New Data from Largest Lovo-cel Gene Therapy Trial in Sickle Cell Disease

Mark Walters, MD

Data from the largest clinical trial of gene therapy for sickle cell disease (SCD) was presented at the American Society of Hematology (ASH) Annual Meeting and Exposition. Mark Walters, MD, UCSF Benioff Children's Hospital, shared his team's updated clinical results on lovo-cel (bb1111; LentiGlobin) in patients with sickle cell anemia (SCA).

The therapy works through use of autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) transduced with the BB305 lentiviral vector encoding a modified β-globin gene. This results in the production of HbA^T87Q, an anti-sickling hemoglobin (Hb).

Efficacy and safety results for the study's Group C is reported along with the results of additional investigations in 2 patients in the group with persistent anemia.

Progress with the First Gene Therapy in SCD

The ongoing phase 1/2 HCG-206 study (NCT02140554) included patients with sickle cell disease and recurrent severe vaso-occlusive episodes (VOEs) between the ages of 12-50 years.

The participating patients underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and lovo-cel infusion.

Investigators assessed lab evaluations, SCD-related outcomes, and safety. Data are reported by median and all timepoints are from lovo-cel infusion.

Study Outcomes of Gene Therapy in Sickle Cell Disease

According to the study, adverse events (AEs) experienced with the lovo-cel treatment regimen generally reflected the known AEs of HSPC collection and busulfan conditioning regimen, or those commonly seen in this population. At least one serious adverse event occurred in 15 patients (43%) after lovo-cel infusion. Abdominal pain, drug withdrawal syndrome from opiates, nausea, vomiting, and dehydration, were reported the most.

Complete resolution of severe VOEs was achieved in 28 of 29 total patients after lovo-cel infusion during the 2-year parent study, which was compared with 3.5 annual events in the 2 years prior to study enrollment.

In long-term follow up study, no severe VOEs were reported and key hemolysis markers approached normal levels.

A total of 35 patients in Group C had received a lovo-cel infusion by July 2021, with a median follow-up of 20.9 months. Neutrophil engraftment was achieved on Day 20, and platelet engraftment was achieved on Day 36.

No cases of veno-occlusive liver disease, graft failure, replication-competent lentivirus, vector-mediated insertional oncogenesis, or hematologic malignancies were observed.

From 6 months after last infusion, through the final study visit, the median vector copy number in peripheral blood remained stable in all patients (≥1 c/dg) which resulted in median HbA^T87Q levels of ≥5 g/dL during time.

Without transfusions, patients' median total Hb level increased from 6 months through last visit (8.5 g/dL to ≥11 g/dL). Investigators reported that at least 40% of total Hb was a contribution of HbA^T87Q.

Could α-Globin Trait Contribute to Anemia After Lovo-cel Infusion?

As of March 2022, additional investigations had been conducted in 2 patients presenting with persistent anemia. Investigators stated that their clinical and pathological findings led them to initially suspect myelodysplastic syndrome (MDS). However, there were no clinical symptoms that suggested hematologic malignancies. According to Integration Site Analysis and Next-Generation Sequencing, no driver mutations nor clonal process were identified, and no chromosomal abnormalities on karyotyping among up to 205 metaphases.

One patient presented with neutropenia and both were experiencing persistent anemia despite also exhibiting adequate production of HbA^T87Q . Additionally, their bone marrow morphology showed erythroid specific dysplasia (binucleated or trinucleated cells) consistent with dyserythropoiesis, which according to investigators, has been seen in other hemoglobinopathies. Trisomy 8 levels were low (≤7.7%), and only observed by fluorescence in situ hybridization analysis.

At Month 18, anemia was present in both patients. One patient maintained total Hb of 9.8 g/dL without transfusions. Chronic infusions were necessary for the other patient to maintain Hb 10.3 g/dL at this time, though they had otherwise normal complete blood counts.

Similarly to Group C, after lovo-cel infusion both patients experienced a reduction or resolution of severe VOEs. Alternatively, these are the only patients of the study to have 2 α-globin deletions (−α3.7/−α3.7). Therefore, investigators proposed that α-globin trait may contribute to anemia and dyserythropoiesis after lovo-cel infusion.

"In Group C of the HGB-206 study, one-time treatment with lovo-cel resulted in sustained production of HbAT87Qand near-complete resolution of severe VOEs," they wrote. "Investigations to date in both patients with anemia have not confirmed MDS; thus, currently no hematologic malignancies have occurred in Group C. Ongoing long-term follow-up should be continued for all pts receiving GT."