Clinical Trial Updates

Recent Clinical Trial Updates  (Last Updated: June 14, 2021)

I.  Clinical Trials of Gene Therapy in Transfusion-Dependent Beta Thalassemia

(a) beti-cel (LentiGlobin):

Findings from Long-Term Follow-up study (LTF-303)

After completing any of the Phase 1/2 or Phase 3 studies of beti-cel in transfusion-dependent β-thalassemia, participants were invited to enroll in a 13-year long-term follow-up study (LTF-303). 51 of the 63 total treated patients across age groups and genotypes have enrolled in LTF-303 to date. Of the 51 patients enrolled in LTF-303, 40 patients achieved transfusion independence: 15/22 (68%) of patients treated in Phase 1/2 and 25/29 (86%) patients treated in Phase 3 trials. All patients who achieved transfusion independence remained free from transfusions through their last follow-up. Weighted average hemoglobin in patients who achieved transfusion independence reached normal or near-normal levels: in the Phase 1/2 studies it was 10.3 g/dL, and in the Phase 3 studies it was 11.8 g/dL. Liver iron concentration (LIC) in patients who achieved transfusion independence decreased toward normal levels over time, particularly in patients with a high iron burden at baseline. Patients with severe (LIC >15 mg/g, n=5) and significant (LIC ≥7 – 15 mg/g, n=14) iron burden at baseline had a median reduction of 59% and 37%, respectively, from baseline to Month 48.

Prior to beti-cel infusion, all patients were on iron chelation. Of the 40 patients who achieved transfusion independence following treatment with beti-cel, 73% restarted iron chelation after beti-cel infusion and the majority (59%) of patients who restarted iron chelation after infusion have since stopped; 28% were able to receive phlebotomy (blood removal), which is a preferred method for iron reduction. Of the 11 patients who were able to receive phlebotomy, 10 have not received phlebotomy in more than seven months and their total unsupported Hgb at last study visit ranged from 10.5 to 14.0 g/dL.

There were no deaths, and no events of insertional oncogenesis or malignancy have been reported in patients enrolled in LTF-303.

Findings from pediatric patients treated in Phase 3 trials

As of March 9, 2021, 27 pediatric patients (16 of whom were <12 years, and 11 of whom were ≥12 to <18 years) had been treated in the Northstar-2 and Northstar-3 studies and had a median follow-up of 25.5 months (min-max: 4.1 – 41.5 months).

Following treatment with beti-cel, 91% of evaluable patients under the age of 18 years, including 10 patients under age 12, achieved transfusion independence. These patients continue to be free of transfusions through their last follow-up, with median weighted average Hb levels of 10.0 g/dL in patients under age 12 (n=10) and 11.7 g/dL in patients age 12-18 (n=10).

Adverse events in pediatric patients during the HGB-207 and HGB-212 trials that were considered related or possibly related to beti-cel were non-serious and included tachycardia (Grade 1, n=1) and abdominal pain (Grade 1, n=2) on the day of infusion, and Grade 3 thrombocytopenia in one patient post-infusion. Grade 4 veno-occlusive liver disease occurred in two patients (ages ≥12 to <18 years) and one Grade 2 event occurred in a patient age <12 years; all events resolved after treatment with defibrotide. There were no deaths, no graft failures or Graft Versus Host Disease, and no cases of insertional oncogenesis. No clonal predominance has been observed.

Further information is available in the press release at:

II.  Clinical Trials of Gene Editing in Transfusion-Dependent Beta Thalassemia

(a) CTX-001:

All Fifteen Thalassemia Patients Treated with CTX001 Gene Editing Therapy Are Now Transfusion Independent

CRISPR Therapeutics and Vertex Pharmaceuticals have announced early results from their CLIMB-111 Study in which transfusion-dependent beta thalassemia patients are treated with a gene editing therapy called CTX001. CTX001 is a therapy in which CRISPR/Cas9-based gene editing is performed on a patient’s hematopoietic stem cells in order to reactivate fetal hemoglobin production. The results of the first 15 patients treated in the study, who have achieved at least 3 months of follow-up, are now available:

All 15 patients are now transfusion independent, with follow-up ranging from 4 to 26 months after CTX001 infusion. All 15 patients showed clinically meaningful improvements in their total hemoglobin levels (from 8.9 to 16.9 g/dL) and fetal hemoglobin levels (from 67.3% to 99.6%) at last visit. This includes six patients with the beta zero/beta zero or other severe genotypes.

The safety data from all 15 patients are consistent with what is typically observed following autologous stem cell transplant and myeloablative conditioning. As previously reported, one patient experienced four serious adverse events considered related or possibly related to CTX001: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome. All four serious adverse events occurred in the context of HLH and have resolved. The majority of non-serious adverse events were considered mild to moderate.

Further information about these findings is available in the press release at:

(b) ST-400:

Sangamo Therapeutics/Sanofi have announced preliminary findings from the first 3 beta thalassemia patients treated with their ST-400 gene editing therapy in the Phase 1/2 THALES Study. ST-400 is a therapy that involves gene editing of a patient’s own hematopoietic stem cells (HSCs) in order to reactivate fetal hemoglobin production. The first treated patient, who has a β0/β0 genotype, initially showed increased fetal hemoglobin levels and became transfusion-independent for a period of 6 weeks. However, after an initial transfusion-free period, this patient subsequently resumed intermittent transfusions. The second treated patient, who is homozygous for the severe β+ IVS-I-5 (G>C) mutation, showed increased fetal hemoglobin levels relative to baseline. However, this patient was still receiving intermittent transfusions, 26 weeks after treatment. The third treated patient, who has a β0/β+ genotype, initially experienced a transfusion-free period of 7 weeks. However, this patient also subsequently resumed intermittent transfusions following the initial transfusion-free period.

