Advanced therapies including cell and gene therapies are exploding in demand, but the manufacturing process can be difficult. Jean-Christophe Hyvert, president of biologics and cell & gene at the CDMO Lonza, sheds light on the latest trends in advanced therapies and how manufacturers are keeping up.
In 2021, global funding going to cell and gene therapies smashed records, totaling $23.1 billion. This has been accompanied by a surge in demand for manufacturing of these advanced therapies and other emerging modalities such as antibodies and microbiome therapeutics.
To meet this growing demand, major contract development and manufacturing organizations (CDMOs) like Lonza Group and Fujifilm Diosynth are investing big cash to scale up their capacity. Earlier this year, for example, Lonza invested CHF 500 million ($517 million) in a new Swiss manufacturing facility and expanded its Chinese and U.S. facilities to grow its offerings to customers around the world.
The field of advanced therapies continues to evolve, and manufacturers must keep pace with the speed of progress. New technologies are emerging each decade, including different types of antibodies; personalized cell therapies derived from the patient’s own cells such as CAR-T; and gene therapy delivery vectors with improved organ tropism — the ability to affect selected organs and avoid other tissues.
Lonza’s president of biologics and cell & gene, Jean-Christophe Hyvert, spoke to us about the most interesting advanced therapies on the horizon in addition to how manufacturers are adapting their processes to incoming innovations. Hyvert joined Lonza in 2017 and had originally qualified as a physicist and worked in operations, before moving into a financial role.
What are some of the most interesting trends in emerging modalities?
One trend that stands out is the increasing number of bispecific antibodies (bsAbs) entering the clinical pipeline. BsAbs can be described as molecules that recognize two different antigens or epitopes, compared to conventional monoclonal antibodies (mAbs) that can only recognize one. BsAbs range from small proteins – two linked antigen-binding fragments – to large immunoglobulin molecules with other attached domains.
To date, a total of 273 bispecific molecules have successfully entered the clinic since 2001, and they can play a significant role for patients receiving cancer care outside traditional treatment environments. We expect bispecific proteins and other complex protein formats to dominate the drug development pipeline in the next 5 to 10 years.
This biotherapeutic class offers improvements in treatment precision and flexibility — factors that have played decisive roles in the pursuit of bispecific therapies by drug developers. Leveraging familiar modes of administration, bispecifics may play a meaningful role for patients receiving cancer care outside traditional treatment environments, potentially creating inroads to access for patients unable to travel to receive care.
We also see rapid growth in the field of in vivo gene therapy, with several therapies nearing late-stage clinical readouts. Scalable manufacturing platforms will be key in ensuring sufficient commercial supply for emerging modalities. New vectors are being designed to improve organ tropism and reduce immunogenicity, and Lonza has been involved in developing scalable manufacturing platforms for these new technologies.
Another important trend is the exponential increase of mRNA-based development projects. This trend is driven by the clinical and commercial success of the two mRNA-based COVID-19 vaccines, validating this promising technology after years of development.
The main advantages associated with mRNA-based compounds over other modalities include the low amount of drug needed for a biologic effect, the opportunity of creating one manufacturing platform for multiple different mRNA compounds and finally, the ability of mRNA – using the right carrier, such as lipid nanoparticles – to enter into cells which is usually not possible for protein-based therapeutics. The intracellular mode of action is expected to allow the treatment of diseases that so far could not be tackled, such as genetic diseases where patients lack intracellular proteins.
A recent trend is also using mRNA to code Cas9 enzymes or gene-editing enzymes. Applying this mRNA together with guide RNA – both encapsulated in LNPs – opens a new and potentially better tolerable avenue for ex vivo and in vivo gene therapy, as shown in a first clinical trial in patients with transthyretin amyloidosis.
