Generic Name: Lovotibeglogene autotemcel

Proprietary Name: Lyfgenia^® (Bluebird Bio)

Therapeutic Category: Autologous Cellular Immunotherapy

FDA Approval: December 8, 2023

Sickle Cell Disease Background: Sickle cell disease is characterized by sickle hemoglobin (HbS) and impaired red cell function because of a single point mutation in the gene encoding β-globin.¹ Sickle hemoglobin production and its subsequent polymerization leads to RBC sickling, which is when RBCs become crescent- or “sickle”-shaped and, in turn, do not bend or move easily, resulting in blocked blood flow to the body.^2,3 Complications of sickle cell disease include vaso-occlusive crises (VOCs), progressive vasculopathy, and chronic hemolytic anemia, all of which increase patient mortality.¹

Episodes of vaso-occlusion remain the key symptom of sickle cell disease. Early in vitro studies have highlighted sickle RBC adhesive interactions with the endothelium causing vaso-occlusive events. It is proposed that activated adherent leukocytes initiate VOCs in collecting venules, whereas sickle cell RBCs affect the smaller vessels. Vaso-occlusion can be triggered by stress, inflammation, increased viscosity, decreased flow, hemolysis, or a combination of factors. A combination of factors can include endothelial activation by sickle cell RBCs and inflammatory mediators, adherent leukocyte recruitment, activation of recruited neutrophils/leukocytes, sickle cell RBCs and adherent neutrophil interactions, vascular clogging by cell aggregation, increased transit time for deoxygenation-induced hemoglobin polymerization, and ischemia. Because they are the hallmark symptom of sickle cell disease, vaso-occlusive events have been used as clinical end points and efficacy measures in advancing therapeutic treatment.⁴

A vaso-occlusive event in Bluebird Bio–sponsored clinical studies for lovotibeglogene autotemcel was defined as episodes of acute pain with no medically determined cause other than a vaso-occlusion lasting more than 2 hours and severe enough to require care at a medical facility. This included acute chest syndrome (ACS) requiring oxygen treatment and/or blood transfusion, acute hepatic sequestration, acute priapism lasting 2 hours and requiring care at a medical center, and acute splenic sequestration. Severe vaso-occlusive events were defined as a 24-hour hospital stay or ED visit, or at least 2 visits to a hospital or ED over a 72-hour period, with both visits requiring intravenous treatment. All vaso-occlusive events of priapism were considered severe vaso-occlusive events.^1,5

Before recent clinical trials, disease-modifying therapies such as HLA-matched sibling allogeneic hematopoietic stem cell transplantation could help reduce symptoms or halt disease progression but have been associated with transplant-related mortalities like graft-vs-host disease and graft rejection.^1,3 Another disease-modifying agent is voxelotor, which has been shown to increase Hb concentrations and reduce markers of hemolysis consistent with the inhibition of HbS polymerization. Despite these findings, voxelotor has not shown a significant decrease in vaso-occlusive events in patients.⁶ Alternatively, crizanlizumab, an anti–P-selectin monoclonal antibody, has been shown to decrease rates of sickle cell–related pain crises with association of low incidences of adverse events. Subsequently, there were 5 deaths in the crizanlizumab trial—2 associated with high-dose crizanlizumab (5 mg/kg), 1 associated with low-dose crizanlizumab (2.5 mg/kg), and 2 in the placebo group.^7,8 Lovotibeglogene autotemcel is unique compared with these other therapies, given that in most patients who had at least 6 months of follow-up, the occurrence of vaso-occlusive events was resolved, and no deaths were directly related to its treatment in clinical trials.¹

Indication: Treatment of patients 12 years or older with sickle cell disease and a history of vaso-occlusive events⁹

Treatment Process³:

