises or acute chest syndrome events. (NCT02151526)
Latest
news:
- • On December 11, 2017, bluebird bio announced updated data from the ongoing HGB-205 clinical study of its LentiGlobin gene therapy product candidate in patients with severe sickle cell disease (SCD) and transfusion-dependent ?-thalassemia (TDT). The findings have been presented in a poster session at the 59th Annual Meeting of the American Society of Hematology (ASH) by Marina Cavazzana, M.D., Ph.D., Professor of Medicine at Paris Descartes University and Research Director at the Centre for Clinical Research in Biotherapy, Necker Hospital, and at the Institute of Genetic Diseases, Imagine, Paris, France. Professor Cavazzana is the primary investigator of the HGB-205 study. “All seven patients in this study continue to experience notable clinical improvement. Since being treated with LentiGlobin therapy, the four patients with TDT have been free of chronic transfusions with near normal and stable levels of total hemoglobin,” said Professor Cavazzana. “While progress has been made with medications to treat SCD and TDT, we are in need of better options for our patients. This study suggests that LentiGlobin has the potential to be a transformational one-time therapy for people with SCD and TDT.”
- SCD: All three treated patients showed rising HbAT87Q levels in the first six months. Patient 1204 was 13 years old at study enrollment. At last follow-up (35.2 months), this patient had a total hemoglobin of 12.4 g/dL, of which 6.1 g/dL was HbAT87Q (52 percent anti-sickling Hb). HbAT87Q concentration in this patient has remained stable since approximately nine months post-infusion. The patient continues to show marked clinical improvement.
Patient 1207 was 16 years old at study enrollment. At last follow-up (8.9 months), this patient had a total hemoglobin of 10.0 g/dl, of which 0.7 g/dl was HbAT87Q (14 percent anti-sickling Hb). This patient had a pre-treatment history of frequent episodes of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) despite hydroxyurea prior to beginning regular transfusions. Patient 1207 had episodes of ACS and hospitalization at six and eight months post-treatment, and received three transfusions.
Patient 1208 was 21 years old at study enrollment. At last follow-up (6.0 months), this patient had a total hemoglobin of 10.6 g/dL, of which 2.7 g/dL was HbAT87Q (46 percent total anti-sickling Hb). This patient had a pre-treatment history of frequent episodes of VOCs and ACS prior to beginning regular transfusions, and was still symptomatic while receiving regular transfusions. Following LentiGlobin treatment, Patient 1208 has had no episodes of VOCs or ACS (with six months follow-up).
- TDT: All four patients with TDT have remained free of chronic transfusions since shortly after receiving LentiGlobin DP. Patient 1201 (Beta 0/Beta E genotype) has been free of transfusions for 45.2 months with total hemoglobin of 10.1 g/dL, of which 6.7 g/dL was HbAT87Q.
Patient 1202 (Beta 0/Beta E genotype) has been free of transfusions for 40.1 months with total hemoglobin of 12.9 g/dL, of which 10.1 g/dL was HbAT87Q.
Patient 1206 (Beta 0/Beta E genotype) has been free of transfusions for 23.8 months with total hemoglobin of 11.1 g/dL, of which 8.0 g/dL was HbAT87Q.
Patient 1203, who is homozygous for the severe ?+ mutation IVS1-110, has been free of transfusions for 20.9 months with total hemoglobin of 8.7 g/dL, of which 6.7 g/dL was HbAT87Q.
Three of four patients (1201, 1202 and 1206) were able to begin therapeutic phlebotomy. Patient 1202 subsequently discontinued iron chelation and phlebotomy.
The safety profile of LentiGlobin DP continues to be consistent with myeloablative conditioning with single-agent busulfan. No DP-related adverse events have been observed, and there is no evidence of clonal dominance.
- • On June 23, 2017, bluebird bio announced new data from the ongoing HGB-205 clinical study evaluating its LentiGlobin gene therapy product candidate in patients with transfusion-dependent Beta-thalassemia (TDT) and severe sickle cell disease (SCD). These data have been presented by Elisa Magrin, Ph.D., Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France in a poster session on Saturday, June 24 at the European Hematology Association (EHA) Annual Meeting in Madrid, Spain. Marina Cavazzana, M.D., Ph.D., Professor of Medicine at Paris Descartes University and Research Director at the Centre for Clinical Research in Biotherapy, Necker Hospital, and at the Institute of Genetic Diseases, Imagine, Paris, France, is the primary investigator of the HGB-205 study.
- Update on the First Patients with Severe Hemoglobinopathies Treated with LentiGlobin Gene Therapy (HGB-205) (Abstract P631)HGB-205 is an ongoing, open-label, single-center Phase 1/2 study designed to evaluate the safety and efficacy of LentiGlobin drug product in the treatment of patients with TDT and severe SCD. Four patients with TDT and three patients with severe SCD have undergone infusion with LentiGlobin drug product in this study as of June 2, 2017.
