Phacilitate and Rooster bio interview with Jon Rowley reducing complexity in clinical translation of advanced therapies

Reducing complexity in clinical translation and scale-up of advanced therapies

An interview with Dr Jon Rowley, Founder and Chief Product Officer, RoosterBio, Inc
Cell therapy product development is notoriously complex, expensive and time-consuming. How can the field reduce complexity during clinical translation of products without sacrificing quality?
You are correct - regenerative medicine product development involves highly complex processes that are fraught with expense and timeline uncertainties. Luckily, there are multiple opportunities for the field to reduce complexity during product development by industrializing the regenerative medicine supply chain. The industry can standardize on cellular systems designed to seamlessly transition from discovery research to product and process development and then from process development into cGMP manufacturing. Cell systems used during research should have scalable manufacturing processes already associated with them and bioprocess media systems that can move from small scale flask culture to larger-scale 3D bioreactors with demonstrated comparability. Additionally, media systems compatible with cGMP manufacturing should be utilized earlier in development to minimize re-qualification of multiple growth factors or chemicals or second-guessing of expression systems of existing protein components which simply adds unneeded complexity to all development programs.  
The transition to cGMP manufacturing is even more complex and time-consuming but for different reasons. It can take multiple years to develop and transfer the cell banking process and make and test sufficient numbers of master cell banks and working cell banks that can supply a phase I or II trial with sufficient product of sufficient quality. If every company managed 100% of its supply chain, it would be like having every technology company manufacturing its own microchips. The CMC sections for both the cell and media aspects of the IND filing alone can take multiple FTEs to assemble and months to build, eventually consuming as much as 70% of the total IND filing. There is a tremendous amount of redundancy in the field right now that is being removed with these new standardized cell bank products coming to markets. Since speed to market is so important in therapeutic development, those going it alone are falling behind due to the time and expense of owning every last part of a complex supply chain.
With an industrialized supply chain, the advanced therapies field will evolve so that a few suppliers will manage multiple types of ‘off the shelf’ cell banks, fully tested to the appropriate regulations, with type II drug master files that regulators have access to that will replace the hundreds of pages of documenting that currently, each company has to do. These cell banks will have scalable production processes that have are already been vetted, with any comparability challenges already worked out. In a perfect world, these materials will be compliant across multiple geographies around the world. As the field matures, the hundreds of regenerative medicine companies will rely on standardized manufacturing reagents and materials that a few cGMP suppliers will manage the regulatory paperwork for – removing a tremendous amount of redundancy and inefficiency from the field.
We are just now starting to see these types of products and systems become available. In fact, many of our early customers are getting into cGMP manufacturing years faster than they would have if they had to build their entire hMSC supply chain from scratch. They are achieving their milestones faster, needing to raise less capital and are overall achieving a much more efficient product development cycle than possible just a few years ago. We are definitely at the dawn of a new day in the field of regenerative medicine.
MSCs are one of the most clinically translated cell types today and there are at least ten MSC products on the market globally. What's behind the early use and success of this cell type, and do you see them continuing in use?
Yes, MSCs have by far been the most clinically translated cell type over the last ten years, with well over 1,000 clinical trials initiated globally since 2010! The early use and success of hMSCs as cell therapies is mainly due to their well-established safety profile, as well as their versatility in treating multiple indications. The commercialized products include both autologous and allogeneic formats and range from treating multiple cardiovascular disorders, several orthopaedic indications, as well as immunomodulatory disorders such as GvHD and Crohn’s disease.  hMSCs are unique to the cell therapy field in that, due to the lack of immune response and persistence in vivo, allogeneic strategies can be used as therapies. Because of this, cGMP manufacturing has been commonplace for hMSCs since the mid-90s, and, over the past five years, scalable bioreactor expansion challenges have been worked through, with the potency functions being maintained when this is done correctly. This large-scale allogeneic manufacturing paradigm provides economic advantages of a reduced the cost per dose, making this a cell type of choice for many pharmaceutical and biotech companies.
The future of hMSCs is very bright indeed. With an excellent safety profile, we are seeing MSCs being used in many novel gene therapy applications with potency either being enhanced or forward engineered. The general regenerative processes that these cells tend to orchestrate are leading to their incorporation into next-generation medical devices. Coupled with built-in, scalable manufacturing, low CoGs and a readily available supply chain, we believe the number of products incorporating hMSCs will increase ten-fold over the next ten years.
Because cell culture media decisions are made early on, how should the later stages of a cell culture development workflow be considered?
Cell culture media decisions are foundational to any biologics manufacturing process, as well as the final product quality attributes such as identity and potency, thus, early decisions need to be made with long term considerations of manufacturing platforms. Unfortunately, there are very few media on the market today that support cell therapy research and discovery, early-stage product and process development and then later-stage product development and go-to-market scales, leading to significant delays during product development and clinical translation. When choosing a media system, the decisions should be made around the quality aspects (always!) as well as the ability to transition from small scale flasks to large scale closed system multi-layer vessels and then to suspension bioreactors in economical media use formats such as fed-batch systems. The concept of starting with the end in mind comes into play very strongly in media decision making, and the good news is that because hMSCs are one of the most mature cell types within regenerative medicine, these systems are now readily available for use – only accelerating the use of this novel cell type within product development applications.
Extracellular vesicles (EVs) are increasingly being explored as potential therapeutic agents. How do different cell types factor in EV production and final product quality?
There have been numerous reports that demonstrate parent cell phenotype and genetic makeup dictates that of their EVs. There is data showing EVs from human embryonic kidney cells (HEK293T) produce EVs with very little genetic cargo. HEK EVs make ideal candidates when using them for exogenous cargo loading and delivery. On the contrary, EVs from MSCs are highly enriched in biological cargo including angiogenic and immunomodulatory miRNAs, proteins and lipids, which make them more suitable for targeting certain pathological conditions. It has been found that in many therapeutic applications, MSC-EVs recapitulated the effects of MSCs.
Besides the loaded cargo, EVs are also enriched in surface proteins, antigens and receptors that have been shown to vary from cell type to cell type. These membrane proteins play a large role in the bioactivity of the EVs from uptake profiles to targeting specific recipient cells. For example, in an animal model of spinal cord injury, intravenously injected MSC EVs specifically targeted the injury site (Lankford et al. 2018), likely as a result of their distinct surface protein expression. We strongly believe that cell type, and even tissue type, significantly impact therapeutic and targeting potential of EVs and we can leverage that into rationally designing and manufacturing EVs with specific functions.
The 1000+ clinical trials with MSCs have laid the groundwork for the hMSC-EV clinical translation that is happening today. This is where manufacturing comes into play…
GMP manufacturing of EVs has many challenges as a new platform. The first challenge is simply generating sufficient material to treat a patient then making a large enough manufacturing lot to treat hundreds of patients to fit within the scalability requirements of pharmaceutical manufacturing. Recognizing this challenge presents the opportunity to address it early during EV product development. A scalable, GMP-compatible manufacturing process with readily-available GMP-grade materials like cells and media that is implemented in the research and development phase will lead to a more rapid translation of EVs into the clinic as therapeutics. Indeed, while EVs are a very new pharmaceutical paradigm, the platform is benefitting from the supply chain that has already been established for cell and gene therapies, leading to a quite rapid progression into the clinic. RoosterBio is lucky to have a front-row seat to this activity via our customer base.
With cell therapy research using human umbilical cord (hUC)-derived MSCs rapidly growing in popularity, specifically in Asia Pacific, what can help expand the use of hUC-MSCs to other regions?
Umbilical Cord MSC, or UC-MSC, use has been growing quite rapidly around the globe. The UC source tissue is fetal-derived (not maternal) so the cells are younger, more active and actually have some manufacturing advantages. While the cells have some differences from traditional bone marrow-derived hMSCs, they do have many of the same therapeutic properties. This coupled with the source tissue being a readily available and a ‘discarded product’ after childbirth, makes MSC-UCs the fastest growing tissue type in both peer-reviewed research publications and clinical trials over the last 10 to 15 years. The greatest adoption has been geographically tied to Asia, with North American and Europe lagging behind. We believe that this slower adoption is due to a combination of availability of cells for early research, plus the intellectual property landscape that is more complex than with the more used bone marrow and adipose-derived hMSCs. To enable new market engraftment in North America (and beyond), RoosterBio has recently collaborated with Tissue Regeneration Therapeutics, leaders in umbilical cord hMSCs and brought to market an hUC-MSC bioprocess system with all of the cost, quality and scale benefits of our bone marrow product lines. Furthermore, these hUC-MSC bioprocess systems come with the earliest patent portfolio for this type of hMSC that we are also making widely available for licensing. We do hope that by industrializing the supply chain for hUC-MSCs and providing scalable manufacturing solutions, that product development efforts will start to take off in this part of the world.

