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Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
The approval and acceptance of monoclonal antibody biosimilars is necessary if the biosimilars market is to experience real growth.
The biosimilars market, many analysts believe, is on the cusp of significant growth. This growth in large part is due to the fact that numerous monoclonal antibody (mAb) biosimilars are expected to be launched in the next few years as patents on key drugs, such as infliximab (Remicade from Johnson & Johnson), trastuzumab (Herceptin from Roche), and Adalimumab (Humira from Abbott), expire. The European Medicines Agency (EMA) approved the first mAb biosimilar developed by Celltrion and Hospira in 2013 (infliximab: Remsima/Inflectra). Development of clear, regulatory approval pathways for biosimilars in emerging markets is creating large, additional opportunities for biosimilar mAbs. Education of physicians, pharmacists, and patients by biosimilar manufacturers and strong support for adoption by individual governments is, however, also required if biosimilar mAbs-and the biosimilar market as a whole-are to reach their full potential.
Importance of mAbs
McKinsey & Company estimates that 40% of biosimilars in development are mAbs, and that percentage will only increase as fewer first-generation biosimilars are introduced and the competitive focus keeps turning to mAbs. In March 2012, 73 biosimilar mAbs were under development, with 59 at the preclinical stage, five in Phase I or II, and nine in Phase III. At least 20 companies are, for example, developing biosimilars for trastuzumab. “Biosimilars from only a few, small, product classes have been approved to date. mAbs comprise a much larger class, and by 2020, patents are set to expire on several mAb-based drugs with annual sales greater than $5 billion each in the year of US expiry,” says Jorge Santos da Silva, a principal in the Swiss office of McKinsey & Company.
mAbs are also extremely costly, and biologic versions are needed to maintain functioning healthcare systems, according to Theodor Dingermann, a professor and director of the Department of Pharmaceutical Biology at Goethe University, Frankfurt, Germany. Biosimilar versions of mAbs have the potential to offer cost reductions of 25-30%, according to Srinivas Sashidhar, a senior research analyst for life-sciences with Frost and Sullivan. He adds that mAbs are also available for a much wider range of indications than the protein-based biosimilars available today. “Antibodies are revolutionary drugs that address previously unmet medical needs by binding to specific targets. However, countless patients around the world do not have access to these state-of-the-art therapeutics due to their high price. Celltrion’s goal is to make antibodies more affordable to patients through the development of biosimilar mAbs,” says Joon Seok Kim, public relations manager for Celltrion.
More complexity equals more development challenges
Compared to the relatively small protein-based drugs for which biosimilars have been approved by EMA, such as epoetins, filgrastims, growth hormones, and follitropin alfa, mAbs are much larger and more complex molecules that can be difficult to fully characterize and thus demonstrate biosimilarity. This complexity requires more complex manufacturing processes, according to Kate Keeping, senior director of biosimilars research with Decision Resources. With mAbs, notes Dingermann, glycostructures are important because they can affect the pharmacodynamics of the drug.
“A very strong set of capabilities similar to those of innovator companies, including state-of-the-art analytics for determining primary and higher-order structures, animal models, simulation tools and complex algorithms, expertise in designing clinical trials that target the appropriate end points and do so with as few patients and as quickly as possible, plus modern manufacturing facilities and technologies, is needed to develop and produce mAb biosimilars,” observes Santos da Silva.
With such extensive requirements, it is not surprising that many companies, particularly smaller firms, that do not have sufficient capacity, are forming partnerships, according to Sashidhar. Examples in addition to Hospira and Celltrion include Merck Serono and Dr. Reddy’s Laboratories, Samsung and Merck with Biogen, Amgen and Actavis or Daiichi, Baxter and Coherus, highlights Santos da Silva.
In addition, it is quite expensive to develop more complex biosimilar mAbs, as much as a $200 million investment for one candidate, including the necessary mammalian cell culture facility built in compliance with GMP regulations and a highly educated and experienced workforce, according to Kim. “Since 2002, we have made significant investments in facilities, human resources, and technology to become a global and innovative biopharmaceutical company,” he says.
