“Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease”, Julie Kanter, Mark C. Walters, Lakshmanan Krishnamurti, Markus Y. Mapara, Janet L. Kwiatkowski, Stacey Rifkin-Zenenberg, Banu Aygun, Kimberly A. Kasow, Francis J. Pierciey Junior, Melissa Bonner, Alex Miller, Xinyan Zhang, Jessie Lynch, Dennis Kim, Jean-Antoine Ribeil, Mohammed Asmal, Sunita Goyal, Alexis A. Thompson, John F. Tisdale2021-12-12 (; similar)⁠:

Background: Sickle cell disease is characterized by the painful recurrence of vaso-occlusive events. Gene therapy with the use of LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces an antisickling hemoglobin, HbAT87Q.

Method: In this ongoing phase 1–2 study, we optimized the treatment process in the initial 7 patients in Group A and 2 patients in Group B with sickle cell disease. Group C was established for the pivotal evaluation of LentiGlobin for sickle cell disease, and we adopted a more stringent inclusion criterion that required a minimum of 4 severe vaso-occlusive events in the 24 months before enrollment. In this unprespecified interim analysis, we evaluated the safety and efficacy of LentiGlobin in 35 patients enrolled in Group C. Included in this analysis was the number of severe vaso-occlusive events after LentiGlobin infusion among patients with at least 4 vaso-occlusive events in the 24 months before enrollment and with at least 6 months of follow-up.

Results: As of February 2021, cell collection had been initiated in 43 patients in Group C; 35 received a LentiGlobin infusion, with a median follow-up of 17.3 months (range, 3.7 to 37.6). Engraftment occurred in all 35 patients. The median total hemoglobin level increased from 8.5 g per deciliter at baseline to 11 g or more per deciliter from 6 months through 36 months after infusion. HbAT87Q contributed at least 40% of total hemoglobin and was distributed across a mean (±SD) of 85±8% of red cells. Hemolysis markers were reduced. Among the 25 patients who could be evaluated, all had resolution of severe vaso-occlusive events, as compared with a median of 3.5 events per year (range, 2.0 to 13.5) in the 24 months before enrollment. 3 patients had a nonserious adverse event related or possibly related to LentiGlobin that resolved within 1 week after onset. No cases of hematologic cancer were observed during up to 37.6 months of follow-up.

Conclusion: One-time treatment with LentiGlobin resulted in sustained production of HbAT87Q in most red cells, leading to reduced hemolysis and complete resolution of severe vaso-occlusive events. (Funded by Bluebird Bio; HGB-206 ClinicalTrials.gov number, NCT02140554.)

Figure 3a: Changes in the Rate of Vaso-Occlusive Events before and after LentiGlobin Infusion. Severe vaso-occlusive events (Panel A) and all vaso-occlusive events (Panel B) were assessed in 25 patients in the transplant population with vaso-occlusive events who had met the criterion of a minimum of 4 severe vaso-occlusive events during the 24 months before study enrollment and also met the minimum follow-up of 6 months after the LentiGlobin infusion required for analysis. The gray shaded area represents the period during which the patients were receiving preharvest transfusions. A vaso-occlusive event was defined as an episode of acute pain with no medically determined cause other than a vaso-occlusion, including acute episodes of pain, acute chest syndrome, acute hepatic sequestration, acute splenic sequestration, and acute priapism. A severe vaso-occlusive event was defined as such an event leading to a visit to a hospital or emergency department lasting for at least 24 hours, at least two visits to a day unit or emergency department during a 72-hour period (with both visits requiring intravenous treatment), or an episode of priapism lasting more than 2 hours and resulting in a visit to a medical facility. In Panels A and B, the asterisk indicates the death of a patient from sickle cell-related cardiopulmonary disease that was deemed to be unrelated to the LentiGlobin infusion. An adjudication committee is currently assessing reported vaso-occlusive events.
Figure 3b: All Vaso-Occlusive Events.

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Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease