December 16, 2021 PAO-12-21-CL-06
Tim Kelly (TK): I am a biochemist by training and have a Ph.D. in molecular genetics and biochemistry. After completing my studies, I went straight into industry, joining a contract development and manufacturing organization (CDMO) that eventually became Fujifilm Diosynth Biotechnologies. I was there for about six years in a quality control function and during that time the facility transitioned from clinical to commercial, with two licensed biologics. Next, I worked at the CDMO KBI Biopharma for 15 years and participated in its significant growth, including launching a cell therapy CDMO business focused on autologous immunotherapy applications.
After that, I worked at the gene therapy company Asklepios Biopharmaceutical (AskBio) to launch their manufacturing business unit. I had previously met Jon Rowley (RoosterBio’s founder) and also had relationships with some of Rooster’s Series B investors at Dynamk Capital. As a result, I was aware of the company’s history and growth opportunities. It is rewarding to again be in a position to help a company achieve that transition to where it can really have a commercial impact on drug development and manufacturing, and it’s going to be a very exciting next several years for us at RoosterBio.
TK: Cell and gene therapies are the most rapidly growing area of our industry, and they bring unbelievable promise and opportunity, but also a really unique set of challenges, particularly on the CMC and manufacturing side. That’s really where I’ve spent 25 years of my career: solving development and manufacturing challenges for biologics. So, this is where my background and RoosterBio’s value proposition really intersect, and we hope to amplify these areas over the next 12–24 months..
The team at RoosterBio has clearly done a tremendous job getting these products developed, commercialized and into the hands of customers. But what we want to do in the years to come is to extend the value proposition from a complete product solution to a complete systems solution that incorporates the development and manufacture of our customers’ products –– including both the mesenchymal stromal/stem cells (MSCs) therapeutics, as well as next-generation MSC products, such as extracellular vesicles (EVs) and exosomes, which are really exciting elements of MSC therapy. Additionally, we are building solutions to enable the genetic modification of MSCs during GMP manufacturing to forward-engineer cells that produce specific targets that can then be potentially incorporated into those EVs and provide other unique therapeutic opportunities.
The key is to establish a position of technology leadership. We were able to do that in the AAV space at AskBio and in analytical characterization and formulation development at KBI. RoosterBio has already done that for MSCs. Now, we are poised to expand on that technology leadership in terms of our development services capabilities and our manufacturing solutions toolbox, which could include building our own GMP manufacturing capacity. In the near term we will leverage partners in the space that are well-aligned with us and for whom we know will be able to deliver successful solutions.
So overall, my hopes and plans for RoosterBio fall into two areas. The first is expanding the services business so that we can provide end-to-end support beyond the cellular starting materials and bioprocess media to include complete solutions that help our customers get into the clinic and get their products to patients. The second is to facilitate end-to-end solutions for next-generation MSC technologies and products.
TK: Rooster has certainly been on that path toward next-generation MSC products and applications. In fact, Rooster customers have been using our MSCs for genetic engineering and to make EVs for years. Perhaps the difference I bring to the business is my experience in CMC manufacturing and my ability to operationalize Rooster’s development and manufacturing strategy. I have built this part of several businesses in the past and feel like I have a pretty good sense of who we need, what we need, and how to approach customers and effectively partner with them to deliver successes in process development and manufacturing services.
I bring a focus on building the CMC and contract services element as a way to introduce our products to more customers and fundamentally to ensure that our customers are going to be successful with our products. We don’t want them to buy our cells and media and then run off and try and figure it out themselves. We want to enable them to be successful and to really leverage the unique power of our toolbox to accelerate their path to the clinic.
TK: It isn’t just about having GMP-grade materials available; there is much more to it. RoosterBio has redesigned the way that MSC-based products can be produced by establishing standardized, off-the-shelf, and GMP-certified cell banks derived from multiple donors paired with GMP-grade media. This has been achieved through upfront tissue sourcing, designing GMP-grade materials suitable for scalable manufacturing, and optimizing a process for the rapid expansion of MSCs. Altogether, these efforts have made it possible to get the right cells, in the right manufacturing-friendly formats, at the right quality grade, and available “off-the-shelf”; which accelerates product development, innovation, and the rapid transition from development to cGMP manufacturing.
