The Arrival of Biosimilar Therapies

Patient safety concerns surround issues of similarity and interchangeability.

Biologic therapies have changed the way gastroenterologists treat Crohn’s disease and ulcerative colitis. Although biologic therapies can be effective for many patients, these newer treatment options cost significantly more than conventional therapies.

Biologically derived therapies that are biosimilar to the original, patent-holding biologic agents, known as innovator or reference products, are manufactured through alternate methods that produce a similar product with similar demonstrated efficacy and comparable safety profiles. Licensure of biosimilars would introduce products in competition with reference products, with the real potential to decrease the price, and thus enable broader access to these therapies for patients with inflammatory bowel disease and other conditions.

In the European Union (EU), biosimilars have been approved by the European Medicines Agency (EMA) since 2005. Since the Biologics Price, Competition and Innovation Act (BPCIA), a provision found within the Affordable Care Act, was signed into law by President Barack Obama on March 23, 2010, Zarxio (filgrastim, Sandoz), a biosimilar for G-CSF, Neupogen (filgrastim, Amgen) has been the only approval. Several applications for monoclonal antibodies (mAbs) for treatment of inflammatory bowel disease and rheumatic diseases have been submitted.

Cost Reduction

During a U.S. Senate hearing with Janet Woodcock, MD, the FDA’s director of the Center for Drug Evaluation and Research (CDER), acting director of CDER’s Office of Pharmaceutical Quality and a rheumatologist, and Sen. Christopher S. Murphy (D-Conn.) both agreed that while biologic therapies comprise less than 1% of the U.S. health care prescription drug market, these treatments account for 28% of prescription drug spending and both the frequency of use and costs are expected to increase.

“This increased cost is borne by our health care system as a whole, but more specifically, by patients, as more and more insurance companies place higher cost-sharing burdens on biologics,” Murphy stated in opening remarks.

During the hearing, Sen. Elizabeth Warren (D-Mass.) said eight biologic drugs comprise 40% of all Medicare Part B spending, and biosimilars are projected to save $44 billion during the next 10 years. However, the history of generic drugs has shown that prices do not come down until at least two manufacturers enter the market with the lower priced drug, according to Warren, and she said manufacturers won’t have the confidence to bring the alternatives to the market until a known regulatory structure is in place.

“I suspect we will see changes in cost once there are competing biosimilars — as in EU where CT-P13 is marketed by at least 2 different companies and compete with each other,” Vibeke Strand, MD, MACR, FACP, adjunct clinical professor in the Division of Immunology/Rheumatology at Stanford University School of Medicine and Biopharmaceutical Consultant told Healio Gastroenterology. “So far we don’t see competing products in the United States.”

The precedence in the EU has shown biosimilars “to be cost saving and enable more patients to use these agents when medically appropriate,” Gary Lichtenstein, MD, FACG, AGAF, director of the Center for Inflammatory Bowel Disease at the University of Pennsylvania School of Medicine, told Healio Gastroenterology. “The cost savings are estimated to be anywhere from 20% to 30% of the cost of the index biologic agent, and the hope is these will enable use throughout the United States. to those populations that are truly in need of such. The overall projection is by 2020 or so there may be upwards of $250 billion in biologics that are going to be available at that time, and a good percentage of those will hopefully be in the biosimilar area.”

Approval Process

Strand told Healio Gastroenterology that part of the goal of the BPCIA is to provide the framework to reduce the time to approval, thereby reducing the cost to develop and test biosimilar products. She said the goal of manufacturers is to invest less in the process compared with the costs invested in developing the reference product.

To that end, Strand said, “There has to be some kind of abbreviated pathway, and the abbreviation is in the clinical trials. [Researchers] are going to do a lot more to characterize [the biosimilar] both structurally and functionally and to make the product, and to characterize it in every way that we know how to do, which is a lot more sophisticated than we knew how to do in the past with the reference product.”