Another emerging trend is the rise of exosome-based therapies. Exosomes are membrane-bound nanovesicles produced by almost every cell type to regulate metabolism and interact with other cells within the body. These new therapies leverage the ability of exosomes to interact with specific tissues to deliver drugs or naturally occurring regenerative and anti-inflammatory molecules to diseased tissues. Being produced by cells, exosomes do not trigger adverse immune reactions and their targeted delivery limits drug toxicity and improves efficacy. Exosomes can be engineered to load multiple therapeutic modalities, including viruses, for multi-drug therapeutic strategies or to engage with the immune system for immune therapies or vaccine development.
To date, there are more than 50 exosome therapies in the pipeline. More than 80% are at the preclinical stage, and no products are commercially available yet. In the next decade, we expect exosomes to become a dominant non-viral vector modality, especially in therapeutic indications where targeted delivery and repeat dosing are required to achieve sustained efficacy.
How is the growing use of personalized cell therapies changing the way the manufacturing process works?
Personalized cell-based therapy is considered one of the most effective treatments for patients diagnosed with cancer or genetic diseases. Its effectiveness is due to therapies being created with specific patients in mind – making it both a very effective treatment and a complex one to develop.
Unlike other treatment options and modalities, such as antibody-based therapies, personalized medicines are difficult for patients to access – they are usually only available at specialty hospitals, require complex supply chains and may require 3- to 4-week vein-to-vein times. This complicates the patient experience when you consider the medical condition they are already living with.
In the pharma industry, we are focusing on solving this problem from our side – that is, creating systems that make it easier for patients to receive personalized medicine.
At Lonza, we address these challenges by automating the otherwise manual manufacturing process and bringing the manufacturing closer to the point of care. Lonza’s Cocoon platform is an automated patient-scale cell therapy manufacturing platform that aims to increase access to life-saving cell-based therapies. The platform is improving access to personalized medicines by manufacturing therapies on-site at hospitals at the point of care. The cell processing device can make therapies for a variety of diseases and speeds up treatment timelines by reducing the vein-to-vein time to just 10 days.
How far is the industry from fully automating the manufacturing process for cell and gene therapies?
The successes in the cell therapy field have led to rapid growth in the number of therapeutic strategies that are transitioning from the laboratory into the clinic. Despite this progress, there are still challenges to implementing fully automated manufacturing processes that will enable effective clinical and commercial deployment of novel therapies. Because different cell therapy developers require different processes, ideal automation platforms will need to be customizable and able to support a range of process steps and conditions. Moreover, considerations regarding commercial scale needs and scale-up or scale-out strategies will be important to ensure the development of platforms that can support commercially-viable processes.
Though there has been great momentum, automated manufacturing technologies continue to evolve to address the needs in the field, and we anticipate that in the next few years, we will see a refinement in standalone and integrated platforms that will improve processing efficiency and drive the cost of goods down. These developments, in turn, will contribute to expanding the implementation of fully automated cell and gene therapy manufacturing platforms.
What are some of the biggest challenges to tackle in the coming years?
Choosing the right format for a biologic is critical. The more complex the format is, the more challenging it will be to choose the right protein engineering technology, cell line development, process optimization and development. In addition, the analytics to evaluate the product must be adapted or developed from scratch.
Specifically to cell therapies, the field is progressing toward integrating in-process analytics to refine process development and ensure that critical quality attributes are achieved in the final product. Technology developers will need to integrate solutions within automated platforms to enable these capabilities to address this demand.
What advice would you give to new startups planning to develop these newer modalities of therapies?
My advice would be to choose an established CDMO partner to help the clinical and commercial manufacture of these new modalities. An experienced partner like a CDMO will have decades of expertise in developing biologics and will likely have the experience to overcome common development and manufacturing problems as well as the mitigation or de-risking procedures to solve them quickly and appropriately. In addition, an experienced CDMO should have the capabilities to advise and solve increasingly complex development and manufacturing challenges.
Likewise, when choosing a CDMO partner, be diligent. Ensure that they are factoring risk mitigation into their timelines. If they are promising manufacturing timelines shorter than industry standards, they may compromise your molecule’s manufacturability, safety or critical quality attributes. As most biologics fail in first-in-human trials, de-risking the early stages of development can lead to the re-engineering of that molecule or a different lead candidate selected, which can save time and resources.