Abstract
Unable to agree with European payers on pricing for its gene therapies, bluebird bio said it will refocus its severe genetic disease gene therapy business in the United States and wind down its operations in Europe.
The company said it will also explore how to ensure that European patients can still access its gene therapies. Options under consideration, according to bluebird bio, include potentially out-licensing ex-U.S. rights to its three lead products to a company with European experience and capabilities.
The planned pullout from Europe was announced 4 months after bluebird withdrew ZYNTEGLO (betibeglogene autotemcel or beti-cel) from Germany after failing to come to terms with payers on pricing. The company sought to price the one-time gene therapy for beta-thalassemia at $1.8 million after European Commission approval in 2019, but talks with reimbursement authorities failed to yield an agreement.
ZYNTEGLO did not reach Germany until January 2021 due to manufacturing issues—and only after bluebird reached value-based agreements with multiple statutory health insurers tied to patient outcomes.
“bluebird's decision to focus on the U.S. market is driven by the challenges of achieving appropriate value recognition and market access for ZYNTEGLO™ in Europe, which makes bringing its transformative gene therapies like ZYNTEGLO and SKYSONA™ to patients and physicians in Europe untenable,” said Andrew Obenshain, president, severe genetic diseases, bluebird bio. “While European regulators have been innovative partners in supporting accelerated regulatory paths for these therapies, European payers have not yet evolved their approach to gene therapy in a way that can recognize the innovation and the expected life-long benefit of these products.” 1
SKYSONA—the trade name for elivaldogene autotemcel (eli-cel, Lenti-D™)—was approved in Europe on July 21 as a one-time gene therapy for early cerebral adrenoleukodystrophy (CALD) in some patients under age 18.
In the United States, however, the Food and Drug Administration (FDA) has placed eli-cel on clinical hold after bluebird received a reported Suspected Unexpected Serious Adverse Reaction of myelodysplastic syndrome that the company said was likely mediated by Lenti-D lentiviral vector (LVV) insertion, in a patient who was treated with eli-cel, or Lenti-D drug product for CALD over a year ago in the Phase III ALD-104 trial (NCT03852498).
Specific design features of Lenti-D LVV likely contributed to this event, bluebird said, citing evidence currently available. The company added that the information was shared with the trial's independent data monitoring committee.
Danaher's Cytiva, Pall Plan $1.5B Manufacturing Expansion
Two companies within
Cytiva and Pall plan to hire 2,000 full-time employees as part of the expansion effort.
The effort includes construction of an additional factory at Cytiva's bioprocessing equipment manufacturing campus in Cardiff, South Wales; a doubling of Cytiva's cell culture media production capacity in Logan, UT; construction of a new second chromatography resin plant at a U.S. location to be determined; construction of a new single-use technology manufacturing site for Pall in Duncan, SC; and expansion of all 13 existing Cytiva and Pall sites.
“Our customers tell us they need access to manufacturing agility, a robust global supply chain and more regional options. This investment further fuels our expansion program so we can rapidly meet the current and future needs of our customers and ultimately, their patients,” said Emmanuel Ligner, group executive, Danaher Biotechnology Group, who is also president and CEO of Cytiva. 2
Ligner said biopharma's ongoing quest to develop COVID-19 drugs and vaccines, plus growing industry demand for producing various types of new therapies, are fueling the expansion.
“Cytiva and Pall both have responded very, very well to the pandemic. We've been able to grow, we'll be able to accelerate the growth, accelerate M&A, and accelerate the capacity of deployment,” Ligner said. “Our objective is to serve the industry better in order to achieve our mission, which is to advance and accelerate therapeutics.” 3
At the peak of COVID-19 activity last September, Ligner said, Cytiva and Pall were working on >400 products related to developing drugs and vaccines against the virus.
COVID-19 drug and vaccine production has been among key drivers of growth for Danaher's Life Sciences segment. The segment, which generated >$10.5 billion in sales last year, includes Cytiva, Pall, and six other companies: Beckman Coulter Life Sciences, Integrated DNA Technologies (IDT), Leica Microsystems, Molecular Devices, Phenomenex, and SCIEX.
Moderna Eyes Expansion Into Gene, Gene-Edited Therapies
After investing in its existing RNA-based drug and vaccine business—including its successful COVID-19 vaccine mRNA-1273—the executives said: “Our second priority is to expand our horizons by complementing our platform with external technologies or products. This means we are interested in nucleic acid technologies, gene therapy, gene editing, [and] mRNA,” Moderna CEO Stéphane Bancel said. 4
When Salveen Richter of Goldman Sachs sought details in a follow-up question, Moderna President Stephen Hoge responded: “We've watched the space quite interestingly or quite significantly in terms of ways that we could help with delivering gene-editing cargoes across a range of different tissues where our nanoparticles have been shown to go even in humans. And we think it's the right time for us to start to expand in that direction.” 5
Hoge continued by suggesting two potential delivery vehicles for those gene and gene-edited therapies: “Messenger RNA and lipid nanoparticles are perhaps the way to go. And that's something we strongly agree with having spent the last decade working in the technology. So, you'll be looking for us to bring new payloads, new capabilities, new enzymes into our existing technological capabilities, which we think are best in class.” 5
Two Gene Therapy Developers Complete Private Financings
Two gene therapy developers have recently completed private financing rounds.
