Defining Risk-Sharing In Cell & Gene Therapy Manufacturing Partnerships

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

It’s regularly proclaimed that cell and gene therapies have necessitated new approaches to partnership. There have been several oft-discussed examples demonstrating how biotechs and CDMOs have been challenged to establish the “best” manufacturing infrastructure for ATMPs. In some of my previous articles, I’ve covered the benefits of implementing a hybrid manufacturing model (biotechs), while also looking into some of the business decisions facing CDMOs (and biotechs) as they invest in technologies to build the foundation for flexible manufacturing platforms. Such capabilities-building strategies are hardly unique to the CGT space. However, we can’t ignore that our advanced therapy candidates bring with them an invigorating (and equally frustrating) amount of scientific and financial “baggage” which ultimately influences the “how,” “when,” “why,” and “who” of partnering.

“Risk sharing” — or “value sharing,” if you prefer — is a concept as old as time in biotech partnerships. But aside from some general comments on the importance of exploring risk-sharing frameworks, discussions laying bare the nuances of such frameworks in the ATMP industry have been few and far between. In turn, it’s been increasingly difficult to align around a common understanding (or at least more streamlined definitions) of what such collaborations look like today — and, more importantly, what they can become in the future.

Though risk-sharing is traditionally spoken about in a financial context, as I argued in a previous article, there is much more than just financial risk at play in CGT partnerships. Many biotech/service provider partnerships are also being established to account for the scientific risks and/or technological learnings that will inevitably shape a product’s journey to patients. I intend to home in more closely on the dynamics emerging between CGT sponsors and CDMOs in a future article series. However, equally worthy of attention are the partnerships being established between biotechs and emerging technology companies. As I see it, there is no more “symbiotic” a relationship than the one between these two parties, both of which are placing the development of their “darlings” (i.e., the therapy and the technology) into each other’s hands.

A great example of such a partnership was announced late last year, when Inceptor Bio signed on to Ori Biotech’s LightSpeed Early Access Program (LEAP). I took this announcement as a sign from the universe that it was time to dig deeper into how CGTs are upending partnerships today — with a special focus on the “why” and “how” of risk-sharing in the cell therapy field.

Here in part 1 of this two-part article, Jason C. Foster, CEO and executive director of Ori Biotech, and Abe Maingi, VP of business development and co-founder of Inceptor Bio, share their perspectives on how partnerships (and, in some cases, the underlying psychology around manufacturing) must evolve to mitigate the unique scientific and financial risks facing autologous cell therapies.

How Cell Therapy Impacts The Manufacturing & Partnership Mindset

We already know that cell therapy is “hard.” If we’re not proclaiming the difficulties of working with variable patient starting materials and a logistics framework that could rival the complexity of the NYC subway system, there’s also the fact that cell therapy doesn’t boil down to a single cell type. Hence why the phrase “seen one CAR-T, seen all the other CAR therapies” does not exist in our vocabularies.

Like many of the cell therapy biotechs in the industry today, Inceptor Bio is taking an ambitious, multi-pronged approach to tackle solid tumors. In addition to preparing its first candidate — a CAR-T therapy — to enter the clinic in 2024, the company is also working with two other cell types, including a CAR-M (preclinical) and a CAR-NK therapy (currently in discovery). Of course, tackling multiple cell types is an important competitive differentiator. However, such therapeutic/pipeline differentiation can also be a double-edged sword, given that it requires the company (and its partners) to learn the biological nuances of each cell type and how to nurture them using a robust and reproducible process. Though it’s not in any biotech’s nature to shy away from a good biological/scientific challenge, I appreciated that Inceptor’s Abe Maingi also put manufacturing on the same pillar of importance to the company.

