From The Editor | November 20, 2019

Biosimilars: Not Just Big Pharma's Playground

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By Anna Rose Welch, Editor, Biosimilar Development

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When I first started writing about the biosimilar space in 2015, I was always interested to talk to experts about their company’s business model. Even a meager four-plus years ago, the landscape was seemingly much larger and diverse in terms of company size and business strategy. Of course, we had the Big Pharma and Big Generics players, a majority of which have approved and launched their biosimilars on the global markets today. But we also had a handful of smaller companies looking to play in the space — Cinfa (now Mundipharma), Adello Biologics, Oncobiologics, Pfenex, Momenta, Epirus, and amp biosimilars, to name just a few. This list has changed pretty drastically since 2015. While several small companies — namely Coherus and the former Cinfa — have succeeded in approving and launching a biosimilar, many have since shifted away from biosimilars or have disappeared altogether.

This is why, when I get word that a small company has made forward progress, I am all ears. And lately, it seems, we’ve gotten word that several small companies are truly fighting the good fight. Coherus and Formycon have been announcing great news in terms of their biosimilar pipelines. And the same goes for NeuClone, a small Australian biotech which boasts over 20 biosimilars in its pipeline. In mid-October, the company announced that it began dosing subjects with its biosimilar of Stelara (ustekinumab) in Phase 1 trials. So, when I was offered the chance to chat with the company’s founder and CEO, Noelle Sunstrom, and Thomas Wakim, a business development analyst at NeuClone, I jumped at the opportunity.

Given that many of the biosimilar players today are larger companies with innovative products and biosimilars, I wanted to learn about the biggest challenges NeuClone has had to overcome as a small company in its pursuit of becoming a global biosimilar player. In addition to discussing past challenges, Sunstrom and Wakim provided me with a number of the critical analytical, manufacturing, and clinical considerations that are important to make for any company — but especially for smaller companies — when developing biosimilars.   

A Brief History Of NeuClone

NeuClone was founded 11 years ago, back when biosimilars were much less familiar than they are today. In fact, one of the earliest challenges the company faced was overcoming the claims that monoclonal antibodies could not be copied. (We always love a good challenge, though, don’t we?) It was in-part because of this attitude among larger companies that Sunstrom was spurred to create NeuClone and make biosimilars — in particular monoclonal antibodies — its focus.

“Since a number of larger companies at the time were not going into biosimilars of any description, we saw a great opportunity to make a place for ourselves in the industry,” she shared with me. “We had the know-how to make these products and to make them just as well as Big Pharma, so there was a lot of space for a small company to have the skill, the talent, and the expertise to pursue biosimilars to these big blockbuster drugs.”

Of course, as we’re all well aware, larger firms did eventually enter the biosimilar industry. This added a manner of complexity for smaller companies, including competing with a firm that not only had greater financial resources, but also carried a substantial amount of brand equity. “It became very difficult for a small company like ours to have a voice in the industry,” Sunstrom said.  

But this is hardly slowing the company down. Today, NeuClone has upwards of 30 employees. As Sunstrom shared, about three-quarters of the employees are on the scientific development side, but the company has also broadened its scope to include several business development experts. Given the size of the company and the current venture capital challenges for biotech in Australia, the company is currently partnered with Serum Institute of India to manufacture 10 biosimilars for the global market in its FDA and EMA GMP-certified facilities.

Now that it has two products in clinical trials, NeuClone is actively seeking partners to help carry the product through clinical equivalence trials and to commercialize in the targeted markets of the U.S., Australia, New Zealand, Europe, Canada, Japan, South Korea and China. The Serum Institute will be in charge of commercializing the product for the rest-of-world markets.

