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Gene Therapy

ZYNTEGLO (ex-Lentiglobin) for patients with TDT

 

Update: 31 March 2020

  • BIOLOGICS LICENSE APPLICATION (BLA) SUBMISSION – Discussions with the FDA are underway so the BLA submission is completed in the second half of 2020. However these timelines are likely to be impacted by the COVID-19 situation, moving them to mid-2021.
  • NORTHSTAR-2 ( HGB-207) Phase 3 trial (non- β0genotype) – In January 2020, the final patient enrolled in the paediatric cohort and was infused with LentiGlobin for β-thalassaemia.
  • COVID-19 EFFECTS – It is expected that the COVID-19 pandemic will shift the timing of enrollment and completion of clinical studies by at least three months and expects timing shifts to vary by clinical trial and by program.
  • COMMERCIAL LAUNCH OF ZYNTEGLO® –
    • Due to COVID-19, the treatment of the first commercial patient in Germany is expected to be shifted to the second half of 2020.
    • bluebird bio continues to engage in reimbursement discussions and undertake commercial preparation activities in the priority launch markets in Europe. The company expects the COVID-19 pandemic to impact its ability to achieve market access and reimbursement in Europe.

Sources:

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-fourth-quarter-and-full-year-2019-financial

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-provides-assessment-impact-covid-19-update-business

 

Update: 31 January 2020

New data from ongoing studies of LentiGlobin™ gene therapy for β-thalassaemia (betibeglogene autotemcel) in pediatric, adolescent and adult patients who have transfusion-dependent β-thalassaemia (TDT), including results from the Phase 3 Northstar-3 (HGB-212) study in patients with a β0genotype or IVS-I-110 mutation, and the Phase 3 Northstar-2 (HGB-207) study in patients who do not have a β0genotype. These data, as well as updated results reflecting up to five years of follow-up from the completed Phase 1/2 Northstar (HGB-204) study, were presented at the 61stAmerican Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.

A total of 52 pediatric, adolescent and adult patients with TDT who do not have a β0genotype or have a β0genotype have been treated with LentiGlobin for β-thalassaemia across all trials, achieving and maintaining transfusion independence, with improvements in multiple markers of bone marrow red blood cell production, as well as reductions in iron overload.

Northstar (HGB-204) (5 year follow up of Phase ½; non- β0genotype & β0genotype or IVS-I-110 mutation):

  • 8/10 non- β0genotype continued to maintain transfusion independence for up to 51.3 months with a median Hb of 10.3 g/dL.
  • Transfusion volumes were reduced by 79% and 52% in the two patients with non- β0genotype who did not achieve transfusion independence.
  • 3/8 β0genotype continued to maintain transfusion independence with a current duration up to 30.4 months and a median Hb of 9.9 g/dL.
  • LIC began to decrease after 48 months of available data for 8/11 patients who achieve transfusion independence with a 44% reduction of LIC was reported. 

Northstar-2 (HGB-207) Phase 3 trial (non- β0genotype):

  • 23 patients were treated and have been followed for a median of 11.6 months. These patients ranged in age from 8 to 34 years, including six pediatric (<12 years) and 15 adolescent/adult (≥12 years) patients.
  • 9/10 patients followed for more than 12 months achieved transfusion independence with Hb levels of 12.2g/DL; transfusion independence is maintained for a median duration of 15.2 months.
  • 18/20 patients with at least five months of follow-up had not received a transfusion​ for at least 3.5 months and total Hb was near normal in most, with the median total Hb at Months 6, 12 and 18 at 11.5 (n=17), 12.3 (n=11) and 12.2 g/dL (n=8), respectively.
  • 3 patients with more than 24 months of follow-up are enrolled in the long-term follow-up study LTF-303.
  • In an exploratory analysis, bone marrow from nine patients who had reached 12 months of follow-up and were transfusion independent showed improvement in bone marrow RBC

Northstar-3 (HGB-212) Phase 3 trial (β0genotype or IVS-I-110 mutation):

  • 13 patients (eight β00, two β0/IVS-I-110, three homozygous IVS-I-110genotypes) were treated with a median follow-up of 8.8 months.
  • 2 patients had at least 12 months of follow-up and were evaluable for TI. ​Both patients, one patient with a β00genotype and one pediatric patient with a β0/IVS-I-110 genotype, achieved TI, and continued to maintain it with Hb levels of 13.2 g/dL and 10.4 g/dL, respectively, at last visit.
  • 9/11 patients with at least six months of follow-up did not receive a transfusion for more than three months as of last follow-up. In these patients, total Hb levels ranged from 8.3–14.2 g/dL at last visit.

