NCT02151526

A Study Evaluating the Safety and Efficacy of LentiGlobin BB305 Drug Product in β-Thalassemia Major (Also Referred to as Transfusion-dependent β-Thalassemia [TDT]) and Sickle Cell Disease

Completed Phase 1, PHASE2 Results posted Last updated 26 April 2022

What this trial tests

Phase 1, PHASE2 trial testing LentiGlobin BB305 Drug Product in Beta-Thalassemia Major in 7 participants. Completed in 26 February 2019.

Timeline

7 June 2013

Primary endpoint
26 February 2019

26 February 2019

Quick facts

Lead sponsor	Genetix Biotherapeutics Inc.
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	7
Start date	7 June 2013
Primary completion	26 February 2019
Estimated completion	26 February 2019
Sites	1 location across France

Drugs / interventions tested

• LentiGlobin BB305 Drug Product — full drug profile →

Conditions studied

• Beta-Thalassemia Major — all drugs for Beta-Thalassemia Major →
• Sickle Cell Disease — all drugs for Sickle Cell Disease →

Sponsor

Genetix Biotherapeutics Inc. — full company profile →

Who can join

Adults 5 to 35, any sex, with Beta-Thalassemia Major or Sickle Cell Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Treated Participants With Successful Neutrophil and Platelet Engraftment Primary · From time of drug product infusion through Month 24

Neutrophil engraftment was defined as the first of absolute neutrophil count (ANC) \> or = 0.5 × 10\^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value less than (\<) 0.5 × 10\^9/L. Platelet engraftment was defined as the first of 3 consecutive platelet values \> or =20 × 10\^9/L for participants with TDT and values \> or =50 × 10\^9/L for participants with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the

Participants with Neutrophil Engraftment

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	3
LentiGlobin BB305 Drug Product for TDT	4

Participants with Platelet Engraftment

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	3
LentiGlobin BB305 Drug Product for TDT	4

Time to Successful Neutrophil and Platelet Engraftment Primary · From time of drug product infusion through Month 24

Neutrophil engraftment was defined as the first of ANC \> or = 0.5 × 10\^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value \< 0.5 × 10\^9/L). Platelet engraftment was defined as the first of 3 consecutive platelet values \> or =20 × 10\^9/L for participants with TDT and values \> or =50 × 10\^9/L for participants with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the first day of the 3 consecutive platele

Time to Neutrophil Engraftment

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	32	27 – 38
LentiGlobin BB305 Drug Product for TDT	16.5	14 – 29

Time to Platelet Engraftment

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	51	39 – 92
LentiGlobin BB305 Drug Product for TDT	23	20 – 26

Incidence of Transplant Related Mortality Primary · From screening through 365 days post-transplant

This was the safety outcome measure related to mortality. Transplant related mortality was defined as any death occurring in the study post drug product infusion deemed related to the transplant by the investigator.

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	0
LentiGlobin BB305 Drug Product for TDT	0

Number of Participants With Overall Survival (OS) Events Primary · From time of drug product infusion through Month 24

Overall survival was defined as time from date of LentiGlobin BB305 Drug Product infusion (Day 1) to date of death. Overall survival was censored at the date of last visit if the participant was still alive. Number of participants with OS events were reported.

Censored Participants

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	3
LentiGlobin BB305 Drug Product for TDT	4

Participants reported OS events

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	0
LentiGlobin BB305 Drug Product for TDT	0

Percentage of Participants With Vector-Derived Replication-Competent Lentivirus (RCL) Primary · From time of drug product infusion through Month 24

Blood samples were analyzed for detection of RCL using RCL co-culture assay.

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	0
LentiGlobin BB305 Drug Product for TDT	0

Number of Treated Participants With Greater Than (>) 30 Percent (%) Contribution of an Individual Clone As Per Integration Site Analysis (ISA) Primary · From time of drug product infusion through Month 24

Clonal dominance was defined as an ISA result greater than (\>) 90% of the total insertion sites (IS) at any time and a vector copy number (VCN) \> or =0.3, or an initial ISA result of \> 30% of the total IS with a VCN \> or =0.3 followed by a result \> 30% and less than or equal to (\< or =) 90% at first repeat and a result \> 50% at second repeat.

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	0
LentiGlobin BB305 Drug Product for TDT	0

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Primary · From date of Informed Consent signing up to Month 24

An AE was any untoward medical occurrence associated with the use of a drug in participants, whether or not considered drug related. An AE may include a change in physical signs, symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical study. This definition includes inter-current illnesses or injuries, and exacerbation of pre-existing conditions. An SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in per

Number of Participants with any Adverse Event

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	3
LentiGlobin BB305 Drug Product for TDT	4

Number of participants with any SAE

Group	Value	95% CI
LentiGlobin BB305 Drug Product for SCD	3
LentiGlobin BB305 Drug Product for TDT	3

Percentage of Treated Participants With Transfusion-Dependent β-Thalassemia (TDT) Who Achieved Transfusion Independence (TI) Secondary · From time of drug product infusion through Month 24

TI was defined as a weighted average hemoglobin (Hb) \> or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of \> or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb \> or =9 g/dL with no transfusions in the preceding 60 days.

Group	Value	95% CI
LentiGlobin BB305 Drug Product for TDT	75

Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) Secondary · From time of drug product infusion through Month 24

TI was defined as a weighted average hemoglobin (Hb) \> or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of \> or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb \> or =9 g/dL with no transfusions in the preceding 60 days.