Layered on top are the regulatory advantages that come with having drug master files (DMFs) in place for our MSC and media products. Most of the CMC section for an MSC-based product involves the tissue source, the manufacture and thorough safety testing of the cell banks, as well as the media. If a customer chooses to partner with RoosterBio, they already have 70% of their CMC section completed simply by cross-referencing the DMF, which shaves multiple years off of their development timelines and many millions of dollars.
In addition, having development-grade materials in manufacturing-friendly formats that are aligned with our GMP-grade products is key to the industrialization of MSCs. Research materials are affordable and accessible, and the transition from research into development and manufacturing is seamless. By enabling applied research, we are contributing to the development of novel medicines that will help patients, which is the ultimate goal.
The analogy our team has used is to think of MSCs like microprocessors in computers. If you want to bring a new high-tech product to market and you start by designing and building your own microprocessor, it will take many years and millions of dollars just to do that part. If you partner with Intel or a similar company and leverage existing standardized components, you get your technology product on the market years faster than you otherwise would have — and with best-in-class technology. That allows you to focus on the value proposition of your product and less about re-inventing a supply chain that already exists elsewhere. We are essentially standardizing and industrializing what is currently a highly fragmented supply chain for the cell therapy market, certainly the MSC-focused part of the industry.
In one recent example, a synthetic biology company developing a COVID-19 treatment was able to take a modified MSC from proof-of-concept to an approved IND in less than six months. Of course, the biology and timing can vary depending on the clinical specifics. But even for a COVID-19 application, it would not have been possible to move that quickly without being able to leverage the DMF and GMP-ready materials provided by RoosterBio. That example is somewhat unique, considering the COVID-19 regulatory landscape, but it does illustrate what is possible in terms of being able to accelerate these products by multiple years and reduce the overall cost to bring MSC products to market.
TK: One of the nice things about our business model is that there is a hyper-focus on customers. If customers only want research-grade cells and media, we make them readily available and affordable. We have MSC1.0 customers that are using native cells essentially as we have banked them to produce products used in different types of tissue repair and regeneration applications, such as traumatic brain injury, acute kidney injury, macular damage, etc. There are at least 10 MSC1.0 products approved globally — with several close to approval in the United States.
Our next-gen MSC2.0 customers are developing advanced MSC products, with many of them focused on using native MSCs in combination with medical devices or as subcomponents of engineered tissues or organs. Our MSC banks are also being expanded and used as a source of EVs/exosomes, and these MSC2.0 products are being used for cardiac, cancer, pulmonary, and other therapeutic areas with significant unmet need.
In my view, some of the most exciting work is being performed by customers that are genetically modifying our MSCs and then deriving EVs from them for use in a broad range of therapeutic areas, including oncology and many other diseases. These products are not primary cells, which is important, because primary cells can be challenging, not only with respect to regulatory considerations but also with regard to concerns about how they may behave once administered — such as, for example, whether they will become cancerous. Having all of the power of the cell in a non-cell vesicle that has been modified for targeted delivery is really powerful.
TK: I think their potential is really broad. Once you get into the area of genetic engineering, you can target lots of different applications outside of regenerative medicine. Even with MSC 1.0, which really involves regenerative medicine applications, there are many interesting projects, including several looking at how MSC-derived products could be used to address different aging considerations. Bioprinting of artificial tissues is also an exciting area with lots of opportunity and the potential to address a huge unmet need. MSCs are already being investigated in almost all therapeutic areas and will be a big part of how regenerative medicines get developed.
TK: There are a lot of people in the cell therapy and regenerative medicine fields that are not working with MSCs. They may be working with induced pluripotent stems cells (iPSCs), other types of stem cells, T cells, NK cells, and more. It is not always easy, given the biases that folks have in terms of what MSCs can potentially bring to a project.
What translates the most is the fact that there is no other cell type that has an industrialized supply chain. In fact, with iPSCs (induced pluripotent stem cells), there are some unique challenges or barriers to the effort to establish an industrialized supply chain. Often, when people see what RoosterBio has done in terms of our products and processes and how those combined can accelerate clinical development, that really resonates.
