We had the pleasure of discussing the booming field of cell therapies with Jason Foster, CEO of Ori Biotech. The company is developing a closed, automated, and scalable platform for cell therapy manufacturing. He shares his thoughts on the field and what it means for programs to be viable.

To start, can you tell us a little bit about your background

After business school in 2006, I was one of the first five management team members in a small molecule specialty pharma business focused on CNS disorders. From 2006 to 2010, we grew that business to 400 people. In 2010 they said, “Do you want to go to London and help start the European business for us?”. At this point, we had a 2-year-old, and my wife was 5 months pregnant, and we had just bought a house. Of course, we said, “Sure! The timing is perfect, let’s go to London!”

Once in London, we built the European arm of that business to about 200 people and about $250M in turnover. We listed that business, called Indivior, in 2014 on the LSE. At that point, we had grown to >$1B in revenue and about 1,100 people in 37 countries. Once that journey was over, I was ready to get back to my roots of building businesses, working with founders, and being part of the early building phases of a company, so I started working very closely with venture capital and private equity firms in Europe and the US. This led me into consulting and investing, which is how I met Ori Biotech!

Wow, that’s quite the adventure. Can you tell us a little bit about Ori Biotech and your closed manufacturing platform?

Ori Biotech is on a mission to enable widespread patient access to lifesaving cell and gene therapies. Five years ago, we started out by focusing on Biology First. This approach enabled us to develop a manufacturing platform that has industry-leading biological performance while taking advantage of the obvious benefits of automation. Our goal has always been to deliver a platform that is both flexible enough to do R&D and scalable enough to do commercial GMP manufacturing.  For too long, researchers and developers have had to trade-off biological performance for automation.  Not anymore.

Our manufacturing platform can consistently start with 50M cells and deliver yields of up to 12B cells, with 95% viability and transduction efficiencies of 50-60% (MOI:1.0) while producing cells with potent cancer-killing activity. The data our partners, like CTMC, have generated suggests the platform outperforms the current “gold standard” manual and automated cell culture systems.

This is clearly an area of significant need for the field of cell therapies and as a result, there are multiple closed manufacturing systems with various technology developers attempting to solve the manufacturing challenge in different ways. What are your thoughts on an end-to-end approach vs. a modular approach? What are the key things to consider for each of these approaches?

It is great to see so much innovation coming into the field to try to solve the major challenges that are limiting patient’s access to today’s approved therapies. Unfortunately, today’s therapies are too hard to make and too expensive to even treat 5% of the total patient population who needs them. As you mentioned, there are different schools of thought about how to solve this problem in the best way, but what is crystal clear is that flexibility and scalability are both critical.

To date, bioprocessing “tools”, or the enabling technology industry as I like to call it, hasn’t been able to unlock flexibility and scalability with the first-generation technologies that have been on the market for 10+ years. The legacy, largely repurposed technologies that are most often used today offer either scalability or flexibility, sometimes neither, but certainly not both. This is a clear market need, which has caused a new generation of innovators, like Ori, to emerge. Some of these companies are trying to automate every unit operation by redesigning each from scratch, and some, like Ori, are enabling therapy developers to take a “best-of-breed” approach.  This allows therapy developers to retain the flexibility to use proven technologies and service providers that they trust and have already validated while still being able to take advantage of the benefits of next-generation technologies like Ori.

Both approaches can lead to a similar level of automation, but a modular process designed around best-of-breed technologies gives added flexibility and helps ensure optimal biological performance. We think end-to-end approaches tend to reduce flexibility and force therapy developers to sacrifice biological performance for automation, a tradeoff they shouldn’t be forced to make.  From our perspective, a modular approach is the best way to provide the flexibility, scalability, and biological performance required to make these products efficiently and cost-effectively at scale. For too long, therapy developers have had to sacrifice biological performance for automation, but no more; Ori is Automating Better Biology.   

That’s interesting. How do you envision your technology integrating with other technologies? Would this be on a unit-operation basis?

We wanted to develop a system that doesn’t limit a therapy developer’s choices on which manufacturing service providers and technologies they can use in their process. We believe anything that limits flexibility is bad for our partners, bad for patients, and bad for the industry.

With this approach, a drug developer can utilize whatever other technologies they want alongside the Ori platform, whether that be proven tools for selection, washing/concentration, transfection, fill/finish, or others. Similarly, if partners would like to leverage external manufacturing expertise, several leading CDMOs are integrating and designing workflows around the Ori platform (more details coming soon!). By offering this flexibility, we hope to empower scientists to give the industry the foundation it needs to continue to innovate and bring these life-saving therapies to patients as fast as possible.

Fair enough! How do you think about present bottlenecks in CGT manufacturing today and how they can be addressed?

