Anticipating the Next Decade of Gene Therapy

With more and more organizations looking to pursue gene therapies for a range of indications, there remain a number of barriers to entry. However, the next decade will bring improvements across existing gene therapy modalities, including the development of alternative approaches to gene delivery, and advances in upstream and downstream processing, analytical methods and intensified/continuous processing.

Current State of Gene Therapy

The first efforts to develop gene therapies took place about a decade-and-a-half ago. The technology was found, however, to be too nascent. Clinical failures resulted, and the field ultimately fizzled out for a time. Since then, three critical developments have occurred.

An enhanced understanding of vector biology has enabled the design of better, safer vectors, which has played a key role in restoring people’s confidence in this field. There are also more choices for manufacturing technologies. Perhaps not of least importance is the overall enthusiasm across the industry and among advocacy groups, which is reflected in the funding that has flowed into this space and the overall willingness to take risks in this promising but still uncertain field of medicine. 

At present, companies are pursuing both viral and non-viral approaches. Viral vector-based therapies — which use viruses as vehicles for gene delivery — account for the majority of approved and candidate gene therapies. Non-viral approaches include RNA-based therapeutics and antisense oligonucleotides and related modalities. These therapies do not rely on viral constructs as a mode of delivery. There are a few gene therapies based on these technologies that are on the market. Other non-viral, non-RNA–based approaches are being explored but remain more experimental for the time being.

Key Challenges

Gene therapy is a challenging field due to urgency, uniqueness, and uncertainty. First, there is a tremendous demand on accelerating time to the clinic and to market. Development is urgent because biopharma companies, physicians, and advocates want to get these potential treatments to patients as soon as possible, because there is often no other available treatments; every year that the launch of a therapy is delayed, some patients will age out of the window when they are eligible for this treatment or even eligible to participate in the clinical trial.

In addition, gene therapy manufacturers and developers are passionate and driven by the goal of curing patients, particularly small patient populations suffering from rare diseases that did not previously attract the industry’s attention. This passion creates an interesting dynamic. Because gene therapies are curative medicines, there may no longer be a large enough patient population in target markets available to be switched to the next better therapy — the patient population disappears. The first to launch a gene therapy for a specific disease, therefore, will likely capture the majority of the market. Being second to market puts you at a significant disadvantage.

The second type of challenge relates to the uniqueness of each of these individual therapies. Despite all of the processes being developed using established processing technologies, each of these processes is ultimately unique. Currently, there is no established convention in terms of industry standards for process performance or norms for certain platforms, such as those that exist in monoclonal antibody (mAb) manufacturing.

In a real sense, for the majority of gene therapies, the process is the product. Since each process is unique, manufacturers are often  hesitant to modify the process because one small change could have serious effects on the outcome. In this context, the problems are also unique. In mAb development and manufacturing, process templates have been established to improve product consistency and process efficiency. On the other hand, the uniqueness of gene therapies makes it more challenging for developers and manufacturers to learn from one another. This ultimately it makes it more difficult for technology providers to support innovation in this space. If all companies take a different approach, it’s that much more challenging to create an optimal solution that will have broad applicability. 

The third challenge is the uncertainty associated with this field — uncertainty not just in terms of clinical outcomes, but in terms of scale-up and advancing processes to the next stage. There are many examples in which early-stage development looked promising, data in mouse models was compelling, but, ultimately, in large-scale clinical trials, the products failed to deliver on the promise, either because they did not replicate earlier results or because the processes could not be replicated at larger scale. Programs in recent years have been held back because of complexities on the manufacturing side as well as complexities on the clinical side. If you have an inefficient large-scale manufacturing process, the therapy will ultimately be very expensive, perhaps prohibitively so. In addition, if you cannot make enough doses, it will be impossible to dose enough patients in your clinical trials. 

The result is that companies have devoted more funding than they normally would have to this research. The clear evidence of uncertainty around the lack of correlation between early-phase and later-phase work — whether related to clinical performance or manufacturability — can be a significant hurdle. Since each product and process are unique, there are also regulatory uncertainties. The U.S. FDA has reviewed a limited number of these applications yet, so there is not a lot of precedent work from either. 


Overcoming Viral Vector Manufacturing Issues

One of the key sources of uncertainty for many gene therapy developers relates to the manufacturing of viral vectors. There remains a great shortage of viral vector manufacturing capacity across the industry, and not only a dearth of physical capacity, but a lack of sufficient talented and skilled people who can develop and run those processes.

There are also challenges associated with the viral vector manufacturing process. On the upstream side, transient transfection — which is very expensive but also the fastest, and perhaps the least complicated — remains dominant. Essentially, this reflects a research method that has been scaled beyond a practical point, and this problem is one with which the industry as a whole has struggled. There is plenty of opportunity for innovation in cell line engineering to increase productivity, generate higher virus titers, higher percentage of full AAV capsids and enable the transfer from adherent to suspension cell culture.

On the downstream side, there are very few purpose-built tools for viral vector purification. While some tools have been designed for this specific application over the last few years, the scale at which these processes must be performed, the containment required, and the cold chain demands have not previously been faced by the industry.

To compensate, viral vector producers are borrowing tools used for the manufacture of mAbs and other biologics and trying to retrofit them into a gene therapy process. The result is lower process efficiencies and lower yields, with less vector produced per batch, along with significant product losses.

In addition, there are shortcomings in the analytics for viral vectors. Potency assays that reflect mechanism of action are currently not available for gene therapies. Limited understanding of how in vitro assays translate to in vivo assays is another hurdle. Overall, there needs to harmonization of standards and best practices for gene therapy assays across the industry. 