Shape Therapeutics (ShapeTX), a Seattle company whose gene therapies are based on RNA technologies, has completed a $112 million Series B financing, saying it will use the proceeds to build a growing portfolio of RNA technologies, and accelerate the development of groundbreaking treatment approaches through key partnerships.
ShapeTX said its suite of technology platforms broadly enable RNA targeting, RNA editing, and RNA replacement for patients suffering from genetic disorders with high unmet need. The company recently presented the discovery of next-generation adeno-associated viruses (AAVs) that are specific to the central nervous system or muscles in nonhuman primates. ShapeTX has also developed a human stable cell line technology designed to enable scalable and reliable AAV production.
“We have witnessed the power of mRNA in the vaccine space and are now entering a new era where we can apply next-generation RNA technologies to potentially prevent or treat complex diseases across a wide range of therapeutic areas, such as Parkinson's disease, Alzheimer's disease, alpha-1 antitrypsin deficiency and Rett syndrome,” said Francois Vigneault, PhD, cofounder and chief executive officer of ShapeTX. 6
ShapeTX's financing was co-led by Decheng Capital and Breton Capital, with participation from Willett Advisors, and continued participation from New Enterprise Associates, and Mission BioCapital.
Ring Therapeutics, a Cambridge, MA, company founded by Flagship Pioneering to develop gene therapies based on its Anellogy™ platform, has completed a $117 million Series B funding round. Anellogy is designed to harness the properties of anelloviruses to target specific tissues through a pipeline of redosable vectors compatible with the human immune system.
Founded by Flagship Labs in 2017, Ring has developed gene therapies that are delivered through Anellovirus™ vectors designed to carry circular single-stranded DNA molecules that do not integrate with a person's existing DNA. Ring has developed what it says is the world's first and only anellovirus database with thousands of newly discovered anello-based vector candidates.
“Ring has successfully built a novel platform based on the commensal virome to create a completely new class of vector, giving us the potential to revolutionize gene therapy, a field that has historically been hindered by limited breadth, inability to re-dose, and poor tolerability,” said Dr. Tuyen Ong, CEO of Ring Therapeutics and CEO-Partner of Flagship Pioneering. 7
Participating investors included Invus, Altitude Life Science Ventures, Partners Investment, UPMC Enterprises, as well as funds and accounts advised by T. Rowe Price Associates, Inc., among others, alongside Flagship Pioneering.
Castle Creek Biosciences Files For Initial Public Offering
The company estimated the amount it is seeking to raise through the IPO at $100 million.
Castle Creek's most advanced product candidate is dabocemagene autoficel (D-Fi or FCX-007), an autologous cell-based gene therapy to address the deficiency of functional type VII collagen protein, or COL7, in patients with autosomally recessive or dominant dystrophic epidermolysis bullosa (DDEB).
D-Fi is under study in a Phase III clinical trial (NCT04213261) for the treatment of recessive dystrophic epidermolysis bullosa. Topline data from that trial are expected in the second half of 2022. Castle Creek also plans to initiate a Phase III trial of D-Fi for the treatment of DDEB in the second half of this year.
The company's second most advanced candidate, FCX-013, is being developed as a disease-modifying autologous cell-based gene therapy that uses LVVs to deliver functional matrix metalloproteinase 1 genes, or MMP-1, to patients with moderate to in combination with veledimex severe localized scleroderma.
FCX-013 is under study in a Phase I/II open-label trial (NCT03740724) designed to evaluate the therapy in moderate to severe LS, with the company saying it anticipated treating 10 adult patients in the study, from which preliminary safety and efficacy data are expected in the first half of 2022. 8
Sana Plans Biomanufacturing Facility In Fremont, CA
The facility is intended to support the manufacture of late-stage clinical development and early commercial product candidates across the multiple technologies in Sana's pipeline, the company said.
“Manufacturing remains a key bottleneck to the development and broad accessibility of cell- and gene-based medicines. This facility is a key component in enabling our aspirations to rapidly innovate, consistently manufacture, and scale production of these medicines,” said Steve Harr, Sana's President and CEO. “Sana is making significant investments to create the scientific insights, supply chain stability, and operational capabilities to transform the potentially disruptive scientific insights of the cell and gene therapy field into important medicines for patients.” 9
Sana is based in Seattle. The manufacturing facility's location in Fremont, Sana said, makes it close to the company's existing technical and scientific capabilities, and enables access to a strong biotechnology talent base.
Sana also said it intends to work with contract manufacturing partners to advance its product candidates to the clinic as early as next year.