Getting the science right helps biopharma startups overcome development and commercialization challenges.
By Cynthia A. Challener
Process development can be challenging at the best of times, even for the most established companies with deep resources. Emerging biopharma companies working to develop novel gene and cell therapies face even greater obstacles. They lack access to revenue streams from existing drug sales to fund their process development efforts, so money must be raised, which requires convincing investors that the ideas they are developing will become successful products and provide a healthy return.
Young companies also often have more difficulty attracting the necessary skilled talent. And company owners and managers are often so involved in getting established that process development becomes an afterthought, rather than being implemented as early as possible to determine what it will require to make the translation from concept to commercial product really happen. Unknown companies also don’t attract the attention of equipment and material vendors, and it can be difficult to demonstrate credibility and convince suppliers to invest in new relationships.
What is process development for emerging biopharma?
For emerging biopharma companies developing next-generation therapies, process development can have several different meanings. BriaCell Therapeutics (BriaCell) is an immuno-oncology company that develops novel targeted immunotherapies for multiple cancer indications. These immunotherapies include Bria-IMT and Bria-OTS, which consist of cancer cell lines with the capability to directly present cancer antigens to the immune system and further stimulate the immune system with stimulatory factors. For BriaCell’s CEO, Bill Williams, there are three aspects to process development: process development in the production of its novel therapeutics (both drug substance and drug products), in the design and implementation of clinical trials, and in the selection of new drug targets.
In the context of cell therapies, process development is a uniquely important space because it is such a new and evolving field, according to Armon Sharei, CEO of SQZ Biotech, a company developing cell therapies for immuno-oncology and autoimmune indications using its proprietary SQZ cell therapy platform, also known as cell squeezing. “There are no established protocols for how to go about process development for cell therapies, unlike for conventional biologics and small-molecule drugs. We are engineering patient cells to produce a response inside that specific patient. Given the cost and time involved, being able to develop a practical and scalable process is essential to achieving success,” Sharei explains.
For Krystal Biotech, which is developing gene therapies for skin diseases using a new vector for delivery, process development has involved cell-line engineering as well as determination of the optimum process for production of the viral vector, according to founder and chief operations officer Suma Krishnan. “We built a GMP facility to manufacture the products entirely in-house, so process development was a fundamental activity for us,” she adds.
In-house or outsource?
The decision to build its own facility was based on the determination that an external vendor could not be relied on to develop a process for the new type of vector Krystal Biotech is focusing on, according to Krishnan. The company first built an inhouse process development group to establish the optimum process, then transferred that final process to a contract manufacturing organization.
SQZ Biotech, after debating early on, chose also to conduct all of its process development work in-house. “Our decision went back to the fact that cell therapies are an emerging area and the process has a direct impact on the viability of the commercial model. We did recognize that we needed to build process development expertise, so our efforts began three years ago. The work has paid off; we will be going into the clinic in 2019,” observes Sharei.
Celyad, a company developing chimeric antigen receptor (CAR)-T cell therapies, built on its previous work with a stem-cell therapy that it took from preclinical development to two Phase II trials in Europe and FDA approval for an investigational new drug (IND). “What we learned while carrying out tech transfer, scaling up the process, and manufacturing over 300 autologous clinical batches that were then delivered to close to 10 countries served as a basis for our decision to keep internal all process development activities for CAR-T cell products,” notes Jean-Pierre Latere, chief operating officer of Celyad.
BriaCell, meanwhile, has generally overseen process development for production of its therapeutics, working with clinical research organizations (CROs) that have tremendous experience in the development of cellular therapies and in collaboration with regulatory experts, according to Williams. For the implementation of clinical trials, BriaCell designs the studies and selects the CROs to implement them. The clinical investigators are generally responsible for patient recruitment and treatment. “It all falls into place based on who possesses the appropriate expertise and access to the corresponding resources,” says Williams. New drug target selection and the design of strategies to develop effective drugs against these targets are done entirely in-house at BriaCell.
Challenges: From funding to vendor relationships
The technical aspects involved in the development of processes for the production of next-generation therapies can be challenging on their own. Emerging biopharma companies face many others as well.
The biggest challenge for BriaCell has been accessing funding, according to Williams. “We possess the intellectual resources for both selection of new drug targets and clinical trial design, and have access to the proper expertise and facilities for therapeutic development and drug production. “The main problem is convincing investors that we have ideas that will result in viable therapeutics. The process of drug development is a long one due to tight regulations by the regulatory bodies in the United States and Europe, and hence, biotechnology is not a suitable investment for an investor who expects a quick return on investment in a short period of time,” he explains. But he notes that patience can be amply rewarded, as it was for him when he was at Incyte Corporation, where the stock price rose from $2–3 per share in 2009 to more than $110 per share in 2015.
Accessing talent, which is crucial in process development for cell-based therapies, can also be a challenge, according to Latere. “Because cell therapy is a new field, there are few people with a lot of experience and expertise. Complicating this situation is the fact that the mindset for process development of cell therapies can be quite different from that needed for process development of traditional biologics and small-molecule drugs,” adds Sharei. Reliance only on private funding can make it difficult to attract people as well, according to Krishnan.
Finding appropriate commercial equipment is a third challenge. Because few cell and gene therapies have yet to be approved, most work has been performed in laboratory equipment; commercial solutions are limited to a few plug-and-play options, according to Sharei. Establishing relationships with and between vendors can help tackle challenges in process transfer, a lesson that Krishnan learned through difficult experiences. “It is challenging for new biopharma companies to establish the partnerships with multiple vendors that can significantly facilitate process development and process transfer,” she says.
