Gene Therapy LentiGlobin Continues to Show Promising Results, Phase 1/2 Trial Data Shows

LentiGlobin, Bluebird Bio’s investigational gene therapy for sickle cell disease (SCD), continues to show promising results in SCD patients participating in the company’s Phase 1/2 HGB-206 clinical trial, according to the latest study data.

The new findings — which included data from additional patients treated in the trial, updated data from those previously reported, and exploratory analyses — were presented at the 61^st American Society of Hematology (ASH) Annual Meeting and Exposition, held Dec. 6-10 in Orlando, Fla.

LentiGlobin is a gene therapy that has been developed to increase the levels of hemoglobin — the protein that transports oxygen in the blood — in people with SCD.

The therapy works by delivering functional copies of a modified form of the beta-globin gene (β^A-T87Q-globin gene) into patients’ red blood cell precursors, known as hematopoietic stem cells, or HSCs. Once these precursors differentiate, their red blood cells start producing a modified version of hemoglobin, called HbA^T87Q.

By boosting the production of this anti-sickling form of the protein, LentiGlobin reduces the proportion of defective hemoglobin in patients’ red blood cells. That, in turn, reduces the sickling and destruction of these red blood cells and other complications associated with SCD.

The safety and efficacy of LentiGlobin is currently being evaluated in three groups — identified as A-C — of SCD patients participating in Bluebird’s ongoing open-label, Phase 1/2 HGB-206 trial (NCT02140554).

Those in group A were treated per the original trial protocol. Meanwhile, those in groups B and C received an enhanced treatment protocol, approved in 2016, that is designed to increase the therapy’s efficiency. In groups A and B, patients’ HSCs were extracted from the bone marrow, while in group C, they were extracted from the blood.

As of the data cutoff date of August 26, 2019, seven participants in group A, two in group B, and 17 in group C had been treated with LentiGlobin. According to new data presented at the meeting, only two patients from group A required regular blood transfusions after the treatment.

In addition, the updated findings revealed that the levels of anti-sickling HbA^T87Q  remained stable in all participants from groups A and B over a post-treatment follow-up period of three years.  Similarly, levels of total hemoglobin also were found to have remained stable in both patient groups over a two-year follow-up.

At the trial participants’ last visit, the median levels of anti-sickling HbA^T87Q were 0.9 g/dL among those from group A, and 3.6 g/dL and 7.1 g/dL in the two patients from group B. The median levels of total hemoglobin were 9.0 g/dL among patients from group A, and 11.3 g/dL and 13.0 g/dL among those from group B.

Normal levels of hemoglobin in the blood range from 12.5 to 17.5 g/dL.

Among 12 patients from group C who were followed for at least six months, the median levels of anti-sickling HbA^T87Q made up at least 40% of their total hemoglobin. At their last visit, the levels of anti-sickling HbA^T87Q ranged from 2.7 to 9.0 g/dL, and the levels of total hemoglobin from 9.3 to 15.2 g/dL.

In groups A and B, LentiGlobin reduced the frequency of painful vaso-occlusive crises (VOCs) and acute chest syndrome (ACS) in the two years following treatment.

Nine patients from group C who were followed for at least six months had experienced four or more VOCs or ACS episodes in the two years prior to receiving LentiGlobin. Treatment with the gene therapy led to a reduction of 99% in the frequency of annual VOCs and ACS. In this group, there were no reports of ACS or severe VOCs for up to 21 months following treatment.

Moreover, among those from group C, LentiGlobin reduced the levels of different markers of red blood cells’ destruction, including reticulocytes, lactate dehydrogenase (LDH), and bilirubin.

LentiGlobin’s  safety profile was consistent with previous data. No serious adverse events related to treatment were reported during the study. Only one mild, non-serious event of hot flush was found to be related to LentiGlobin. That event was rapidly resolved and did not require treatment.

Exploratory analyses were performed in a sub-group of patients from all three groups. In 12 participants who had been followed for at least six months, more than 70% of the individuals’ red blood cells were found to contain the anti-sickling HbA^T87Q at the last study visit, these analyses showed. Moreover, in four of these patients, nearly all their red blood cells (90%) were positive for HbA^T87Q.

In addition, exploratory analyses revealed that participants’ red blood cells were less prone to sickling following treatment with LentiGlobin.

“At ASH, the growing body of data from our clinical studies of LentiGlobin for SCD reflects results from 26 treated patients with up to four years of follow-up,” David Davidson, MD, Bluebird Bio’s chief medical officer, said in a press release.

“We continue to observe patients treated in Group C producing high levels of gene-therapy derived anti-sickling hemoglobin, HbA^T87Q, accounting for at least 40% of total hemoglobin in those with six or more months of follow-up, and exploratory assays show that HbA^T87Q is present in most red blood cells of treated patients,” Davidson said.

“The robust production of HbA^T87Q was associated with substantial reductions of sickle hemoglobin, HbS, as well as improvement in key markers of hemolysis [red blood cells’ destruction]. Most importantly, patients in Group C have not experienced any episodes of acute chest syndrome or serious vaso-occlusive crises following LentiGlobin for SCD treatment,” he added.

The company is recruiting participants with transfusion-dependent β-thalassemia (TDT) for a Phase 3 trial (NCT03207009) testing LentiGlobin. Moreover, according to the company’s pipeline, there is a Phase 2/3 trial planned in sickle cell disease for this gene therapy.