Due to the highly technical and specialized nature of administering gene therapy in rare diseases, Bluebird Bio is working with institutions that have expertise in stem cell transplant as well as in treating patients with TDT to create qualified treatment centers that will administer ZYNTEGLO.

Bluebird Bio has established a collaboration with the University Hospital of Heidelberg as the first qualified treatment center in Germany.

Moreover, the company has entered into value-based payment agreements with multiple statutory health insurances in Germany to help ensure patients and their healthcare providers have access to ZYNTEGLO, and that payers only pay if the therapy delivers on its promise.

 

Sources:

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-new-data-demonstrating-long-term

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-launch-germany-zynteglotm-autologous-cd34

 

Update: 25 November 2019

  • Manufacturing specifications have been refined in order to aim for the first ‘commercial’ patient to undergo treatment in early 2020.
  • Designation of qualified centres in the EU, signing paperwork and training is underway and will be announced by the end of 2019.
  • In discussions with national health authorities and reimbursement agencies, aiming first for Germany (with a specific health insurer for ‘sick funds’ not the government) and France, to be followed by the UK and Italy. Subsequent expansion is planned taking into consideration possible cross-border healthcare policies.
  • Application to the FDA is expected to be filed by the end of 2019.

Sources:

TIF Meeting with company representatives.

https://www.biopharma-reporter.com/Article/2019/10/29/Bluebird-tweaks-manufacturing-for-gene-therapy-launch

https://medcitynews.com/2019/11/bluebird-bio-eyes-clinical-updates-on-blood-cancer-blood-disorder-programs-by-year-end/

 

Update: 27 September 2019

No update available

 

Update: 30 July 2019

Updated results from the completed Phase 1/2 Northstar (HGB-204) study, and new data from the Phase 3 Northstar-2 (HGB-207) and Phase 3 Northstar-3 (HGB-212) clinical studies of its LentiGlobin® gene therapy for patients with transfusion-dependent β-thalassemia (TDT), were presented at the 24th European Hematology Association (EHA) Congress in Amsterdam, the Netherlands.

 

Northstar (HGB-204):

  • Eight of 10 treated patients who do not have a β00genotype achieved transfusion independence (TI), and had not received a transfusion for at least 12 months or more and maintained a weighted average Hb ≥9 g/dL. These eight patients had a median weighted average Hb during TI of 10.3 g/dL (min–max: 9.3–13.2 g/dL) and continued to maintain TI for up to 45 months.
  • In patients who have a β00genotype, three of the eight achieved TI and maintained a median weighted average Hb ranging from 9.5–10.1 g/dL for a median duration of 16.4 months(min–max: 16.1–20.8 months).
  • Over time, LIC began to decrease in all 11 patients with the largest decrease observed in patients who had 48 months of data available (n=4). A median 56 percent reduction (min–max: 38–83 percent) was reported in these four patients.

 

Northstar-2 (HGB-207) Efficacy:

  • 20 patients who do not have β00 genotypes have been treated in the Phase 3 Northstar-2 study. Patient age ranged from 8–34 years, with five pediatric (<12 years) and 15 adolescent/adult (≥12 years) patients.
  • Four of five evaluable patients achieved TI and maintained a median weighted average Hb of 12.4 g/dL (min–max: 11.5–12.6 g/dL). These four patients continued to maintain TI for a median duration of 13.6 months (min–max: 12–18.2 months) at the time of the data cut off.
  • Thirteen of 14 patients with at least three months of follow-up were free from transfusions for at least three months. Total Hb levels in these patients ranged from 8.8–13.3 g/dL at the time of the last study visit. HbAT87Q levels were stable over time in patients who were free from transfusions; at Month 6 (n=10) median HbAT87Q was 9.5 g/dL and at Month 12 (n=7) median HbAT87Q was 9.3 g/dL.

 

Northstar-3 (HGB-212) Efficacy:

  • 11 patients with TDT and a β00 genotype or an IVS-I-110 mutation had been treated in the Phase 3 Northstar-3 study.
  • The one patient evaluable for TI achieved and maintained it and had a total Hb of 13.6 g/dL at the Month 16 follow-up.
  • Five patients had stopped transfusions for at least three months and had Hb levels of 10.2–13.6 g/dL at the time of the last study visit (5 – 16 months post-treatment). Of these patients, all of those who reached six months of follow-up (n=4) had HbAT87Q levels of at least 8 g/dL.

