EFFICACY

Help them let go of chronic transfusions1

PATIENTS ≥12 YEARS OF AGE WITH TRANSFUSION-DEPENDENT β-THALASSAEMIA (TDT) WHO DO NOT HAVE A β00 GENOTYPE AND WHO DO NOT HAVE AN HLA-MATCHED RELATED DONOR ARE EVALUATED WITH ZYNTEGLO IN 4 CLINICAL TRIALS AND CONTINUE TO BE FOLLOWED IN A LONG-TERM FOLLOW-UP STUDY FOR UP TO 15 YEARS1

The majority of patients* treated with ZYNTEGLO achieved transfusion independence and continue to be transfusion-independent at last follow-up.1

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*Patients are eligible for assessment of transfusion independence if they have completed the parent study or achieved transfusion independence or will not achieve transfusion independence in the parent study.1

ZYNTEGLO enables the production of gene therapy-derived HbA (HbAT87Q) that can be quantified over time.†1,6


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The primary endpoint for HGB-204, HGB-205, and HGB-207 was transfusion independence.1

Reduced iron overload was shown at 48 months in HGB-204 and HGB-205.1,7



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Data from beyond 24 months are from LTF-303.1


TRANSFUSION INDEPENDENCE

The majority of patients* treated with ZYNTEGLO achieved transfusion independence1

Transfusion independence was defined as a weighted average Hb of ≥9 g/dL without any transfusions for a continuous period of ≥12 months at any time during the study after infusion of ZYNTEGLO.1

*Defined as patients who have completed the parent study or achieved transfusion independence or will not achieve transfusion independence in the parent study.1

All patients who achieved transfusion independence maintained transfusion independence.1
79% achieved transfusion independence in Phase 1/2 studies and 100% maintained it
100% maintained transfusion independence at Month 30 (min, max: 21.2+, 56.3+)

PHASE 1/2 - COMPLETED1 

(HGB-204, HGB-205)

(Primary endpoint: transfusion independence by Month 24)

Data beyond 24 months are from the LTF-303 study.

80% achieved transfusion independence in Phase 3 studies and 100% maintained it
100% maintained transfusion independence (min, max: 12.0+, 18.2+ months)

PHASE 3 - ONGOING1

(HGB-207)

(Primary endpoint: transfusion independence by Month 24)

As the phase 3 trial is ongoing, data shown here are for the patients who are currently eligible for assessment of transfusion independence.

These data are from the HGB-207 study only.

All patients who achieved transfusion independence maintained it at last follow-up1
  • Follow-up in the phase 1/2 trials and LTF-303 (min, max) is up to 58.6 months (29.3, 58.6)1
  • Follow-up in the ongoing phase 3 trials (min, max) is up to 22.2 months (1.3, 22.2)1
Median total Hb over time in non-β00 TDT patients treated with ZYNTEGLO who have achieved transfusion independence1
Chart shows total Hb levels maintained above 9 g/dL over 60 months for HGB-207, HGB-205, and HGB-204
The four patients with non-β00 TDT who did not achieve transfusion independence experienced transfusion reductions1
HGB-204 + HGB-2051 (n=3/14)
Patient 1 showed 100% reduction in transfusion volume and 100% reduction in transfusion frequency
Patient 2 showed 86.9% reduction in transfusion volume and 85.3% reduction in transfusion frequency
Patient 3 showed 26.8% reduction in transfusion volume and 20.7% reduction in transfusion frequency

Reductions observed in the phase 1/2 studies between Month 6 and Month 24 visits when compared with their pre-study levels of transfusions1

*Patient did not achieve Hb levels ≥9 g/dL, per the definition of transfusion independence.1

HGB-207 (ONGOING)1 (n=1/5)
Patient 1 showed 75.8% reduction in transfusion volume and 74.9%% reduction in transfusion frequency

Reductions observed in the phase 3 study between hospital discharge through last recorded visit when compared with pre-study levels of transfusions1

Patients evaluable for transfusion independence.1

TOTAL Hb DURING TRANSFUSION INDEPENDENCE

Patients treated with ZYNTEGLO achieved Hb levels that enabled transfusion independence1
Median Hb levels in patients with non-β00 TDT achieving transfusion independence1
Median 10.5 g/dl

HGB-204 + HGB-205
(n=11)

Weighted average Hb during transfusion independence.

Phase 1/2 - COMPLETED1

Median Hb for ongoing Phase 3 study was 12.4 g/dL, minimum 11.5, maximum 12.6

HGB-207
(n=4)

Weighted average Hb during transfusion independence.

