Biosimilars in the United States: Current Status and Future Implications

Biosimilars in the United States: Current Status and Future Implications

Disclosures: Hanauer reports consulting for AstraZeneca, Catalys Pacific, Cosmos, Covance, Merck, Progenity, Salix, Samsung Bioepis, Seres Therapeutics, Sorriso, TLL Pharma and VHsquared; consulting or doing clinical research for Allergan, Amgen, Celgene, Genentech, GSK, Eli Lily & Co., Novartis, Receptos and UCB Pharma; consulting, doing clinical research or speaking for Abbvie, Janssen, Pfizer and Takeda; consulting or being on the DSMB of Arena, Boehringer Ingelheim and Prometheus; consulting, speaking or being on the DSMB of Bristol Myers Squibb; and being on the DSMB of Gossamer and Protagonist. Seck reports being an employee of Boehringer Ingelheim. Snow reports no relevant financial disclosures.
January 07, 2022
6 min read
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Cyltezo 'paid the price' for interchangeable biosimilar approval: Will it be worth it?

Disclosures: Hanauer reports consulting for AstraZeneca, Catalys Pacific, Cosmos, Covance, Merck, Progenity, Salix, Samsung Bioepis, Seres Therapeutics, Sorriso, TLL Pharma and VHsquared; consulting or doing clinical research for Allergan, Amgen, Celgene, Genentech, GSK, Eli Lily & Co., Novartis, Receptos and UCB Pharma; consulting, doing clinical research or speaking for Abbvie, Janssen, Pfizer and Takeda; consulting or being on the DSMB of Arena, Boehringer Ingelheim and Prometheus; consulting, speaking or being on the DSMB of Bristol Myers Squibb; and being on the DSMB of Gossamer and Protagonist. Seck reports being an employee of Boehringer Ingelheim. Snow reports no relevant financial disclosures.
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In October, Boehringer Ingelheim’s adalimumab-adbm secured a landmark FDA approval as the first interchangeable biosimilar to AbbVie’s blockbuster drug, Humira — but, as rivals scramble for second place, will the designation be worth the price?

Although its ‘interchangeable’ designation will give Cyltezo (adalimumab-adbm) a competitive edge over the six other adalimumab biosimilars launching in 2023 — allowing pharmacists to substitute it for Humira without the need for the prescriber to alter the prescription — whether this offsets the costs of developing the product and the extensive patent battle with AbbVie remains to be seen.

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Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern Medicine and professor of medicine at the Feinberg School of Medicine, explained the significance of this trial. “The price of FDA approval for interchangeability is a clinical trial with multiple switches between the two drugs,” he said. “Boehringer Ingelheim paid the price.”

Depending on the success of Cyltezo in the 2023 drug market, interchangeable biosimilars could radically change the landscape for biosimilar development in the U.S. and have far-reaching implications for both doctors and their patients.

Stephen B. Hanauer

“I welcome this addition to the ever-increasing biosimilar market and am excited that we have data demonstrating that multiple switches between adalimumab and adalimumab-adbm are safe and effective for the patient,” Marcus Snow, MD, FACR, assistant professor at the University of Nebraska Medical Center and chair of the American College of Rheumatology’s Committee on Rheumatologic Care, said in an interview.

With a boom of biosimilars to the highest-grossing drug in the world expected to shake-up the drug market in 2023, it is uncertain whether Cyltezo’s coveted interchangeability will hold its competitors at bay or set off a new race for all contenders in the biosimilar space to obtain interchangeable status.

Big Step Forward

Snow believes that the importance of the approval of a biosimilar as interchangeable cannot be understated. “It is a huge deal to have a product that has proven its effectiveness and safety with multiple switches,” he said. “One of the biggest unknowns regarding biosimilars is the long-term effect of multiple switches between medications. Having actual data on multiple switches is a great step.”

That said, many more long-term studies are needed to understand the impact of exposure to different biosimilars. In addition, whether this was an isolated event or the first of many products to go the extra step to achieve interchangeability status remains unknown. If it does portend more such approvals, Snow suggested that the impact on the market is still uncertain.

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Marcus Snow

“We do not yet know how this approval will impact the marketplace for biosimilars,” he said. “It remains to be seen if others will try to match the interchangeability status moving forward. It should be noted that this approved biosimilar is not yet available for use in the United States and it will not be for a while.”

Despite that potential wait, Thomas Seck, MD, senior vice president of medicine and regulatory affairs at Boehringer Ingelheim, remains hopeful about this development. “We continue to believe in the value of the interchangeability designation for all stakeholders,” he told Healio.

While Seck was unable to comment on the specific development strategies of other companies, he believes in the importance of “stimulating a competitive marketplace to bring more affordable treatment options to U.S.patients.”