As such, there is a clear need to improve the manufacturing process, but it isn’t possible to do so, because the right yardsticks for measuring performance are not available. Everything remains custom and very labor-intensive. Furthermore, large volumes of product are often required to run these custom tests, contributing even more to the testing burden for this space. 

Fortunately, we can expect to see advancement in this area, both through the development of better testing methodologies and a move from quality-by-testing to quality-by-design as process understanding matures. The hope is to have faster and cheaper analytics, either by virtue of maturation in the space or the introduction of new technologies generated by other scientific breakthroughs.

Finally, in addition to the upstream, downstream, and analytical challenges, there are challenges around process design and product formulation. For the latter, thermal stability is a key issue. Viral vectors require low-temperature storage and shipment. There is tremendous value in investigating potential solutions that would reduce the cold-chain burden.

Overall, there is significant potential to disrupt the way that viral vectors are currently manufactured. Over time, the FDA is making some of these issues clearer in terms of CMC guidance. In addition, industry bodies, such as the Parenteral Drug Association, the American Society of Cell and Gene Therapy, and the Alliance for Regenerative Medicine, are championing some type of harmonization across the industry on standards and expectations from the process. Hopefully, within the next few years or so, all of these efforts will come to fruition. 

If that occurs, on the one side there will be more or less normalization or standardization of what a gene therapy process looks like. On the other side, there will be scientific breakthroughs regarding the process and the modality itself, which will make it less complex to produce gene therapies. Between these two developments, the earlier prediction of 10–20 approvals per year doesn’t seem unrealistic. It just may be that the time horizon is pushed a little bit further out. 


Need to Control Costs

There is a high degree of customization involved in the development of gene therapy manufacturing processes, with each process requiring a bespoke solution for a specific product. Patient groups are also often small, and gene therapy developers are developing highly specific and individualistic treatments for them.

One of the consequences is the development of often complex and inefficient processes. In these cases, many manufacturing runs must be performed, even to serve a small set of patients. The facilities and equipment required for viral vector production are highly specialized (very high containment)  and expensive to build and operate. 

It is important to remember, though, that in many cases gene therapies offer life-long therapies and/or cures, and as such. they offer real value for patients. At the same time, as processes become less complex and more efficient, those savings may be transferred to the patients. There are two general areas to address: fixed costs and variable costs. One of the largest variable costs is associated with the plasmids used for transient transfection. One of the breakthroughs needed is access to stable producer cell lines and the ability to develop platform processes that resemble mAb manufacturing, which would reduce spending on plasmid consumption. On the downstream side, more efficient and effective purification technologies could also significantly reduce costs, particularly with respect to capture (affinity) resins, which are extremely expensive and in many cases are not reused.

There is potential to control facility spend. In many cases, companies are renting this specialized space from a contract development and research organization (CDMO). Even for those with internal capacity, it is still necessary to maintain a very expensive BSL-3 environment. These costs could also be reduced by making the upstream and downstream processes more efficient and productive. In addition, progression to a more intensified, connected process that occupies less footprint would potentially enable the use of existing infrastructure, eliminating the need to build a new manufacturing facility or rely on outsourcing.  A combination of these approaches has the potential to significantly reduce the cost of gene therapy manufacturing.

Expect More Holistic Thinking

Rather than just looking at one unit operation at a time or just the upstream or downstream, manufacturers and developers are taking a step back and trying to increase the efficiency of all aspects of gene therapy manufacturing. We have already observed this trend at MilliporeSigma in terms of customer demands, as they are increasingly seeking expert support as well as products. 

By 2030, we will see advances in the modalities themselves in terms of better delivery mechanicals and more novel modalities that will lend themselves to better manufacturing. Processes for existing modalities will be more efficient, connected, and intensified. 

As a technology provider, MilliporeSigma focuses on bioprocessing products and testing and manufacturing services. With respect to consumables, for upstream processes we are building high-productivity cell lines that enable the production of high dosage therapies at lower cost. On the downstream side, we are developing purpose-built tools, particularly in areas where there are still significant unmet needs. 

For analytics, the focus is to move away from custom assays for efficacy, toxicity, and potency toward more scalable and rapidly deployable methods. Ideally, these solutions will eliminate the need to send samples out to testing labs by enabling at-line and, perhaps, inline analysis. To that end, we have made investments over the last several years, not only cater to our existing customers but to push the envelope. We are clarifying the expectations of regulators concerning testing for cell and gene therapies and working with them to define what the standards should be for these assays.

Finally, on the facility side, we are heavily invested in continuous processing, especially for mAb processing. As a corollary to that line of thinking, there is a need to re-imagine what a gene therapy manufacturing facility looks like, in terms of the instrumentation, operations, and footprint. Imagine a facility that requires one-fourth of the footprint for the same amount of manufacturing and only one-third of the operators. Such a scenario represents tremendous potential. That kind of advance would essentially multiply the existing manufacturing capacity and almost lower the barriers to entry into the gene therapy space.

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

Ranjeet S. Patil

Ranjeet Patil heads a global team of bioprocessing experts for cell and gene therapy segment. In current role, he and his team provide consultative expertise to address process challenges and guide development of innovative solutions by MilliporeSigma. For past 10 years, he has been working in MilliporeSigma’s technical functions in North America and Asia. His previous roles include early stage bioprocess development, virus clearance validation, and process optimization and troubleshooting. Ranjeet is a bioprocess engineer and holds a postgraduate degree from Northeastern University, Boston, Massachusetts.