A roundtable featuring:
Karen King, President, DSM Biologics
Nancy Gillett, corp. executive VP and president, Global Preclinical Services, Charles River
Sally Waterman Ph.D., COO, PolyTherics Limited
What are biobetters? How do they differ from biosimilars/follow-on biologics?
Gillett: Biosimilars are seen in some non-U.S. countries as a "biologic generic." They are intended to be identical to the originator biologic drugs. But, since they are manufactured using a new process, they will have subtly different structures and possibly different actions. For these reasons, the United States is unlikely to allow them as substitutes for originator biologics without proof from expensive clinical trials. In contrast, biobetters are not copies and will never be considered generics. Biobetters are new molecular entities that are related to existing biologics by target or action, but they are deliberately altered to improve disposition, safety, efficacy, or manufacturing attributes. One example is Centocor/J&J's new anti-TNF (tumor necrosis factor); the first was highly immunogenic — their biobetter is humanized to reduce this undesirable effect.
King: Biosimilars are generally defined as protein therapeutics generated to be highly similar to and substitutable for existing branded protein products. Biobetters are also based on some of the intellectual property of the branded innovator drug, but are intended to be superior/differentiated in some fashion. For example, biobetters may be targeted to have improved pharmacodynamics leading to less frequent dosing or reduced side-effect profiles or may have sustained or slow release formulations.
Waterman: Biobetters differ from biosimilars in that they are not identical to the original product and have been designed to have some advantage; there is not, to my knowledge, a "regulatory" definition of a biobetter. "Follow-on biologics" is a term more often used in the United States and can encompass both biosimilars and biobetters, but more usually it is the former that are meant.
How are CROs and CMOs working with clients to develop biobetters?
Gillett: Charles River and other CROs all work with sponsors of new biologics agents and have evolved testing paradigms based on experience. These same paradigms can be applied to biobetters, or approaches can be further customized. Accordingly, regulatory guidelines allow for many options, and a program design can be just a "best guess" on what will satisfy the FDA.
King: The majority of CMOs will support developers of either biosimilars or biobetters. Unlike generic small molecules, there is a very high development expense (up to $100 million+) associated with biosimilars or biobetters. By utilizing CMOs, biosimilar developers can avoid the extensive capital (up to several hundred million) and technological risks associated with also bringing on new biopharmacuetical manufacturing capacity. CMOs like DSM Biologics have technology solutions that can assist a biosimilar developer in achieving an optimal cost position which will also be important in a highly competitive field.
Waterman: I am not aware that CROs have chosen to work in a different way with clients who are developing biobetters — they will nearly always work on a fee-for-service basis. Some kind of risk-sharing that involves them working at cost in return for some future payments may be used in certain (rare) circumstances, as it is for other types of products.
What preclinical development challenges do makers of biologics and biobetters face?
Gillett: A biobetter may have an easier clinical road since it benefits from prior knowledge of clinically effective targets/pathways. Based on this, some sponsors might fall into the trap of presuming the preclinical program will be easier; consequently, they may underestimate their preclinical program costs and milestones. But this is a case where clinical streamlining doesn't cross-apply to preclinical safety — just like me-too drugs, biobetters may provoke unexpected toxicity, and the FDA expects the same quality/extent/nature of preclinical work to be done for any originator biologic or biobetter.
King: One of the most difficult preclinical challenges with biosimilars/biobetters is achieving similarity to the originator molecule. This is exacerbated by the fact that gaining access to the originator's data can, at times, be challenging.
Waterman: The guidelines on the preclinical development of biologics are now well-established, but the varying nature of the products and their potential to be immunogenic in animal models means that the preclinical development of each has to be considered on a case-by-case basis, and the specific advice of regulatory agencies is usually sought. There are no specific guidelines for biobetters, and it is anticipated that a full preclinical package will be required unless it can be argued that the differences between the biobetter and the original product are small and some reduction can be negotiated with the regulatory agencies (for instance, running only single species toxicology studies).
Why are companies placing a larger focus on biobetter production?
Gillett: Biobetters allow companies to target an established mechanism, safety, and efficacy profile but gain the benefit of the patent protection and sales of a new molecular entity. The development costs are the same as developing a new biological product, but the chances of successful registration are significantly higher. This means the business risk in developing a biobetter is significantly reduced and the potential for return on investment for a manufacturer is greatly improved.
