An Update on Lovotibeglogene Autotemcel (Lovo-cel) Clinical Trials for Sickle Cell Disease (SCD) and Analysis of Early Predictors of Response to Lovo-Cel

Speaker: Stacey Rifkin-Zenenberg, Hackensack University Medical Center, USA

Key Highlights:      

Dr. Zenenberg highlighted Lovo-cel—a groundbreaking FDA-approved gene addition therapy for sickle cell disease. The presentation focused on pivotal clinical trials, including HGB-206, HGB-210, and long-term follow-up HGB-307.

Study Overview: As of July 2024 data, key findings from the study included:

• Patient Enrolment & Transplantation: 71 patients underwent mobilization; 58 proceeded to transplantation. Of these, 50 met hemoglobin (Hb) response evaluation, and 38 had complete resolution of vaso-occlusive events (VOEs).
• Follow-Up & Demographics: Median follow-up was 4 years, with a maximum of 6.6 years. 16 participants were under 18 years old.
• Mobilization Success: 83% of participants required just 1–2 mobilization cycles to reach the target CD34+ cell dose.

Key Findings:

Lovo-cel Demonstrates Durable Efficacy and Transformative Clinical Benefit:

• 90% of participants achieved globin response (composite endpoint: Hb levels and T87Q expression).
• 87% of participants achieved VOE complete resolution (VOE-CR).
• 95% of participants achieved severe VOE complete resolution (SVOE-CR).
• Pediatric patients had exceptional results, with 100% achieving VOE-CR.

T87Q Expression Predicts Clinical Outcomes:

• T87Q, the functional gene product from lovo-cel, showed strong correlation with VOE-CR, SVOE-CR, and globin response.
• Patients with ≥30% peripheral blood T87Q levels at 6 months post-infusion were more likely to achieve VOE-CR.

Drug Product Characteristics Strongly Predict T87Q Expression:

• A random forest model identified lentiviral vector (LVV) transduction efficiency as the strongest predictor of T87Q levels:
• LVV ≥60% in drug product corresponds to ≥30% T87Q in peripheral blood at 6 months.

Safety Profile: The safety profile was consistent with prior findings linked to sickle cell disease and myeloablative busulfan conditioning.

Durable Clinical Benefits with Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia

Speaker: Franco Locatelli, Bambino Gesù Children's Hospital, Rome

Key Highlights:

Exa-cel is the first ex vivo CRISPR-Cas9 gene-editing therapy approved for patients aged ≥12 years with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD). It targets and edits the BCL11A erythroid-specific enhancer to reactivate fetal hemoglobin (HbF) synthesis, reducing disease burden.

Study Design and Population: CLIMB-111 (TDT) and CLIMB-121 (SCD) with long-term follow-up in CLIMB-131.

1. Eligibility: TDT: ≥100 mL/kg/year RBC transfusions or ≥10 units annually for 2 consecutive years. Age: 12–35 years; 1/3 adults and 2/3 adolescents.
2. Endpoints:
   1. Primary: Transfusion independence (TDT); freedom from severe VOEs (SCD).
   2. Secondary: Duration of TI, HbF levels, and safety parameters.

Key Efficacy Results:

1. High Rate of Transfusion Independence (TI) in TDT:
   1. 98% (53/54) of patients achieved transfusion independence (primary endpoint).
   2. The remaining patient was transfusion-free, with an Hb of 10 g/dL, suggesting delayed benefit.
   3. Sustained HbF production reached a plateau at 9 months post-infusion and remained stable long-term, ensuring durability of clinical benefit.
2. SCD Outcomes:
   1. In the CLIMB-121 study, Exa-cel led to 93% of patients achieving freedom from severe VOEs for ≥12 months (primary endpoint).
   2. Chronic pain episodes post-therapy primarily occurred in adults with a prior history of pain and were unrelated to HbF levels.
3. Iron Overload Reduction:
   1. Significant improvements in iron overload parameters:
   2. Decreased serum ferritin levels and liver iron concentration over time.
   3. 50% of evaluable patients discontinued iron chelation therapy following sustained transfusion independence.

