On Tuesday, 20 June 2017, BioProcess International presented a panel discussion from 2:20 to 3:30 pm as part of the “Emerging Therapies” session of its BPI Theater at the BIO annual convention in San Diego.
Moderated by David Brindley (University of Oxford and Harvard University), the panel comprised Morrie Ruffin (managing partner of the Alliance for Regenerative Medicine), David Backer (head of commercial development for gene editing and novel modalities at MilliporeSigma), Robert Preti (president and chief executive officer of PCT, a Hitachi Company), and Lynne Frick (vice president of business development of IsoPlexis).
After many trials, errors, and milestones, regenerative medicine has become a mainstream part of the biologics industry supported by at least 670 companies and clinics of all sizes. This panel introduced and discussed key lessons to be gleaned from the evolution of bioprocessing to support the optimal future development of regenerative medicines; reviewed rapid changes in bioprocess materials, operator specialization, and changing uses of processing technologies that shape current therapeutic development pathways; and proposed expectations of what could happen in the future.
Robert Preti (PCT)
Preti set the stage for the panel with these key assertions: The cell therapy industry is experiencing a high degree of complexity and a lack of consistency in product and service solutions. Unlike for contract development and management organizations (CDMOs) in the larger biologics industry, currently no platform is available to standardize manufacturing. The industry needs a set of consistent solutions for delivery; then it could move easily toward an automation solution (not just automation of process but of tasks).
Preti identified three major challenges: Manufacturing today is labor intensive, with a lack of suitable analytics and incomplete understanding of product characterization. Facilities have idle capacity, particularly at companies with only one or two products in their pipelines, which creates a difficult cost of goods (CoG) situation. Scalability and sustainability are no longer biology problems, but rather engineering challenges.
Through the lenses of quality, sustainability, CoG, and scalability, PCT provides solutions for planning, sharing infrastructure and business models using “the factory of the future.”
Lynn Frick (IsoPLexis)
Lynne Frick followed by asking the question, “What do we need in cell therapy?” Her suggested answers were risk mitigation (e.g., biomarkers as predictive tests), accelerated development and failure (if necessary), and product characterization. “We must do better than the early monoclonal antibody days, when the process was the product.”
In cell therapy, she was surprised to learn that a lot of patients don’t respond. However, those who do often have good, durable responses, although some do relapse. Engineered T cells elicit low response in some patients, but no one knows why. There is no predictive test. IsoPlexsis began by creating a microchip on which patient’s cells actively secrete cytokines. With a resulting profile of secreted proteins, that patient’s response to treatment can be predicted.
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Brindley asked the panel a series of questions.
What areas in bioprocessing are not analogous to regenerative medicine? Preti pointed out the differences between patient-based (autologous) and allogeneic (off-the-shelf) therapies and tissue engineering. Allogenic therapies have some parallels to bioprocessing: Large batches can be stored for a time and shipped later, but that’s where the comparison ends. Tissue engineering is challenging to evaluate. “How do we test whether they work or not?” Autologous therapies have the same end challenge of product characterization. The weight of everything you do rests on every product when each product is for an individual. The challenge is to bring some simplicity to all this complexity. No one fully understands what cells are doing, “but that is why we are using them — because they know what they’re doing.” The central challenges are understanding mechanism of action (MoA) and pharmacokinetic/pharmacodynamic (PK/PD) and determining what a final product looks like.
On the viral side, where do you see a bottleneck? Backer said that one big issue is how to make more viruses upstream. Many different cell lines are used to produce viral vaccines. Adenoassociated virus (AAV) and lentivirus have become the vectors of choice, so some consolidation is in progress, but neither is made at scale yet. Adding complexity are four ways to make AAV and two ways to make lentivirus. The industry is working toward consolidation.
As long as the manufacturing process looks good for a monoclonal antibody (MAb), a company can move forward. From an investment standpoint, how does that work for gene therapies? Ruffin said that this is a big question for investors. They want to know whether a real business and commercial opportunity can be found here. Can gene therapy be scalable and sustainable? The answer is yet to come.
For cell therapies, what are the key innovations? How can we spread that knowledge to move the industry forward while protecting originators? Because product characterization and exact MoA are as yet unclear, sponsors need to look at their processes one step at a time, try improvements there before moving on, and make sure that final product remains the same. Big companies are getting involved with more ability to invest in solutions than can smaller companies with fewer resources. Tool suppliers are applying their products to this new area. Innovation has not stalled because interest and investment are spurring it. Ruffin expressed his concern over how to get beyond the clinic (assuming the products do work) so that patients can be treated on a larger scale with commercial and sustainable products.
The first thing investors want to know is who will pay for these therapies. Has the industry come up with reimbursement strategies? It won’t be the same for all products in this sector. Autologous therapies pose a real challenge, but the issues are not unsolvable. The industry needs to anticipate what kind of market and reimbursement it will need in 10 years. It is in a unique situation for which support (reimbursement, regulatory, and so on) lags behind the clinical development programs, so the industry is playing catch-up. These therapies are transformative. If they continue to work how they appear to be working in late clinical trials, then sponsors will have to figure this out because “you can’t deny patients working treatments for deadly diseases.”
An audience member shared how the European Medicines Agency (EMA) has already put forth a reimbursement strategy for cell therapy because a Novartis product is ready for market. The EMA uses “quality of life” years offered (e.g., a five-year cure) to determine the cost. Whether that is sustainable is unknown. The audience member also shared issues with quality control on samples: “No one knows how to QC something from an individual because it is individual.”
If a company wants you to get them up to GMP manufacturing with its own cell therapy process, how do you do that? When a customer brings in an early phase product, the biggest challenge is the speed at which it wants to move it through the clinical pipeline. The developer has investors and wants to get going; the CMO wants to fix the process first before moving on. In the real world, this depends on “development by design.” Scale challenges will arise, and CMOs have to convince their clients to think about those early on. They need to determine which unit steps will need replacing for scale-up to keep costs down while maintaining quality.
What were ARM’s key issues five years ago, and how have they changed? Has the membership changed? The organization is different today in size, scope, and diversity. “Five years ago,” Ruffin said, “we weren’t even sure that there was an industry. We are now on the verge of commercialization, and that has changed everything — especially interest. Cost and reimbursement are now pertinent and must be addressed.”
If you have a single-dose therapy with a single expiration date, can you separate that out into batches to simplify cost? Cell therapy can be curative, and curative implies durability. How long will a single dose keep someone in remission? That is a major question for reimbursement, whether we’re paying for a cure or a number of years’ worth of remission. Part of the manufacturing challenge is expiry of incoming and outgoing materials, particularly in patient-specific cell therapy. These questions remain to be resolved.
Alison Center is editorial assistant (firstname.lastname@example.org) for BioProcess International, PO Box 70, Dexter, OR 97431.