I look at the bottlenecks in CGT manufacturing according to the Theory of Constraints. To expand capacity today, the industry is trying to parallelize low throughput, manual processes which is a very inefficient way to increase production volumes.  Instead, I think there’s so much to improve upon by leveraging technology like Ori’s to address the major bottleneck (i.e., the 6-10 days of activation, transduction and expansion), thereby increasing the throughput of the existing manufacturing system without needing to replicate it. This process of identifying and resolving constraints should be repeated until we’ve reduced the cost to manufacture and increased the throughput of these therapies such that therapy developers can scale their impact by providing therapies to all the patients who need them.

Trying to parallelize existing inefficient processes has led to large, underutilized facilities producing relatively few doses with high failure rates and high COGS. By first addressing the major bottleneck present in manufacturing today, we can increase throughput by 10x, while simultaneously reducing the facility footprint by ~50%. This improvement alone could lower COGS by 30-50% depending on your process.

Now, a key piece of Ori’s offering that you have presented on is the automated fluid handling system. Why is this feature so important in your mind?

If we critically assess the CGT manufacturing landscape today, we as an industry have shown that we haven’t figured out how to manufacture these products at scale. Ultimately, one of the core challenges we face as an industry in achieving scale is automating the process of moving fluids from one process step to another in a sterile fashion. Ori’s closed, automated technology solves this problem, by providing an automated means of adding or removing fluid from cell culture in a sterile fashion, removing the possibility of human error and contamination, in a Grade C or even in Grade D or a Controlled Non-Classified space.

Without a technology like this, the industry will always be reliant on tube welding (or manual sterile connectors) for transfers between consumables, bags, and various other pieces of equipment, which is expensive, inefficient, leaves dead volumes of precious cells behind, and has high failure rates. The beauty of the Ori proprietary sterile connection technology is that it removes human intervention from the fluid handling process lowering human resource requirements, improving reliability, and increasing throughput.

We certainly agree on the value of automation to enable scalable cell therapies at a lowered cost. Where does automation rank across other potential manufacturing parameters that could be optimized?

As you know, at Ori, we’ve built an in-house Total Cost to Manufacture model to help inform the industry’s thinking on this. Looking at the cost profile of manufacturing at scale on a cost-per-dose basis (assuming a fully utilized capacity in increments of 1,000 doses a year), the cost breakout for today’s mostly manual processes, which really aren’t currently fully utilized, is approximately 50% consumable costs (e.g., virus, media, tubing sets, etc.), 40% labor costs (i.e., indirect and direct), and 10% other costs (e.g., amortized fixed costs, shipping, traceability, etc.).

Despite being a large driver of costs, consumable costs are currently hard to reduce. While certain items like viral vector usage can be reduced via the Ori platform or by non-viral transfection methods, many of the costs of other consumables (e.g., media, growth factors, freezing / thawing agents, etc.) can be harder to address. I believe this makes automation the core lever the industry can pull immediately to lower costs by removing labor, shrinking facility size, and increasing reliability to improve the commercial viability of CGT products and bring down costs. The Ori platform also more efficiently uses some of the most expensive reagents in the process, reducing COGS even further.

So, we’ve touched on it indirectly, but there are obviously two ways to go about this automation: with a closed system like Ori’s or through umbrella automation over the top of existing equipment and unit operations. How do you view these two strategies?

From our perspective, automating existing unit operations and work steps is an option to remove some of the required labor from the process, but it doesn’t address a few key challenges to reaching scale. These challenges likely include an inability to lower cleanroom grades (from Class B to C / D), large amounts of dead volumes from existing tubing sets and bags, high failure rates, and the inability to shrink the footprint of manufacturing to achieve higher throughput per square ft²/m², all of which may cause difficulties when trying to decrease costs and increase throughput.  We have specifically designed the Ori platform as a closed system that can be multiplexed dramatically increasing throughput per ft²/m² so you can run 30 batches or more in parallel in 1000 sq ft of cleanroom space.

Zooming out a bit, we’ve seen a lot of chatter around non-viral-based production and the field slowly trying to move away from viral-based manufacturing. How impactful might a move like this be and what sort of cost improvements could it bring to manufacturing?

With viral vector comprising up to 30% of the total cost of an autologous CAR-T cell therapy today, any movement to reduce or remove the use of virus has the potential to significantly lower the cost per dose, which would be an exciting outcome for both the industry and patients!  To that end, we are also working with transfection technology companies to create pre-defined workflows for our shared partners.  

However, most processes are viral vector-based today for good reason, namely, virus is a very effective means of delivering genetic material while retaining cell health and viability. While innovators will hopefully unlock non-viral transfection at scale, it’s important for us as an industry to appreciate that viral manufacturing will likely be the predominant means of manufacturing (especially at scale) in the short term. The internal and external data coming out of our system suggests that we can enhance transduction efficiency, thereby reducing the amount of virus required today. 