The Importance Of Single-Use Continuous Manufacturing For Biosimilars

As I mentioned previously, one of the biggest challenges for a small biotech is garnering venture capital in order to be able to fund and, hopefully, expand its operations over time. In Australia in particular, venture capital support is difficult to come by, given a greater emphasis on the local mining industry as opposed to biotechnology. That said, however, NeuClone has benefited from the generosity of several critical shareholders, and, in the long-term, is eyeing the potential of raising money via the U.S. market in the future.

Given these financial challenges, efficiency is an incredibly important goal to strive for in biologic development. Obviously, one of the most universal ways to ensure efficiency at the beginning of the manufacturing process is to ensure that the cell lines have the greatest possible yield (or mass of the purified protein) while maintaining the same quality. It’s of the utmost importance that a company’s cell line has a good titer, meaning that it is producing as many grams per liter of the protein as it can, Sunstrom said. This, in turn, goes a long way to promoting greater innovation in manufacturing.

As she explained, achieving a higher titer enables a company to produce commercial volumes of a product using smaller, single-use bioreactors as opposed to large stainless-steel fed-batch facilities. The latter facilities require an enormous capital investment. Consider, for instance, that most stainless-steel bioreactors are 10,000 to 20,000 liters; the largest single-use bioreactors are only 2,000 liters.

“By being more efficient in the processes that go into the scale-up, processing, and downstream purification, you can actually reduce the size of the bioreactors via continuous manufacturing,” she added.

Continuous manufacturing, as opposed to batch manufacturing, is one method Sunstrom expects will be crucial for biosimilar makers to offer more cost-effective products. Not only is single-use praised for its abilities to reduce capital, cut operational costs and increase productivity, but it enables a company to manufacture products in smaller batches and switch more efficiently between different products without the time-consuming cleaning and sterilization of the equipment.

As Sunstrom shared, the Serum Institute is currently exploring continuous and semi-continuous manufacturing processes using single-use bioreactors for NeuClone’s products. But even before the product reaches that level, NeuClone must carry out the analytical characterization of each biosimilar. To do this, the company came up with its “Right from the Start” approach, which was inspired by Sunstrom’s experiences early on in the biosimilar industry.

“Right from the Start”: Analytical Considerations For Biosimilar Development

In NeuClone’s earliest days, Sunstrom attended a number of conferences, primarily located in Asia. At the time, one of the biggest stumbling blocks she heard from companies endeavoring to make biosimilars was determining and matching the originator’s amino acid sequence.

“I was hearing from companies — even big companies — that they were arriving at their large clinical equivalence trials and finding that their biosimilar didn’t have the correct amino acid sequence,” Sunstrom explained. “So, at the very beginning, we knew we couldn’t afford to make that mistake.” After all, demonstrating that the molecule has the same amino-acid sequence as the originator is the first critical criteria a biosimilar developer must accomplish in order to actually demonstrate biosimilarity of its molecule. When I asked where the biggest stumbling block was in the process of determining this crucial sequence, Sunstrom surmised that a number of developers were likely attempting to glean information from literature, be it academic or patent-related documentation for the originator, as opposed to undergoing analytical comparability exercises. In many cases, this literature was not accurate, Sunstrom said.

To ensure NeuClone got off on the right foot with its biosimilar candidates, the company turned to the use of x-ray crystallography to confirm the originator’s amino acid sequence and, in turn, the biosimilar product’s own sequence. Following the completion of preclinical testing in 2018, the company announced that it was able to confirm the 3D structure and the amino acid sequence of both Stelara and NeuClone’s biosimilar product, as well as its other biosimilars, thanks to the use of x-ray crystallography analysis.

Now, it’s hardly unusual for a biopharma company to employ this technique particularly in drug discovery, but as one 2017 publication discussed, it’s rare that this analytical effort is used in the characterization of biologics — a common and confusing oversight the authors attribute partially to “outdated thinking.” In fact, as another publication in Biopharm International highlighted, this technique is recommended for the analysis of higher-order structures in determining biosimilarity.  