On the technical front, predicting process capability and performance is another important challenge, while scaling up lab processes also carries an element of risk, according to Latere. He gives as an example large-scale cryopreservation, which can result in a significant level of stress on cells leading to challenges during the final step of clinical manufacturing. In addition, development work at Celyad is usually performed with healthy donor materials such as blood and bone marrow taken via apheresis; clinical manufacturing deals with starting materials collected from patients with various diseases, sometimes with complex medical histories or medication profiles that can impact cell biology and affect certain cell functionalities, all of which can lead to unpredictable clinical manufacturing, according to Latere.
Celyad has also observed cell fratricide (cells killing each other or even committing suicide) during the culture of CAR-T cells, which lowers the manufacturing success rate and requires important process changes to tackle cell fratricide during a clinical trial. Optimizing cell yield is crucial in cell therapies because cell yield has a direct impact on the quantity of cells available for administration to the patient. “Unlike with batch processes where maximizing the yields affects cost, maximizing the yield of cell therapies directly impacts the performance for the patient. It is important to select the best equipment and develop a process that minimizes losses, from choosing the shortest plastic tubing to minimizing the number of process steps,” Sharei explains.
Another issue for autologous cell therapies is the need to scale out, rather than scale up. When moving from preclinical to early clinical studies, the process must be scaled to work for one patient. Manufacturing the cell therapy for many different patients requires the process to be repeated in parallel—or scaled out. There is no opportunity at that time for further process optimization, so it is important to be thoughtful about process development early on, according to Sharei.
Lastly, the quantity of effort required can be daunting, according to Krishnan. “We have a team comprised of only a few people, so it took many long hours, endless experiments, and learning from our mistakes,” she says. On the other hand, she notes that the small group was nimble, very focused, had great tenacity, learned quickly, and was able to make great strides in improving the yield, purity, efficacy, and cycle time, and ultimately developed a process suitable for the manufacture of clinical material.
Converting challenges to opportunities
While emerging biotechs face these numerous challenges, they also have some advantages over established pharma companies and can in some cases convert those challenges into opportunities.
Emerging biotechs are more likely to hit on novel ideas that are actual game changers in the industry, according to Williams, because fewer people are involved in making decisions compared to those at larger companies. “Ideas are more easily discussed with the decision makers, and changes in the strategy, acquisition, and development of novel therapies can be implemented more rapidly at smaller firms. Additionally, emerging biotechs tend to operate more cost-efficiently compared to their larger counterparts,” he says.
Adversity can also lead to creativeness and success, according to Krishnan. “Because we had to use a brute force approach, conducting many countless experiments, we learned a tremendous amount about the process. In addition, it was often necessary to think ‘outside the box’. With the extensive knowledge and expertise we have gained about our unique viral vector, we now have a smoother path forward. In addition, we have established an extensive set of trade secrets available for future development efforts,” she observes.
Many lessons learned
Learning from mistakes is perhaps one of the most important lessons that any emerging biopharma company should take to heart. “It is important to continually evaluate processes and continually improve them. Mistakes happen and are actually needed to fuel future directions almost as much as new insights gained,” Williams says. He also advises emerging biotech companies to cultivate good relationships with their investors and make sure they understand the company’s vision and its potential.
BriaCell has also learned to select novel therapeutics with new strategies based on the best science available and to cultivate an in-depth understanding of the field of cellular immunotherapy that builds on the experience of multiple investigators in the field. “This strategy has permitted us to streamline our approach to clinical trials, targeting the patient’s most likely to benefit from our therapies,” comments Williams. “Overall, we have learned that expertise is the main key to success and how to locate and exploit it,” he adds.
For Latere, too, understanding the science supporting a product is paramount. “As a start-up develops, ensuring the supporting cast puts an emphasis on the underlying science and the ability to translate such science into a desirable product that can be manufactured consistently is key,” he notes. He goes on to add that it is important to dare to challenge conventional wisdom and not be stopped by engineering challenges, as they are solvable, while scientific flaws are not.
On a similar note, Sharei observes that it is important to be comfortable implementing custom manufacturing systems. “As long as you know the problem you are trying to solve and are designing for GMP manufacturing, developing proprietary systems can provide significant advantages, particularly in nascent fields such as cell and gene therapy,” he remarks. “The systems we have implemented have tremendous advantages over commercially available equipment on the market. Investing in the system at the right time and with confidence can have a huge impact,” Sharei adds. Similarly, he points out that establishing a manufacturing site early and initiating technology transfer and training as early as possible will ensure that a company is well-prepared to move into the clinic when the time comes.
In fact, emerging biopharma firms working in the fields of cell and gene therapy face significant competition for contract manufacturing capacity, according to Krishnan. It is important to begin the selection process early on if a company is intending to have its product manufactured by an external provider. Developing a comprehensive process in-house and only requiring production of material for Phase I and II studies can be an advantage, she adds.
Pay attention to details
The key to successful process development at emerging biopharma companies, in the end, appears to be a commitment to focusing on the details. “There is a lot of blocking and tackling in the process development piece. The overall strategy may be great, but if there is not sufficient attention paid to the details, the process will fail and so will the company,” Williams states. He adds that proper expertise is also essential, and companies need to be humble and ask for help when they are out of their depth.
Enough emphasis cannot be placed on how important process development is in the context of novel therapies, according to Sharei. “Staying on top of process development—and in many cases that means performing the work internally—makes a huge difference and can have a dramatic impact on the success of novel therapies down the line,” he stresses.
Krishnan goes on to note that the most important thing about process development is the process development itself. “It does no good to have a great idea if it cannot be translated into an efficient, practical, scalable, cost-efficient process that meets specifications and regulatory requirements and can be used to produce material for clinical trials and ultimately commercialization,” she concludes.