Development of biosimilars as regulated by the FDA “follows a very different pathway than originator drugs, [which] go through preclinical development ... before marketing,” Stephen B. Hanauer, MD, AGAF, FACG, professor of medicine at Northwestern University Feinberg School of Medicine in Chicago, told Healio Gastroenterology. “With biosimilars, it’s different. The majority of the effort is in developing the analytics and both the chemical and functional properties in vitro, and the clinical development is much smaller. That’s where the cost savings come in and allow biosimilars to enter the marketplace at a savings of anywhere between 15% and maybe up to 50% or 70% eventually, depending on how many biosimilars actually enter into the marketplace.”

The concept of extrapolation informs this abbreviated regulatory pathway, David T. Rubin, MD, AGAF, FACG, professor of medicine and chief of the section of gastroenterology, hepatology and nutrition at University of Chicago Medicine, told Healio Gastroenterology. “If a company demonstrates that a biosimilar has similar efficacy and safety in another disease state that the biologic originator is already approved for, they can then receive extrapolation of their biosimilar across all indications that that agent is already approved for. In other words, biosimilars do not need to repeat pivotal trials and clinical trials for biological agents ... so extrapolation from a biosimilar that works in RA, for example, can be applied to IBD.”

The guidance documents issued by FDA have changed through the process, but it is known that pharmacokinetic studies which include healthy volunteers will be required in addition to randomized controlled clinical trials, Strand said.

“At the present time the patents for both infliximab and adalimumab are still current, but eventually they will be completing their patency years, and a number of large pharmaceutical companies are beginning to develop biosimilars,” Hanauer said.

Product Pipeline

Applications for competing products, including Humira (adalimumab, AbbVie), Enbrel (etanercept, Amgen) and Remicade (infliximab, Janssen) have been submitted to the FDA, and many products are in development.

“Sandoz announced they have submitted their 351(k) for etanercept — despite the fact that Amgen has a very tight patent position until 2026,” Strand said.

People are closely following the outcome with the FDA application for Remsima (CT-P13/infliximab, Celltrion), according to Strand. “It has already been approved by EMA and it has even been approved by Canada. There are a lot of mAb biosimilars out there, so someone has to be the first [U.S.] example, the guinea pig, so this is the one,” Strand said.

However, the timeframe for approval of new biosimilar mAbs is unclear. An FDA Arthritis Advisory Committee hearing on CT-P13 for patients with RA, ankylosing spondylitis (AS), psoriatic arthritis (PsA), psoriasis, Crohn’s disease and ulcerative colitis slated for March 17, 2015 was postponed “due to information requests pending with the sponsor of the application,” according to the FDA website. No information regarding a new date for the committee meeting has been released, and the FDA did not respond to a request for comment on the matter.

“Acceptance of an application for licensure of a biosimilar by the FDA, with scheduling of an advisory board hearing signifies clearing a major hurdle on the path to its approval,” Jonathan Kay, MD, director of clinical research and professor of medicine at the University of Massachusetts Medical School told Healio Gastroenterology.

Strand said a further complication to the approval of CT-P13 surrounds its development and time spent in clinical trials, which were conducted before the FDA issued guidance documents, and its study followed European guidelines.

“It is unclear if they had done everything the FDA wanted, even though they are approved by EMA,” Strand said, and noted that Canada tends to follow EMA’s guidelines.

Biosimilarity and Interchangeability

Some questions about biosimilars surround the issues of similarity and interchangeability, according to sources interviewed.

Biosimilars are “very well studied and highly similar to their reference products,” Kay said. He also said the FDA has not yet issued specific, final guidance related to the requirements that a biologic must meet to be considered interchangeable. Interchangeability is a provision of the BPCIA that would allow pharmacies to substitute one brand of biologic or biosimilar for another without being directed by the prescribing physician unless the prescriber were to order it to be dispensed as written, according to Woodcock and the FDA’s definition. However, biosimilars are not to be confused with generic drugs, many caution.

“Biosimilars are not generic drugs — they are not identical compounds [but] similar to other biologic compounds,” Hanauer said. “These compounds have a protein background — they are essentially antibodies, and that’s the primary structure, but there is a secondary structure related to post-translational carboxylation. In other words, these proteins are surrounded by carboxyl or sugar moieties that are very sensitive to the way that the compound is being developed. It’s sensitive to temperature, to acidity, to the bath that these compounds are made in, so the difficult aspect of developing a biosimilar is to have both the initial structure as well as the tertiary and quaternary structures to be as close as possible to the originator compound.”