Makes sense. Virus has had many years to hone their delivery capabilities! Continuing to look a bit more holistically at the field, what do you believe manufacturing / logistics for cell therapies will look like in the next 3-5 years?

From our perspective, the real question is what does the cell therapy landscape need to look like to make these therapies affordable and accessible so we can help shape that future. To make that a reality, we must: 1) Remove human beings from the process wherever possible (via automation, robotics, etc.), 2) Reduce the cost of goods, increase throughput, and improve reliability by reducing batch failures, and 3) Shorten vein to vein times.

While there are current challenges in achieving all three of these, we must make all of these items a reality to be successful in reaching scale in the next 3-5 years. We believe the industry needs purpose-built technologies for this new generation of living, personalized medicines. Repurposing old technologies and solutions born out of regenerative medicine or biologics manufacturing has not proven the ability to solve this problem at scale over the last 10 years.

What impact do you think the tough funding climate has had on cell therapy companies? What role has that potentially played in shaping the present situation?

The funding climate in the past two years has been very tough and has absolutely impacted the field’s ability to deliver viable cell therapies to the market. In today’s world, fundraising for early-stage companies is often tied to reaching the next safety or efficacy milestone. Given their cash constraints, many therapy developers become singularly focused on proving out the science of their products and neglect to pay proper attention to ensuring their product will be commercially viable, early enough in development. This has led to the development of products that are approvable but aren’t accessible or affordable for health systems, which ultimately results in commercial failure.

I would like to see CGT therapeutics investors elevate viability to the same level as safety and efficacy early in development by encouraging therapy developers to focus on the commercial viability of their products during R&D/PD.  By elevating viability alongside safety and efficacy, investors will ensure that products can reach their target patient population at scale, gain market access, and deliver a return on investment. Without this paradigm shift, I think we risk relegating cell and gene therapies to being a cool science experiment rather than a viable therapeutic modality, which would be unfortunate for all the patients who could have been helped by these therapies.

I’ll point to two pieces of evidence that I think suggest this shift has not yet occurred: 1) It seems investors have recently turned their attention away from CGT and are currently looking at other modalities beyond cell and gene like ADCs, bi-specifics, radio pharm and others, which may fit the historic development and commercial launch model better than CGT can today and 2) We are seeing late stage companies like Iovance and BlueBird that do not have Big Pharma licensing partners for their approved products. This is unusual and raises the question of whether Big Pharma BD&L teams and therapeutics investors believe that cell and gene therapies can be commercially viable and deliver the necessary financial return on investment.

That would be a sobering outcome for this field which has shown such incredible clinical promise. On the optimistic front, what near-term trends are you watching most closely? What will shape the cell therapy field in the coming years?

As an enabling technology provider to the CGT industry, we obviously keep a close eye on new technological innovations in the manufacturing space such as new in-line PAT/sensing capabilities, but we also try to look more broadly as well. 

In terms of what’s next, we expect that innovation will continue in the manufacturing equipment space, of course. I’m also hopeful many more technologies will enter the market, advancements in non-viral technology will make transfection more prevalent clinically and commercially, and that therapy developers will start adopting automation earlier in their lifecycle, as the focus moves towards viability alongside safety and efficacy.  

I’ll offer maybe a bit of a contrarian take as well, which is that I don’t think allogeneic approaches will solve our patient access challenges in the short to medium term.  I haven’t yet seen any credible COGS models that clearly demonstrate that allo will be substantially cheaper than auto and the challenges with potency and durability for allo are well documented.  Ori stands ready to support both allo and auto approaches, but I think allo is probably further out than most people think (5-10 years) from hitting the mainstream.

Lastly, what does 2024 have in store for Ori Biotech?

As you may have seen, 2024 is going to be a particularly special year for Ori as we are launching our first product at ISCT in Vancouver on May 29^th! The team has put in an incredible amount of hard work to bring this platform to market in only 5 years and we are extremely excited to pull back the curtain and show the world what we have built.

Obviously, the proof is in the performance but the data we have generated with partners suggests the platform can provide both the flexibility and the scalability the industry requires.  Jason Bock, CEO at our partner CTMC said himself…”I expected automation, I expected more process insights but I never expected better biological performance right out of the gate.”  At ISCT, we will not only be showcasing our new platform but also Jason Bock will be presenting data and insights from their direct experience using the Ori platform.  We will also be conducting live platform demos throughout the conference, where people can come to touch and feel the platform for themselves. You should book a demo and come experience the platform firsthand!

Beyond ISCT, we will continue to conduct technology evaluations at partner sites throughout the second half of the year, with the first commercial units planning to be installed at customer sites starting in early 2025.   We also hope that 2025 will bring our first opportunity to support a partner’s clinical trial, which will be the most important milestone for Ori to date.

You have a full plate, Jason. Very exciting and we look forward to the announcements at ISCT. Thanks for speaking with us.

Thank you

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