KEY SAFETY RESULTS

Safety results following treatment with ZYNTEGLO1

Median duration of follow-up was 44.6 months (min, max: 35.8, 61.3) in the Phase 1/2 trials and 15.9 months (min, max: 5.6, 26.3) in the Phase 3 trials1

No cases of LEUKAEMIA OR LYMPHOMA have been reported in clinical studies with ZYNTEGLO in patients with TDT1
No cases of GRAFT FAILURE measured by neutrophil engraftment1
Median time to NEUTROPHIL ENGRAFTMENT* was 21 days
(min, max: 13, 38) (N=45)1
Median time to NEUTROPHIL ENGRAFTMENT* was 21 days (min, max: 13, 38) (N=45)1
Median time to PLATELET ENGRAFTMENT was 42 days (min, max: 19, 191) (N=45)1
Median time to PLATELET ENGRAFTMENT was 42 days
(min, max: 19, 191) (N=45)1
Serious events of HEPATIC VENO-OCCLUSIVE DISEASE (VOD) occurred in 11.1% of patients following MYELOABLATIVE CONDITIONING1
ALL PATIENTS with TDT receiving treatment with ZYNTEGLO in the clinical study program ARE ALIVE at last visit1

The long-term follow-up study (LTF-303) will continue to monitor the safety of ZYNTEGLO in the clinical trial setting for a total of 15 years4

*Neutrophil engraftment: Failure of neutrophil engraftment is a short-term but potentially severe risk, defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥500 cells/μL obtained on different days by Day 43 after infusion of ZYNTEGLO.1

†Platelet engraftment: Platelet engraftment is defined as three consecutive platelet values ≥20×109/L obtained on different days after ZYNTEGLO infusion, with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period.1


Adverse reactions related to ZYNTEGLO

The safety of ZYNTEGLO has been characterised in clinical trials of 45 patients with TDT1

VERY COMMON (≥10%) ADVERSE REACTIONS ATTRIBUTED TO ZYNTEGLO IN CLINICAL TRIALS1

GASTROINTESTINAL DISORDERS

  • Abdominal pain

COMMON (≤1% TO <10%) ADVERSE REACTIONS ATTRIBUTED TO ZYNTEGLO IN CLINICAL TRIALS1

BLOOD AND LYMPHATIC SYSTEM DISORDERS

  • Thrombocytopenia, leukopenia, neutropenia

VASCULAR DISORDERS

  • Hot flush

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS

  • Dyspnoea

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

  • Pain in extremity

GENERAL DISORDERS AND ADMINISTRATION-SITE CONDITIONS

  • Non-cardiac chest pain
Infusion-related reactions to ZYNTEGLO were observed in 13.3% of patients and occurred on the day of ZYNTEGLO infusion; all reactions resolved and the majority were mild. Pre-medication for infusion reactions was managed at physician discretion.1
Given the small patient population and size of cohorts, adverse reactions above do not provide a complete perspective on the nature and frequency of these reactions.
  • The most common adverse reaction attributed to ZYNTEGLO was abdominal pain1

  • The only serious adverse reaction attributed to ZYNTEGLO was thrombocytopenia (2.2%)1

  • Bleeding is a potential complication of thrombocytopenia subsequent to myeloablative conditioning and treatment with ZYNTEGLO1

  • The majority of all recorded bleeding reactions were nonserious1

  • A risk of bleeding exists before platelet engraftment and may continue after platelet engraftment in patients who have continued thrombocytopenia1

  • Following platelet engraftment, all patients maintained platelet levels of ≥20x109/L1

  • Median times to unsupported platelet counts of ≥50x109/L and ≥100x109/L were 51 days (min, max: 20, 268; N=45) and 63.5 days (min, max: 20, 1231; N=42), respectively1

For AEs associated with mobilisation and conditioning, see the ZYNTEGLO EU SmPC or the relevant product SmPC.