1. Pre-collection and hematopoietic stem and progenitor cell (HSPC) collection
2. Lovotibeglogene autotemcel manufacturing through the ex vivo transduction of autologous HSPCs with the BB305 lentiviral vector containing the β^A-T87Q transgene
3. Myeloablative conditioning
4. Lovotibeglogene autotemcel infusion
5. Engraftment of HSPCs leading to the production of HbA^T87Q with subsequent follow-up

Limitations of Use: Some patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that requires chronic RBC transfusions.⁹

Clinical Pharmacology: Autologous transplantation of HSPCs transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces anti-sickling hemoglobin (HbA^T87Q).¹ HbA^T87Q, similar to wild-type HbA, reduces intracellular and total HbS concentrations and is designed to inhibit the polymerization of HbS, which limits the sickling of RBCs.⁹

Pharmacodynamics: HbA^T87Q increased after administration and stabilized by month 6 after infusion. At month 6, patients had a median HbA^T87Q of 5.2 g/dL, which remained consistent with a median of 5.5 g/dL at month 24. HbA^T87Q comprised a median 45.7% of total non-transfused Hb at month 24.⁹

Clinical Efficacy:

Group A and B Trials³

In this phase 1 and 2 nonrandomized, open-label, multisite clinical study, a total of 9 patients were placed among 3 groups to receive lovotibeglogene autotemcel for sickle cell disease. Eligible patients were 18 years or older with a documented β^S/β^S, β^S/β⁰, or β^S/β⁺ genotype and a severe sickle cell disease diagnosis determined by the investigator. Patients with severe sickle cell disease must have experienced recurrent (2 or more per year in the prior 2 years) severe VOCs, recurrent episodes of ACS (2 or more in the prior 2 years, with 1 or more episode in the prior year), a history of overt stroke, or a tricuspid regurgitant jet velocity greater than 2.5 m/s. Seven patients were in the first group and were treated with lovotibeglogene autotemcel produced using the original manufacturing process, which resulted in suboptimal expression of HbA^T87Q. To optimize biologic and clinical outcomes, patients in group B received lovotibeglogene autotemcel produced from a more refined manufacturing process in addition to changes in the treatment protocol. Eligibility for group B was expanded to include patients who satisfied other clinical severity criteria before chronic red cell therapy (CRCT) was instituted, including 2 or more severe, recurrent VOCs per year in the 2 years before initiating CRCT and/or 2 or more episodes of ACS with 1 or more episode in the year before initiating CRCT. Group B was stratified into group B1 and group B2. Group B1 received lovotibeglogene autotemcel produced using both the original and the refined manufacturing process, whereas group B2 consisted of a patient who received lovotibeglogene autotemcel produced only by the refined manufacturing product.

Before treatment, patients underwent pre-harvest transfusions. In group A, patients were required to have a simple or exchanged packed RBC transfusion within 7 days or less before bone marrow harvest to establish a mandatory Hb target of 10 to 12 g/dL and an HbS proportion of less than 30% of total Hb. Patients in group B underwent the same procedure for more than 60 days before collection to reduce stress erythropoiesis. The patient in group B2 specifically also underwent rescue HSPC collection by plerixafor mobilization/apheresis. Finally, before treatment, myeloablative conditioning with single-agent busulfan was administered to patients over 4 days, and after 1 week with a minimum 72-hour washout period, patients received the lovotibeglogene autotemcel infusion.

Biological efficacy end points included functional β^A-T87Q-globin expression, Hb proportions (HbS/HbA^T87Q), total non-transfused Hb (HbS + fetal hemoglobin [HbF] + hemoglobin A₂ [HbA₂] + HbA^T87Q), and vector copy number (VCN). Clinical efficacy end points were the frequency of VOCs and ACS after lovotibeglogene autotemcel infusion compared with the 24 months before informed consent. Safety end points included successful neutrophil engraftment (absolute neutrophil count, 50 cells/mm³ for 3 days), platelet engraftment (Plt, 50/μL for 3 days without platelet transfusions), and evaluation of adverse events.

