Pharma’s Almanac Scientific Editor in Chief David Alvaro discusses the challenges to gene therapy development and manufacturing created by the pandemic and lessons learned from the rapid vaccine development efforts that can be applied to transform the gene therapy field going forward, with Ratish Krishnan, David Loong, and Nargisse El Hajjami, Senior Consultants, Novel Modalities Strategy Operationalization at MilliporeSigma.

David Alvaro (DA): What were some of the unique manufacturing challenges in the gene therapy space directly caused by the pandemic?

Ratish Krishnan (RK): If you look at the big picture, the bioprocessing field in itself was accelerating globally throughout the pandemic. We observed significant localization and regionalization of bioprocessing activities. As expected, there was a lot of emphasis on securing supplies and backups, which clearly revealed that the biopharma supply chain needs to be strengthened, including greater transparency across the supply chain. 

Nargisse El Hajjami (NEH): As the pandemic took over the globe, supply chains were significantly impacted, particularly for raw materials and the equipment and consumables required for single-use production systems. 

David Loong (DL): The pandemic dramatically increased awareness regarding the fragility of the global medicine supply chain. Many governments are now focused on building internal capabilities within their borders to avoid supply shipment disruptions in the event of a future pandemic. The emphasis is clearly currently on vaccine facilities, but that will have a knock-on effect for cell processing facilities like those required for gene-modified cell therapies like chimeric antigen receptor (CAR)-T cell therapies.  

DA: What strike you as the real lessons learned from the push to rapidly develop vaccines for this pandemic that can be applied to gene therapy manufacturing?

RK: Essentially, the pandemic has shown us what can happen when funding meets emergency need. I think it has also forever changed the way we look at vaccine development. The industry reduced the time to develop a vaccine from 10 years to 10 months, and there will now, in the post-pandemic era, always be that lens for people to look through and compare.

With respect to manufacturing, the pandemic revealed the true value of templated processes. While mRNA vaccines became mainstream due to the pandemic, decades of research preceded the overnight success, including the development of vaccines for other coronaviruses, for example SARS and MERS. The wheel didn’t need to be fully re-invented. With sufficient funding and an unprecedented need, the industry was able to turn the switch on and get the work done very quickly. The timing was perfect.

One of the biggest lessons that can be applied to gene therapy manufacturing is the value of collaboration. Companies are working with each other — even direct competitors have been helping out with additional production capacity, logistics, and other support in this time of dire need. Partnerships between governments and biopharma companies were established to secure doses. We also observed expedited regulatory approval pathways being developed without compromising patient safety.

Speed does not translate to shortcuts on safety is also an important takeaway from the pandemic that can be applied to gene therapy. Generally, there is a shorter time to market for gene therapies than conventional monoclonal antibody drugs, because gene therapies target niche populations with rare and ultra-rare diseases for which no treatments yet exist. The rapid development of safe and effective mRNA vaccines has shown that accelerated approvals are possible without risking safety — just what is needed for gene therapies, because there are patients waiting for lifesaving treatments.

NEH: The fact is that the industry was ready, but no one knew that because the processes that had been developed and optimized had not yet been applied to approved vaccine products. mRNA was discovered more than 60 years ago, and much research and many clinical trials have been conducted. The knowledge gained during these efforts is what allowed the approved mRNA vaccines to be developed and enter into clinical studies with such unprecedented rapidity. The same is true for viral vector vaccines, for which the production process is very similar to that for gene therapies. Here again, vaccines could be rapidly developed because companies already had the knowledge and established platforms that made it possible to develop processes quickly.

DL: I would add that another factor really accelerating mRNA vaccine development is the rolling review of clinical trials by regulatory authorities. These successes have really shown how fast and effective this approval process can be if there is a focus on a single disease. Perhaps one of the difficulties in the past that has led to such protracted development times is the need for regulatory agencies to keep shifting their priorities among many different diseases and indications.

DA: Were there any developments during the pandemic that might point the way toward solutions to reduce the cost — and hence the prices — of gene therapies?

RK: You can approach cost in a lot of different ways: material costs, labor costs, and manufacturing costs, so on and so forth. The crucial debate is about the expected enhancement in the quality of life provided by these supposedly one-shot gene therapies. One has to weigh this along with the existing standard of care (if there is any) that tends to be expensive over the lifetime of the patient and can be inconvenient and uncomfortable without considering the effectiveness between the two treatments. 

Establishing cost of treatment is undoubtedly complex. We are seeing optimism in terms of insurance companies being willing to develop new strategies for reimbursement and models that are outcome based. Improving the manufacturing productivity for viral vectors is also an important focus area, because the current processes struggle with low yields (sometimes less than 20%) and are not desirable in the long run.

DL:  I’ll just add that the gene therapy field is still in its infancy, and because there is such a rush to get to market, less-than-optimum processes are being implemented and then getting locked in. The same situation existed for monoclonal antibodies (mAbs): the first mAb therapy was produced using thousands of roller bottles, and that process is still employed today, because that was the process registered with the FDA. Today, gene therapy processes that are not very efficient are also being locked in, because it is difficult to change them without conducting new clinical trials.