For consideration prior to use of ZYNTEGLO

TRACEABILITY1

  • The traceability requirements of cell-based advanced therapy medicinal products must apply

GENERAL1

  • Warnings and precautions of the mobilisation agents and the myeloablative conditioning agent must be considered

  • Patients treated with ZYNTEGLO should not donate blood, organs, tissues, or cells for transplantation at any time in the future

  • This information is provided in the Patient Alert Card, which must be given to the patient after treatment

RISKS ASSOCIATED WITH TDT AND IRON OVERLOAD1

  • Patients with TDT experience iron overload due to RBC transfusions that can lead to end organ damage

  • HSC transplantation with myeloablative conditioning is not appropriate for patients with TDT who have evidence of severely elevated iron in the heart (ie, patients with cardiac T2* <10 msec by MRI)

  • MRI of the liver should be performed on all patients prior to myeloablative conditioning

  • It is recommended that patients with MRI demonstrating LIC ≥15 mg/g undergo liver biopsy for further evaluation

  • If the liver biopsy demonstrates bridging fibrosis, cirrhosis, or active hepatitis, HSC transplantation with myeloablative conditioning is not appropriate

RISK OF INSERTIONAL ONCOGENESIS1

  • No cases of leukaemia or lymphoma have been reported in clinical studies with ZYNTEGLO in patients with TDT

  • There are no reports of LVV-mediated insertional mutagenesis resulting in oncogenesis

  • Nevertheless, there is a theoretical risk of leukaemia or lymphoma after treatment with ZYNTEGLO

  • Patients should be monitored annually for leukaemia or lymphoma (including with a complete blood count) for 15 years post treatment with ZYNTEGLO

  • If leukaemia or lymphoma is detected in any patient who received ZYNTEGLO, blood samples should be collected for integration site analysis 

SEROLOGICAL TESTING1

  • All patients should be tested for HIV-1/2 and HTLV-1/2 prior to mobilisation and apheresis to ensure acceptance of the apheresis material for ZYNTEGLO manufacturing

INTERFERENCE WITH SEROLOGY TESTING1

  • It is important to note that patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false positive test for HIV

  • Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR-based assay

ENGRAFTMENT FAILURE AS MEASURED BY NEUTROPHIL ENGRAFTMENT1

  • In clinical trials, no patients failed to engraft bone marrow, as measured by neutrophil engraftment (N=45)

  • Failure of neutrophil engraftment is a short-term but potentially severe risk, defined as failure to achieve three consecutive absolute neutrophil counts (ANCs) ≥500 cells/μL obtained on different days by Day 43 after infusion of ZYNTEGLO

  • Patients who experience neutrophil engraftment failure should receive rescue treatment with the back-up collection

DELAYED PLATELET ENGRAFTMENT1

  • Platelet engraftment is defined as three consecutive platelet values ≥20x109/L obtained on different days after ZYNTEGLO infusion, with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period

  • Patients with TDT treated with ZYNTEGLO who achieved platelet engraftment had a median platelet engraftment on Day 42.0 (19, 191) in clinical trials (N=45)

  • No correlation was observed between incidence of bleeding and delayed platelet engraftment

  • Patients should be made aware of the risk of bleeding until platelet recovery has been achieved

  • Patients should be monitored for thrombocytopenia and bleeding according to standard guidelines

  • Platelet counts should be monitored according to medical judgment until platelet engraftment and platelet recovery are achieved

  • Blood cell count determination and other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise

ANTI-RETROVIRAL USE AND HYDROXYUREA1

  • Patients should not take anti-retroviral medications or hydroxyurea from at least 1 month prior to mobilisation until at least 7 days after ZYNTEGLO infusion

  • If a patient requires anti-retrovirals for HIV prophylaxis, ZYNTEGLO treatment, including mobilisation and apheresis of CD34+ cells through ZYNTEGLO infusion, should be delayed until an HIV western blot and viral load are negative at 6 months post-HIV exposure