 

LentiGlobin for TDT Safety:

  • Non-serious adverse events (AEs) observed during clinical studies that were attributed to LentiGlobin for TDT were hot flush, dyspnoea, abdominal pain, pain in extremities and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for TDT.
  • Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.
  • As of the data cut off dates stated above, a total of 49 pediatric, adolescent and adult patients with TDT and a non-β00or β00 genotype, including patients with IVS-I-110 mutations, have been treated with LentiGlobin for TDT in the Northstar, Northstar-2 and Northstar-3 studies.

Sources:

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-long-term-efficacy-and-safety-data

 

Update: 30 May 2019

  • Upon receipt of marketing authorisation from the European Commission by the end of June, Bluebird expects to launch first in Germany, followed by Italy, France and the U.K. in 2020
  • Analysts estimate prices of $900,000 in Europe and $1.2 million in the U.S. for Zynteglo
  • FDA approval is anticipated in 2020 for TDT patients
  • Treatment centers in each country will be set up and physicians trained.
  • Discussions for payment models with national health authorities will begin.

Sources:

https://www.fiercepharma.com/pharma/bluebird-details-conservative-eu-rollout-plan-for-tdt-gene-therapy

 

Update: 29 March 2019

  • The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines  Agency (EMA) adopted a positive opinion recommending conditional marketing authorization for ZYNTEGLO™ (autologous CD34+ cells encoding β A-T87Q-globin gene), a gene therapy for patients 12 years and older with transfusion-dependent β-thalassemia (TDT) who do not have a β00
  • ZYNTEGLO™ previously known as LentiGlobin, is the first ever gene therapy to be recommended for approval in the EU for TDT!
  • This positive opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for ZYNTEGLO in the
  • A final decision by the EC for ZYNTEGLO is anticipated in the second quarter (April – June) of 2019.

Sources:

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-receives-positive-opinion-chmp-zynteglotm#

 

Update: 01 February 2019

  • The developing company has proposed an instalments model for the payment of gene therapy. This essentially entails a 20% payment up front before the gene therapy is applied and the remaining 80% to be paid if the treatment works (‘works’ needs to be specified) over a five-year period. If the treatment does not work, the 80% of the cost does not need to be paid to the company.
  • EMA approval for Europe is expected in mid-2019. Will then move on to secure market access and set up qualified treatment centres (in accordance to their own criteria) in 4 European countries in 2019 (i.e. UK, France, Germany and Italy). In 2020 these will extend to include Belgium, Netherlands, Greece, Cyprus, Israel, Sweden, Denmark, Switzerland and Austria. Exact countries are to be determined.

Sources:

https://www.wsj.com/articles/biotech-proposes-paying-for-pricey-drugs-by-installment-11546952520

TIF Meeting with company representatives.

 

Update: 02 October 2018

  1. New data from (1) the completed Phase 1/2 Northstar (HGB-204) study in adolescents and adults with transfusion-dependent β-thalassaemia (TDT) and any genotype and (2) the ongoing Phase 3 Northstar-2 (HGB-207) multi-centre clinical study of LentiGlobin™ investigational gene therapy in patients with TDT and non-β0genotypes for the assessment of efficacy and safety were presented at the Annual Congress of the European Hematology Association (EHA), held between 14 – 17 June 2018 in Stockholm, Sweden.

The data collected over a period of more than 3 years suggest that one-time treatment with LentiGlobin may address the underlying genetic cause of TDT, with the majority of patients with TDT and non-β00 genotypes are transfusion-free and producing total hemoglobin at normal or near-normal levels.

 

Northstar (HGB-204) results:

  • All 18 patients have completed the primary two-year study and are continuing into the long-term follow-up study LTF-303.
  • 8 of 10 patients with non-β00genotypes were transfusion independent for a median of 33 months as of last follow-up.
  • One serious adverse event of HIV infection was reported 23 months after infusion. HIV was contracted from typical exposure and is not related to treatment with LentiGlobin. This was confirmed by two laboratory tests that differentiate between HIV and the lentivirus used in LentiGlobin. The Northstar clinical study Safety Review Committee (an independent group of experts in bone marrow transplant), determined that the HIV infection is not related to LentiGlobin treatment and therefore the benefit/risk profile of LentiGlobin treatment has not changed. This assessment that the HIV infection is not related to LentiGlobin treatment was concurred with by an independent Data Monitoring Committee (DMC) for the Northstar-2 (HGB-207) trial.