Need for clear regulatory pathways
The need to meet varying regulatory requirements in different countries/regions of the world and a lack of clarity in the approval process are challenges for developers of biosimilar mAbs. Europe is the leader in this area and has had an established biosimilar approval pathway in place since 2006. In 2012, the EMA also published final guidance, the non-clinical and clinical requirements for biosimilar mAbs, including information on pharmaco-toxicologic, pharmacokinetic, pharmacodynamic, efficacy, and safety studies. In 2013, the agency also issued a draft concept paper on the comparison of biosimilars with reference products; the similarity guidelines and clinical and non-clinical requirements were updated, and adjustments were made so that clinical trials in emerging markets can be performed with locally sourced originators.
The US lags behind Europe with respect to establishment of a biosimilar pathway. While a pathway has been in place since March 2010, a lack of guidance from FDA regarding specific requirements has created significant uncertainty for biosimilar manufacturers. That uncertainty was somewhat alleviated in 2012, when the agency published draft guidance documents on how to demonstrate biosimilarity and the data that can be used to assess biosimilarity, as well as advice on the development process and working with FDA. Additional guidance on the substitution of biosimilars for branded products is also expected. In 2013, the agency launched its biosimilar user fee program.
In the guidance documents, FDA emphasizes interactions between the agency and biosimilar manufacturers and indicates that each product will be evaluated on a case-by-case basis. While this approach gives biosimilar producers more flexibility, it may also lack the level of detail they need to feel comfortable about investing in product development for the US market. Companies are also faced with possible state-level regulations on the substitution of biosimilars for branded drugs, as recently observed in California.
In Asia-Pacific, Japan also has an established regulatory pathway for biosimilars, and several products have been launched there. South Korea has an approval process as well. In 2013, the Therapeutic Goods Administration in Australia issued guidance for biosimilar approvals.
“Many emerging market countries are actively developing pathways for biosimilar approvals and are rapidly catching up. Brazil, Mexico, Venezuela, Colombia, and India now have at least draft, if not established, regulations for biosimilar approval in place. Russia is also developing an approval pathway, as are countries across Asia and Africa. The China Food and Drug Administration has also begun discussions on the development of a biosimilar approval process,” observes Santos da Silva.
Each of these approval pathways is different, though, even in the developed countries, where they tend to be very strict. “Manufacturers are required to plan clinical trials and development processes to satisfy various stringent regulations applicable for each distinct country. Consequently, Celltrion employees and executives have thoroughly reviewed the guidelines of every relevant country and managed the details of our biosimilar mAb development strategy with these requirements in mind from the very beginning,” says Kim.
Because of the nature of biosimilars, including mAbs, regulatory determinations do need to be made on a case-by-case basis. “Each evaluation must be specific to the innovator product and the biosimilar product from a specific company and consider the characteristics of each and how closely they are matched,” explains Keeping. She adds that it is the totality of evidence that is crucial when determining biosimilarity, because differences are expected. It is the job of the biosimilar sponsor to demonstrate that the differences result in no clinically meaningful effect on quality, safety, or efficacy compared to that of the innovator drug.
A clear step-wise process for characterizing the reference product and biosimilar to compare the physico-chemical properties, conducting clinical trial evaluations to determine comparable therapeutics performance, and evaluating the weight of the evidence and determining whether identified differences affect efficacy and safety is crucial for speeding up the approval process and lowering the cost of bringing biosimilars to market.
Role of emerging markets
The market penetration of mAbs is limited in emerging markets, largely due to their high cost. Therefore, there is a huge opportunity for biosimilar mAbs in these countries given the size of the market and because there is less competition from branded products in the non-private markets, according to Santos da Silva. Sashidhar also notes that both domestic (e.g., Brazil and India) and international companies are looking to introduce biosimilar mAbs in developing countries where the approval pathways are often less stringent or currently under development. Biosimilar mAbs can be launched relatively quickly in these emerging markets, and companies can gain market experience and market data that can be used for the approval process in developed markets. It also provides a way for companies to more rapidly recoup some of their investment, according to Dingermann.
