Sickle Cell And Beta-Thalassemia Bend To Gene Manipulation By CRISPR/Vertex And Bluebird
Executive Summary
Data for new genetic methods to tackle severe hemoglobinopathies presented at the EHA meeting bring more confidence for bluebird’s gene therapy LentiGlobin and early suggestions of a functional cure with CRISPR gene editing with CRISPR Therapeutics/Vertex’s CTX001.
CRISPR Therapeutics AG and Vertex Pharmaceuticals Inc.’s investigational CRISPR-based gene editing therapy CTX001 looks like it could offer a new treatment strategy for beta-thalassemia and sickle cell disease, new data presented at the virtual European Hematology Association meeting suggest.
The data came amid more mature results also presented at the virtual meeting for bluebird bio Inc.’s gene therapies LentiGlobin and betibeglogene autotemcelin the same indications, and together they reinforce the potential for genetic manipulation to provide life-changing treatment for these conditions.
In recent years, the two hemoglobinopathies have seen novel treatments come to the market that ameliorate their symptoms but these new genetic-based approaches seek to tackle their underlying genetic causes and offer the hope of functional cures.
Bluebird’s product is closer to market having already been approved as Zynteglo in the EU for transfusion-dependent beta-thalassemia (TDT) and additional filings for sickle cell disease (SCD) and TDT in the US are expected next year.
Bluebird announced new data from its ongoing Phase I/II HGB-206 study of LentiGlobin for adult and adolescent patients with SCD that showed a near-complete reduction of serious vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). The company is hoping to make an accelerated approval application for the product in the second half of 2021, it said, having already reached an agreement with the US Food and Drug Administration.
SCD is caused by a mutation in the β-globin gene that leads to the production of abnormal sickle hemoglobin (HbS). LentiGlobin for SCD works by adding functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic stem cells (HSCs) so that their red blood cells can produce anti-sickling hemoglobin, HbAT87Q. This decreases the proportion of HbS, reducing the amount of sickled red blood cells, and thereby hemolysis and other complications such as VOCs and ACS.
The new data from HGB-206, in which a total of 34 patients have been treated, are specifically from the 25-patient group C cohort that uses the new manufacturing process for LentiGlobin and takes HSCs collected from peripheral blood after mobilization with plerixafor, rather than via bone marrow harvest.
In 16 patients of these patients who have six or more months’ follow-up, median levels of gene therapy-derived anti-sickling hemoglobin, HbAT87Q, were maintained with HbAT87Q contributing at least 40% of total hemoglobin.
There was a 99.5% mean reduction in annualized rate of VOC and ACS among the 14 patients who had at least six months of follow-up and a history of VOCs or ACS. These 14 patients had a median of eight events in the two years prior to treatment.
The VOC/ACS data were particularly impressive, analysts said, increasing from the 99% reduction that was presented at the American Society of Hematology in December. SC141319
Patients demonstrated consistent expression of HbAT87Q hemoglobin over time, with 44% expression six months after treatment and 52% expression at 24 months.
Next it will be key, commented analysts at SVBLeerink in a 12 June note, to show consistency of drug product and durability of treatment effect out to 18 months post-treatment.
These data will form the basis of the planned accelerated filing , which is now similar in timing to the planned US filing of the product in TDT in the second or third quarter of 2021, lining up the company for potential back-to-back approvals in 2022, the analysts noted.
Meanwhile, the updated data for betibeglogene autotemcelin in TDT from the Phase III Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies were also positive, showing sustained transfusion independence (TI) and TDT across ages and genotypes; again these will support the upcoming US filing.
Achieving TI (defined as no red blood cell transfusion requirements for 12 or more months while maintaining normal hemoglobin levels (9 g/dL or higher) is the main aim of treatment. The data from younger patients is important as treatment with gene therapy earlier in life is thought to be associated with better overall outcomes.
Twenty three patients have been treated to date, with a median follow-up of 19.4 months andage range of 4-34. 89% of evaluable patients (17/19) achieved the primary endpoint of TI, with median weighted average total Hb levels of 11.9 g/dL, well within the normal hemoglobin range of 9g/dL or higher. These 17 patients previously required a median of 17.5 transfusions per year.
In the Northstar-3 study, 75% (six of eight) of evaluable patients achieved TI, with median weighted average total Hb levels of 11.5 g/dL during TI, and continued to maintain TI for a median of 13.6 months as of the data cut off.
85% of patients (11/13) with at least seven months of follow-up had not received a transfusion in more than seven months at time of data cut off; they previously required a median of 18.5transfusions per year. In these patients, gene therapy-derived HbAT87Q supported total Hb levels ranging from 8.8–14.0 g/dL at last visit.
CRISPR Therapy
For CRISPR Therapeutics/Vertex’s CTX001, the new results are from a just a handful of patients in two Phase I/II studies (CLIMB-111 and CLIMB-121) but they hint at the novel treatment’s potential for producing durable therapeutic effects; the safety results also augur well so far.
The CLIMB-111 study in TDT became the first industry-sponsored clinical trial of a CRISPR gene editing therapy when it was launched in 2018, and the companies say the new data show clinical proof of concept for CTX001 in this disease. (Also see "CRISPR Therapeutics, Vertex Initiate First Industry-Sponsored Trial – What’s Next?" - Scrip, 6 Sep, 2018.)