Northstar-2 (HGB-207) results:

  • 11 patients had been infused with LentiGlobin and the median follow-up was 8.5 months (range: 0.3 – 16.2 months).
  • 7 of 8 patients are producing ≥ 7.6 g/dL of HbAT87Qand are maintaining total hemoglobin levels of 11.1 – 13.3 g/dL by 6 months.
  • These 7 patients with ≥ 6 months follow-up remain transfusion free for 4.7 – 15.1 months.

Source: http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-new-data-northstar-hgb-204-and-northstar-2

 

  1. Investigational LentiGlobin™ gene therapy for the treatment of transfusion-dependent β-thalassaemia (TDT) was granted an accelerated assessment by the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) for its upcoming marketing authorization application. Accelerated assessments can reduce the active review time of an MAA from 210 days to 150 days once it has been validated by the EMA. The company intends to submit a marketing authorization application before the end of 2018.

Source: http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bios-lentiglobintm-gene-therapy-granted-accelerated

 

  1. The U.S. Food and Drug Administration (FDA) also granted LentiGlobin Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT.

Source: http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bios-lentiglobintm-gene-therapy-granted-accelerated

 

Update: 20 December 2018

New data from the Phase 3 Northstar-2 (HGB-207) [for non β00 genotype]  and Northstar-3 (HGB-212) [for only β00 genotype] clinical studies of LentiGlobin gene therapy in the treatment of patients with transfusion-dependent β-thalassaemia (TDT) were presented at the 60th Annual Meeting of the American Society of Hematology (ASH) in San Diego, held on 01 – 04 December 2018. A total of 37 paediatric, adolescents and adult patients with TDT and a non-β00 or β00 genotype, including patients with IVS-I-110 mutations, have been treated with LentiGlobin in the Northstar, Northstar-2 and Northstar-3 studies.

 

Northstar-2 (HGB-207) results:

  • 16 patients with non-β00genotypes (aged 8 – 34 years); 2 paediatric and 14 adolescents/adults with TDT have been treated in the Phase 3 Northstar-2 study.
  • 10 patients stopped receiving transfusions and had haemoglobin levels of 11.1 – 13.3 g/dL at the time of the last study visit (3 – 18 months post-treatment).
  • HbAT87Qlevels in these 10 patients ranged from 7.7 – 10.6 g/dL and significantly contributed to total haemoglobin (67 – 92%).
  • In 5 patients, all of whom had stopped chronic transfusions, an increase in the myeloid to erythroid ratio was observed, suggesting improvement in red blood cell production.

Northstar-3 (HGB-212) results:

  • 3 patients with TDT and a β00genotype or an IVS-I-110 mutation had been treated with LentiGlobin in the Phase 3 Northstar-3 study.
  • All 3 patients had total haemoglobin of greater than 10 g/dL at their last assessment, including 1 paediatric patient.
  • Patient 2 had their last transfusion 1.9 months post-treatment and last assessment at month six, Patient 3 had their last transfusion at 1.4 months post-treatment and last assessment at month three.

 Source:http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-new-data-lentiglobin-gene-therapy

 

OTL-300  for patients with TDT

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

No update available

 

Update: 25 November 2019

No update available.

 

Update: 27 September 2019

No update available

 

Update: 30 July 2019

No update available.

 

Update: 30 May 2019

An oral presentation at the 22nd American Society of Gene & Cell Therapy (ASGCT) Annual Meeting in Washington, D.C. reported that:

  • Nine TDT patients (six pediatric and three adult), with severe phenotypes including β+/β+, β0/β+ and β0/β0, participated in the trial.
  • All nine patients met the safety endpoint of survival with follow-up ranging from 16 to 43 months (3.6 years).
  • No adverse events related to the product were reported.
  • Of the six pediatric patients treated, four achieved transfusion independence and one showed a reduction in transfusion requirement.
  • All three adult patients had a reduction in their transfusion requirements
  • One pediatric patient did not have a reduced transfusion requirement compared to pre-treatment levels at 12 months, which was attributed to poor engraftment of the gene-modified cells.

Sources: https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-clinical-proof-concept-data-gene

 

Update: 29 March 2019

OTL-300, an autologous ex vivo lentiviral gene therapy program being studied in individuals with transfusion-dependent beta-thalassaemia.

Data from all nine patients in this proof of concept trial is anticipated later in 2019.

Sources:

https://www.globenewswire.com/news-release/2019/01/22/1703283/0/en/Orchard-Announces-Publication-by-San-Raffaele-Telethon-Institute-for-Gene-Therapy-of-OTL-300-Clinical-Data-for-the-Treatment-of-Transfusion-Dependent-Beta-Thalassemia-in-Nature-Med.html