King: Some companies are choosing biobetters, while many are also pursuing biosimilars. The field of participants entering is expected to be large. I term the entry to biosimilars/biobetters to be the new industry "Gold Rush." While many will enter, it is also generally predicted that the market will only bear a certain number of players, so many may not ultimately succeed. Due to the highly competitive expected nature of the developing market, some players are focusing on points of differentiation. Those points of differentiation can be having a low cost position, offering improved pharmacodynamics, or having improved formulations, among others.
Waterman: A biological product is partly defined by its manufacturing process, so to produce a biosimilar it has to be manufactured in the same, or virtually the same, way as the original product. Since the original biologics were approved, manufacturing technology has improved considerably, which also has improved quality and yields and probably the cost of goods. There will thus be benefits from using newer methods of manufacture but once this is done, the product is no longer a biosimilar.
Do you see any markets in particular focusing on biobetter production?
Gillett: A number of biosimilar products have been on the market in Europe and Asia. But in the United States, follow-on biologics, particularly monoclonals, are projected to have significant clinical trials costs and have limits on their market penetration (e.g. not substitutable). This significantly favors biobetters in the United States. Additionally, there is evidence of companies in Asia wanting to demonstrate their ability to produce biobetters rather than being copiers of others' designs.
King: Intuitively, it would seem biobetter production would be better aimed at Western markets where access to the originator molecules was already well-established and where expected market pricing would support the differentiation.
Waterman: As with all biologics manufactured, there is a drive to countries that can produce material of high quality consistently and at a reasonable cost.
Are there difficulties bringing these compounds to the market? How does the United states compare to Europe or Asia?
Gillett: Yes, for biosimilars. More biosimilars are available in Europe because the early molecules coming off patent were simple proteins like growth factors, and it was easier there to establish a straightforward pathway for approval. Additionally, regulatory expectations are not yet established for biosimilars in the United States, adding an element of uncertainty. Another factor is that EU clinical trials are done with EU comparator innovators, and often, these innovators are not the market leader in the United States. As a result, worldwide approval even for growth factors can be made more expensive through the need to fund multiple comparator studies. Monoclonals, which have large markets especially in autoimmune disease and cancer, will provide more challenges worldwide due to their relatively complex structures and manufacturing.
King: In general, bringing biosimilars to market is extremely difficult when compared to small molecule generics. An extensive development program, including an abbreviated clinical requirement, is required, leading to development costs of up to $100M or more. Once biosimilarity is established, the marketing requirements will be more difficult than small molecules, as the substitutability of biosimilars is also not yet clear in all markets. The EU has been leading the Western World in developing and issuing guidelines for the development of biosimilars.
Waterman: I am not aware that there are any difficulties over and above those that would apply to biologics in general, but there could be problems if a company considers its product a biosimilar and the agency disagrees and the package of data on which approval is sought is not adequate. I envision there will be protracted negotiation with the agencies with respect to the claims that could be made to the product being "better." The studies to demonstrate improvement might be quite onerous in some circumstances.
How do regulatory bodies address biobetters?
Gillett: Biobetters are handled exactly as innovator molecules in the United States, and similar regulatory standards are expected elsewhere. They are new molecular entities and will be subject to the standards applied to all new drugs – that said, certain programs may gain advantage due to pharmacologic comparability, which may help accelerate programs. For instance, prior related drugs may help with dose choices and choices of biomarkers in both nonclinical and clinical settings, and the FDA might use this prior knowledge to help reduce the scale/duration of Phase 2 trials and focus safety monitoring on known side effects of the target pathway.
King: Given that regulatory bodies are only just getting the guidelines in place for biosimilars, there is still some uncertainty around biobetters. It can be expected that the more "different" the biobetter is from the originator, the higher the bar will be in proving its safety and efficacy, and hence the regulatory hurdles and the price tag to develop biobetters will also correspondingly increase.
Waterman: There are no specific guidelines for biobetters so, as I previously indicated, it will come down to negotiating the package of data required for approval with the regulatory agencies on a case-by-case basis.