Things definitely can depend on the customer and the application. In some cases, there might be an opportunity, perhaps through genetic engineering, to create an MSC product that could address that same need. In other cases, MSCs simply aren’t the answer.
TK: We definitely get lots of questions about our interest in expanding into other cell types. As we observe how the industry is developing, we definitely see opportunity in applying the RoosterBio business model to other areas of the advanced therapies supply chain. We are interested, but the question that must be addressed is how to prioritize that type of work given everything else that RoosterBio is currently trying to do in the business.
Expanding into other cell types or technology areas, however, does present opportunities for us in the years to come — trying to apply our business model to other cell types and achieve a similar type of value in the cells that have both similar and different applications to MSCs.
The most obvious candidate is iPSCs, because there is huge interest in that space. Although there is much more clinical development occurring with MSCs in terms of the numbers of INDs and clinical trials, iPSCs have different potential applications, because MSCs have fixed differentiation capabilities relative to iPSCs. We might perhaps consider partnering with a company with iPSC expertise to apply what we’ve done with in MSCs to the iPSC space. Other types of stem cells, such as embryonic stem cells, also present unique opportunities, but iPSCs are the obvious first choice.
It is worth mentioning at this point that there are different source tissues in the MSC space itself. Historically, RoosterBio has mainly worked with bone marrow, but we do offer umbilical cord–derived stem cells as a research-grade product. We are currently working to introduce GMP-grade umbilical cord–derived MSC working cell banks. Additional work is also underway on adipose-derived MSCs. The goal is to expanding the range of products so that customers with specific applications can choose MSC products with the optimum properties.
TK: It is still important for both applications. To date, no robust MSC-based therapeutics have been approved by the U.S. Food and Drug Administration, but they are on the market in Europe and Asia and other parts of the world. Even in the 1.0 applications, having that really well-thought-out and comprehensive quality and regulatory package is critical. I expect that we will soon see approvals of MSC products in the United States, and the fact that none have occurred yet contributes to skepticism in some quarters about the effectiveness of MSC-based approaches.
In terms of the 2.0 applications, the regulatory pathway for EVs is actually simpler, because the living cell component is removed. Whether scientifically based or not, there are concerns about administering primary cells outside of autologous treatments, which have become reasonably well accepted from a safety point of view, because each patient’s cells are manipulated and then returned to that same patient. But administering cells as therapeutics poses different types of challenges than administering a protein, small molecule, or even a viral vector, which of course have their own considerations. I hope that, as EVs continue to advance, they will enable a new wave of MSC-related therapies, because when you take the cell out of the equation, you have a product that is easier to characterize, store, and administer. As a result, some of the regulatory considerations are taken off the table.
Regardless, there will definitely be challenges with respect to setting appropriate specifications for purity, quality, identity, potency, and so forth. These are some of the challenges that we’re working hard at RoosterBio to solve.
For instance, our MSC research products and cGMP cell banks are better characterized than any other MSC available on the market today. We do more to characterize and understand our cells and ultimately our EVs than any other suppliers, because we know that a higher level of knowledge is essential to getting these products through the regulatory hurdles. There has been some latitude given to next-generation therapies targeting orphan indications with significant unmet need with respect to providing limited characterization data, because manufacturers have claimed that these products are very difficult to characterize, and only so much can be done.
The truth is that we can do more, and companies are choosing not to. That is not the case with RoosterBio; we are pushing the envelope in that space because we foresee that the FDA will ultimately increase its expectations to the point where cells and vectors need to be characterized as well as monoclonal antibodies. The faster we can get there, the more products we will get approved and the more patients we will be able to treat and help.
TK: The MSC market is rapidly developing, and we expect it will pass through some inflexion points to eventually reach the level of exuberance now seen for CAR-T and related therapies. A lot of the tools that have been developed by RoosterBio and other players within the industry are going to fuel that, including genetic engineering capabilities.