Sunstrom admits that the use of this analysis in biosimilar development remains less common among biosimilar manufacturers. “This technique is beyond what any company was doing back when we started our biosimilar development program,” she said. “A few companies may be employing this technique now for biosimilars, but it does take quite a bit of time to get it right.” The resources and the complexity of this process alone is one of the main reasons its not for the meek of heart. NeuClone has been able to work closely with this technology thanks to a collaboration with the Garvan Institute of Medical Research in Sydney, as well as relatively affordable access to the technology and innovation hub known as the Australian Synchrotron (ANSTO).  

When I asked about the biggest challenge the company was facing in terms of the overall analytical development of its biosimilars, Sunstrom emphasized just how different each molecule is. Each molecule brings its own nuances to the table. As Sunstrom described, even if you’re working with a protein — for instance, the immunoglobulin protein (IgGs) — there are going to be differences between the subclasses (e.g., IgG1, IgG2, IgG3, and IgG4) that comprise the overall IgG protein. These intricacies are impacted by the stability of the cell line or the vectors and sequences used to increase cell line expression.

I’ve often heard biosimilar development referred to as a “black box,” given how difficult it is for a company to not only understand what a cell inherently wants to do, but also how to make the cell perform the way the company needs it to. Though much of a company’s pipeline selection is based on careful market analysis and funding, there is something to be said for a small company possessing a larger pipeline. Though Sunstrom acknowledged that some molecules can throw the company for a loop, the fact that the company’s current pipeline comprises 20+ molecules, this provides the opportunity to increase and fine-tune its analytical expertise.

What It Takes To Navigate A Complex Market As A Small Company

But having a larger portfolio is also an important risk-management strategy, NeuClone’s business development expert Wakim explained. It’s no secret to any company pondering entering the biosimilar space that it’s going to be a long and potentially uncertain journey to market (depending on the originator). Those in business development, including Wakim, are given the not-so-easy task of keeping tabs on the ever-changing market. While some molecules may seem like a valuable asset for a company at the start, the market may shift to make the arduous task of biosimilar development less feasible — especially for a smaller company with limited resources. Hence why Wakim pointed out the benefit of having a wide pipeline of products in various stages of preclinical and clinical development.

“It’s important that you’re not tethering too many resources into just one or two products,” he shared, “especially, if, down the line, that product faces market difficulties or will not provide the appropriate returns.”

The work being done to analyze product/market opportunities also plays a big role in the company’s clinical development strategies. For instance, as Wakim explained, a company’s clinical development plans can have broader implications for its market launch. This is why the company chose to launch its phase 1 clinical trial in Australia with three arms to include the U.S. and EU comparator products. “We chose to leverage the single, pivotal PK studies for the global market, not just the U.S., the EU, or the Western world,” he added. “Our clinical design is in place to ease our entrance into the markets in which we’d like to launch our products.”

I appreciated Sunstrom’s level-headed look at the current landscape for a small company trying to make it in what is not, traditionally, a cost-effective development model. “It can be incredibly tough for a small company to do it all in biosimilars,” she said. “Everything is expensive, even when you do it by yourself.” And in this current environment where you have large, financially robust companies investing in biosimilar development, it’s easy for production efficiency to fall by the wayside.

In its earliest days, NeuClone was one of the only companies openly stressing the costs of developing biosimilars. Many companies investing in biosimilars jumped into development with no-holds-barred, spending millions on over-the-top, elaborate clinical studies. (If you look at some of the earliest FDA assessment reports for biosimilars, it’s stunning to note just how much effort went into providing additional clinical evidence.)

Sunstrom attributes the company’s ongoing success with its continued efforts to promote greater efficiency in biosimilar development, especially as conversations globally begin emphasizing overall sustainability.

“When we started, cost of goods was never discussed, but today, it’s one of the first questions we receive from partners,” she said. “I think our early and sustained focus on cost and affordability — which was borne out of necessity as a small company — has helped us survive and remain competitive.”