Group	Value	95% CI
LentiGlobin BB305 Drug Product for TDT	11.3	10.6 – 13.1

Duration of Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) Secondary · From time of drug product infusion through Month 24

TI was defined as a weighted average Hb \> or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of \> or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb \> or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be \> or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated participant needs to maintain a weighted Hb of \> or =9 g/dL from that point forwa

Group	Value	95% CI
LentiGlobin BB305 Drug Product for TDT	21.7	21.2 – 21.8

Time From LentiGlobin BB305 Drug Product Infusion to Last Packed Red Blood Cells (pRBC) Transfusion Prior to Achieving Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) Secondary · From time of drug product infusion through Month 24

TI was defined as a weighted average Hb \> or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of \> or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb \> or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be \> or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated participant needs to maintain a weighted Hb of \> or =9 g/dL from that point forwa

Group	Value	95% CI
LentiGlobin BB305 Drug Product for TDT	11	5 – 13

Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT) Secondary · From time of drug product infusion through Month 24

TI was defined as a weighted average Hb \> or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of \> or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when participants achieve a Hb \> or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be \> or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated participant needs to maintain a weighted Hb of \> or =9 g/dL from that point forwa

Group	Value	95% CI
LentiGlobin BB305 Drug Product for TDT	14.9	14.9 – 15.6

Adverse events — posted to ClinicalTrials.gov

Time frame: From date of Informed Consent signing up to Month 24. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

LentiGlobin BB305 Drug Product for SCD

Serious: 3/3 (100%)

Deaths: 0/3

LentiGlobin BB305 Drug Product for TDT

Serious: 3/4 (75%)

Deaths: 0/4

Serious adverse events (12 terms)

Reaction	System	LentiGlobin BB305 Drug Pro…	LentiGlobin BB305 Drug Pro…
Procedural pain	Injury, poisoning and procedural complications	—	—
Hepatic enzyme increased	Investigations	—	—
Acute chest syndrome	Respiratory, thoracic and mediastinal disorders	—	—
Sickle cell anaemia with crisis	Blood and lymphatic system disorders	—	—
Presyncope	Nervous system disorders	—	—
Seizure	Nervous system disorders	—	—
Major depression	Psychiatric disorders	—	—
Cholestasis	Hepatobiliary disorders	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—
Staphylococcal bacteraemia	Infections and infestations	—	—
Tooth infection	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—

Other adverse events (82 terms — click to expand)

Reaction	System	LentiGlobin BB305 Drug Pro…	LentiGlobin BB305 Drug Pro…
Pyrexia	General disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Aspartate aminotransferase increased	Investigations	—	—
Vomiting	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Xerosis	General disorders	—	—
Puncture site pain	General disorders	—	—
Anxiety	Psychiatric disorders	—	—
Insomnia	Psychiatric disorders	—	—
Procedural pain	Injury, poisoning and procedural complications	—	—
Gamma-glutamyltransferase increased	Investigations	—	—
Sickle cell anaemia with crisis	Blood and lymphatic system disorders	—	—
Headache	Nervous system disorders	—	—
Anal inflammation	Gastrointestinal disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Hot flush	Vascular disorders	—	—
Hypotension	Vascular disorders	—	—
Skin papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Non-cardiac chest pain	General disorders	—	—
Chills	General disorders	—	—
Catheter site pain	General disorders	—	—
Fatigue	General disorders	—	—
Feeling cold	General disorders	—	—
Hypothermia	General disorders	—	—
Pain	General disorders	—	—
Injection site inflammation	General disorders	—	—
Disturbance in attention	Psychiatric disorders	—	—
Ovarian cyst	Reproductive system and breast disorders	—	—
Premature menopause	Reproductive system and breast disorders	—	—
Catheter site pain	Injury, poisoning and procedural complications	—	—
Staphylococcus test positive	Investigations	—	—

Most-reported serious reactions: Procedural pain, Hepatic enzyme increased, Acute chest syndrome, Sickle cell anaemia with crisis, Presyncope, Seizure, Major depression, Cholestasis.

Data from ClinicalTrials.gov NCT02151526 adverse events section.

Sponsor's own description

This is a Phase 1/2, open label, safety, and efficacy study of the administration of LentiGlobin BB305 Drug Product to participants with either transfusion dependent beta-thalassemia (TDT) or sickle cell disease (SCD).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Viral vector platforms within the gene therapy landscape.
   Bulcha JT, Wang Y, Ma H, Tai PWL, et al · · 2021 · cited 899× · PMID 33558455 · DOI 10.1038/s41392-021-00487-6
2. Gene Therapy in a Patient with Sickle Cell Disease.
   Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, et al · · 2017 · cited 490× · PMID 28249145 · DOI 10.1056/nejmoa1609677
3. Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia.
   Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, et al · · 2018 · cited 473× · PMID 29669226 · DOI 10.1056/nejmoa1705342
4. Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders.
   Shahryari A, Saghaeian Jazi M, Mohammadi S, Razavi Nikoo H, et al · · 2019 · cited 168× · PMID 31608113 · DOI 10.3389/fgene.2019.00868
5. Clinical development of gene therapy: results and lessons from recent successes.
   Kumar SR, Markusic DM, Biswas M, High KA, et al · · 2016 · cited 155× · PMID 27257611 · DOI 10.1038/mtm.2016.34
6. Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β(A(T87Q))-Globin Gene.
   Negre O, Eggimann AV, Beuzard Y, Ribeil JA, et al · · 2016 · cited 119× · PMID 26886832 · DOI 10.1089/hum.2016.007
7. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease.
   Hoban MD, Orkin SH, Bauer DE. · · 2016 · cited 115× · PMID 26758916 · DOI 10.1182/blood-2015-09-618587
8. A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders.
   Tucci F, Galimberti S, Naldini L, Valsecchi MG, et al · · 2022 · cited 109× · PMID 35288539 · DOI 10.1038/s41467-022-28762-2