Lovo-cel gene therapy ‘transformative’ for sickle cell disease
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SAN DIEGO — One-time treatment with lovotibeglogene autotemcel gene therapy conferred “transformative” benefit to patients with sickle cell disease, according to a presenter at ASH Annual Meeting and Exposition.
The therapy — one of two gene therapies the FDA approved for sickle cell disease on Dec. 8 — resulted in sustained production of HbAT87Q, an anti-sickling hemoglobin, and near-complete resolution of vaso-occlusive events for up to 18 months after treatment.
Patients also reported reduced fatigue, pain intensity and pain interference.
When asked what the findings mean to her and other clinicians who treat individuals with sickle cell disease, investigator Julie Kanter, MD — associate professor in the division of hematology oncology at The University of Alabama at Birmingham and director of the UAB Adult Sickle Cell Clinic — responded with one word.
“Hope,” Kanter told Healio. “This is a transformative opportunity. When our young kids are growing up with this disease, no longer do they have to think about their lives with a fixed time point. They will have an opportunity to say, ‘Maybe I don’t want to do this yet. Maybe I want to wait. But I have that time, and I have an opportunity to be pain free.”
Background
Lovotibeglogene autotemcel (Lyfgenia, Bluebird Bio) — often called lovo-cel — is a gene therapy that uses autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified beta-globin gene.
Kanter presented efficacy and safety results from two studies of lovo-cel that included patients with sickle cell disease aged 12 years or older with a history of vaso-occlusive events.
The studies used the refined manufacturing process. Patients stopped hydroxyurea therapy and underwent a premobilization transfusion regimen, followed by mobilization with plerixafor and apheresis. When stem cells are ready, patients returned to the hospital for busulfan myeloablative conditioning, then received the drug product in a process similar to autologous transplant.
Study protocol established an initial 2-year follow-up period, and then an additional 13 years of long-term follow-up.
The analysis included 47 patients (median age, 23; range, 12-38; 78.7% adults; 21.3% aged 12 to 17 years; 59.6% male).
Four study participants (8.5%) had history of overt stroke, two (4.3%) had history of silent stroke, and the median number of adjudicated vaso-occlusive events was 3.5 (range, 0-16.5).
Median follow-up was 35.5 months (range, 0.3-61).
Results
Median time to neutrophil engraftment was 20 days (range, 12-35) and median time to platelet engraftment was 35 days (range, 19-136).
“In terms of biology, we couldn’t ask for much better from this initial assessment,” Kanter said.
Researchers reported median HbAT87Q levels of 4.5 g/dL or higher from 6 months after infusion to final study visit, as well as an increase in total hemoglobin level, from a median 8.7 g/dL (range, 6.1-12.5) at relative baseline to 11.8 g/dL (range 8.4-15) at final visit.
All patients maintained stable HbAT87Q levels from 6 months to final follow-up, Kanter said.
The median percentage of HbAT87Q as a component of nontransfused total hemoglobin remained around 40% or greater during the follow-up period, with values of 47.4% at month 6, 46.6% at month 12, 45.8% at month 24, 40.8% at month 36, 39.6% at month 48 and 49.3% at month 60.
The majority (86.8%) of study participants achieved globin response.
Thirty participants (88.2%) overall — and all 10 adolescents — achieved complete resolution of all vaso-occlusive events during the 6-month to 18-month assessment period, and nearly all (94.1%) experienced complete resolution of severe vaso-occlusive events.
All study participants who experienced vaso-occlusive events after treatment experienced a reduction of at least 50% vs. baseline, as well as reductions in hospital admissions (from 2.5 to 0.41) and hospital days (from 15.75 to 2.2).
Kanter also presented health-related quality of life data, based on Patient-Reported Outcomes Measurement Information System (PROMIS)-57 domains of fatigue, pain intensity and pain interference.
Results from 20 evaluable study participants showed the majority experienced improvements in pain intensity (57%), pain interference (64%) and fatigue (64%) at 36 months.
Safety analyses revealed the adverse effects observed generally reflected the established adverse effect profile of hematopoietic stem and progenitor cell collection and busulfan conditioning regimen.
All study participants experienced treatment-related adverse events.
Most (93.6%) experiencing grade 3 or higher treatment-related adverse events, the most common of which were stomatitis (70.2%) and thrombocytopenia (59.6%).
More than half (55.3%) experienced serious adverse events, the most common of which was chronic pain or acute exacerbation of chronic pain.
Adverse events related to lovo-cel included two patients with anemia (4.3%), and one (2.1%) each with abdominal discomfort, decrease in diastolic blood pressure, myelodysplastic syndrome and nasal congestion.
One study participant died of significant baseline sickle cell disease-related cardiopulmonary disease. The death was not considered related to lovo-cel, Kanter said.
Researchers reported no cases of veno-occlusive liver disease, graft failure or graft-versus-host disease.
Next steps
Researchers will continue to collect long-term follow-up data to confirm initial findings about the efficacy, safety and patient experience with lovo-cel, including for adolescent patients, Kanter said.
Kanter estimated about 10% of the adults treated for sickle cell disease at her institution would be interested in lovo-cel therapy.
“It doesn’t mean they will all be eligible for it,” Kanter said. “It’s going to be very slow to implement, and there’s a lot of room to do both of these therapies and still have a waiting list of 3 to 5 years.”
Perspective
Back to TopCynthia Dunbar, MD
This is really encouraging news, and it is very important to me personally, as I have worked in this field my entire career and I took care of some of the patients on these trials. Both lovo-cel and the CRISPR-based exa-cel appear to result in comparable impressive efficacy in terms of lower pain crises and organ dysfunction. There is much longer follow up so far for lovo-cel because that is an older technology with lentiviral vectors. Follow-up is about half as long for exa-cel, which uses a CRISPR approach. But over time, they are likely to be quite similar in terms of efficacy, and I think market forces will decide which way this goes.
The hurdle is going to be how to deliver what will be very expensive and complicated therapies — but curative therapies — to patients. Many in the US are on Medicaid or other undercompensated forms of insurance. Also, the vast majority of patients who have sickle cell disease are in sub-Saharan Africa or other less-resourced areas, so figuring out how to deliver some of these curative therapies in a cheaper, more feasible way that doesn’t involve stem cell collection and transplant is going to be very important.
Perspective
Back to Top
Rabi Hanna, MD
The engraftment and safety data are consistent with previously published similar studies, and efficacy remained excellent. Importantly, this study analyzed health-related quality of life from only 25 evaluable patients. Mean scores for PROMIS-57 domains of pain intensity, pain interference and fatigue showed sustained improvement. These patient-reported outcomes — especially in the pain domain — are very important data points to ensure that patient experience and quality of life after gene therapy is improved, in addition to the study endpoints of decreasing vaso-occlusive events. We still need long-term data and quality-of-life data from the adolescent cohort — ages 12 years or older — to help counsel patients as we move forward in real-world experience.
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Kanter J, et al. Abstract 1051. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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