SODIUM CONTENT1

  • This medicinal product contains 391-1564 mg sodium per dose, equivalent to 20% to 78% of the WHO recommended maximum daily intake of 2 g sodium for an adult

     

Adverse reactions associated with mobilisation and apheresis1

VERY COMMON (≥10%) ADVERSE REACTIONS ATTRIBUTED TO MOBILISATION AND APHERESIS

Blood and lymphatic system disorders

  • Thrombocytopenia

Metabolism and nutrition disorders

  • Hypocalcaemia

Nervous system disorders

  • Headache, peripheral sensory neuropathy

Gastrointestinal disorders

  • Nausea

Musculoskeletal and connective tissue disorders

  • Bone pain

COMMON (≥1% TO <10%) ADVERSE REACTIONS ATTRIBUTED TO MOBILISATION AND APHERESIS

Blood and lymphatic system disorders

  • Splenomegaly, leukocytosis

Metabolism and nutrition disorders

  • Hypokalaemia, hypomagnesaemia

Psychiatric disorders

  • Agitation

Nervous system disorders

  • Dizziness, head discomfort, paraesthesia

Cardiac disorders

  • Cardiac flutter

Vascular disorders

  • Hypotension

Respiratory, thoracic, and mediastinal disorders

  • Hypoxia, epistaxis

Gastrointestinal disorders

  • Vomiting, lip swelling, abdominal pain, abdominal pain upper, paraesthesia oral

Skin and subcutaneous tissue disorders

  • Rash, hyperhidrosis

Musculoskeletal and connective tissue disorders

  • Back pain, musculoskeletal discomfort

General disorders and administration site conditions

  • Pyrexia, influenza like illness, chest discomfort, chest pain, injection site reaction, catheter site haemorrhage, catheter site bruise, injection site bruising, fatigue, non-cardiac chest pain, catheter site pain, injection site pain, puncture site pain, pain

Investigations

  • Blood magnesium decreased

Injury, poisoning, and procedural complications

  • Citrate toxicity, contusion, procedural pain 

 

According to available data, the frequency, type, and severity of adverse reactions in adolescents 12 to 17 years of age are similar to adults with the exception that VOD and pyrexia occurred more frequently in adolescents.

For additional safety information on mobilisation, apheresis, and myeloablative conditioning, please refer to the EU SmPC and Risk Minimisation Measures for each medicinal product utilised in this process.
 


Adverse reactions associated with myeloablative conditioning

VERY COMMON (≥10%) ADVERSE REACTIONS ATTRIBUTED TO MYELOABLATIVE CONDITIONING

Blood and lymphatic system disorders

  • Febrile neutropenia, neutropenia, thrombocytopenia, leukopenia, anaemia

Metabolism and nutrition disorders

  • Decreased appetite

Psychiatric disorders

  • Insomnia

Nervous system disorders

  • Headache

Respiratory, thoracic, and mediastinal disorders

  • Epistaxis, pharyngeal inflammation

Gastrointestinal disorders

  • Stomatitis, vomiting, nausea, diarrhoea, gingival bleeding, constipation, abdominal pain, anal inflammation

Hepatobiliary disorders

  • Hepatic veno-occlusive disease (VOD)*, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased

Skin and subcutaneous tissue disorders

  • Alopecia, pruritus, skin hyperpigmentation

Reproductive system and breast disorders

  • Vaginal haemorrhage

General disorders and administration site conditions

  • Pyrexia, fatigue, mucosal inflammation

 

COMMON (≥1% TO <10%) ADVERSE REACTIONS ATTRIBUTED TO MYELOABLATIVE CONDITIONING

Infections and infestations

  • Neutropenic sepsis, systemic infection, staphylococcal infection, pneumonia, lower respiratory tract infection, urinary tract infection, mucosal infection, cellulitis, vaginal infection, rash pustular, folliculitis, gingivitis, vulvovaginal candidiasis

Blood and lymphatic system disorders

  • Lymphopenia, leukocytosis, monocyte count decreased, neutrophilia, mean cell haemoglobin concentration increased