TDT:
- All patients with TDT have remained free of transfusions since shortly after receiving LentiGlobin treatment. At last study visit:
- Patient 1201 (Beta0/BetaE genotype) has been free of transfusions for 41.9 months with total hemoglobin of 11.3 g/dL, of which 8.2 g/dL was HbAT87Q
- Patient 1202 (Beta0/BetaE genotype) has been free of transfusions for 38.7 months with total hemoglobin of 12.9 g/dL, of which 10.0 g/dL was HbAT87Q
- Patient 1206 (Beta0/BetaE genotype) has been free of transfusions for 20.3 months with total hemoglobin of 11.4 g/dL, of which 8.4 g/dL was HbAT87Q
- Patient 1203, who is homozygous for the severe ?+ mutation IVS1-110, has been free of transfusions for 20.4 months with total hemoglobin of 8.3 g/dL, of which 6.6 g/dL was HbAT87Q
- All three patients with TDT and Beta0/BetaE genotype have discontinued iron chelation and transitioned to therapeutic phlebotomy.
- The safety profile continues to be consistent with autologous transplantation. No drug-product related adverse events (AEs) have been observed, and there is no evidence of clonal dominance.
SCD:
- Patient 1204 was 13 years old at enrollment. At last follow-up (31.7 months), this patient was producing 50% HbAT87Q – well above the approximately 30% anti-sickling hemoglobin level predicted to have potential clinical impact on the disease.
- Approximately 30 months post-treatment, Patient 1204 suffered an episode of acute gastroenteritis with vomiting and 2 days of fever up to 40°C (104°F), which was followed by a vaso-occlusive crisis (VOC) and subsequent hospitalization. His HbAT87Q and peripheral blood VCN levels have remained stable (HbAT87Q: 6.1 g/dL, VCN: 2.3 copies/diploid genome at 30 months), suggesting continued durability of the gene therapy.
- Patient 1207 was 16 years old at enrollment. At last follow-up (6.1 months), this patient was producing 20% HbAT87Q. This patient had a pre-treatment history of frequent episodes of VOC and acute chest syndrome (ACS) despite hydroxyurea prior to beginning regular transfusions and had one episode of ACS and a hospitalization at 6 months post-treatment.
- Patient 1208 was 21 years old at enrollment. At last follow-up (3.4 months), this patient was producing 15% HbAT87Q.
- The safety profile continues to be consistent with autologous transplantation. No gene therapy related AEs have been observed, and there is no evidence of clonal dominance.
- • On March 1, 2017, bluebird bio announced the publication in the New England Journal of Medicine of a case study on Patient 1204, the first patient with severe sickle cell disease to be treated with gene therapy. This patient, who was 13 years old at the time of treatment, was treated with LentiGlobin drug product in the HGB-205 clinical study conducted in Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. The data in the publication reflect 15 months of follow-up, and a brief summary of this patient’s outcomes with 21 months of follow-up was presented at the 58th American Society of Hematology Annual Meeting in December 2016.
- Clinical and Biological Outcomes for the First Patient with Sickle Cell Disease Treated with Gene Therapy: Patient 1204, a male patient with ?S/?S genotype, was enrolled in May 2014 at 13 years of age into the HGB-205 clinical study. The patient underwent a regular transfusion regimen for 4 years prior to this study. He had an average of 1.6 SCD-related events annually in the 9 years prior to initiating transfusions, and his complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy. The patient underwent two bone marrow harvests to collect hematopoietic stem cells (HSCs) for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested). CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector. The vector copy numbers (VCN; vector copies per diploid genome) for the drug product lots manufactured were 1.0 and 1.2. The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve (AUC) was 19,363 ?mol*min. After a 2-day washout, Patient 1204 was infused with LentiGlobin drug product in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. RBC transfusions were to be continued after transplantation until a sufficient proportion of HbAT87Q (25-30% of total Hb) was detected.
- Neutrophil and platelet engraftment were achieved on Day +38 and Day +91 post-transplantation, respectively. HbAT87Q levels increased steadily and RBC transfusions were discontinued after the last transfusion on Day +88. HbAT87Q reached 5.5 g/dL (46% of total Hb) at Month 9 and continued to increase to 5.7 g/dL at Month 15 (48%), with a reciprocal decrease in HbS levels to 5.5 g/dL (46%) at Month 9, and 5.8 g/dL (49%) at Month 15. Total Hb levels have been stable between 10.6 and 12.0 g/dL since Month 6 post-transplant. HbF levels have remained below 1.0 g/dL.
- Adverse events (AEs) were consistent with busulfan conditioning, and no AEs related to LentiGlobin drug product have been observed to date.