“A biosimilar will never be identical to its reference product, but they differ from each other only in very small ways that are not clinically significant,” Kay said. “Even different batches of the original biologic agent can vary from one another. On the other hand, a generic of a small molecule drug is identical to the original small molecule drug since that chemical compound can be duplicated exactly.”

He added that because the differences between a biosimilar and its reference product are small, studies enrolling very large numbers of patients would be required to detect any clinical effect of these differences.

Sen. William Cassidy, MD, (R-La.), who chaired the Sept. 17, 2015 hearing, raised concerns with Woodcock at that time because a detailed, specific definition about what would qualify as interchangeable has not been released.

Woodcock responded that providing clear details is “scientifically and practically feasible,” but later said she could not provide a date for the issuance of guidance documents because of the standard set forth in the BPCIA. Stipulations in the BPCIA require that a biosimilar must be expected to produce the same clinical result as a reference product in any given patient, which could take time to establish, according to Woodcock.

Interchangeability “may be ok if the agents are identical and function the same way,” Rubin said, “but we are advocating at the [Crohn’s and Colitis Foundation of America], and ... across our profession ... for transparency regarding this, and for not only notification of the physician and providers, but also for patients to understand this.”

Additionally, Woodcock stated if a product is administered or switched more than once in an individual patient, then the risk of diminished efficacy or safety must not be greater than the use of a reference product alone, which complicates issues related to interchangeability.

“We have to make an interpretation of that statutory standard,” Woodcock said. “It sets a high bar. The basic reason is the human immune response.”

Immune Response

Following approval, Woodcock stated a given biosimilar may produce unexpected immune responses in some patients.

“Unlike most of our small molecule drugs, the body recognizes these large protein molecules that are biosimilars and will make – in some people – an [unexpected] immune response, and the concern has been that continued switching could provide sort of a booster effect and cause an untoward effect.”

Woodcock cited a history of the production of antibodies made by some patients to erythropoietin in the reference product Procrit (epoetin alfa, Janssen) based on changes that occurred during the manufacturing process in 1998. The result was that some patients outside the United States developed pure red blood cell aplasia and became dependent on life-long blood transfusions.

According to Strand, such a change is unlikely.

“Unless there is a major manufacturing change, there really isn’t a great risk of new or increased immunogenicity – and if there is a major manufacturing change such as occurred with etanercept or with rituximab then likely clinical trials as well as immunogenicity [and other studies] are required to compare old with new – but these data are confidential between the FDA and sponsor and even in Europe only associated with a notification from the EMA,” Strand said.

Immunogenicity Issues

To others, the situation appears more complex and less certain.

“The immunogenicity, or the development of antidrug antibodies, is actually related to the quaternary structure in the different sugars, and if there’s a minor variation, that can make a major variation in the immunogenicity,” Hanauer said.

The expectation is that the efficacy, safety and structure of biosimilars should be the same as the originator, and therefore, “it is also expected that antidrug antibodies against an originator agent will cross-react with the biosimilar,” Rubin said. “This is a new concept because up until now, when someone has antidrug antibodies against a biological agent in our field, cycling or switching within the class of therapies was thought to be safe and effective, because the antidrug antibodies did not cross react against different drugs within the class.

“An example would be your patient who is on infliximab and develops antibodies against infliximab,” Rubin added. “If that patient had previously done well with infliximab, cycling them to adalimumab is a reasonable strategy because the antibodies to infliximab will not react against the adalimumab. With a biosimilar ... we have to understand that if you take a patient who has antibodies to infliximab, cycling them to the biosimilar infliximab will result in the same problem because the antibodies will cross-react. That is a major concern ... that we need to resolve and understand before we can fully embrace the use of biosimilars.”

