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Annual Report 2024

GLPG5201: CD19 CAR-T in relapsed/refractory chronic lymphocytic leukemia and Richter transformation

GLPG5201 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 GLPG5201 were evaluated in the EUPLAGIA-1 Phase 1/2, open-label, multicenter study in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), small cell lymphocytic lymphoma (R/R SLL), and Richter transformation (RT).

Patients with CD19+ R/R CLL or R/R SLL with >2 lines of therapy are eligible to participate, and patients with RT are eligible regardless of prior therapy. The primary objective of the Phase 1 part of the study is to evaluate safety and determine the recommended dose for the Phase 2 part of the study. The dose levels that are evaluated in the Phase 1 part of the study are 35x106 (DL1) and 100x106 (DL2) CAR+ viable T cells.

The primary objective of the Phase 2 part of the study is to assess the ORR and the secondary objectives including the analysis of the CRR, duration of response, progression free survival, overall survival, safety pharmacokinetic profile, and feasibility of decentralized manufacturing.

EUPLAGIA-1 Phase 1/2 study design and objectives

EUPLAGIA-1 Phase 1/2 study design and objectives (graphic)
aScreening could take place up to a maximum of 28 days prior to leukapheresis. bConditioning chemotherapy: fludarabine IV (30 mg/m2/day); cyclophosphamide IV (300 mg/m2/day). BCL2i, B-cell lymphoma 2 inhibitor; BTKi, Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; CRR, complete response rate; Cy, cyclophosphamide; DOR, duration of response; ECOG PS, European Cooperative Oncology Group performance status; Flu, fludarabine; IV, intravenous; LOT, lines of treatment; MRD, minimal residual disease; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PI3Ki, phosphoinositide 3-kinase inhibitor.

Baseline characteristics EUPLAGIA-1:
heavily pre-treated CLL and RT patient populations

Baseline characteristics EUPLAGIA-1: heavily pre-treated CLL and RT patient populations

 

CLL
(N = 6)

RT
(N = 9)

Age, median (range), years

68 (58–74)

65 (50–74)

Male sex, n (%)

4 (67)

6 (67)

Race, n (%)

 

 

White

6 (100)

8 (89)

Hispanic or Latino

0 (0)

1 (11)

ECOG PS, n (%)

 

 

0

3 (50)

4 (44)

1

3 (50)

5 (56)

LDH, median (range), U/L

235 (174–297)

242 (152–535)

SPD, median (range), cm2

31.8 (5.2–67.5)

14.6 (3.8–112.8)

ALC, median (range), 109/L

33.97 (1.40–110.40)

1.03 (0.48–1.40)

High-risk molecular features, n/n available (%)a

 

 

17p deletion

1/5 (20)

2/9 (22)

TP53 mutated

1/5 (20)

5/9 (56)

11q deletion

1/5 (20)

2/9 (22) 

Complex karyotype

2/4 (50)

1/2 (50)

IGHV unmutated

5/5 (100)

8/8 (100)

 

 

 

Treatment history in patients with CLL (N = 6)

No. of total prior therapy lines, median (range)

 

4 (2–10)

BTKi and BCL2i, n (%)

 

6 (100)

 

 

 

Treatment history in patients with RT (N = 9)

No. of total prior therapy lines, median (range)

 

3 (3–5)

Prior CLL-directed therapy, n (%)

 

9 (100)

No. of prior CLL-directed therapy lines, median (range)

 

1 (1–3)

Prior RT-directed therapy, n (%)

 

8 (89)

No. of prior RT-directed therapy lines, median (range)

 

2 (0–4)

a

Information on 17p deletion, TP53 mutation, and 11q deletion was reported for 14 patients at data cutoff (CLL, N = 5; RT, N = 9). One patient had missing data. Karyotyping was reported for 6 patients (CLL, N = 4; RT, N = 2). Baseline is defined as the last assessment prior to leukapheresis. Data cutoff: February 21, 2024. ALC, absolute lymphocyte count; BCL2i, B-cell lymphoma 2 inhibitor; BTKi, Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; IGHV, immunoglobulin heavy-chain variable region gene; LDH, lactate dehydrogenase; RT, Richter transformation; SPD, sum of the product of perpendicular diameters.