- Over the 15 months since transplantation, no SCD-related clinical events or hospitalizations have occurred, contrasting favorably with the period before the patient began regular transfusions. All medications have been discontinued, including pain medication. The patient has resumed regular school attendance and reports full participation in normal physical activities.
- • On December 6, 2015, bluebird bio announced the presentation of new data from the ongoing HGB-205 clinical study evaluating its LentiGlobin BB305 product candidate in patients with beta-thalassemia major and severe sickle cell disease (SCD), at the 57th American Society of Hematology Annual Meeting. The data from the HGB-205 study were highlighted in an oral presentation by Marina Cavazzana, lead investigator of the HGB-205 study. This ongoing, open-label, single-center Phase 1/2 study is evaluating the safety and efficacy of LentiGlobin BB305 drug product in the treatment of patients with beta-thalassemia major and severe SCD. As of November 10, 2015, four subjects with beta-thalassemia major and one subject with severe SCD have undergone infusion with LentiGlobin BB305 product candidate in this study. Results as of November 10, 2015, include: Subject 1201 with the Beta0/BetaE genotype of beta-thalassemia major has 23.4 months of transfusion independence with total hemoglobin of 10.8 g/dL, of which 7.9 g/dL was HbAT87Q. Subject 1202 with the Beta0/BetaE genotype of beta-thalassemia major has 20.1 months of transfusion independence with total hemoglobin of 13.1 g/dL, of which 10.3 g/dL was HbAT87Q.
- An additional two patients with beta-thalassemia major, Subjects 1203 and 1206, have been infused, though it is too early to draw any meaningful efficacy conclusions. At their most recent follow ups, three months and one month, respectively, these patients were producing measurable levels of HbAT87Q, which are steadily increasing in Subject 1203.
At the 12-month post-drug infusion follow up for Subject 1204 with severe SCD, the proportion of anti-sickling hemoglobin (HbAT87Q + HbF) accounted for 49 percent of all hemoglobin production (47 percent HbAT87Q + 2 percent HbF) – well above the 30 percent threshold expected to potentially achieve a disease-modifying clinical effect. Prior to infusion, Subject 1204 required chronic blood transfusions; he was successfully weaned off of transfusions and has remained transfusion independent for more than nine months. Since infusion, this patient has had no hospitalizations or acute SCD-related events.
No LentiGlobin-related adverse events have been observed; all of the adverse events observed are consistent with myeloablative conditioning.
All five treated subjects successfully engrafted and insertional site analyses (ISAs) demonstrate highly polyclonal reconstitution without clonal dominance.
- • On June 13, 2015, bluebird bio announced long-term follow up of two patients with beta-thalassemia major and early safety and efficacy data in the first patient with severe sickle cell disease (SCD) treated with LentiGlobin BB305 product candidate in the HGB-205 study. These data were presented at the 20th Congress of the European Hematology Association (EHA) in Vienna, Austria by Marina Cavazzana, lead investigator of the HGB-205 study .
- As of May 2015, two patients with beta-thalassemia major and one patient with severe SCD have undergone infusion with LentiGlobin BB305 product candidate in this study.
- Beta-thalassemia: As of May 2015, Subjects 1201 and 1202 with beta-thalassemia major remained transfusion-independent for 16 and 14 months, respectively, with persistent stable expression of HbAT87Q. Neither has experienced a LentiGlobin-related adverse event.
- Sickle Cell Disease: The proportion of anti-sickling hemoglobin being produced by the first-ever patient with severe SCD treated with gene therapy (Subject 1204) is rising steadily and accounted for 45% of all hemoglobin production (40% HbAT87Q + 5% HbF) at the patient’s six-month visit post-drug product infusion; this is above the 30% threshold expected to potentially achieve a disease-modifying clinical effect. As of May 2015, Subject 1204 had been free of transfusions for more than three months without complications or hospitalizations for SCD-related events post-transplant, and with improvement in hemolysis markers.
- Patients with beta-thalassemia major demonstrated continued transfusion independence: The data presented are an update on those initially presented at EHA in June 2014 and demonstrate a long-term stable and durable response (see below). As reported at ASH in December 2014, Subjects 1201 and 1202 achieved rapid transfusion independence with near-normal hemoglobin levels. As of May 2015, Subjects 1201 and 1202 remained transfusion independent for 16 and 14 months, respectively.
- Early efficacy data is promising in the first subject with severe SCD treated with gene therapy: The production of anti-sickling hemoglobin is consistent with a level expected to potentially achieve a disease-modifying clinical effect in Subject 1204. At the six-month visit post-drug product infusion, the proportion of anti-sickling hemoglobin (HbAT87Q + HbF) accounted for 45% of all hemoglobin production (40% HbAT87Q + 5% HbF). The patient’s vector copy number in peripheral blood leukocytes was 2.2.