What do you see as the most exciting directions for next-gen innovations in MSC technology over the next five years?
The fields of synthetic biology and gene editing are evolving to take cellular therapies to the next level by bringing advanced controls to complex therapeutic environments. The medical device technology segment is also rapidly moving towards incorporating living cells into next-generation products. Researchers and scientists are forward-engineering their products in ways not possible just a few years ago. Rapid implementation in clinical testing to de-risk new business models and therapeutic approaches is of utmost importance to the field.
We are most excited about the convergence of the fields of gene editing, tissue engineering and medical devices. We believe that these technological innovations when coupled with accelerated approval regulations that are sprouting up around the globe, that the field will see products come to market over the next 5-10 years that are not even being conceptualized today. The field of regenerative medicine has a bright path for many years to come.
Dr Jon Rowlet, RoosterBio, Inc Phacilitate interviewDr Jon A. Rowley is the Founder and Chief Product Officer of RoosterBio Inc. Jon started RoosterBio in 2013 as part of his personal quest of having the biggest impact possible on the commercial translation of technologies that incorporate living cells, including cellular therapies, engineered tissues, and tomorrow’s medical devices. Jon holds a PhD from the University of Michigan in Biomedical Engineering and has authored over 30 peer-reviewed manuscripts and 20 issued or pending patents related to biomaterials development, tissue engineering, and cellular therapy. Jon started his industry career at BD as a scientist and R&D manager in a Cell & Tissue Technologies group focused on applying high throughput screening technologies to cell therapy media development and tissue engineering. Jon then contributed to the clinical development of Aastrom Biosciences’ Tissue Repair Cell product, where he was Sr Manager of Process Development responsible for manufacturing process improvements and cell delivery to the patient. Jon most recently spent 5 years as Director of Innovation and Process Development in Lonza’s Cell Therapy CMO business.

Jon has had a successful scientific career at the intersection of tissue engineering, biomaterials science, stem cell science and the translation of cell-based technologies into commercializable products. His last ten years has been focusing on applying manufacturing sciences to cellular therapies and engineered tissues, where scale-up biomanufacturing technologies had to be applied to stem cells to manufacture at volumes consistent with commercial-scale while not losing the critical biological functions that make stem cells therapeutically active. Jon is considered a thought leader in the regenerative medicine field has been very active in sharing his research and thoughts on technology direction and roadmaps. He has championed solution-focused R&D aimed at solving the industry’s biggest challenges, including driving the cost of therapeutic cells down to increase the chance of building a sustainable industry. Jon has keynoted every major cell therapy manufacturing conference over the last five years, has over 15 publications in the last ten years, as well as over 75 conference presentations since 2005. Jon continues his quest at his start-up, RoosterBio, where he and his team are working to simplify adult stem cell technology to increase adoption of new biomanufacturing technologies such as 3D bioprinting and accelerate the development of tomorrow’s next-generation high tech regenerative medicine products.

Jon currently resides in Walkersville, MD with his wonderful wife and their three young children.