If there is another key consideration to this development, it pertains to how the FDA defines the efficacy of a medication, according to Seck. “Under the current definition of strength, the FDA encourages, or at least permits, manufacturers to use minor concentration changes as an anti-competitive tactic, depriving patients from more affordable biological products, contrary to the goal of the Biologics Price Competition and Innovation Act (BPCIA),” he said. “For example, any currently approved adalimumab biosimilar cannot be considered biosimilar or interchangeable to the same dose of Humira’s high-concentration formulation.”

Seck noted that based on the way the FDA defines and interprets the efficacy of a medication, a brand biologic manufacturer could take extreme steps to avoid competition. “They could add or remove a single drop of water to its product and thereby block approval of a 351(k) application for a competing product,” he said. “The FDA’s current interpretation completely forecloses licensure of biosimilar and interchangeable products with concentration differences from the reference product, even if they could be proven to have no clinically meaningful differences in terms of safety, purity or potency than the reference product.”

Patients in Practice

Hanauer was measured about the importance and implications of this development for the average rheumatologist. “I don’t think it means that much,” he said.

The main issue for Hanauer is that many rheumatologists have spent enough time using bio-originator products that there will be some resistance to changing therapies, even one that has been deemed interchangeable.

“There will be a few stalwarts, particularly those who are highly attached to originator companies,” he said. “The tentacles of the originators run deep into both clinical practice and patient education, access and availability.”

Other experts, like Snow, are slightly more optimistic. “Two separate issues are helped by this designation,” he said. “First, this will provide some comfort in the long-term effectiveness of Humira when interchanged with adalimumab-adbm.”

Clinician comfort with switching is one thing; educating patients that such a switch will not lead to a decline in efficacy is another.

“For patients, this approval gives some proof that switching between these two medications can be done safely and without alteration in the effectiveness of either,” Snow said. “Until this approval, there had been very little data on the effect of multiple switches on outcomes.”

Despite the compelling nature of the data, not every patient will be convinced, according to Hanauer. “Remember, there is a general concept in psychology called cognitive dissonance, where the more thought and effort you put into something, the more you think it is likely to happen,” he said. “When a patient hears that they are going to switch drugs, they only see one potential outcome: that they are going to do worse.”

Similar fears were voiced by Snow, who suggested that once he has control of inflammatory disease in a patient, he does not want to switch drugs for fear of losing control during the change. “This fear is one of the biggest concerns about biosimilar medications,” he said.

Beyond these concerns about efficacy, there are also practical worries for patients.

“Many patients on the originator drugs are on some sort of assistance program,” Hanauer said. “If they are switched to the biosimilar, are they going to have the same assistance, the same nurse ambassador, the same support systems? Maybe, maybe not.”

The subtext is that rheumatologists should be vigilant before, during and after a switch in order to assuage patient concerns, because these concerns can play out as an impact on real-world outcomes, regardless of what the efficacy data may say.

Cost Savings?

Another potential implication of the interchangeability designation voiced by Snow is one that many rheumatologists saw in biosimilars from the start: The hope for cost savings resulting from a glut of comparable drug options on the market.

“I hope this is the beginning of a reduction in the extreme cost of biologic medications for inflammatory disease,” he said. “Biologics are very effective medications that are life altering for millions with inflammatory disease, but their high cost is limiting access to these therapies.”

Like most rheumatologists, Snow hopes that the continued approval of more biosimilars — and especially those with interchangeable designations — would begin to drive down costs of care for those on biologics. “But, unfortunately, I do not think we can expect any changes to benefit patients for a while,” he said.

It is with this in mind that Boehringer Ingelheim filed a Citizen Petition asking the FDA to correct its interpretation of the term “strength” as used in the BPCIA, according to Seck.

“It is important to understand Boehringer Ingelheim's Citizen Petition is not about competitor strategies but how FDA’s interpretation affects the future uptake of biosimilars,” Seck said. “We believe that a positive action from the FDA regarding the definition of strength will ensure robust biosimilar competition, providing increased therapeutic choices for stakeholders leading to further savings for patients.”

It is uncertain if or when the FDA may weigh in on this definition of strength. In the meantime, the courts are likely to be involved in one way or another, according to Hanauer. “There are ongoing legal battles regarding the patent rights for all of these agents moving forward,” he said.

For more information:

Stephen B. Hanauer, MD, can be reached at 16th Floor, Clinic: 259 E Erie Street, Chicago Illinois 60611; email: shanauer@northwestern.edu.

Thomas Seck, MD, can be reached at 900 Ridgebury Road, Ridgefield, CT 06877; email: susan.holz@boehringer-ingelheim.com; @boehringerus.

Marcus Snow, MD, can be reached at 110 N 175th St, Omaha, NE 68118; email: jgivens@rheumatology.org.