Safety Profile:

• Adverse events (AEs) were consistent with those seen following busulfan-based myeloablative conditioning.
• A fatal VOD event occurred in a pediatric patient, underscoring the importance of therapeutic drug monitoring (TDM) to avoid overexposure.

Conclusion

Exa-cel provides durable and transformative benefits for patients with TDT and SCD, achieving high rates of transfusion independence and VOE-free status. HbF levels and edited alleles remained stable long-term, ensuring sustained efficacy.

Initial Results from the BEACON Clinical Study: A Phase 1/2 Study Evaluating the Safety and Efficacy of a Single Dose of Autologous CD34+ Base Edited Hematopoietic Stem Cells (BEAM-101) in Patients with Sickle Cell Disease with Severe Vaso-Occlusive Crises

Speaker: Matthew Heeney, Boston Children's Cancer and Blood Disorders Centre, USA

Key Highlights:

Overview of BEAM-101

BEAM-101 uses adenine base editing to introduce a hereditary persistence of fetal hemoglobin polymorphism by targeting the BCL11A erythroid binding site. This approach reactivates HbF without causing double-strand breaks, reducing sickling, hemolysis, and vaso-occlusive crises (VOCs).

BEACON Trial Design & Initial Results:

The Phase 1/2 BEACON study evaluates the safety and efficacy of BEAM-101 in patients (ages 18–35) with severe sickle cell disease and ≥4 VOCs in the prior 24 months.

Key Findings:

1. Participants: 7 patients (ages 19–27); 6 with homozygous SS disease.
2. Engraftment & Mobilization: Target CD34+ dose achieved with 1–2 mobilization cycles. Neutrophil engraftment by Day 21, platelet engraftment by Day 34, with minimal neutropenic days (mean 6.3).
3. HbF Levels: >60% HbF by 1 month post-treatment, sustained throughout follow-up.
4. HbS Reduction: Levels dropped to <40%, with anemia resolved in all but one case.
5. Safety: No treatment-related Grade ≥3 adverse events or VOCs; 1 fatality linked to busulfan, not BEAM-101.

Clinical Implications

1. Safety Profile: BEAM-101 has a favourable safety outcome with rapid engraftment and sustained HbF induction.
2. HbF Impact: Protective HbF levels minimized sickling risk and improved hemolysis markers.
3. Efficient Mobilization: BEAM-101's base editing mechanism enables faster engraftment compared to traditional nuclease-based therapies.

Conclusion:

• Patients treated with BEAM 101 required a low number of mobilization cycles to achieve target dosing.
• Achieved rapid neutrophil and platelet engraftment with a low number of neutropenic days.
• Initial safety data align with busulfan conditioning and autologous hematopoietic stem cell transplantation, with no VOE post-engraftment.
• All patients experienced a rapid and sustained increase in total and HbF, maintaining levels above protective thresholds during follow-up.
• Sickle Hb levels decreased rapidly, and markers of haemolysis were normalized in all patients.

Prime Editing Enables Precise and Efficient Single Amino Acid Substitutions to Shield CD34+ Hematopoietic Stem Cells from Anti-CD117 Antibody-Based Conditioning

Speaker: Jack Heath, Prime Medicine

Key Highlights:

Prime Editing Technology:

Prime editing is a CRISPR-Cas9-based gene-editing tool enabling precise “search-and-replace” modifications of single DNA strands. Unlike other gene-editing methods, it does not create double-strand breaks (reducing risks of off-target effects and cell stress).

Objective:

• Develop prime editors to introduce a shielding mutation into the KIT gene encoding CD117 to protect CD34+ hematopoietic stem cells (HSCs) from targeted anti-CD117 antibody conditioning.
• Enable selective depletion of unshielded HSCs, while shielded cells are preserved and can repopulate the bone marrow.