Allan Gibofsky, MD, JD, MACR, FACP, FCLM, professor of Medicine and Public Health at the Weill Cornell Medical College and attending rheumatologist at the Hospital for Special Surgery, said the landscape for patients could be further complicated by decisions insurance companies may make to limit payment for certain biosimilars or those made by a particular manufacturer or other factors that may result in repeated switching of brands, which could have unknown consequences. He noted that, while it is unknown if any negative effects may result, switching between biologics could occur following a sale of a patent or manufacturing license. He also stated uncertainty about how insurers may handle situations in which patients have a negative response to inactive ingredients used in the manufacturing or packaging process.

“You can hypothesize about what ought to happen, but until the studies are done, biologically, you just don’t know,” Gibofsky said.

Multiple Indications

Some products in the tumor necrosis factor-alpha inhibitor class of biologics have been approved for RA, PsA, AS, psoriasis, ulcerative colitis and Crohn’s disease, but it is unclear if the FDA will consider extrapolating indications with a biologic for all indications already approved for the reference product.

“If you understand the function, the mechanism of action, then extrapolation should make sense,” Strand said. “There are a lot of physicians who are very concerned about extrapolation, but those mechanisms are the same in [two or more indicated] diseases,” she said, and explained that an anti-cytokine mAb works the same way in RA as it would in Crohn’s disease, even though the two diseases may seem unrelated.

Gibofsky said many aspects of pharmacokinetics and immunogenicity are still biologically unknown, particularly in indications where a combination of medications may be involved. He said in rheumatology, it is common to prescribe a biologic, such as infliximab, to be used concomitantly with methotrexate for patients with RA, but a patient with Crohn’s disease may be more likely to receive infliximab as monotherapy, and thus detailed studies of immunogenicity in one population might be different from that in another, therefore requiring large numbers of patients in appropriately designed and powered studies.

Naming Convention

Another issue as yet not completely resolved by the FDA is a naming convention for biosimilar drugs. Draft guidance has been issued, and key provisions are supported by the American College of Rheumatology (ACR) in addition to multiple physicians’ and patients’ groups, but the draft leaves some questions unanswered.

Under the draft, each biosimilar will share a core name with the reference product and a distinct four-letter suffix, but the document reads, “For interchangeable products, the FDA is considering whether the designated suffix should be unique or should be the same as its reference product.”

The use of a suffix rather than a prefix may create a more reliable environment for entry into databases, while separating different products made by different manufacturers. Strand said this system is better for pharmacovigilance.

Gibofsky said he also does not support a single-name system, which is favored by CMS.

“I have a problem with every biosimilar produced by every manufacturer together with the reference product,” Gibofsky said. “While a study of a cohort may be similar for each product, we may well see different efficacy and safety in individual patients – it depends on how and thus knowledge of specifically which agent was used will be necessary.”

With the potential for discrepancies between treatments, Gibofsky said separate CMS codes are important.

“One of first things an internal medicine physician is taught when you have a patient with a stable disease who experiences a sudden flare, is to ask, ‘Have you refilled your prescription recently? Is it from the same manufacturer as your last prescription?’ While the pharmacodynamics and pharmacokinetics of prescribed agents are required to be identical in a population, it may be different in that one individual,” Gibofsky said. “I would want to know if a patient had loss of efficacy or reaction to adalimumab-a or to adalimumab-b.”

The initial proposal from CMS uses one billing code for reference and biosimilar products. The ACR and five additional groups sent a letter to CMS Acting Administrator Andrew Slavitt in early September, urging CMS to develop a system with unique codes for biosimilars unless the biologic is deemed interchangeable by the FDA.

While physicians, regulators and indus-try partners may be closely monitoring dev-elopments in the biosimilar regulatory process, patient interest is unclear, according to Gibofsky.

