The decision was supported by efficacy data from 36 patients from the ongoing phase 1/2 HGB-206 trial (NCT02140554) and 2 patients in the phase 3 HGB-210 trial (NCT04293185).
The FDA has approved bluebird bio’s lovotibeglogene autotemcel (lovo-cel), marketed as Lyfgenia, as a treatment for sickle cell disease (SCD) in patients aged 12 years and older.1 The therapy consists of autologous CD34+ hematopoietic stem cells collected by plerixafor mobilization and apheresis, transduced with BB305 lentiviral vector (LVV) encoding the human beta-A-T87Q globin gene.
The company’s biologics license application (BLA) was supported by efficacy data from 36 patients from the ongoing phase 1/2 HGB-206 clinical trial (NCT02140554) and 2 patients in the phase 3 HGB-210 clinical trial (NCT04293185). Its efficacy was assessed based on the complete resolution of vaso-occlusive events (VOEs) between 6 and 18 months after infusion, at which time 88% (n = 28) of the 32 included patients achieved this milestone.
Lovo-cel was approved alongside Vertex and CRISPR Pharmaceuticals' exagamglogene autotemcel (exa-cel; Casgevy), which was greenlit for the same indication simultaneously. Exa-cel is the first CRISPR-based gene therapy to be approved in the United States.
"The dual approvals for 2 distinct gene therapies for severe sickle cell disease are groundbreaking. A patient population that has been overlooked for far too long now has 2 durable, and potentially curative, treatment options. These 2 therapies represent the fourth and fifth FDA approvals of gene therapies targeting rare genetic diseases in 2023, doubling the number of such therapies on the market from just 1 year ago. These milestones will propel future advancements for gene therapy across many different disease states," Tim Hunt, JD, CEO of the Alliance for Regenerative Medicine, said in a statement issued to CGTLive™.
“Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field especially for individuals whose lives have been severely disrupted by the disease by approving 2 cell-based gene therapies today,” Nicole Verdun, MD, director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, said in a statement.1 “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.”
The safety data included in the BLA for lovo-cel included 50 patients treated across multiple clinical trials; 6 of these patients had at least 6 years of follow-up. The serious adverse events (AEs) related to lovo-cel in this dataset included cases of anemia in 2 patients with alpha-thalassemia and leukemia (not resulting from insertional oncogenesis) in 2 patients. Nonserious AEs related to lovo-cel in this dataset include cases of infusion reactions, namely hot flush and decreased blood pressure, in 2 patients. Three of the 50 patients included in the BLA submission’s dataset have died: 1 patient died from sudden cardiac death and 2 patients died from leukemia.
Hematologic malignancy has occurred in patients treated with lovo-cel, and as such, a black box warning is included in the label for the therapy with information regarding this risk. The FDA noted that patients receiving lovo-cel should have lifelong monitoring for these malignancies. In October 2023, CGTLive™ spoke with Mark Walters, MD, a professor in residence of pediatrics at the Sickle Cell Center of Excellence at the University of California, San Francisco, and an investigator on the phase 1/2 HGB-205 and HGB-206 clinical trials, about these safety risks.
“The most concerning safety question is whether or not going through a gene therapy treatment like this might increase the risk of developing a blood cancer, like acute myelogenous leukemia. And we tend to worry about that more in the youngest patients because their lifespan will be longer and will perhaps have more potential for developing leukemia than in the older patients," he said at the time.
Notably, the BLA submission incorporated feedback that the company received from the FDA in February 2022 related to vector and drug product analytical comparability evaluations between the product used in clinical trials and the product the company plans to use for commercial sale.2,3 bluebird bio had responded to this feedback in March; prior to this, lovo-cel's progress was also delayed by a partial clinical hold placed on HGB-210 by the FDA that suspended enrollment, cell collection, conditioning, and infusion of patients under the age of 18 from December 2021 to December 2022.4 The hold was related to a case of persistent, non-transfusion-dependent anemia in a pediatric patient. Adult patients were able to continue enrolling in the trial during this time. In March 2023, while awaiting the FDA’s response to the manufacturing compatibility data it submitted, bluebird bio stated that if the BLA was approved, it expected a commercial launch of lovo-cel in early 2024.
Additionally, CGTLive spoke earlier this month with Julie Kanter, MD, the director of the Adult Sickle Cell Clinic and an associate professor of hematology and oncology at the University of Alabama Birmingham, as well as an investigator on multiple of lovo-cel's clinical trials, about the impact of this potential incoming approval. She discussed her anticipation for the upcoming decision but stressed that it will be a complicated process to integrate the new mode of treatment into patients’ regimens.
“I do support [lovo-cel's] approval. I think it's going to be very complicated, because we need to support sickle cell disease centers in delivering this product, as well as the product itself, which are sort of 2 different price streams. And I think it'll be a little bit complicated as we wander into this new territory of high-priced therapies. But I think the patients that I have taken care of would tell you it is absolutely worth it. It is truly a transformative therapy," Kantor said.
Watch Kantor's discussion with CGTLive in the video below.
“The approval of the first gene therapies for SCD represents a tremendous step forward for the SCD community, which has been historically overlooked and underfunded. While these new gene therapies are potentially life-changing for individuals living with SCD, they must be accessible to be effective," Robert A. Brodsky, MD, president of the American Society of Hematology, said in a statement. "ASH remains committed to improving the availability of innovative treatments for blood disorders such as gene therapies for SCD and providing resources to clinicians to help implement these evolving therapies. People with SCD need more—they need comprehensive care.”