By Anna Rose Welch, Editor, Biosimilar Development
There is, inevitably, a point in any new industry when the anticipation of great success and optimism is replaced by a healthy sense of realism. In the biosimilar space over the past few years, we’ve braced ourselves for the arrival of the dreaded biosimilar business inflection point, the time at which companies previously gung-ho about the market would find it no longer a good strategic fit. By the end of 2018, it felt like we’d arrived at that point. A handful of companies had, by then, announced decisions to put pipelines on hold or not launch already approved products for a variety of reasons. Others — typically smaller companies — had disappeared from the biosimilar world entirely.
But now, as we’re on the cusp of 2020, I feel I was wrong to assume an inflection point had to be a strictly negative thing for the industry. Though we did see some migration away from biosimilars, as we’re facing what is set to be a busy launch period during the first quarter of 2020, I feel confident in arguing that we’re facing another, more positive inflection point.
In addition to pipeline and market expansion announcements from Sandoz, Biogen/Samsung Bioepis, Celltrion, and Coherus, we also heard from an array of smaller companies like NeuClone, Formycon, and Bio-Thera, all of which have been making progress with future-wave biosimilar products. But I was also thrilled to hear some big news out of Fresenius Kabi; the company opened a new biosimilar R&D facility in which it plans to continue advancing the development of autoimmune and oncology biosimilars.
Following the inauguration of the lab, I reached out to Michael Soldan, the EVP of the biosimilars business unit for Fresenius Kabi. We discussed the current challenges in biosimilar R&D, including maintaining the delicate balance between biosimilar R&D and commercial teams as Fresenius Kabi prepares for a long future in the biosimilar space.
Two Ways This New Facility Will Improve R&D Efficiency
In his role with the biosimilar business unit, Soldan keeps a close eye on the development of each molecule, including the manufacturing and supply-chain strategies for each molecule. As he pointed out, it takes anywhere from six to 10 years — and for some molecules, even longer — to “bring each biosimilar to life.” Because of this long development timeline, it’s critical that the company keep a close handle on the supply needs, regulations, and market dynamics in each country. Given the variable growth of the biosimilar industry to date from country to country, Soldan said one of the biggest challenges he faces is flagging and preparing for any of the barriers that could arise and impact a product’s development down the road.
No matter who I speak to in this industry, flexibility remains one of the most important aspects of biosimilar development, especially as companies strive for overall sustainability of the development process. As Soldan shared, this new R&D facility was built to help the company work towards and attain an increasingly efficient biosimilar development process.
One of the ways it will help with this is by improving collaboration within the organization. As we all know, the biosimilar industry comprises a number of different players, many of which are Big Pharma or Big Generics companies. The cultural change required within organizations to successfully launch biosimilars has been a common growing pain among many. In other product development programs, there is typically little to no inter-departmental collaboration on a molecule between the CMC, regulatory, policy, and commercial teams. However, biosimilars require great interplay among the different teams. So, to improve collaboration, Fresenius Kabi constructed its new facility next door to the biosimilar business headquarters, which houses the company’s commercial, clinical, regulatory, and policy teams. These teams and those involved in the analytical and manufacturing efforts can now be as close as possible to ensure greater collaboration, Soldan explained.
The lab also will play a great role in helping the company keep biosimilar development in-house, which Soldan expects will be an important time-saver during the R&D process. The lab contains all the analytical, down-stream and upstream process development, and staff the company needs for its biosimilar development efforts. Soldan emphasized how important it is to have all the scientists housed within the same building, especially when the end goal is to be one of the first competitors on the market.
“We can be much faster if we no longer have to outsource tasks to several different companies,” he said. “We no longer have to go back and forth to find the best route of development. Now, we have all the experts in the same building, and we can work together to find the best manufacturing pathways and the right analytical approach. Our main goal with this new center was to create the right environment for teamwork and to limit the amount of outsourcing we have to do to very specific cases.”
Though efficiency is one of the most important goals for any company striving to development biosimilars (and novel biologics, for that matter), Soldan also makes the case for taking your time in the R&D of biosimilars. In biosimilar development, R&D begins with an analysis of multiple batches of the originator, not only to see what the molecule looks like close-up, but also how the molecule has changed from batch-to-batch. After gaining understanding of these aspects of the originator, the company needs to design the cell line that will produce the highest quality clones.
But to do this well, Soldan stressed taking care at the beginning of the development process, as this decreases the risk the program will run into insurmountable issues down the road. It requires great internal expertise and collaboration to be able to implement an analytical program that will enable your own biosimilar to capture the reference product’s mode of action in the necessary quality and performance ranges, Soldan explained. Proving biosimilarity is much more than just demonstrating that the amino acid sequence matches that of the originator (though this is an absolute necessity). As you likely noted from the FDA’s Comparative Analytical Assessment and Other Quality-Related Considerations guidance, for instance, there’s a lot of other data regulators recommend that biosimilar makers may or may not be providing enough of today. It’s no wonder, in light of these challenges and ever evolving technology, that Soldan anticipates the R&D process (which is individual to each molecule) will continue to be one of the forefront challenges facing the company in the years ahead.
