Supporting approval of a first-in-class one-time gene therapy with a population pharmacodynamics (PD) model

By Shaun Kumar, Associate Director, Clinical Pharmacology, Modeling and Simulation

4 min

Supporting approval of a first-in-class one-time gene therapy with a population pharmacodynamics (PD) model

During development, bluebird bio optimized its manufacturing process while Parexel helped them model the impact for their biologics license application (BLA).

Key facts

  1. Beta-thalassemia is a rare genetic blood disease caused by mutations in the β-globin gene which impair β-globin production.
  2. Patients experience severe anemia and life-long transfusion-dependence, which leads to iron overload, life-threatening co-morbidities, lower quality of life, and decreased survival.
  3. Zynteglo is a one-time gene therapy that adds functional copies of a modified β-globin gene into patients' autologous hematopoietic stem cells via transduction with a lentiviral vector (LVV): it produces functional adult hemoglobin (HbAT87Q).
  4. At the time of BLA submission, 89% of evaluable beta-thalassemia patients in Phase 3 studies achieved transfusion independence.


Founded in 2010, bluebird bio pursues curative gene therapies for severe genetic diseases and has the largest and deepest ex-vivo gene therapy data set in the world. In 2022, bluebird emerged as a commercial-stage gene therapy company, with a validated LVV platform built on more than a decade of scientific leadership. In a dynamic and challenging environment, the company hit all its operational milestones, including nearly simultaneous launches of two first-in-class gene therapies, Zynteglo and Skysona.


During development, bluebird refined the manufacturing process to increase the efficiency of transducing hematopoietic stem cells. As a result, the two pivotal Phase 3 trials used a second-generation process, while the Phase 1/2 trials used first-generation processes. Because gene therapies are highly sensitive to manufacturing changes, bluebird needed to demonstrate that the two processes were comparable. For example, it was unknown how factors, such as the manufacturing method or a patient’s age, weight, race, genotype, or sex, might influence the dose-exposure-response relationship. Uncertainties about product potency or clinical outcomes can lead to regulatory delays.

Solution and results

  • Parexel proposed that bluebird use predictive population PD modeling to assess the impact of different manufacturing processes on the drug product Zynteglo’s PD and clinical efficacy responses.
  • After evaluating several mathematical frameworks, we developed fit-for-purpose models. We analyzed the time course of the peripheral blood vector copy number (PB VCN), a measure of transduction efficiency, and production of the protein, HbAT87Q, a PD parameter that directly contributes to clinical efficacy (Transfusion independence is defined as a weighted average total Hb ≥9 g/dL without any pRBC transfusions for a continuous period of ≥12 months, where high HbAT87Q contributes to high total Hb). The models also assessed the impact of patient-specific factors (weight, race, genotype, or sex). 
  • Our simulations showed that bluebird’s optimized manufacturing process produced higher levels of steady-state PB VCN and HbAT87Q than the original. The most important covariate impacting PB VCN and HbAT87Q levels was the percent of LVV-positive cells. There were no obvious impacts of age, weight, sex, race, or genotype.
  • The models provided a robust method to characterize the PD profiles and were included in bluebird’s marketing submission package to the FDA.
  • On June 10, 2022, an FDA advisory committee voted unanimously that the benefits of Zynteglo outweighed its risks, and the FDA approved it for patients with transfusion-dependent beta-thalassemia patients on August 17, 2022.

Parexel provided expert pharmacodynamic modeling services utilizing empirical models to extrapolate steady-state values. They also identified important covariates for key pharmacodynamic markers after the gene therapy infusion.

Marisa Gayron
Head of Biometrics,
bluebird bio

Contributing Expert