Rationale for Selective Conditioning:

Traditional myeloablative conditioning (chemo/radiation) carries significant toxicity. CD117 antibody-based conditioning offers a targeted, less toxic approach by depleting HSCs. Shielded, prime-edited CD34+ cells resist depletion, allowing safer conditioning and potential for improved engraftment.

Applications:

1. Allogeneic Transplants: Boost donor cell engraftment by selectively clearing the bone marrow niche.
2. Autologous Transplants: Combine shielding edits with therapeutic edits to correct genetic diseases and selectively expand corrected cells post-infusion.

Key Results

1. Ex Vivo Studies:
   1. Shielding edits successfully protected primitive HSC progenitors from anti-CD117 depletion.
   2. Prime editing maintained cell viability and functional potency.
2. In Vivo Studies:
   1. Shielded CD34+ cells showed robust, durable engraftment in immunodeficient mice.
   2. 100% shielding efficiency was observed with 80% biallelic edits.

Safety: No off-target effects or chromosomal rearrangements detected.

Clinical Implications:

• Improved Safety: Selective anti-CD117 antibody conditioning reduces risks and toxicity.
• Enhanced Engraftment: Shielded cells can be enriched post-infusion, improving chimerism and long-term success.
• Multiplex Prime Editing: Combines shielding mutations with therapeutic edits, offering a dual approach to correct genetic diseases and enhance transplantation outcomes.

In Vivo HSC Gene Editing for Correction of the Sickle Cell Mutation Using RNA Gene Writers

Speaker: Lorenzo Tozzi, Associate Director, Tessera Therapeutics

Key Highlights:

RNA Gene Writing Technology:

• Inspired by mobile genetic elements, RNA gene writers use target-primed reverse transcription for efficient genomic modifications.
• Enable precise single-nucleotide substitutions without inducing double-strand breaks, reducing safety concerns linked to traditional gene-editing methods.
• Capable of small insertions, deletions, or large gene modifications.

In Vivo Gene Editing via Lipid Nanoparticles (LNPs):

1. LNPs facilitate in vivo delivery of RNA gene writers, targeting hematopoietic stem cells (HSCs) directly.
2. Overcomes the challenges of traditional gene therapy, such as:
   1. High costs.
   2. Limited accessibility.
   3. Toxic conditioning.

Successful Correction of the Sickle Cell Mutation: RNA gene writers corrected the beta-globin gene mutation in CD34+ cells from SCD patients.

1. Efficient correction led to restored normal Hb levels.
2. Reversal of sickling under hypoxic conditions in red blood cells.
3. Edited cells expanded preferentially during erythroid differentiation.

Long-Term Stability of Gene Edits: Tested in healthy donor CD34+ cells to determine the impact on self-renewal.

• 60% biallelic editing persisted in hematopoietic progenitors 12 weeks post-transplant in immunocompromised mice.
• Edits remained stable across hematopoietic lineages.

Successful Targeting in Non-Human Primates (NHPs):

1. Optimized LNP delivery achieved ~74% editing of the beta-2 microglobulin gene.
   1. Stable editing was maintained for 84 days post-treatment.
   2. Edited cells contributed to multi-lineage hematopoiesis.
2. Beta-globin gene editing in NHPs showed 24% editing efficiency after two LNP doses.
   1. Secondary transplantation confirmed long-term engraftment and stable edits.

Clinical Implications:

• Reduced Ex Vivo Manipulation: LNPs eliminate the need for toxic conditioning or ex vivo editing, improving gene therapy's safety and accessibility.
• Durable Edits: Long-term stability in mouse and NHP models indicates sustained therapeutic effects.
• Optimized Delivery with LNPs: Promising results with proprietary LNPs show minimal off-target effects and efficient targeting.

ASH Annual Meeting and Exposition, 7-10 December 2024, San Diego, California