Biosimilar Therapies in Rheumatology

Some Questions Remain About the Issues of Similarity and Interchangeability

Biologic therapies to treat rheumatic diseases have changed the way rheumatologists treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus and potentially other indications that are pending trials. 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.

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 Barrack Obama on March 23, 2010, Zarxio (filgrastim, Sandoz), a biosimilar to G-CSF, Neupogen (filgrastim, Amgen) has been the only approval. Several applications for monoclonal antibodies (mAbs) for treatment of 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 rheumatologist, 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.

“Rooms full of wheelchairs are now a thing of the past in rheumatology clinics,” Woodcock said, and added surgery was once the only option to treat rheumatoid arthritis (RA).

“What I hear from some of my colleagues in rheumatology is that these transformative medicines are still inaccessible to some Americans because of the cost. Since the biosimilars pathway created by Congress in 2010, a lot of progress has been made ... but people are anxious to see more progress.”

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 two 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 Rheumatology. “So far we don’t see competing products in the United States.”

Approval Process

Strand told Healio Rheumatology 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 to 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.”

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.

Product Pipeline

Applications for competing products, including Enbrel (etanercept, Amgen) and Remicade (infliximab, Janssen) have been submitted to 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 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 could not be reached 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 Rheumatology.

Strand said a further complication to the approval of CT-P13 surrounds its development and time spent in clinical trials, which were conducted before 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 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.

“Interchangeable biologics are not generics,” Jim Greenwood, president and CEO of Biotechnology Industry Organization, stated in an industry association press release. “Even slight changes to a biologic drug can change its properties entirely. Unlike conventional generic medicines, interchangeable biologics are not the same as the drugs they seek to substitute. In fact, two biologics made using different cell lines and differing manufacturing processes will rarely, if ever, be exactly the same. Those suggesting interchangeable biologics and generics are the same are wrong.”

“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 September 17 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. Additionally, she 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 raise that could provide sort of a booster effect and cause an untoward effect.”

Strand said the large molecules seen in mAbs can contain as many as 1,100 amino acid groups.

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. As a result, 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.

“[The biological agents] can change, but this is ‘drift’ and, 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 FDA and sponsor and even in Europe only associated with a notification from EMA,” Strand said.

Immunogenicity Issues

To others, the situation appears more complex and less certain. Switching may cause additional problems for patients, according to 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. Gibofsky said there could be immunogenicity issues when switching, or repeatedly switching through multiple biosimilars or reference products or when a certain form of a biologic is or is not combined with background therapy.

Gibofsky 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 told Healio Rheumatology.

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 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 disease 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, 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 FDA.

While physicians, regulators and industry partners may be closely monitoring developments 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 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.
• Jonathan Kay, MD, can be reached at Jonathan.Kay@umassmemorial.org.
• 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, Pfizer, Johnson & Johnson, GSK and Regeneron and is a consultant to AbbVie, Amgen, AstraZeneca, Pfizer, Horizon, Iroko, Relburn, Celgene, Takeda, Medac Speaker-AbbVie, Amgen, Pfizer and Celgene. Kay reports he has 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 Amgen, AbbVie, 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. 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.