With the U.S. biosimilars market undergoing many changes, countless growth opportunities arise both nationally and globally.
The biosimilar industry, as many of you well know, has undergone an instrumental change in the U.S. over the past year.
According to PwC’s (PricewaterhouseCoopers’) industry report: “[f]inally entering the US market, biosimilar drugs have the potential to be as disruptive as generic drugs following the Hatch-Waxman Act of 1984.”
Sandoz’s Zarxio was the first U.S. biosimilar to enter the market, receiving approval in 2015 and entering the market at a 15 percent discount. PwC also reports that “[a]t least four biosimilar applications are pending FDA review in 2016, with another 50 in the FDA review process.” Sandoz is the generics arm of Novartis.
Michael Wyand, DVM, PhD, Chief Technical Officer of EPIRUS Biopharmaceuticals—a biopharmaceutical company that specializes in the global development and commercialization of biosimilar monoclonal antibodies (mAbs)—participated in an exclusive Q&A with Pharmaceutical Processing about the biosimilar landscape in 2016. His edited responses are below.
Q: Prior to the approval of the first biosimilar approval in the U.S., how would you describe the biosimilar industry?
Wyand: There is a decade of global experience behind biosimilars, as they’ve existed outside of the U.S. prior to the first FDA approval last year. Before this first approval in the U.S., the industry was very focused on the European market. The industry was engaging with the European Medicines Agency (EMA), but there was obvious discomfort as the U.S. was such a big opportunity and the FDA was not providing guidance.
Since the landmark approval of the first biosimilar in Europe April 2006, there have been approximately 40 biosimilars approved in markets all over the globe. This number may not sound like a lot, but considering the wide variances in regulatory processes and market dynamics, it is a testament to the appetite for biosimilars as part of the solution to provide more affordable options to patients. It is rather disconcerting as the FDA has been slow to provide guidance, which is what gives developers a pathway to follow for approval.
Q: Currently, what are some of the greatest markets for biosimilars and why?
Wyand: Markets within Europe are among the world’s most advanced biosimilars markets and have been a particularly noteworthy microcosm for the rest of the biosimilar landscape to take cues from. We believe that 50 percent of sales will be in markets outside of the U.S. European markets are the clearest from the regulatory sense, while the U.S. is more fragmented.
Q: In your opinion, what were some of the most pivotal moments in the emergence of biosimilars?
Wyand: Hatch-Waxman helped lay the foundation for biosimilars. Fast forward to today and the biotech industry is now experiencing a similar seismic shift with the gradual introduction of biosimilars. In 2009, the Affordable Care Act implemented the Biologics Price Competition and Innovation Act (BPCIA), which provides a pencil sketch for the introduction of biosimilars in the U.S and allows companies to submit an abbreviated data set opening the doors for biosimilar development. Since then, the FDA has published numerous guidance and implementation documents culminating in the approval of the first U.S. biosimilar, Novartis’ Zarxio, in March 2015.
In addition, the Safe Harbor law allows companies to do development work on molecules prior to an existing patent running out, so that the company is ready to submit the data set for approval as close to expiration as possible.
Q: Could you describe EPIRUS Biopharmaceuticals’ role in the development and commercialization of biosimilar mAbs?
At EPIRUS, we are developing and commercializing biosimilars by focusing on three core areas:
- Leading technical capabilities
- Sustainability through pipeline growth
- Retaining future vale
We are a sustainable, profitable, pure-play biosimilar company that is fully integrated and can handle everything from the initial development of the drug cell line to the final clinical trials that are necessary for approval.
EPIRUS has in-house technical capabilities based in Utrecht, the Netherlands, consisting of a proprietary CHOBC® suspension cell line and state-of-the-art laboratories. With technical product development professionals globally, we have core competencies in cell line generation, assay development, upstream and downstream process development, and analytical characterization.
EPIRUS seeks to build a sustainable platform through a therapeutically-focused pipeline of monoclonal antibodies, or mAbs. Our development pipeline currently consists of six products: BOW015 (infliximab, reference biologic Remicade®), BOW050 (adalimumab, reference biologic Humira®), BOW070 (tocilizumab, reference biologic Actemra®), BOW080 (eculizumab, reference biologic Soliris®), BOW090 (ustekinumab, reference biologic STELARA®), and BOW100 (golimumab, reference biologic SIMPONI®)—all of which are used to treat autoimmune/inflammatory or rare diseases. Cumulatively, these respective reference products generated approximately $29.2 billion in global sales for 2014, according to EvaluatePharma.
Q: In general, what is your process once you find an originator that you want to research? Could you describe the steps of getting a biosimilar created and to market?