There are a few ways in which Inceptor is a prime example of a biotech that is living the CGT gospel of “starting early” with manufacturing and “keeping the end in mind from the beginning.” As CMC began taking center stage in the ATMP space a few years ago, it was a regularly offered word of wisdom that a “newborn” CGT company should hire a manufacturing expert right out of the gate. In this way, Inceptor Bio has been “blessed with good genes,” if you will. Its leadership team and board is stacked with manufacturing experts, many of whom have experience working in the CDMO industry. It’s partially thanks to the leaderships’ connections to manufacturing — and, of course, a build vs. buy analysis — that the company is the proud owner of its own manufacturing facility in Gainesville, Florida. The recently announced partnership with Ori Biotech, which was also regularly championed by the leadership team, goes a long way to demonstrating the company’s early commitment to architecting a manufacturing and digital infrastructure while in the preclinical/R&D phase.

“We wanted to solve for manufacturing and secure our supply chain at the earliest stages of our company,” Maingi said. In fact, as he went on to explain, Inceptor saw the “biology vs. process development” challenge underlying its multi-product pipeline as an important opportunity to differentiate itself on the development and manufacturing side.

In today’s tenuous funding environment, we cannot discount the importance of good clinical data as a competitive differentiator (i.e., source of much needed funding). But to understand that data, a knowledge of how your process informs that clinical performance is key, and as we know well, the process/structure/function relationship remains one of the biggest “question marks” hanging over every ATMP. Naturally, answering these questions will take time and broader clinical and regulatory experience. But there is also something to be said about the importance of “thinking outside the box” as it relates to establishing your manufacturing paradigm.

Our discussions of manufacturing differentiation today are often limited to owning a facility or improving an autologous product’s turn-around time — neither of which are easy feats to manage. But as Maingi explained, given today’s tenuous funding environment, pursuing risk-sharing/value-based partnerships can also play an important role in learning more about your process, as well as make your cell therapy manufacturing process stand out from the crowd.   

Throughout our discussion on manufacturing differentiation, I found myself thinking back on my time in the biosimilar space, during which the concept of the (often patent-extending) “me-too” drug stimulated great ire. In the past few months in the ATMP space, I’ve begun to hear (albeit sparingly) the phrase “me too” being applied to that of emerging manufacturing platforms. While the hope is that we will arrive at standardized, potentially plug-and-play (ish) manufacturing platforms someday, we’re still very much at the stage in the industry where true innovation could drastically shape the future of what those platforms can do for our products/manufacturing processes. As such, adopting a “me too” mindset in the realms of manufacturing and partnering may be more limiting than helpful at this time.

Truly differentiating to solve the scalability and accessibility challenges facing cell therapy is not an easy task, especially considering that we inherently try to solve new problems by resurrecting old solutions. Look no farther than our regular reversion back to our experiences with monoclonal antibodies. Though the mAB space is a comforting success story that reassures us of a more standardized future for manufacturing, I appreciated Jason Foster’s alternative take on how such a mindset can also hold us back from what we need to do to achieve a successful future for autologous cell therapies.

“We often draw on the parallels between where we are today and where biologics’ manufacturing originated,” he explained. “But this can mean we think myopically about the opportunities available to us.” For example, not only do our past experiences/success with biologics limit us to a centralized manufacturing model, but we’re also inherently drawn to believing that our economies of scale issues can only be solved by scaling up (and up and up…).

“I don’t envy therapy developers,” Foster admitted. “It’s no longer the case that you just need to develop an efficacious and safe therapy and get it approved to treat patients. An essential aspect of reaching cell therapy patients today is also recognizing that the standard paths to scaling and reducing COGS have changed fundamentally.” In turn, a company must adapt its mindset and strategies to achieve a cell therapy’s unique economies of scale. And there is truly no better place to see such adaptations than in some of the partnerships emerging across the ATMP industry.    

