GLPG5101: CD19 CAR-T to expand to eight aggressive B-cell malignancies, broadening patient reach and impact

GLPG5101 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as a single fixed intravenous dose. The safety, efficacy and feasibility of decentralized manufactured GLPG5101 are currently being evaluated in the ATALANTA-1 Phase 1/2 study in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL).

The primary objective of the Phase 1 part of the study is to evaluate safety and to determine the recommended dose for the Phase 2 part of the study. Secondary objectives include assessment of efficacy and feasibility of decentralized manufacturing of GLPG5101.

The dose levels that were evaluated in Phase 1 are 50x10⁶ (DL1), 110x10⁶ (DL2) and 250x10⁶ (DL3) CAR+ viable T-cells.

The primary objective of the Phase 2 part of the study is to evaluate the Objective Response Rate (ORR) while the secondary objectives include Complete Response Rate (CRR), duration of response, progression free survival, overall survival, safety, pharmacokinetic profile, and the feasibility of decentralized manufacturing. Each enrolled patient will be followed for 24 months.

ATALANTA-1 phase 1/2 study design and objectives

Demographics and baseline characteristics of ATALANTA-1:
heavily pre-treated NHL patient population

In December 2024, we presented new data⁴ from the ongoing ATALANTA-1 Phase 1/2 study at the 2024 Annual Meeting of the American Society of Hematology (ASH) Meeting, which included updated data on patients with mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) / follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

As of the data cut-off on April 25, 2024, 49 patients had received cell therapy infusion, and safety and efficacy results were available for 45 patients and 42 patients, respectively. The results are summarized below:

• High objective response rates (ORR) and complete response rates (CRR) were observed in the pooled Phase 1 and Phase 2 efficacy analysis set, split by indication:
  • In MCL, all 8 of 8 efficacy-evaluable patients responded to treatment (ORR and CRR 100%).
  • In MZL/FL, objective and complete responses were observed in 20 of 21 efficacy-evaluable patients (ORR and CRR 95%).
  • In DLBCL, 9 of 13 efficacy-evaluable patients responded to treatment (ORR 69%), with 7 patients achieving a complete response (CRR 54%). Of the 7 patients with DLBCL who received the higher dose, 6 responded to treatment (ORR 86%) while 5 achieved a complete response (CRR 71%).
• Of the 15 minimal residual disease (MRD)-evaluable patients with a complete response, 12 patients (80%) achieved MRD negativity and remained in complete response at data cut-off.
• The median study follow-up was 3.3 months for FL and DLBCL with a range of 0.9-21.2 months, and 4.4 months for MCL with a range of 1-24.4 months.
• GLPG5101 showed an encouraging safety profile, with the majority of Grade ≥ 3 treatment emergent adverse events being hematological. One case of CRS Grade 3 was observed in Phase 1 and one case of ICANS Grade 3 was observed in Phase 2.
• 96% of patients (47 of 49) received an infusion with fresh, fit, stem-like early memory (naïve/stem cell memory and central memory) CD19 CAR T-cell therapy, with 91.5% (43 of 47) achieving a vein-to-vein time of seven days, thereby avoiding cryopreservation, and eliminating the need for bridging therapy. 
• Strong and consistent in vivo CAR-T expansion levels and products consisting of stem-like, early memory phenotype T-cells were observed in all doses tested. This early phenotype reflects the differentiation status of the cells, which is associated with enhanced functionality and persistence of CAR-T cells, which could potentially be an early predictor of durable responses after infusion.
• Beyond MCL, MZL/FL and DLBCL, the ATALANTA-1 study also includes high-risk first line DLBCL, Burkitt lymphoma (BL), and primary CNS lymphoma (PCNSL). Patient recruitment is ongoing in Europe. With the U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) application clearance secured, leading cancer centers in Boston have been activated, and patient screening has begun. Boston-based Landmark Bio is operational and serves as the decentralized manufacturing unit (DMU) for ATALANTA-1. 
• Building on these encouraging data and in line with its goal to streamline the business, we are focusing our resources on accelerating GLPG5101 as our flagship CD19 CAR-T program, and pending the advancement of GLPG5101 in additional indications, are deprioritizing activities for GLPG5201, our second CD19 CAR-T candidate. With the addition of double-refractory chronic lymphocytic leukemia (CLL) and Richter transformation (RT) of CLL, both indications with significant unmet needs, GLPG5101 would be developed across eight aggressive B-cell malignancies, further unlocking its broad potential to address significant unmet medical needs.
• We aim to present additional new data at a medical meeting in 2025.

Encouraging efficacy data:
ATALANTA-1 preliminary pooled Phase 1/2 results in heavily pretreated patient population

High OR and CR rates were observed (best response at any time after infusion)^a

Encouraging safety profile:
ATALANTA-1 preliminary results in heavily pretreated patient population

GLPG5101 product characteristics

• The CD4:CD8 ratio of CAR+ T cells increased in the final product as compared to the ratio of CD4:CD8 T cells in the starting material (median [Q1, Q3] increase of 0.8 [0.05, 2.02]) 
• The proportion of early phenotype CD4⁺ and CD8⁺ CAR T cells increased significantly in the final product, compared to the early phenotype CD4⁺ and CD8⁺ T cells in the starting material

The fitness of the final product was evaluated by measuring the level of CAR T-cell expansion. We observed robust CAR T-cell expansion in treated patients across all dose levels. At the cut-off date of April 24, 2024, 15 out of 18 evaluable patients (83%) had detectable CAR T-cells at 6 months post-infusion: 75% in Phase 1 and 100% in Phase 2. Persisting CAR T-cells could be detected up to 21 months post-infusion. These findings support persistence of GLPG5101, which could be an early predictor of durable responses.

Cellular expansion and durable persistence of GLPG5101
Quantification of GLPG5101 up to Day 28 post-infusion (Phase 1)^a

Persistence after Day 28 post-infusion^a,b

• 15/18 (83%) patients had detectable GLPG5101 in peripheral blood at Month 6 post-infusion:
  • 9/12 (75%) in Phase 1
  • 6/6 (100%) in Phase 2
• Persisting CAR T cells could be detected up to 21 months post-infusion

Quantification of GLPG5101 in peripheral blood using ^aqPCR (LOQ: 1000 vector copies) and ^bdPCR (LOQ: 50 vector copies/μg DNA).  AUC_d0–28, area under the curve from Day 0 to 28; D, Day; (d/q)PCR, (digital/quantitative) polymerase chain reaction; DL, dose level; LOQ, limit of quantification; S, screening

These initial results reinforce the potential of Galapagos’ innovative, decentralized cell therapy manufacturing platform to deliver fresh, stem-like, early memory CD19 CAR T-cell therapy, with a median vein-to-vein time of seven days.

Building on these encouraging data and in line with our goal to streamline the business as announced on January 8, 2025 and February 12, 2025, we are focusing our resources on accelerating GLPG5101 as our flagship CD19 CAR-T program, and pending the advancement of GLPG5101 in additional indications, are deprioritizing activities for GLPG5201, our second CD19 CAR-T candidate. With the addition of double-refractory chronic lymphocytic leukemia (CLL) and Richter transformation (RT) of CLL, both indications with significant unmet needs, GLPG5101 would be developed across eight aggressive B-cell malignancies, further unlocking its broad potential to address significant unmet medical needs.