Group C Trial¹

In this nonrandomized, open-label clinical trial, 35 patients were treated with a refined and optimized version of lovotibeglogene autotemcel and followed for a median of 17.3 months. Patients were included if they were between 12 and 50 years of age, had been diagnosed with sickle cell disease, and had a clinically stable Karnofsky or Lansky performance. The primary efficacy end point was the complete resolution of severe vaso-occlusive events between 6 and 18 months after the lovotibeglogene autotemcel infusion. All vaso-occlusive events were reported and assessed. Secondary end points included the change in Hb concentration from baseline, the absolute total Hb concentration, and the change in markers of hemolysis. Vector copy number over time was also included as a pharmacodynamic end point.

Twenty-five patients were included in the transplant population with vaso-occlusive events, which was defined as patients who had experienced 4 severe vaso-occlusive events in the 24 months before enrollment. Results from a non-prespecified interim analysis showed that among the 25 patients with at least 6 months of follow-up after the lovotibeglogene autotemcel infusion, no severe vaso-occlusive events were reported compared with a median rate of 3.5 per year (range, 2.0-13.5 years) in the 24 months before enrollment. Three patients had vaso-occlusive events after the infusion with an overall median rate of 0 per year (range, 0-5.9 years).

The VCN in peripheral blood remained stable 6 months after the infusion until the last study visit, which indicated the persistence of vector-positive, long-term repopulating HSPCs capable of sustaining erythroid cell generation and the production of HbA^T87Q. The median total Hb value increased from 8.5 g/dL at baseline to 11.0 g/dL at 6 months and was durable for 36 months, with HbA^T87Q contributing to at least 40% of total Hb. Sickle Hb levels were about 50% from 6 to 36 months after infusion, and HbF production was minimal after the lovotibeglogene autotemcel infusion. The median total Hb and median HbA^T87Q concentrations were 13.4 g/dL and 5.9 g/dL, respectively, for the 8 adolescent patients who had received follow-up care for at least 6 months. Exploratory data showed that HbA^T87Q expression was seen at least 6 months after infusion. About 15% of RBCs did not contain β^A-T87Q and remained at risk of sickling.

Twelve patients had at least 1 serious adverse event after the lovotibeglogene autotemcel infusion. The most commonly reported adverse events were abdominal pain, drug withdrawal syndrome (opiate), nausea, and vomiting.

Overall, 25 patients in the transplant population with vaso-occlusive events with at least 6 months of follow-up had complete resolution of severe vaso-occlusive events after lovotibeglogene autotemcel treatment. One-time treatment led to stable and durable production of HbA^T87Q with expression in around 85% of red cells, reduced levels of HbS and key hemolysis markers, and normalization of total Hb during 54.8 patient-years of follow-up.

After FDA approval of lovotibeglogene autotemcel, Bluebird Bio presented clinical data outside the non-prespecified interim analysis describing the effectiveness of lovotibeglogene autotemcel for sickle cell disease. When evaluating the end points of complete resolution of vaso-occlusive events and severe vaso-occlusive events in the 6 to 18 months after infusion, 30 of 32 patients (94%) had resolved severe vaso-occlusive events, and 28 of 32 (87.5%) did not experience any vaso-occlusive events at all.⁹

Safety:

• Side Effects: Decreased appetite, stomatitis, anemia, febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, sickle cell anemia with crisis, pyrexia, increased γ-glutamyl transferase, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, pharyngitis, nausea, increased serum bilirubin, bacteremia, fever, hematologic malignancy, and infusion-related reactions^9,10
• Adverse Reactions: Hematologic malignancy, delayed platelet engraftment, neutrophil engraftment failure, insertional oncogenesis, and hypersensitivity reactions⁹
• Black Box Warning: Hematologic malignancies have occurred in patients treated with Lyfgenia. Patients should be monitored closely for evidence of malignancy by checking CBCs at least every 6 months and through integration site analysis at months 6 and 12 and as warranted.⁹
• Special Populations:

