After Analysis,Bluebird Bio Says Vector “Very Unlikely” Cause of Acute Myeloid Leukemia

Abstract

Bluebird bio said its BB305 lentiviral vector (LVV) was very unlikely to have played a role in the acute myeloid leukemia (AML) reported in a participant in the Phase I/II HGB-206 trial (NCT02140554)—one of two suspected unexpected serious adverse reactions (SUSARs) that prompted the company to temporarily and voluntarily suspending two clinical studies of its LentiGlobin gene therapy for sickle cell disease (SCD; bb1111).

“The data from our assessments provide important evidence demonstrating that it is very unlikely our BB305 lentiviral vector played a role in this case and we have shared with the FDA that we believe these results support lifting the clinical holds on our β-thalassemia and sickle cell disease programs,” stated Philip Gregory, chief scientific officer, bluebird bio.¹

In February, bluebird bio reported laboratory analyses showing that mutations in the RUNX1 and PTPN11 genes had been detected in the leukemic cells of the AML patient. Preliminary findings suggested that the BB305 LVV was present in the AML blast cells, but there was not sufficient information to determine causality, the company said.

Since then, bluebird bio has performed additional scientific assessments to determine where in the genome the LVV insertion occurred, and whether this integration was responsible for any change in gene regulation or gene expression nearby. The company said its assessments were conducted with several independent leading academic experts in LVV gene therapy, whom it did not identify.

Bluebird also acknowledged that it is investigating a second SUSAR of myelodysplastic syndrome (MDS) in another participant in the HGB-206 study, to determine whether the clinical findings meet the criteria to be classified as a case of MDS and, if so, whether LentiGlobin for SCD had any role.

The MDS diagnosis was based on prolonged anemia following LentiGlobin for SCD infusion coupled with the observation of trisomy 8 in a small percentage of the patient's bone marrow cells. However, no blasts or dysplastic cells were seen in the patient's bone marrow. Although trisomy 8 is associated with myeloid malignancies, this finding is not sufficient for a diagnosis of MDS in the absence of blasts or dysplastic cells, bluebird said.

Elevatebio Raises $525M

Cell and gene therapy company ElevateBio has completed a $525 million Series C financing, with plans to use the proceeds toward developing and expanding its technology platforms, growing its network of process development and good manufacturing practice (GMP) manufacturing capacity, advancing industry partnerships, and continuing to develop candidates through its portfolio of companies.

Based in Cambridge, MA, ElevateBio is a creator and operator of a portfolio of companies across multiple cell and gene therapy and regenerative medicine technology platforms—including gene editing; induced pluripotent stem cells; and protein, viral, and cellular engineering.

ElevateBio has built those companies through a centralized innovation and manufacturing center in Waltham, MA, it calls BaseCamp, designed to provide fully integrated capabilities—part of the company's “ElevateInside” approach, which encompasses basic and transitional research, process development, clinical development, current GMP (cGMP) manufacturing, and regulatory affairs.

“While we see remarkable breakthroughs in the earliest days of the cell and gene therapy revolution, accelerating innovation requires next-generation technology, analytics, and production capabilities to deliver therapies better, faster, and cheaper. We are poised to power the field today and for many decades to come,” ElevateBio Chairman and CEO David Hallal said.²

Through one of the company's strategic partnerships, Massachusetts General Hospital (MGH) has gained preferred access to ElevateBio's BaseCamp research, process development, and manufacturing facility. The partners have agreed to work together in identifying cell and gene technologies and creating therapeutics companies, with ElevateBio supporting MGH's cell and gene therapy research programs.

WuXi AppTec Buys Oxgene for $135M

WuXi AppTec has acquired OXGENE™, the British provider of gene and cell therapy contract R&D services, for $135 million. The acquisition deal, completed 1 month shy of OXGENE's 10th birthday, brought the Shanghai-based biopharma its first European facility and broadened its portfolio of technologies for designing and developing scalable cell and gene therapies.

OXGENE—founded in 2011 as Oxford Genetics Ltd. and rebranded in 2019—continues to operate as a wholly owned subsidiary of WuXi AppTec's cell and gene therapy business unit.