Lead author Haydar Frangoul of the Sarah Cannon Research Institute said the encouraging data, “demonstrate, in essence, a functional cure for patients with beta-thalassemia and SCD.”
The results consist of longer-duration follow-up data for the first TDT patient treated with CTX001 and new data for the second TDT patient treated that show they are transfusion independent at five and 15 months after CTX001 infusion. CRISPR Therapeutics and Vertex announced initial data for the first TDT patient in November.
These are complemented by data from the first SCD patient that shows them to be free from vaso-occlusive crises at nine months after CTX001 infusion.
In total, the companies say, five patients with beta-thalassemia and two patients with SCD have been treated to date with CTX001 and all have successfully engrafted.
CTX001 exploits the fact that both inherited hemoglobinopathies – caused by mutations in the β-globin gene – can be tackled by increasing the expression of fetal hemoglobin (HbF) in patients.
Fetal hemoglobin produced by an unborn baby gradually gives way to the adult form during the six months before and after birth, and as only adult hemoglobin contains the disease-causing mutations, symptoms of these diseases do not appear until the hemoglobin switching has occurred.
But individuals who have a rare benign hereditary condition where they continue to produce fetal hemoglobin into adulthood, and who also have beta-thalassemia or SCD, have reduced or no disease symptoms, because their fetal hemoglobin substitutes for the diseased adult hemoglobin.
The CRISPR Therapeutics/Vertex therapy takes advantage of this phenomenon. The treatment involves isolating a patient’s CD34+ hematopoietic stems cells from their blood, editing them using CRISPR/Cas9 to increase fetal hemoglobin expression, and then returning the edited cells to the patient. Over time, the stem cells start to produce red blood cells with increased levels of fetal hemoglobin to reduce or eliminate patient’s symptoms.
Despite the small number of patients to date, analysts have deemed the data highly encouraging and say they bode well for the program as a whole.
CTX001 has already been designated a regenerative medicine advanced therapy (RMAT) by the FDA and has both US and EU orphan drug status, plus an FDA fast-track designation for both SCD and TDT.
The updated data for patient 1 in CLIMB-111 shows that at 15 months after CTX001 infusion, the patient was transfusion independent and had total hemoglobin levels of 14.2 g/dL, fetal hemoglobin of 13.5 g/dL, and F-cells (erythrocytes expressing fetal hemoglobin) of 100.0%. Bone marrow allelic editing was 78.1% at six months and 76.1% at one year. Before treatment, the patient had a transfusion requirement of 34 units of packed red blood cells per year.
At five months after CTX001 infusion, patient 2 – who before therapy needed 61 units of packed red blood cells per year – was transfusion independent and had total hemoglobin levels of 12.5 g/dL, fetal hemoglobin of 12.2 g/dL and F-cells of 99.4%.
Strong SCD Data
In sickle cell disease, updated data from the first patient in the CLIMB-121 study showed that at nine months after CTX001 infusion, the patient was free of VOCs, was TI and had total hemoglobin levels of 11.8 g/dL, 46.1% fetal hemoglobin, and F-cells of 99.7%. Bone marrow allelic editing was 81.4% at six months. Previously, this patient had seven VOCs and five packed red blood cell transfusions per year.
None of the patients had serious adverse events deemed to be related to the treatment.
Analysts at Jefferies said the key biomarker data show efficient gene editing and engraftment, adding in a 12 June note that the trajectory of patient 2’s fetal hemoglobin levels out to five months was in line with patient 1’s, demonstrating some consistency. “Overall, these data support BCL11A editing in bone marrow CD34+ cells with sustained engraftment potentially supportive of long-term clinical efficacy.”
CRISPR Therapeutics CEO Samarth Kulkarni said, “With these new data, we are beginning to see early evidence of the potential durability of benefit from treatment with CTX001, as well as consistency of the therapeutic effect across patients.” Vertex’s CEO Reshma Kewalramani called the data “remarkable.”
Other Therapies
Until recently, there were no approved treatments for SCD, but 2019 brought two to the market: Novartis AG’s P-selectin antagonist, Adakveo (crizanlizumab), which treats crisis precipitated by vaso-occlusion in sickle cell anemia; and Global Blood Therapeutics Inc.’s Oxbryta (voxelotor) an allosteric modifier of hemoglobin oxygen affinity, which allows red blood cells to deliver oxygen more efficiently. Neither product tackles the underlying cause of the disease.
For beta-thalassemia, Acceleron Pharma Inc./Bristol-Myers Squibb Co.’s erythroid maturation agent Reblozyl (luspatercept) was first approved in the US last November for the treatment of anemia in TDT patients.
Other similar therapies under development include Sangamo Therapeutics Inc./Sanofi’s BIVV-003 for SCD, and ST-400 for TDT, which use Sangamo's proprietary zinc finger nuclease genome-editing technology platform.
China’s Shanghai Bioray Laboratory is developing a gamma-globin reactivated autologous hematopoietic stem cell therapy for TDT, which uses a CRISPR/Cas9 gene editing system and is in Phase I/II.