Subject 1204 had his last red blood cell (RBC) transfusion at day 88. Since his infusion with LentiGlobin, this patient has had no hospitalizations, and has demonstrated improvements in markers of hemolysis, including normalization of reticulocyte count (from 283.3 x 109/L to 131.7 x 109/L) and lactate dehydrogenase (LDH) (from 626 U/L to 254 U/L).
- • On October 14, 2014, bluebird bio announced that the first subject with severe sickle cell disease has undergone infusion with bluebird bio’s LentiGlobin BB305 drug product in an autologous hematopoietic stem cell transplantation. This patient is enrolled in the HGB-205 Study being conducted in Paris, France. bluebird has also opened a separate US-based trial (HGB-206) in the United States for the treatment of up to 8 severe sickle cell disease patients with the company’s LentiGlobin BB305 drug product. The phase 1 study is designed to evaluate the safety and efficacy of LentiGlobin BB305 drug product in the treatment of subjects with severe sickle cell disease. The study is designed to enroll up to eight subjects. Subjects will be followed to evaluate safety and efficacy will be measured based on changes in red cell function tests, hemolysis markers and frequency of clinical events secondary to sickle cell disease (e.g. vaso-occlusive crises or acute chest syndrome events).
- • On June 14, 2014, bluebird bio released initial positive clinical data from its HGB-205 clinical study of its LentiGlobin BB305 product candidate in beta-thalassemia major subjects at the 19th Annual Congress of the European Hematology Association (EHA) in Milan, Italy. The principal investigator of the HGB-205 Study, Marina Cavazzana, M.D delivered an oral presentation at the EHA Congress entitled “Improving gene therapy for beta-thalassemia major: initial results from Study HGB-205”. The presentation included data from the prior LG001 Clinical Study and the ongoing HGB-205 Study.
- LG001 Clinical Study: Clinical update provided on two subjects treated in the prior LG001 Study (subjects 3 and 4) using the prior lentiviral HPV569 product candidate Subject 3 remains blood transfusion independent 72 months after being transplanted with the lentiviral HPV569 product candidate Subjects 3 and 4 are producing 2.7 g/dL and 0.4 g/dL of therapeutic betaA-T87Q-globin post-transplant, respectively. No drug product related adverse events were reported in the LG001 Study.
- HGB-205 Clinical Study: Clinical data were presented on two subjects (subjects 1 and 2), both with beta-thalassemia major and the Beta E/Beta 0 genotype who were treated using the new lentiviral vector BB305. At 4.5 months following autologous transplant subject 1 had a total hemoglobin of 10.1 g/dL of which 6.6 g/dL was therapeutic betaAT87Q-globin, and at 2 months post-transplant subject 2 had a total hemoglobin of 11.6 g/dL of which 4.2 g/dL was betaAT87Q-globin. Subjects 1 and 2 received their last blood transfusion on day 10 and 12, respectively, post-transplant and both subjects remain blood transfusion independent. Vector copy number in the drug product for subjects 1 and 2 were 1.5 and 2.1, respectively; multiple times higher than the drug product vector copy numbers reported in the prior LG001 Study (VCN 0.6 and 0.3 for Subjects 3 and 4, respectively). No drug product related adverse events were reported, and the integration site analysis performed on subject 1 at the 3-month time point showed polyclonal reconstitution. bluebird bio anticipates reporting additional data from the HGB-205 Study and from its ongoing Northstar Study (HGB-204) in late 2014.
- • On December 2, 2013, bluebird bio has announced that the first subject with beta-thalassemia major has been enrolled in its phase 1/2 HGB-205 study in France and has undergone infusion with LentiGlobin in an autologous hematopoietic stem cell transplantation. “We believe gene therapy represents a potentially new and exciting treatment option for patients with severe forms of beta-thalassemia and sickle cell disease,” stated Marina Cavazzana, MD, Professor of Medicine at Paris Descartes University and Research Director at the Centre for Clinical Research in Biotherapy, Necker Hospital, Paris France. “The beta-hemoglobinopathies are the most prevalent inherited disorders worldwide, and they result in substantial morbidity and mortality. The HGB-205 study builds on early and encouraging clinical data from the LG001 study based on the pioneering work of Professor Philippe Leboulch and colleagues at the Universities of Paris and Harvard, Inserm and the French Atomic Energy and Alternative Energies Commission (CEA) research center in Paris.”
- Another phase 1/2 study is also currently ongoing in the US. The HGB-204 is a non randomized, open label, multi-site, single-dose, Phase 1/2 study in up to 15 adults with beta-thalassemia major. The study will evaluate the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin® BB305 Drug Product [autologous CD34+ hematopoietic stem cells transduced with LentiGlobin® BB305 Lentiviral Vector encoding the human Beta-A(T87Q)-globin gene]. (NCT01745120)
Is
general: Yes