“Patients have conflicting demands. On one hand, they want to reduce their health care costs,” Gibofsky said. “On the other, if they are clinically stable on a particular medication, they may be less willing to chance loss of efficacy on a biosimilar agent. Even now, when we can offer injections or infusions of the same agent, or injections less frequently of the same agent, patients are often reluctant to change, telling me ‘it ain’t broke, Doc, so don’t fix it!” – by Adam Leitenberger and Shirley Pulawski

• References:
• Dörner T, et al. Ann Rheum Dis. 2012;doi:10.1136/annrheumdis-2012-202175.
• Dörner T, Kay J. J Nat Rev Rheumatol. 2015;doi:10.1038/nrrheum.2015.110.
• Eastern Research Group Inc. Review of biosimilar biologic product applications: Study of workload volume and full costs. Aug. 3, 2015.
• U.S. Department of Health and Human Services. Nonproprietary naming of biological products: Guidance for industry – Draft guidance. August 2015.
• www.bio.org/media/press-release/california-governor-brown-signs-bill-ensuring-patient-access-interchangeable-bio
• www.fda.gov

• For more information:
• Allan Gibofsky, MD, JD, MACR, FACP, FCLM, can be reached at GibofskyA@hss.edu.
• Stephen B. Hanauer, MD, AGAF, FACG, can be reached at shanauer@northwestern.edu.
• Jonathan Kay, MD, can be reached at Jonathan.Kay@umassmemorial.org.
• Gary Lichtenstein, MD, AGAF, FACG, can be reached at Gary.Lichtenstein@uphs.upenn.edu.
• David T. Rubin, MD, AGAF, FACG, can be reached at drubin@medicine.bsd.uchicago.edu.
• Vibeke Strand, MD, MACR, FACP, can be reached at vibekestrand@me.com.

Disclosures: Gibofsky reports he is a stockholder in AbbVie, Amgen, Bristol-Myers Squibb, GSK, Johnson & Johnson, Pfizer and Regeneron, is a consultant to AbbVie, Amgen, AstraZeneca, Celgene, Horizon, Iroko, Medac, Pfizer, Relburn, Takeda and a speaker with AbbVie, Amgen, Celgene and Pfizer. Hanauer reports financial relationships with AbbVie, Actavis, Amgen, Arena, Astellas Pharma Global, Boehringer Ingelheim, Bristol-Myers Squibb, Catabasis, Celltrion, Ferring, Genentech, GlaxoSmithKline, Hospira, Janssen, Lilly, Novartis, Novo Nordisk, Pfizer, Prometheus, Receptos, Salix, Seres Health, Shire and Takeda. Kay reports he received research support (paid to the University of Massachusetts Medical School) from AbbVie, Genentech, Pfizer and Roche Laboratories and has received honoraria for consultations from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Epirus Biopharmaceuticals, Genentech, Hospira, Janssen Biotech, Merck Sharp & Dohme, Nippon Kayaku, Novartis Pharmaceuticals, Pfizer, Regeneron, Roche Laboratories, Samsung Bioepis and UCB. Lichtenstein reports he is a consultant for Abb-Vie, Actavis, Alaven Corporation, Ferring, Hospira, Janssen Ortho Biotech, Luitpold/American Reagent, Pfizer, Prometheus Laboratories, Salix Pharmaceuticals, Santarus, Shire, Takeda and UCB; and receiving grant/research support from Ferring, Janssen Ortho Biotech, Prometheus Laboratories, Salix Pharmaceuticals, Santarus and UCB. Rubin reports financial relationships with AbbVie, ACG, Amgen, Cornerstones Health, Emmi, Genentech, Janssen, Pfizer, Prometheus Laboratories, Shire, Takeda and UCB. Strand reports she is an independent biopharmaceutical consultant in clinical development and regulatory affairs; is a consultant to AbbVie, Alder, Amgen Corporation, Anthera, AstraZeneca, BiogenIdec, Biotest, Bioventus, BMS, Carbylan, Celgene, Celltrion, Corrona, Crescendo, Daiichi Sankyo, Eupraxia, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Lilly, MerckSerono, Novartis, Pfizer, Regeneron, Sandoz, Sanofi, SKK, and UCB; and serves on advisory boards for AbbVie, Amgen, BiogenIdec, BMS, Crescendo, Genentech/Roche, GSK, Janssen, Lilly, MerckSerono, Novartis, Pfizer, Regeneron, Sandoz, Sanofi and UCB.