Clinical Trial Results

Clinical trial patients receiving ZYNTEGLO continue to be followed long term, with 7 patients who have completed their 3.5-year follow-up visit

Those eligible for clinical trials were patients with beta-thalassemia (also known as beta-thalassemia major or Cooley's Anemia) requiring regular transfusions categorized as either:

In the 2 years before entering the trial:

At least 100 mL/kg/year of red blood cells, or
Eight or more regular red blood cell transfusions per year

PHASE 3: ONGOING (AS OF MARCH 2021)

PHASE 3: ONGOING
(AS OF MARCH 2021)

PRIMARY OUTCOME	Transfusion Independence
	STUDY 1	STUDY 2
NUMBER OF PARTICIPANTS	23 PATIENTS	18 PATIENTS
	4-34	4-33
AGE (YEARS)	14 PEDIATRICS 9 ADULTS	13 PEDIATRICS 5 ADULTS
GENOTYPES	non-β⁰/β⁰ 23	non-β⁰/β^0* 6 β⁰/β⁰ 12
MEDIAN FOLLOW-UP STUDY	29.5 MONTHS (min, max: 13.0, 48.2)	24.6 MONTHS (min, max: 4.1, 35.5)
ENROLLED IN FOLLOW-UP STUDY	19/23 PATIENTS^†	10/18 PATIENTS^†
	^*Non-β⁰/β⁰ patients in Study 2 included severe genotypes similar to β⁰/β⁰. ^†Remaining patients are still in the process of completing their initial clinical trial before they have the option to continue in the follow-up study. Pediatric is defined as people under the age of 18.

PRIMARY OUTCOME
Transfusion Independence
STUDY 1	STUDY 2
NUMBER OF PARTICIPANTS
23 PATIENTS	18 PATIENTS
AGE (YEARS)
4-34	4-33
14 PEDIATRICS 9 ADULTS	13 PEDIATRICS 5 ADULTS
GENOTYPES
non-β⁰/β⁰ 23	non-β⁰/β^0* 6 β⁰/β⁰ 12
MEDIAN FOLLOW-UP STUDY
29.5 MONTHS (min, max: 13.0, 48.2)	24.6 MONTHS (min, max: 4.1, 35.5)
ENROLLED IN FOLLOW-UP STUDY
19/23 PATIENTS^†	10/18 PATIENTS^†
^*Non-β⁰/β⁰ patients in Study 2 included severe genotypes similar to β⁰/β⁰. ^†Remaining patients are still in the process of completing their initial clinical trial before they have the option to continue in the follow-up study. Pediatric is defined as people under the age of 18.

Achieved Transfusion Independence

STUDY 1	STUDY 2
91% 20/22 patients with non-β⁰/β⁰	86% 12/14 patients with non-β⁰/β⁰, β⁰/β⁰

STUDY 2 represents patients with severe genotypes, including β⁰/β⁰ and non-β⁰/β⁰ patients with IVS-I-110 genotypes (similar to β⁰/β⁰)

Median Total
Hemoglobin Level

STUDY 1	STUDY 2
11.8g/dL	10.2g/dL

Patients who achieved transfusion independence (32/36) had a near-normal median total hemoglobin level driven by ZYNTEGLO-derived adult hemoglobin
Total hemoglobin levels reflect weighted average total hemoglobin during transfusion independence, which is defined as the average across hemoglobin levels taken at each patient visit during the clinical study, factoring in a weighting based on the time duration between study visits