International companies tend to form partnerships with local pharmaceutical or biotechnology firms to more easily access emerging markets. One such example is the Product Development Partnerships in Brazil, notes Santos da Silva. Another is the collaboration between generic firms Mylan and India’s Biocon on the development of a Herceptin (trastuzumab) biosimilar, which has been approved in India. It should be noted, however, that Roche has filed an injunction against Biocon and Mylan that temporarily prevents them from referring to Canmab and Hertraz as ‘biosimilars of Herceptin’ because Roche claims they were not developed in line with the regulatory guidelines for biosimilars. A hearing is scheduled for February 28, 2014.
Impact of the approval of infliximab
The EU approval of Celltrion’s and Hospira’s mAb biosimilar infliximab (Remsima/Inflectra) is an important milestone in the development of the biosimilar market and for future mAb approvals. The biosimilar was approved for the same range of autoimmune diseases as the branded product (i.e., “extrapolation”), including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), psoriatic arthritis (PsA), and psoriasis. This approval is important not only because it is the first mAb biosimilar approved in a mature market, but also because it included indication extrapolation for all of indications, according to Keeping. “We have not seen an approval for such a wide range of indications based on the results of ‘just’ two clinical trials (RA and AS). Indication extrapolation enables biosimilar developers to achieve significant cost and time savings, which will ultimately have an impact for patients,” she says.
The design of Celltrion’s clinical trials is also worth noting, according to Santos da Silva. “The company conducted a global trial in 20 countries with just 874 patients and clearly designed the study to optimize acceptance by regulators in several different countries around the world.” He adds that the company’s open approach to development of this biosimilar mAb, including many interactions with regulators and leader in the RA field, should set an example for other mAb biosimilar development projects. Celltrion will be launching Remsima in France, Germany, Italy, Spain, and the United Kingdom (the EU5) in 2015, when J&J’s recently won patent extension for Remicade elapses in February of that year.
Getting approval for a mAb biosimilar does not guarantee success, however. Biosimilar manufacturers must first convince physicians, pharmacists, and patients that biosimilar mAbs are safe and effective. “Acceptance of biosimilars is highly variable from country to country and depends on the molecule type and indications,” notes Keeping. Biosimilar erythropoiesis-stimulating agents and granulocyte colony-stimulating factors (G-CSFs) that are available in Europe are used in oncology indications, so oncologists are potentially more familiar with them and receptive to new products. Many mAbs, however, can also be used for other indications, such as respiratory disorders, according to Sashidhar. He believes, therefore, that biosimilar mAbs will be more likely to be accepted initially in regions where the emphasis is on low-cost drugs.
“There are definitely reservations among physicians and pharmacists in the EU, and it is up to biosimilar manufacturers to educate them, which will require improved marketing efforts,” asserts Dingermann. Strong government support that encourages the uptake of mAb biosimilars, together with strong clinical data (such as for G-CSFs), is also needed, according to Santos da Silva.
Recent activity and future expectations
In addition to its approval in the EU, Celltrion has received approval for Remsima in South Korea and Canada, and has applied for approval in Japan. The company also received approval in South Korea in January 2014 for its second biosimilar mAb Herzuma (trastuzumab). In India, Intas Pharmaceuticals launched its rituximab biosimilar of Rituxan (Genentech/Biogen Idec) in May 2013. Biocon received approval for CANMAb (trastuzumab, developed with Mylan) in November 2013 and announced the launch of the product in January 2014. Dr Reddy’s Laboratories and Intas Pharmaceuticals are also developing trastuzumab biosimilars for the Indian market. It should be noted that there is a debate as to whether these products should be considered biosimilars.
Notably, most major international pharmaceutical companies are developing biosimilar mAbs, including Pfizer, Amgen, Merck Serono, and Boehringer Ingelheim. Leading generic-drug firms, including Sandoz, Mylan, and Teva, are active in this area as well. As a result, analysts expect that several additional mAbs will be approved in both developed and emerging markets over the next several years, which should, if they are accepted, contribute to significant growth of the biosimilars market.
About the Author
Cynthia A. Challener is a contributing editor to BioPharm International.