In December 2024, we presented initial encouraging safety and efficacy encore data from the EUPLAGIA-1 Phase 1/2 study during a poster session at the 2024 Annual Meeting of the American Society of Hematology (ASH) Meeting.

As of the data cut-off on February 21, 2024, patient recruitment of the Phase 1 dose-finding part of EUPLAGIA-1 has been completed and, 15 patients (6 at dose level 1 (DL1); and 9 at dose level 2 (DL2)) were enrolled, all of whom were diagnosed with R/R CLL, and 9 with additional RT. All 15 Phase 1 batches were manufactured using Galapagos’ decentralized platform and infused as a single fresh, fit product within a median vein-to-vein time of seven days, with 80% of patients receiving the product in seven days. Safety and efficacy results were available for 15 patients.

The results are summarized below:

  • Overall, 13 of 15 efficacy evaluable patients responded to treatment (Objective Response Rate (ORR) of 93%) and 10 of 15 patients achieved a Complete Response (CRR of 66.7%). 8 of 9 patients with RT responded to treatment (ORR of 89%) and 6 of 9 RT patients achieved a Complete Response (CRR of 67%). At time of analysis, 10 of 13 of responding patients (77%) were in ongoing response with a median follow-up of 6 months; 2 of 3 patients who progressed after an initial response had confirmed CD19-negative disease.
  • At the higher dose level (DL2), 8 of 8 patients responded to treatment (ORR of 100%), 5 of 8 patients achieved a Complete Response (CRR of 63%), and 6 of 6 patients with RT responded to treatment (ORR of 100%).
  • GLPG5201 showed an encouraging safety profile with most treatment emergent adverse events (TEAEs) of Grade 1 or 2, mostly hematological. Cytokine release syndrome (CRS) Grade 1 or 2 was observed in 53% of the patients, and no CRS Grade ≥ 3 or any immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Two deaths occurred in patients with RT: one event of cytomegalovirus colitis 14.5 months post-infusion in a patient with complete response (CR), and one death due to disease progression 110 days post-infusion.
  • The proportion of early T-cell phenotypes was higher in the final product (FP) compared with leukapheresis starting material (SM): CD4+ T cells median (range) change +23.6% (−17.9 to 39.3), with an increase observed in 10 out of 13 patients; CD8+ T cells median (range) change +50.8% (7.6 to 73.3), with an increase observed in 13 out of 13 patients. The ratio of CD4+:CD8+ CAR T cells increased in the FP. Robust CAR T-cell expansion was observed by qPCR in all patients, independent of DL. Peak expansion and exposure were comparable between patients with CLL and RT. Median time to peak expansion was 14 days for both subgroups.
  • Persistence was durable and could be detected in peripheral blood up to 15 months post-infusion.

Encouraging efficacy data:
EUPLAGIA-1 preliminary results in heavily pretreated patient population

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

EUPLAGIA-1 preliminary results in heavily pretreated patient population (graphic)
aCombined response: iwCLL criteria for patients with CLL and Lugano classification for patients with RT, as per investigator’s assessment. CLL, chronic lymphocytic leukemia; CR, complete response; CRR, complete response rate; DL, dose level; iwCLL, International Workshop on CLL; OR, objective response; ORR, objective response rate; PR, partial response; RT, Richter transformation.