The best solution is to begin development with processes designed to be manufacturing-ready, scalable, and suitable for commercial production. Adopting this approach can bring down the cost of goods for gene therapy production, and it is one that MilliporeSigma is developing hand-in-hand with gene therapy manufacturers.

NEH: The issue of pricing will need to be addressed one way or another given the fact that more and more new gene therapies, possibly more than 40, will be launched in the next 5, 7 or 10 years. This anticipated rapid expansion of commercial gene therapies intensifies the pressure on insurers and health systems, governments, and pharmaceutical companies to review pricing strategies and determine the best manner in which to present these lifesaving medicines to patients.

DA: Do you think the industry is prepared for such accelerated development in terms of the infrastructure for manufacturing and other supportive operations, or is significant preparation, building, and expansion necessary?

RK: mRNA vaccine development benefited from the laser-like focus from biopharma companies. The story is a bit more complicated for gene therapies. Every company is working on several different indications, often in the realm of personalized medicines and bespoke therapies. In addition, many gene therapy developers are in the startup/emerging biotech space and have decisions to make about in-house versus outsourced manufacturing, the former of which requires facility construction, and the latter of which can be limited due to scarce capacity and expertise within the CDMO space.

NEH: It is also true that gene therapy manufacturing can be very long and complex and requires high levels of control at different steps. It requires a bigger ecosystem, including hospitals, the manufacturing site, the suppliers, and logistics companies to handle the shipment of both patient samples and the finished treatment, and so on. We do have approved therapies today, though, and those routes have been established, which gives more assurance and clarity about the overall process to manufacturers, regulators and patients.

RK: There is also the challenge that demand is always greater than supply for these potentially curative therapies. Manufacturing shortages exist and disruptions are likely expected in the short term. Companies like MilliporeSigma/ are investing in additional manufacturing capacities to help solve customer’s problems.

Overall, the pandemic has exposed certain known weaknesses and uncovered new ones. What’s really reassuring is that companies have developed strategies to support the commercialization of lifesaving treatments.

DL:  I agree that not just manufacturers, but governments as well, are becoming wise to the production gaps that exist for specialized drug products, such as vaccines and gene therapies. While everyone was excited with the initial launch of gene therapies, I don’t believe anyone realized that the field would expand so rapidly or that there would be a need for comprehensive manufacturing and logistics solutions at potentially very large scales.

DA: To what extent do you expect to see more convergence on a limited number of manufacturing platforms and delivery approaches for gene therapies?

RK: The quest for a templated or platform approach for viral vector bioprocessing has always been the Holy Grail. It’s easier said than done, but the industry is taking steps towards fulfilling that dream, where just the transgene can be changed and everything else in the entire process remains similar. There are some examples of successful templating of sections of the process. For example, some of our customers have templated upstream, midstream, and downstream processes and then strung them together.

While we focus on the differences and complexities of viral vector bioprocessing,  it is also important to consider their similarities in bioprocessing of mAbs, which is highly templated — and thus instills promise for templating viral vector processes in the future.

DA: Do you see any shift from viral vector–based therapies to nonviral approaches in the aftermath of the pandemic?

NEH: With the approval of the first mRNA vaccines, there is more hope and assurance in the cell and gene therapy industry about the potential for nonviral delivery solutions. Indeed, there are growing numbers of candidates in the pipeline, especially in preclinical stages, with several published patents. There is real interest, because nonviral delivery has significant advantages over viral vector–based delivery in terms of safety, efficiency and manufacturing process simplicity. On the other hand, it is a new field, and manufacturing challenges remain for the various delivery systems, with innovation and optimization needed in regard to process optimization, product stability, storage, and so on.

Today, however, viral vector–based gene therapies are established and validated, with AAV and lentiviruses as the predominant vector types. Most gene therapy developers are looking to optimize these processes rather than switching to nonviral approaches. Companies interested in mRNA and other nonviral technologies and gene-editing tend to be new players.

RK: While there are advantages to eliminating the use of viruses for delivery, proof in the clinic for non-viral approaches in gene therapy is a long way from being established. CRISPR-based therapies in particular are still more exploratory, though they do show a lot of promise. But in terms of clinical experience, viral vectors are farther ahead for rare diseases and ultra-rare diseases at this point.

DA: To wrap up, could you share what you believe are the most important insights from the current pandemic experience that companies active in the gene therapy field should really take to heart and work diligently to apply?

RK: I do see an emergence of themes that could be worth mentioning here. One is to emphasize process development and establishing templated processes. It is not possible to get into the clinic rapidly without focusing on process development of commercial-ready processes. The second is an emphasis on partnerships between vendors and their customers, as well as between gene therapy developers and their CDMOs if applicable. The third is planning early; implementing single-use, flexible manufacturing techniques and being prepared. The fourth key learning for me is parallelization of work — completing development efforts in parallel rather than sequentially. This was a significant contributor to the acceleration of vaccine development. Companies gambled on large-scale manufacturing while still developing their processes.

DL:  I want to add one additional thought: platform processes for viral vector manufacturing and testing/analysis. Such processes are beginning to emerge now, and the key will be to ensure that the correct platform is selected for a given viral vector and gene therapy product and that companies stay on top of process development when using these emerging platforms.

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.