Endocrine Disorders

  • Primary hypogonadism

Metabolism and nutrition disorders

  • Hypocalcaemia, hypokalaemia, metabolic acidosis, fluid overload, fluid retention, hypomagnesaemia, hyponatraemia, hypophosphataemia, hyperphosphataemia

Psychiatric disorders

  • Anxiety

Nervous system disorders

  • Dizziness, lethargy, dysgeusia, ageusia, memory impairment

Eye disorders

  • Conjunctival haemorrhage

Ear and labyrinth disorders

  • Vertigo

Cardiac disorders

  • Cardiac failure congestive, atrial fibrillation

Vascular disorders

  • Hypotension, haematoma, hot flush

Respiratory, thoracic, and mediastinal disorders

  • Hypoxia, pulmonary mass, dyspnoea, pleural effusion, rales, upper-airway cough syndrome, cough, laryngeal pain, hiccups, oropharyngeal pain

Gastrointestinal disorders

  • Anal haemorrhage, gastritis, gastrointestinal inflammation, abdominal distension, abdominal pain upper, anal fissure, dyspepsia, dysphagia, oesophagitis, haemorrhoids, proctalgia, lip dry

Hepatobiliary disorders

  • Cholecystitis, cholelithiasis, hepatomegaly, jaundice, transaminases increased, gamma-glutamyltransferase increased

Skin and subcutaneous tissue disorders

  • Petechiae, ecchymosis, pain of skin, palpable purpura, pigmentation disorder, pruritus generalised, purpura, sweat gland disorder, urticaria, dry skin, rash

Musculoskeletal and connective tissue disorders

  • Bone pain, myalgia, pain in extremity, back pain

Renal and urinary disorders

  • Haematuria, pollakiuria

Reproductive system and breast disorders

  • Ovarian failure, menstruation irregular, premature menopause, blood follicle stimulating hormone increased, blood testosterone decreased

General disorders and administration site conditions

  • Face oedema, hypothermia, feeling cold, pain, xerosis

Investigations

  • C-reactive protein increased, aspergillus test positive, blood potassium decreased, weight decreased, blood alkaline phosphatase decreased, blood magnesium decreased, forced expiratory flow decreased, protein total decreased, blood albumin decreased, reticulocyte count decreased, reticulocyte percentage decreased

Injury, poisoning, and procedural complications

  • Transfusion reaction, skin abrasion

 

*Hepatic veno-occlusive disease (VOD): Serious reactions of VOD occurred in 11.1% of patients following myeloablative conditioning; 80% of these patients did not receive prophylaxis for VOD; all patients who experienced VOD received treatment with defibrotide and recovered; patients with TDT may be at an increased risk of VOD following myeloablative conditioning compared with other patient populations.

For additional safety information on mobilisation, apheresis, and myeloablative conditioning, please refer to the EU SmPC and Risk Minimisation Measures for each medicinal product utilised in this process.


ZYNTEGLO was evaluated in four clinical trials and a long-term follow-up study1,4
  • 45 patients were part of the safety assessment of ZYNTEGLO (≥12 years of age with TDT)1
  • 32 patients were part of the efficacy assessment of ZYNTEGLO (≥12 years of age with non-β00 TDT)1

STUDY DESIGNS

Diagram shows study designs: Phase 1/2 studies HGB-205 and HGB- 204; Phase 3 studies HGB-207 and HGB 212; and LTF-303 ongoing long-term study, up to 15 years planned

 

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 enrollment.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 at any time during the study after infusion of ZYNTEGLO.1
‡Transfusion reduction defined as ≥60% reduction in transfusion RBC volume 12-24 months post-DP infusion compared to the 24 months pre-drug product.8

PATIENT CHARACTERISTICS

Evaluable patients treated in the four clinical trials for ZYNTEGLO had the following characteristics:1

*2 years prior to date of informed consent.
†Age range is not provided to protect patient identity.