Further information is available in the press release at:

III. Clinical Trials for Patients with Non-Transfusion-Dependent Thalassemia

(a) Mitapivat:

Oral Mitapivat Increases Hemoglobin Levels in Non-Transfusion-Dependent Thalassemia

Agios Pharmaceuticals provided an update on the preliminary findings from their Phase 2 study of mitapivat in non-transfusion-dependent alpha- and beta-thalassemia at the 2021 European Hematology Association (EHA) virtual medical congress. Mitapivat activates the pyruvate kinase-R enzyme, which improves red blood cell energy metabolism, and was shown to improve ineffective erythropoiesis and anemia in a mouse model of thalassemia.

Mitapivat is currently being evaluated in patients with non-transfusion-dependent α- and β-thalassemia. 20 adult patients with a baseline hemoglobin (Hb) concentration of ≤10 g/dL were enrolled in the trial, including 5 patients with α-thalassemia, and 15 patients with β-thalassemia.

Preliminary findings from the Phase 2 study show that oral mitapivat treatment resulted in a ≥1.0 g/dL increase in Hemoglobin concentration in all 5 (100%) α-thalassemia patients and 11 of 15 (73.3%) patients with β-thalassemia at one or more assessments between weeks 4 and 12 of treatment. During Weeks 12-24, the mean hemoglobin change from baseline was 1.3 g/dL (1.2 g/dL for α-thalassemia patients, and 1.3 g/dL for β-thalassemia patients). Among hemoglobin responders, mean time to first ≥1.0 g/dL increase in hemoglobin concentration was 4.5 weeks. Markers of hemolysis and erythropoiesis demonstrated improvements that were consistent with the hemoglobin increase in both α-thalassemia and β-thalassemia patients.

Mitapivat was well tolerated. The most commonly reported adverse events were initial insomnia (n=10 [50%]), dizziness (n=6 [30%]) and headache (n=5 [25%]). One patient discontinued treatment during the study, although the adverse event leading to drug discontinuation was not treatment-related.

Chris Bowden, the Chief Medical Officer at Agios. said: “Our focus now is to advance the development of mitapivat in thalassemia as quickly and efficiently as possible, with the initiation of two Phase 3 studies of mitapivat, ENERGIZE and ENERGIZE-T, in not regularly transfused and regularly transfused adults with thalassemia.”

Further information about the preliminary Phase 2 findings can be found at:

(b) IMR-687

Imara has Dosed the First Thalassemia Patient in Its Phase 2b Forte Clinical Trial

Imara, Inc has dosed the first thalassemia patient in its Phase 2b Forte clinical trial, which will assess safety and tolerability of IMR-687 in patients with transfusion-dependent and non-transfusion-dependent beta thalassemia.

IMR-687 is an oral therapy that is designed to increase fetal hemoglobin in beta thalassemia. “Multiple preclinical studies show that treatment with IMR-687 enhances both the maturation and production of red blood cells in beta-thalassemia and we are looking forward to advancing this potentially transformative oral therapy for patients” said Imara President and CEO Dr. Rahul Ballal.

This study is currently enrolling adult patients (ages 18 to 65) at California’s Oncology Institute Long Beach.

Further information can be found in Imara’s press release at: 

IV. Clinical Trials of Luspatercept in Non-Transfusion-Dependent Thalassemia (NTDT)

(a) BEYOND Study of Luspatercept in NTDT:

First Data is Reported from the BEYOND Study Evaluating Luspatercept in Non-Transfusion-Dependent Thalassemia

Bristol Myers Squibb and Acceleron Pharma Inc. announced the first data from the Phase 2 BEYOND study evaluating Reblozyl® (luspatercept) in adult patients with non-transfusion dependent (NTD) beta thalassemia. The results demonstrated that 77.7% of NTD beta thalassemia patients treated with Reblozyl achieved a hemoglobin increase (≥1.0 gram/dL) compared to 0% of patients in the placebo arm. This was achieved by 72.7% of patients in the Reblozyl arm who had a mean baseline Hgb of <8.5 g/dL (versus 0% of patients in the placebo arm), and by 82.9% of patients in the Reblozyl arm who had a mean baseline Hgb of ≥8.5 g/dL (versus 0% of patients in the placebo arm). 89.6% of patients in the Reblozyl arm remained transfusion free at weeks 1-24 versus 67.3% of patients in the placebo arm. Improvements in patient-reported quality-of-life outcome measures, such as tiredness and weakness, improved along with these increases in hemoglobin levels.

The most common treatment-emergent adverse events of any grade occurring in ≥5% of NTD beta thalassemia patients were bone pain (36.5% Reblozyl versus 6.1% placebo), headache (30.2% versus 20.4%), and arthralgia (29.2% versus 14.3%). No thromboembolic events were reported in NTD beta thalassemia patients treated with Reblozyl.

“Results from the BEYOND study show the clinical potential of luspatercept to sustain the elevation of hemoglobin levels in a majority of patients regardless of their baseline hemoglobin status, and improvements were noted in quality of life outcomes in adults with non-transfusion dependent beta thalassemia,” said Dr. Ali Taher of American University of Beirut, who is one of the BEYOND study investigators.

Further information about the findings from the BEYOND Trial is available at:

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