That unit, WuXi Advanced Therapies (WuXi ATU), is a global contract testing, development, and manufacturing organization with substantial U.S. operations, and a focus on accelerating time to market for cell and gene therapy products.

The deal came more than a year after the companies began working together when OXGENE licensed its plasmid platform to WuXi AppTec for use in China. Satisfied with OXGENE's plasmid work, WuXi expressed interest in helping fund its partner.

“We initially started talking about investment. And then, as discussions progressed and we realized the synergies between the two companies, this just made more and more sense,” said Ryan Cawood, PhD, OXGENE's founder and CEO.³

WuXi ATU has offered services in cell and gene therapy for more than a decade, with customers in China, Europe, and the United States. Last November, WuXi completed its fourth Philadelphia facility, a 140,000-square-foot (13,006-square-meter) laboratory that tripled its advanced testing capacity and enabled customers to obtain timely characterization and lot of release services.

Caribou Bioscience Raises $115M Series C Financing

Caribou Biosciences, the developer of gene-edited cell therapies cofounded by Nobel laureate Jennifer Doudna, PhD, has raised $115 million in Series C financing—capital that the company plans to use toward developing its CRISPR-based platform, building its pipeline of oncology treatments, and growing its staff and operations.

One apparent factor in attracting investor interest was Doudna's 2020 Nobel Prize in Chemistry shared with Emmanuelle Charpentier, PhD, (Max Planck Institute), for pioneering research into CRISPR gene editing. “I'm sure that can't hurt!” observed Caribou cofounder and CEO Rachel Haurwitz, PhD, who studied biology and CRISPR at Doudna's laboratory at University of California, Berkeley, as a graduate student from 2008 to 2012.⁴

Three of Caribou's four announced pipeline programs are allogeneic genome-edited chimeric antigen receptor T-cell therapies based on Caribou's CRISPR hybrid RNA–DNA guide technology, led by its sole clinical-phase candidate. CB-010, which targets CD19 and has PD-1 deleted by CRISPR genome editing, is being evaluated in a Phase I trial (NCT04637763) in patients with relapsed/refractory B cell non-Hodgkin lymphoma.

During the first half of 2022, Caribou expects to file an investigational new drug (IND) application for CB-011, which targets B-cell maturation antigen-positive tumors and is being developed to treat relapsed/refractory multiple myeloma. Caribou is also developing CB-012, which targets CD371 to treat relapsed/refractory AML.

Caribou's pipeline includes a program to develop induced pluripotent stem cell-derived allogeneic natural killer cell therapies for solid tumors. The first IND is a few years away, Haurwitz said.

Biogen Plans $200M Research Triangle Park Facility for Gene Therapy Manufacturing

Biogen said it plans to build a $200 million gene therapy manufacturing facility at Research Triangle Park (RTP) in North Carolina.

The new facility is expected to create ∼90 new jobs, expanding the company's current workforce of 1,900 people based at two campuses within RTP. The 175,000-square-foot (16,258-square-meter) facility will be designed to support Biogen's growing gene therapy pipeline across multiple therapeutic areas.

“We plan to build differentiated, sustainable and advanced manufacturing capabilities to support our gene therapy programs and collaborations,” said Nicole Murphy, Senior Vice President, Global Manufacturing and Technical Operations. “This additional investment underscores our commitment to RTP and our mission to deliver a reliable supply of high-quality medicines to the patients we serve.”⁵

Biogen said it selected RTP for its new facility due to the region's diverse pool of talent and the company's 26-year track record of attracting highly qualified and passionate employees in North Carolina.

Catalent to Acquire Delphi Genetics

Catalent has agreed to acquire Delphi Genetics, a plasmid DNA (pDNA) cell and gene therapy contract development and manufacturing organization (CDMO) based in Gosselies, Belgium, for an undisclosed price.

Founded in 2001 as a spin off from the Université libre de Bruxelles, Delphi Genetics is a bioproduction CDMO designed to handle the entire pDNA development and cGMP manufacturing process for customers. Delphi's “one-stop-shop” capabilities include process development, pilot production, plasmid design and production, strain screening and stability, and that span from preclinical to Phase III applications, using fully single-use technology.