• Pediatric patients (12 years and younger)

• Has not been studied and no data are available⁹

• Older adult patients (65 years and older)

• Has not been studied in patients 65 and older. Autologous hematopoietic stem cell transplantation must be appropriate for a patient to be treated.⁹

• Patients seropositive for HIV

• Negative serology test for HIV before apheresis is necessary for all patients. Lyfgenia has not been studied in patients with HIV and should not be administered upon a positive HIV test.⁹

• Patients with renal impairment

• Has not been studied in patients with a CrCl of 70 mL/min/1.73 m² or less. The patient’s renal function should be assessed before administration of Lyfgenia.⁹

• Patients with hepatic impairment

• Lyfgenia has not been studied in patients with advanced hepatic disease. The patient’s hepatic function should be assessed before administration of Lyfgenia.⁹

• Pregnancy, Lactation, and Reproductive Health: There are no data on reproductive, developmental, and drug presence in breast milk. Therefore, a negative serum pregnancy test must be confirmed before starting mobilization and reconfirmed before conditioning procedures and before Lyfgenia administration. Lyfgenia should not be administered to women who are pregnant and is not recommended for women who are breastfeeding.⁹
• Drug-Drug Interactions and Testing Interactions: Lyfgenia may interact with antiretrovirals, hydroxyurea, iron chelation, and live vaccines. Proper discontinuation or interruption of therapy is recommended. Lyfgenia may also interfere with PCR-based testing.⁹

Dosing: Lyfgenia is for autologous use only. The minimum recommended dose of Lyfgenia is 3 × 10⁶ CD34⁺ cells/kg.⁹

Administration: CD34⁺ cells are administered in 1 to 4 infusion bags as a 1-time single-dose intravenous suspension.⁹

Storage: Lyfgenia is packaged as a 20-mL infusion bag, overwrap, and metal cassette. It must be kept in the liquid nitrogen phase stored at –140°C or less until ready for thaw and administration.⁹

Conclusion: Lovotibeglogene autotemcel is a gene therapy indicated for patients 12 years and older who have sickle cell disease and a history of vaso-occlusive events. Other disease-modifying therapies such as voxelotor and crizanlizumab have been used to inhibit HbS polymerization and reduce rates of sickle cell–related pain crises, respectively, but have failed to completely resolve the occurrence of vaso-occlusive events. Clinical trial data with lovotibeglogene autotemcel have shown efficacy by attaining clinical end points, described as the reduction of vaso-occlusive events. Lovotibeglogene autotemcel has a black box warning for hematologic malignancies, and patients should be monitored closely on this medication. In addition, this medication has special storage and specific administration requirements. Lovotibeglogene autotemcel is an appropriate therapy for eligible patients who experience vaso-occlusive events.

References

1. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386(7):617-628. https://doi.org/10.1056/NEJMoa2117175
2. National Heart, Lung, and Blood Institute. What is sickle cell disease? Revised August 30, 2023. Accessed January 5, 2023. https://www.nhlbi.nih.gov/health/sickle-cell-disease#:~:text=Normally%2C%20red% 20blood%20cells%20are,the%20rest%20of%20th%20body
3. Kanter J, Thompson AA, Pierciey FJ Jr, et al. Lovo-cel gene therapy for sickle cell disease: treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023;98(1):11-22. https://doi.org/10.1002/ajh.26741
4. Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013;122(24):3892-3898. https://doi.org/10.1182/blood-2013-05-498311
5. Rowlands J, O’Leary C. Bluebird Bio announces FDA approval of Lyfgenia^TM (lovotibeglogene autotemcel) for patients ages 12 and older with sickle cell disease and a history of vaso-occlusive events. Bluebird Bio, Inc; 2023. Accessed January 18, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-fda-approval-lyfgeniatm-lovotibeglogene
6. Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519. https://doi.org/10.1056/NEJMoa1903212
7. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439. https://doi.org/10.1056/NEJMoa1611770