R&D Considerations In A Time Of Regulatory Change
Overall, I appreciated Soldan’s emphasis on continued learning in this space. As we carry out detailed discussions at conferences about regulatory and development efficiency, there are new technologies that provide manufacturers opportunities to better understand and deliver the evidence regulators need. “The more knowledge we have, the more information we can provide,” Soldan said.
Continued learning and attention to new technologies are exceptionally important as more passionate arguments are made to lower the emphasis on clinical trial data. When I asked Soldan about the impact such discussions could have on the overall R&D of biosimilars, he reminded that this will depend on each molecule. We’ve already seen the FDA and EMA give the thumbs up to eliminate comparative studies for insulins in certain cases, and the EMA has an even longer list of highly characterizable molecules that include the filgrastims and pegfilgrastims. The greater a company’s technological and analytical expertise, the more that can be gleaned about safety and efficacy of the molecule at hand. There remain some molecules, however, whose immunogenicity is difficult to predict without digging a little deeper.
It all comes down to the mode of action assays, Soldan offered. If a company is able to mimic the mode of action in one or two orthogonal assays, there is likely a greater chance clinical data will not be needed to clear up residual uncertainty. In fact, he feels that it’s more often the case today that, because we can learn so much more about the molecules at hand, large studies are becoming less necessary.
However, he also cautioned that, as we continue to face hesitations from doctors and patients about biosimilars due to a lack of education, having clinical data can be an important boon to assuage stakeholders. One of the biggest concerns about such an evolution of the development pathway is that many physicians are not educated on what analytical development comprises or what it says about a product’s clinical profile. Clinical trials remain their bread-and-butter for understanding and trusting the safety and efficacy of a biosimilar. Given these concerns, Soldan keeps a level-headed approach about prospective changes to the development paradigm.
“We need to see which studies are providing benefits, and which are simply done because the clinical trial has always been required for biosimilar development,” he offered.
The Impact Of Patents On Future Development Efforts
While much attention is lavished on the analytical know-how necessary to produce biosimilars, it is just as important to turn attention to the manufacturing process. Technological advances not only impact the analytical development, but they also place greater demand on the manufacturing program. As Soldan explained, the manufacturing process must be highly productive (i.e., capable of yielding 5 grams/liter, or more, of the desired protein) and able to evolve overtime. It’s important to reach these levels of productivity early on during the R&D stage, because once that manufacturing process is set, it becomes more difficult to make larger changes. That’s not to say changes can’t or won’t be made. Thanks to comparability, manufacturers typically only provide regulators with analytical data to demonstrate the molecule has not strayed from the necessary ranges. However, larger changes to the manufacturing process later in the game could require clinical data, Soldan added, which would add additional expense. As sustainability is a central focus of the overall industry, it’s important to take the time in the earlier phases of development to ensure high productivity from the cell lines. These advancements can only help drive down the manufacturing costs and cushion the pricing pressures products are beginning to feel in the biosimilar space.
But one area that Soldan considers a potential threat to advancing biosimilar manufacturing is the patenting practices we’re observing in the originator industry. I’ve heard that most biologics today have upwards of 70 patents — and some have a lot more than that. Though we primarily look at patents as problematic from a commercial market access perspective, my conversation with Soldan helped ground how big of an issue patenting practices today can be on the biosimilar manufacturing process.
When building a biosimilar pipeline, the composition of matter patent for a molecule is considered to be the primary patent. But as we’re all more than aware, for many molecules, there is often a wide swath of secondary patents — especially in the U.S. — that also can impact when you’re able to enter the market, which indications you pursue, what materials and tests you use in production, and the design of the device or container for administration. Hence, why knowledge of each patent estate is critical for a company undertaking biosimilar R&D.
“We have to find a way from a scientific perspective to circumvent these patents and bring the product to market,” Soldan said.
Looking into the future, Soldan added that patents remain one of his concerns about the evolution of the biosimilar industry. There is an ongoing push amongst originators to bring next-generation products to the market. Though these efforts can provide patient-friendly benefits, this practice also leads to longer market exclusivity, serving as an additional barrier for biosimilar companies. Moreover, some patent thickets (or shrubs, as I once heard them called), limit the number of indications that may be available to biosimilar makers.
Decisions of whether and how to pursue certain biosimilars in the face of patent thickets can only be made with teamwork across all different areas of the business. In the face of such tricky questions, Soldan again stressed how imperative it is that biosimilar companies promote internal collaboration to determine the best strategy overall.
“Only by frequently sitting together can you jointly review the biggest concerns and questions and, with help from the scientific, commercial, and legal perspectives, find ways to bring the product to the market, even if it looks challenging,” he said. “You cannot do it all without having all of these functions at the same table.”