Catalent will also acquire Delphi's proprietary STABY^® technology, an antibiotic-free selection system for plasmid and protein production in E. coli that has been validated and licensed on a nonexclusive basis to leading pharmaceutical companies.

Delphi is headquartered at a 17,000-square-foot (1,600-square-meter) facility adjacent to Catalent's current cell therapy facilities. Upon completion of the acquisition, all Delphi staff, including R&D and genetic engineering scientists and technicians, regulatory specialists, and other associated roles, will transfer to Catalent's Cell and Gene Therapy business.⁶

Catalent also said it was launching pDNA development and manufacturing services at its Rockville, MD, facility, to enable its customers to derisk and optimize their programs along the entire development pipeline using Catalent's fully integrated cell and gene offering.

The Delphi acquisition will accelerate Catalent's U.S. expansion of plasmid capabilities at its Rockville facility, which it acquired in 2019. Since then, Catalent has invested to upgrade the facility with the addition of dedicated single-use microbial capacity for pDNA production.

Sanofi, SIRION Partner to Develop Modified Adeno-Associated Viruses

Sanofi and SIRION Biotech have agreed to partner on developing improved tissue-selective adeno-associated virus (AAV) vectors for gene therapies designed to treat unspecified disorders affecting major human organs, through a license and collaboration agreement of undisclosed value.

The partnership is intended to combine Sanofi's expertise in virus-based vaccine and viral vector manufacturing with SIRION's expertise and capabilities in AAV vector manufacturing and the AAV capsid evolution technology of Prof. Dirk Grimm of Heidelberg University Hospital in Germany. The partners plan to create new and modified AAV capsids that exhibit a safe product profile with improved specificity and higher gene delivery efficiency.

“AAV vectors with improved efficacy can enable quickly entering into clinical trials with efficient, safe low doses and scalable therapeutic candidates and can expand the impact of gene therapies,” said Christian Thirion, PhD, CEO and cofounder of SIRION.⁷

References

Bluebird Bio. bluebird bio provides updated findings from reported case of acute myeloid leukemia (AML) in LentiGlobin for sickle cell disease (SCD) gene therapy program. 2021. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-provides-updated-findings-reported-case-acute (last accessed March 11, 2021 ).

ElevateBio. ElevateBio scales disruptive cell and gene therapy business model with $525 million series C financing. 2021. https://www.elevate.bio/blogs/elevatebio-scales-disruptive-cell-and-gene-therapy-business-model-with-525-million-series-c-financing (last accessed March 15, 2021 ).

WuXi AppTec and OX GENE. WuXi AppTec completes acquisition of

OXGENE to further strengthen cell and gene therapy service offerings for global customers

. 2021. https://www.oxgene.com/News-and-Events/News/2021/03/WuXi-AppTec-acquire-OXGENE (last accessed March 11, 2021 ).

Caribou Biosciences. Caribou biosciences raises $115M series C financing to advance next-generation CRISPR technologies and allogeneic cell therapy pipeline. https://cariboubio.com/in-the-news/press-releases/caribou-biosciences-raises-115m-series-c-financing-advance-next-generation (last accessed March 11, 2021 ).

Biogen. Biogen announces plans to build a new, state-of-the-art gene therapy manufacturing facility in Research Triangle

Park

, North

Carolina

. 2021. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-plans-build-new-state-art-gene-therapy (last accessed March 11, 2021 ).

Catalent and Delphi Genetics. Catalent to acquire delphi genetics and launch US plasmid manufacturing site to establish global pDNA development and manufacturing capabilities. 2021. https://www.catalent.com/catalent-news/catalent-to-acquire-delphi-genetics-and-launch-us-plasmid-manufacturing-site-to-establish-global-pdna-development-and-manufacturing-capabilities/ (last accessed March 11, 2021 ).

SIRION Biotech. SIRION Biotech announces collaboration with Sanofi to innovate gene therapy treatments with improved adeno-associated virus capsids. 2021. https://www.businesswire.com/news/home/20210223005260/en/SIRION-Biotech-Announces-Collaboration-with-Sanofi-to-Innovate-Gene-Therapy-Treatments-with-Improved-Adeno-Associated-Virus-Capsids (last accessed March 11, 2021 ).