Avoiding The “Partnership On Paper:” The Cell Therapy “Brand” Of Risk/Value Sharing

Whether it be a personal/romantic or a business relationship, there have been many words devoted to the art of creating a fit-for-purpose amalgamation of personalities, dreams, and assets. Of course, “fit-for-purpose” will be unique to each particular need and desired partnership style.  But in the ATMP space, as we attempt to define what flexible manufacturing means/comprises, a standard “hands-off” partnership that may work in more established industry sectors can leave much to be desired. In fact, just as we warn against the concept of the “me too” (i.e., not that differentiated) manufacturing platform, there’s something to be said about breaking from the “partnership-on-paper-only” road.

This was the consistent vibe of Maingi and Foster’s back-and-forth during our discussion. For Foster on the start-up tech provider side, the importance of finding a nimble partner truly interested in putting manufacturing first (and meaning it) was a must. Foster acknowledged that defining a “good” partnership can get subjective quickly. On the one hand, partnering with a CDMO and partnering with a biotech will each have “a different flavor,” Foster acknowledged. But the company knows what they aren’t striving for in any of their partnerships: “We can do more than just install some technology on a site and say, ‘Good luck,” Foster laughed.

For Maingi and Inceptor, the need for a partnership that would help balance the many financial risks facing early-stage preclinical biotechs today was, of course, front-and-center. As Maingi explained, Inceptor has encountered a variety of different models aiming to align incentives between partners, whether it be as simple as milestone payments or as complex as establishing an equity stake in a biotech.

“We’re seeing a number of outsourcing partners getting creative to better work with young, cash-strapped companies, some efforts of which are a blend of the VC and Big Pharma mindsets,” Maingi explained. On the one hand, such creativity is important for a CDMO given the inherent financial risk they take on with small companies and early-stage products. (Believe it or not, outsourcing facilities also have bills to pay.) But given that paying millions upfront for access to a specific technology can also be restrictive for biotechs in today’s climate, innovator companies have been exploring more creative deal-making to ensure they have access to the expertise, capacity, and technology they need without chipping into their financial runways.  

Both Foster and Maingi acknowledged that the fee-for-service model will never go away in the CGT space. However, true risk-sharing in the cell and gene space is instead defined by the biotech’s and the service provider’s desire for and dedication to the growth of the process, product, and technology. Ultimately, both partners must value and realize mutual benefit — both financial and intellectual — in the advancement and success of all three.  

Of course, part of achieving this balance will depend upon a service provider’s willingness to bet on their partners and on their (the provider’s own) abilities to deliver a product into the clinic and onto the market. It also requires the biotech to be open and willing to learn from their partners’ expertise.

“As a biotech, we’re always trying to create a better product,” Maingi said. “Yes, the financials of a partnership need to be mutually beneficial, but we’re always asking what our partners can teach us about how to make our product, whether it be on the viral vector or process development side,” Maingi said.   

As manufacturing experts, the phrase “better, faster, cheaper” has and will always be in our vocabulary. The hope is that a partner will help a client achieve at least two of those three goals, and that both companies will be aligned around the measures necessary to achieve the desired quality. (A 95% confidence interval and a 99.9% confidence interval may look close on paper but achieving the 99.9% will require a different mindset and level of effort.)

There are many ways to structure and sustain partnerships, and no one partnership will be created equal. However, my conversation with Foster and Maingi revealed that establishing a risk/value-sharing partnership in the CGT space today demands each partner to maintain a careful balance between being an expert and a pupil.

Foster summed up this mindset perfectly: “We’re a technology company at our heart; we’re not a therapy developer. While we have some of that knowledge and capability on our biological team, that is not what we do best. That’s why we seek partners who are experts in their biological area and who are willing to kick the tires on the platform and give us feedback. We’ll gather the data and, together, learn how to apply it to our individual and collective missions.” 

Check out part 2 of my discussion with Foster & Maingi exploring how we can begin to define “flexibility” in manufacturing platforms and partnerships.

Like what you’re reading? Sign up to continue following ARW’s writings on the CGT + mRNA manufacturing paradigm.