Phase 3 - ONGOING1

Weighted average Hb.1

Transfusion independence was defined as a weighted average Hb of ≥9 g/dL without any transfusions for a continuous period of ≥12 months at any time during the study after infusion of ZYNTEGLO.1

Hb AT 6 MONTHS

ZYNTEGLO-derived Hb (HbAT87Q) supported total Hb in patients at 6 months who did not receive a transfusion for the prior 60 days6

In the ongoing phase 3 trial HGB-207, median total Hb at 6 months for patients who did not receive a transfusion for the prior 60 days was 11.9 g/dL, primarily driven by HbAT87Q 6

Phase 3 study
HGB-207
(n=11)
MEDIAN HbAT87Q AT 6 MONTHS1,6
MEDIAN TOTAL Hb AT 6 MONTHS1,6
Median HbAT87Q was 9.5 g/dL, minimum 3.4, maximum 10.6. Median total Hb was 11.9 g/dL, minimum 8.4, maximum 13.3

The phase 3 trials are conducted with improved transduction compared to the phase 1/2 studies, resulting in an increased average number of functional copies of the βA-T87Q-globin gene integrated into autologous cells.1

Phase 1/2
studies

HGB-204 (n=10)1,6:
4.2 g/dL (min, max: 1.0, 8.5)

HGB-205 (n=4)1,6:
7.5 g/dL (min, max: 4.9, 9.6) 

HGB-204 (n=7)1,6:
9.2 g/dL (min, max: 7.7, 13.3)

HGB-205 (n=4)1,6:
10.7 g/dL (min, max: 7.6, 13.4)

ZYNTEGLO enables the production of functional gene therapy–derived HbA (HbAT87Q) that can be quantified over time.6

REDUCED IRON CONCENTRATION

Reduced iron overload was shown at 48 months for patients in HGB-204 and HGB-205 who achieved transfusion independence1
Serum ferritin and liver iron content (LIC) in patients who achieved transfusion independence1
(n=3, HGB-204; n=2, HGB-205)
Data from beyond 24 months are from LTF-303.7
Serum ferritin was reduced 75% from baseline. Median baseline serum ferritin was 3778.7 pmol/L, minimum 784, maximum 22517.
MEDIAN CHANGE FROM BASELINE IN SERUM FERRITIN1
Liver iron content was reduced 67% from baseline. Median baseline LIC was 6.75 mg/g, minimum 1.0, maximum 41.0.
MEDIAN CHANGE FROM BASELINE IN LIC1
  • After ZYNTEGLO infusion, patient iron levels were managed at physician discretion.1
  • All patients in HGB-204 restarted iron chelation and continue to use iron chelators. One patient in HGB-205 restarted iron chelation and continues to use iron chelators. Three patients in HGB-205 started phlebotomy.1
  • Of the 11 patients followed for at least 6 months after ZYNTEGLO infusion in HGB-207 and HGB-212, 6 patients did not restart iron chelation or receive phlebotomy, 3 patients restarted iron chelation, and 2 patients received phlebotomy to reduce iron levels.1
Erythropoiesis: ZYNTEGLO increases myeloid/erythroid ratios1

In an exploratory analysis from HGB-207, bone marrow biopsies taken before ZYNTEGLO infusion showed low myeloid/erythroid ratios (n=15), reflective of erythroid hyperplasia and consistent with a diagnosis of TDT1

Baseline and 12-month myeloid/erythroid ratios (n=8)1*
Range 0.1 through 0.5, n equals 7 of 8
BASELINE MYELOID/ERYTHROID RATIO
Over approximately 12 months
Range 0.6 through 1.9, n equals 7 of 8
~12 MONTHS AFTER ZYNTEGLO MYELOID/ERYTHROID RATIO

*Patients who had sufficient on-study follow-up to obtain a 12-month bone marrow assessment.1

**For 8 patients who had sufficient on-study follow-up to obtain a 12-month follow-up bone marrow assessment, myeloid/erythroid ratios for 7 patients increased from a range of 0.1 to 0.5 at baseline to a range of 0.6 to 1.9 approximately 12 months after ZYNTEGLO infusion.1

ZYNTEGLO was evaluated in four clinical trials and a long-term follow-up study1,7
  • 42 patients were part of the safety assessments of ZYNTEGLO (≥12 years of age with TDT)1

  • 32 patients were assessed for efficacy (≥12 years of age with non-β00 TDT)1

STUDY DESIGNS

Patients were assessed for transfusion independence*

  • Open-label

  • Single-arm

  • Patients had a history of RBC transfusions of ≥100 mL/kg/year or ≥8 transfusions per year in the 2 years prior to enrolment

     

*Transfusion independence was defined as a weighted average Hb of ≥9 g/dL without any transfusions for a continuous period of ≥12 months at any time during the study after infusion of ZYNTEGLO.

Study Design

 

In the Phase 1/2 and 3 trials, patients had a history of RBC transfusions of ≥100 ml/kg/year or ≥8 transfusions per year in the 2 years prior to enrolment. Transfusion independence was defined as a weighted average Hb of ≥9 g/dL without any transfusions for a continuous period of ≥12 months at any time during the study after infusion of ZYNTEGLO.1

Median duration of follow-up data is presented as pooled for the Phase 1/2 and Phase 3 trials in the Summary of Product Characteristics.

*HGB-204 and HGB 205 were Phase 1/2 open-label, single-arm 24-month studies that included 22 patients with TDT treated with ZYNTEGLO (N=18, HGB-204; N=4, HGB-205), of whom 14 had a non-β00 genotype (N=10, HGB-204, N=4, HGB-205) and 8 had a β00-genotype in HGB-204. All patients completed HGB-204 and HGB-205 and enrolled for long-term follow-up in the LTF-303 study.1
Transfusion independence is defined as weighted average haemoglobin ≥ 9 g/dL without any RBC transfusions for ≥ 12 months.1
Transfusion reduction defined as ≥60% reduction in transfusion RBC volume 12-24 months post-drug product infusion compared to the 24 months pre-drug product.6