All of the pieces are starting to come together: The MSC cell type has a long-standing safety profile. RoosterBio has developed a bioprocess platform that provides product developers with a nearly unlimited and relatively inexpensive supply of MSCs. And now, the genetic engineering toolbox allows developers to weaponize these cells to maximize their therapeutic potential.
As a result, we expect to see companies exploiting many of the innate capabilities or characteristics of MSCs, from longevity to anti-inflammatory properties, to even using them as drug delivery devices — whether as the cells themselves or in the form of EVs that the cells secrete. We also expect to see companies using MSCs or EVs to transfer their properties to other cells and to prime those other cells with their characteristics, such as in the form of adoptive therapies.
Overall, we believe the MSC market is going to explode as a result of standardized, off-the-shelf tools and as a result of MSCs’ innate therapeutic activity. Those two factors coming together is really going to lead to the rapid increase in the number of MSCs being investigated for therapeutic applications, and eventually an acceleration of MSC products on the market.
A critical milestone for MSCs will be that first FDA approval of an MSC product, which we are confident will happen in the very near term. And it will be followed by approval and commercialization of EV-based products, which will help demonstrate the clinical efficacy of MSCs out in the market, which will be another huge inflection point.
The last stage will be approval of completely unique, genetically engineered MSCs and EVs that deliver clinical efficacy that no one thought possible with MSC-based products and which will require determining how to put everything together from the CMC, regulatory, and clinical points of view. That will be a real watershed moment for the MSC space, when all the advantages of using MSCs will be recognized.
Of course, there is skepticism, but that will be overcome. In fact, once those genetically modified products ultimately become successful in the clinic and get commercialized, they could serve as safer nonviral alternatives — as cells or EVs — to viral vectors for the delivery of genetic payloads.
And at the same time as these developments are occurring, the bioprinting of artificial tissues and organs will continue to progress, and that whole area provides another massive opportunity for MSCs and other cell types due to the sheer volume of cells required for ex vivo tissue engineering.
TK: From a product point of view, we are actively developing expanded portfolio products with a focus on EVs and genetically engineered MCSs. We are also continuing to optimize the products that we already offer, as well as developing GMP-compliant versions of products currently only available as research-grade materials.
RoosterBio has so far largely focused on products for upstream production — growing the cells, getting the cells to secrete EVs, or genetically modifying the cells. Going forward, we will be dedicating some of our work to downstream development, particularly with respect to EV-based products and the development of bioprocess materials that facilitate EV purification and formulation.
With respect to services, we are working to complete the entire value chain for EVs through downstream processing and formulation and analytical characterization, particularly pushing the envelope on the analytics piece and developing more genetic engineering tools. We currently have a product that facilitates highly efficient lentiviral transduction of our MSCs, which we want to expand to include adeno-associated virus (AAV) and also nonviral means of introducing DNA, such as electroporation and transfection. The goal is to have a toolbox so that customers have access to ready-to-go solutions however they intend to develop their products.
Our ultimate aspiration is to meet all of our customers’ needs regardless of the development approaches they are taking and to provide the products, services, and bioprocess solutions that will help them reach the clinic and the market faster than they could otherwise, to ultimately get these innovative therapies to the patients that need them.
Tim Kelly, Ph.D., most recently served as President of Manufacturing at Asklepios Biopharmaceutical, Inc. (AskBio), which was acquired by Bayer in October 2020 for up to $4 billion. At AskBio, Tim was responsible for the manufacturing strategy and delivery of AAV-based gene therapy products for over eight clinical programs. For 15 years prior, he was with KBI Biopharma, Inc., an industry-leading contract development and manufacturing organization, where he ultimately served as President and Chief Executive Officer. As CEO of KBI Biopharma, Tim led four acquisitions and served as Chairman of Selexis SA while leading the integration of Selexis and KBI Biopharma. He began his corporate experience at Diosynth Biotechnology. Tim has overseen development and manufacturing services for over 325 biologics at all stages of development and commercialization and has supported numerous successful FDA and international regulatory inspections throughout his career. Tim earned his Ph.D. in molecular genetics and biochemistry from George State University and his BA in biology from College of the Holy Cross.