Wyand: Once we find an originator that we want to research, we take the following steps to get the biosimilar created and to market:
- Purchase some of the innovator molecule
- Reverse engineer the innovator molecule
- Conduct protein (amino acid) sequencing so we understand the structure of the molecule exactly
- Derive gene sequence
- Make cell lines that produce molecules and create manufacturing process that creates the molecule
- Conduct analytical work that demonstrates molecule is highly similar
- Run necessary clinical trials to resolve residual uncertainty
- Carry out regulatory function of approval
We spend a lot of time in process development researching the manufacturing conditions that will result in a molecule that looks like the originator molecule.
Q: What are some of the greatest patent challenges you have faced with regards to selecting originators?
Wyand: If you look at the patent system in the U.S. and the intent of the patent system going back to 1800s, the intent was that an inventor will have protection on their innovation and others are not able to copy it. The government gives you protection for 20 years and in exchange, the inventor would disclose the invention so after 20 years, the invention could be made by others and used for the benefit of society.
The challenge is that innovator company’s now patent composition of matter, manufacturing process, drug dose, frequency and routes of administration, etc. All of these patents come out at different times. As a biosimilar company, we are required to be exactly like the innovator companies using the same composition of matter, frequency of administration, etc. If these patents come out in different years, the period of protection can go much beyond the 20 years, which is not the intent of the patent system. It is a way for innovator companies to protect their huge franchises.
Q: What are some of the greatest challenges in the development of biosimilars?
Wyand: The greatest challenge is establishing biosimilarity, matching the innovator range of the molecule. According to the BPCIA, biosimilars have to undergo extensive analytical characterization and prove similarity in efficacy and safety to the reference product. Biosimilars are scrutinized by the same regulatory bodies as their reference product in order to be deemed safe and efficacious for the purpose of receiving approval across the globe.
Q: Would you say that certain technologies, such as single-use technologies or cloud platforms, are particularly advantageous in the development of biosimilars?
Wyand: Yes, technologies as these allow EPIRUS to reduce time, cost to market, and overall cost of goods by improving product yields and focus on optimizing product quality. Specifically, single-use technologies are advantageous because they give us the ability to control parts of the manufacturing process. For example, if you were to manufacture a drug in one manufacturing plant and then move it to a second plant, you can use the same single-use technology in both plants. This minimizes changes batch to batch and allows for a greater chance of consistency in the manufacturing process.
Q: How can manufacturers prepare for the production of biosimilars? Any recommendations?
Wyand: As there will be more attention paid to the cost of manufacturer, manufactures are going to have to look at how they can efficiently work to manufacture. Some molecules require small amounts of material, while others require larger amounts. Manufacturers will have to prepare for different scales/amounts of production. We also believe in many cases it will be advantageous for manufacturers to produce multiple products in the same manufacturing facility.
Q: What are some of the greatest challenges in the commercialization of biosimilars?
Wyand: The greatest challenge is that there are going to be price reductions, so it will be a very price-competitive market. In addition, there will be a number of biosimilar players going into the same market leading to a fair amount of competition for the companies.
Q: As far as the Drug Supply Chain Security Act (DSCSA) regulations—do you see these compliance regulations significantly impacting the biosimilar market (and operations) in the U.S. in the coming years?
Wyand: The DSCSA will impact all pharmaceuticals companies, both biosimilar and innovators. We do not have total clarity on how the regulations will work but they will drive packaging equipment investment, downtime, and likely will more complex for the industry to manage. We do believe that the cost impact to the overall product will be small.
Q: How does the biosimilar market in the U.S. compare to other countries?
Wyand: With a decade of experience in international markets behind us, there have been interesting trends and influencing factors that have emerged relating to biosimilar adoption. These insights could hold the keys to understanding the impact as biosimilars mature in the U.S. market. These insights are important, particularly as the U.S. is forecasted to be the single biggest opportunity for biosimilars. Biosimilar uptake varies drastically from country-to-country and class-to-class, ranging from on average approximately 30-80 percent market share. This wide range is likely due to a wide variety of factors, from policies, tenders, and payer attitudes to physician awareness and willingness to prescribe.
Q: What are some of the trends you see developing for the biosimilar market in the U.S.?
Wyand: As biosimilars become more widely available in the U.S., trends that will develop include increased comfort level with biosimilars among payers and patients, as we saw with small molecule generics following the enactment of the Hatch-Waxman Act. In becoming more comfortable with them, payers will have an easier time covering biosimilars, which will help reduce costs. Additionally, as FDA firms up clarity for biosimilar developers, including providing final guidance on naming and interchangeability, more companies will file BLA submissions for their biosimilar candidates. This will increase competition, and in doing so, decrease costs.