*Transfusion independence (TI) meant that patients achieved a weighted average hemoglobin of ≥9 g/dL without any transfusions for a continuous period of ≥12 months at any time during the study after infusion of ZYNTEGLO.
ZYNTEGLO was evaluated in 41 patients aged 4 to 34 years. Of these 41 patients, 36 were evaluable for TI. Patients were evaluable if they had completed 24 months of follow-up in the phase 3 study, or achieved TI, or won’t achieve TI in the phase 3 study.
Total hemoglobin levels presented about ZYNTEGLO reflect weighted average total hemoglobin during transfusion independence, which is defined as the average across hemoglobin levels taken at each patient visit during the clinical study, factoring in a weighting based on the time duration between study visits. ^†Normal Hb ranges for healthy individuals from the American College of Clinical Pharmacy:
• 2–9 years: 11.5–14.5 g/dL • Males 10–17 years: 12.5–16.1 g/dL • Females 10–17 years: 12–15 g/dL • Male adults (≥18 years): 13.5–18 g/dL • Female adults (≥18 years): 12.5–16 g/dL *Transfusion independence (TI) meant that patients achieved a weighted average hemoglobin of ≥9 g/dL without any transfusions for a continuous period of ≥12 months at any time during the study after infusion of ZYNTEGLO.
ZYNTEGLO was evaluated in 41 patients aged 4 to 34 years. Of these 41 patients, 36 were evaluable for TI. Patients were evaluable if they had completed 24 months of follow-up in the phase 3 study, or achieved TI, or won’t achieve TI in the phase 3 study.
Total hemoglobin levels presented about ZYNTEGLO reflect weighted average total hemoglobin during transfusion independence, which is defined as the average across hemoglobin levels taken at each patient visit during the clinical study, factoring in a weighting based on the time duration between study visits. ^†Normal Hb ranges for healthy individuals from the American College of Clinical Pharmacy:
• 2–9 years: 11.5–14.5 g/dL
• Males 10–17 years: 12.5–16.1 g/dL
• Females 10–17 years: 12–15 g/dL
• Male adults (≥18 years): 13.5–18 g/dL
• Female adults (≥18 years): 12.5–16 g/dL

LEARN MORE: PATIENTS WHO DID NOT ACHIEVE TRANSFUSION INDEPENDENCE STILL
REDUCED TRANSFUSIONS.

In the phase 3 trials, 4 out of 36 patients who were evaluated for transfusion independence
didn't achieve it, but were still able to:

Reduce red blood cell transfusion frequency
Reduce red blood cell transfusion volume

STUDY 1
TRANSFUSION FREQUENCY REDUCTION	TRANSFUSION VOLUME REDUCTION
PATIENT 1
30%	32%
PATIENT 2
26%	31%

STUDY 2
TRANSFUSION FREQUENCY REDUCTION	TRANSFUSION VOLUME REDUCTION
PATIENT 3
87%	92%
PATIENT 4
21%	3%

Reductions observed in phase 3 clinical trials from 6 months post-ZYNTEGLO infusion to the
patient's last follow-up visit when compared with their pre-enrollment transfusion requirements.

	STUDY 1	STUDY 2
PATIENTS WHO ACHIEVED TRANSFUSION INDEPENDENCE	20 patients with non-β⁰/β⁰	12 patients with β⁰/β⁰ or non-β⁰/β⁰			DID NOT RESTART CHELATION	RESTARTED THEN STOPPED CHELATION
WERE NOT RECEIVING CHELATION AT LAST FOLLOW-UP	65% (13/20 patients)	58% (7/12 patients)	Of those who were not on chelation at last follow-up	STUDY 1	69% (9/13 patients)	31% (4/13 patients)
Received phlebotomy to remove iron	35% (7/20 patients)	8% (1/12 patients)		STUDY 2	43% (3/7 patients)	57% (4/7 patients)
	^§Iron removal therapy was managed at a doctor’s discretion. Restarting iron chelation after ZYNTEGLO may be necessary.

PATIENTS WHO ACHIEVED TRANSFUSION INDEPENDENCE
STUDY 1 20 patients with non-β⁰/β⁰	STUDY 2 12 patients with β⁰/β⁰ and non-β⁰/β⁰
WERE NOT RECEIVING CHELATION AT LAST FOLLOW-UP
65% (13/20 patients)	58% (7/12 patients)

Of those who were not on chelation at last follow-up
DID NOT RESTART CHELATION
69% (9/13 patients)	43% (3/7 patients)
RESTARTED THEN STOPPED CHELATION
31% (4/13 patients)	57% (4/7 patients)

Received phlebotomy to remove iron
35% (7/20 patients)	8% (1/12 patients)
^§Iron removal therapy was managed at a doctor’s discretion. Restarting iron chelation after ZYNTEGLO may be necessary.