Encouraging safety data:
EUPLAGIA-1 preliminary Phase 1 data in heavily pretreated patient population

EUPLAGIA-1 preliminary Phase 1 data in heavily pretreated patient population

 

Phase 1

TEAEs up to 14 weeks after infusion, n (%)

DL1
n = 6

DL2
n = 9

All patients
N = 15

Any TEAE

6 (100)

9 (100)

15 (100)

Any GLPG5201-related TEAE

6 (100)

8 (89)

14 (93)

Serious TEAE

2 (33)

5 (56)

7 (47)

TEAE leading to death

0

0

0

Any Grade ≥ 3 TEAE

6 (100)

9 (100)

15 (100)

Hematological Grade ≥ 3 TEAEs

 

 

 

Neutropeniaa

6 (100)

7 (78)

13 (87)

Anemiab

3 (50)

2 (22)

5 (33)

Lymphopeniac

0

1 (11)

1 (7)

Thrombocytopeniad

1 (17)

4 (44)

5 (33)

CRSe

 

 

 

Grade 1/2

3 (50)

5 (56)

8 (53)

Grade ≥ 3

0

0

0

Time to onset, median (range), days

4.0 (4–7)

4.5 (1–13)

4.0 (1–13)

Duration, median (range), days

5.0 (3–6)

5.5 (3–9)

5.0 (3–9)

CRS toxicity management

 

 

 

Tocilizumab

2 (33)

5 (56)

7 (47)

Dexamethasone

1 (17)

3 (33)

4 (27)

ICANSe

0

0

0

Infection, Grade ≥ 3

0

2 (22)

2 (13)

Prolonged cytopenia,f Grade ≥ 3

 

 

 

30 days after infusion

2 (33)

3 (33)

5 (33)

60 days after infusion

2 (33)

4 (44)

6 (40)

a

Includes neutropenia/neutrophil count decreased.

b

Includes anemia/hemoglobin level decreased.

c

Includes lymphopenia/lymphocyte count decreased.

d

Includes thrombocytopenia/platelet count decreased.

e

Events can be recorded during the treatment period (up to 14 weeks after infusion) or during follow-up.

f

Includes all events related to neutropenia, thrombocytopenia, anemia, and lymphopenia.

CRS, cytokine release syndrome; DL, dose level; ICANS, immune effector cell-associated neurotoxicity syndrome; RT, Richter transformation; TEAE, treatment-emergent adverse event.
Deaths:
  • 1 patient with RT died of an unrelated infection while in complete response
  • 1 patient with RT died due to disease progression

GLPG5201 product characteristics

Higher proportions of early T-cell phenotypes (naïve/stem cell memory [TN/SCM] and central memory [TCM]) were observed in the final product versus leukapheresis starting material

The ratio of CD4+ to CD8+ CAR T cells increased in the final product compared with the starting material

GLPG5201 product characteristics (graphic)
Exploratory flow cytometry analysis of T-cell subsets in the apheresis starting material and final product for paired patient samples (N = 13). A, Percentage of early phenotypes (sum of TN/SCM [CD45RO−CD197+] and TCM [CD45RO+CD197+]) of CD4+ or CD8+ cells (gated on CAR+ cells for the final product). B, Ratio of CD4+ to CD8+ cells (gated on CAR+ cells for the final product).  Data cutoff: February 21, 2024. CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; FP, final product; Med, median; RT, Richter transformation; SM, starting material; TCM, central memory T cells;  TN/SCM, naïve/stem cell memory T cells.

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 both dose levels.

Cellular expansion of GLPG5201
Robust CAR T-cell expansion was observed, independent of the dose received

Cellular expansion of GLPG5201 (graphic)
Quantification of GLPG5201 in peripheral blood by quantitative polymerase chain reaction. Data available for 15 (DL1, n = 6; DL2, n = 9) patients at data cutoff. Data cutoff: February 21, 2024. D, Day; DL, dose level; M, Month; S, Screening; W, Week.

Upon infusion, abundance of CD4+ and CD8+ naïve/stem cell memory CAR T cells in the FP positively correlated with in vivo CAR T-cell exposure (AUCd0-28) (Spearman rank correlation [95% CI] for CD4+: 0.67 [0.23, 0.91], and for CD8+: 0.80 [0.50, 0.93]).

Early Phenotypes and Exposure
Higher proportions of early memory phenotype CD8+ CAR T cells in the infused product correlated with higher in vivo CAR T-cell exposure (AUCd0–28)

Early Phenotypes and Exposure (graphic)
Black line shows monotonic increasing (P-spline) fit, and the gray area shows the 95% confidence interval. Data cutoff: February 21, 2024. AUCd0–28, area under the curve from Day 0 to Day 28; TCM, central memory T cells; TN/SCM, naïve/stem cell memory T cells.

Building on the encouraging ATALANTA-1 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.

ATALANTA-1
ATALANTA-1 Phase 1/2 study with decentralized manufactured CD19 CAR-T candidate, GLPG5101, in different aggressive B-cell malignancies
CAR-T
Chimeric antigen receptor T cells (also known as CAR-T cells) are T cells that have been genetically engineered to produce an artificial T cell receptor for use in immunotherapy
CD19
CD19 is a protein found on the surface of B-cells, a type of white blood cell. Since CD19 is a hallmark of B-cells, the protein has been used to diagnose cancers that arise from this type of cell, notably B-cell lymphomas
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia is the most common leukemia in adults. It is a type of cancer that starts in cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer (leukemia) cells originate in the bone marrow and migrate to the bloodstream
Complete Response Rate (CRR)
Term used for the absence of all detectable cancer after the treatment is completed
Cytokine release syndrome (CRS)
Condition that develops when your immune system responds too aggressively to infection or after certain types of immunotherapy, such as CAR-T-cell therapy
EUPLAGIA-1
EUPLAGIA-1 Phase 1/2 study with decentralized manufactured CD19 CAR-T candidate, GLPG5201, in patients with replapsed/ refractory chronic lymphocytic leukemia (R/R CLL), R/R small lymphocytic lymphoma (R/R SLL), and Richter transformation (RT)
Efficacy
Effectiveness for intended use
GLPG5101
A second generation anti-CD19/4-1BB CAR-T product candidate currently in Phase 1/2 study in multiple aggressive B-cell malignancies
GLPG5201
A second generation anti-CD19/4-1BB CAR-T product candidate in Phase 1/2 study in R/R CLL/SLL and RT
Immune effector cell-associated neurotoxicity syndrome (ICAN)
Clinical and neuropsychiatric syndrome that can occur in the days to weeks following administration of certain types of immunotherapy, especially immune effector cell (IEC) and T cell engaging therapy
Leukapheresis
Laboratory procedure in which white blood cells are separated from a sample of blood
Objective Response Rate (ORR)
The response rate is the percentage of patients on whom a therapy has some defined effect; for example, the cancer shrinks or disappears after treatment. When used as a clinical endpoint for trials of cancer treatments, this is often called the objective response rate
Phase 1
First stage of clinical testing of an investigational drug designed to assess the safety and tolerability, pharmacokinetics of a drug, usually performed in a small number of healthy human volunteers
Phase 2
Second stage of clinical testing, usually performed in no more than several hundred patients, in order to determine efficacy, tolerability and the dose to use
Product candidate
Substance that has satisfied the requirements of early preclinical testing and has been selected for development, starting with formal preclinical safety evaluation followed by clinical testing for the treatment of a certain disorder in humans
Refractory
"Refractory" refers to a patient with cancer that is/has become resistant to, or does not respond to, treatment
Relapsed
"Relapsed" refers to a patient with cancer that develops cancer again after a period of improvement
Richter transformation
Richter transformation (RT) is an uncommon clinicopathological condition observed in patients with CLL. It is characterized by the sudden transformation of the CLL into a significantly more aggressive form of large cell lymphoma, and occurs in approximately 2-10% of all CLL patients
Small cell lymphocyte leukemia (SLL)
Small cell lymphocyte leukemia is a type of B-cell non-Hodgkin lymphoma, where the SLL cancer is located in lymph nodes and/or the spleen