Hoping for a biosimilar ‘sea change’: Rheumatologists weigh 2023 end of Humira exclusivity
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In 2021, Humira, the blockbuster biologic that has for years been the highest grossing drug in the world, accomplished something that no drug had previously achieved when its global revenues topped $20 billion.
More precisely, Humira (adalimumab) earned $20.7 billion in revenue in 2021 — including $17.3 billion just from U.S. sales — for its manufacturer AbbVie after coming just a few hundred million short of the $20 billion benchmark for three years in a row. However, while this news was no-doubt greeted warmly by the company, AbbVie’s fourth-quarter 2021 financial report included another figure that may have somewhat dampened any board-room festivities.
Source: Stephen B. Hanauer, MD.
It turns out that Humira’s net revenues from outside of the United States — totaling $3.4 billion for the year — had decreased 9.6% on a reported basis, or 12.8% on an operational basis, compared with 2020. According to the financial report, this decrease was due to “biosimilar competition.”
And the situation is unlikely to get any easier for the company come 2023.
The reason: That biosimilar competition, long kept at bay and limited to European and other overseas markets by AbbVie’s use of patent litigation, is coming for Humira in the United States, and it is coming soon. Following a series of legal settlements between AbbVie and various biosimilar manufacturers, at least seven — but possibly as many as 10 — adalimumab biosimilars will be hitting the U.S. marketplace for the first time in 2023.
Meanwhile, AbbVie’s newly arrived exclusive drugs that treat many of the same indications as Humira — Skyrizi (risankizumab) and Rinvoq (upadacitinib) — netted downright paltry revenues of $2.9 billion and $1.7 billion in 2021, respectively.
However, whether or when that influx of competing agents will fundamentally alter the treatment landscape in rheumatology, and offer a much-needed shot in the arm for biosimilar uptake in the United States, is far from certain.
“On an individual patient basis, when all of these adalimumab biosimilars hit the market, it is not likely to make a difference — at least not immediately,” Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern Medicine, and professor of medicine at the Feinberg School of Medicine, told Healio Rheumatology. “Patients with commercial insurance now pay around $5 a month for Humira. I can’t imagine the pricing of biosimilars competing with that.”
However, for those without insurance, the out-of-pocket cost for a month’s worth of Humira can be as high as $7,000. According to Hanauer, this is where newly available biosimilars may actually make a difference.
“They could have more options at a lesser cost,” he said. “Those who fall into the donut hole of Medicare may also have a lower cost.”
Still, experts like Steven Newmark, director of policy and chief legal officer for the Global Healthy Living Foundation (GHLF), are much more skeptical about the cost savings that may result from several new biosimilars.
“It depends on whose wallet you are talking about,” he said.
2023 Release Dates
A total of seven FDA-approved adalimumab biosimilars are now cleared for a 2023 release in the United States. For some of these drugs, it has been nearly a decade since they were first approved for use.
First out of the floodgates will be Amgen’s Amjevita (adalimumab-atto), with a settlement-enforced launch date of no earlier than Jan. 31. Then will come Hadlima (adalimumab-bwwd, Organon), no earlier than June 30; Cyltezo (adalimumab-adbm, Boehringer Ingelheim) and Yusimry (adalimumab-aqvh, Coherus), both starting on July 1; Hulio (adalimumab-fkjp, Mylan), no earlier than July 31; Hyrimoz (adalimumab-adaz, Novartis Sandoz), starting on Sept. 30; and Abrilada (adalimumab-afzb, Pfizer), no earlier than Nov. 23.
Additionally, three companies have inked deals with AbbVie to allow the U.S. release of their own biosimilars in 2023 pending FDA approval. These are Fresenius Kabi, which expects to release its adalimumab biosimilar on Sept. 30; Celltrion, which is eyeing July for its Yuflyma (CT-P17); and Alvotech/Teva, which will be able to legally release AVT02 on July 1 following FDA approval.
Both Fresenius Kabi and Celltrion were, as of the time of this writing, still expecting an FDA decision by the end of 2022. Meanwhile, an FDA decision regarding Alvotech’s Humira biosimilar is on hold until the company can address “certain deficiencies” the administration found during a March inspection of its manufacturing facility in Reykjavik, Iceland.
In a perfect world, multiple new drugs would lead to competition that would lower the burden of copays, deductibles and premiums for patients.
However, Newmark fears that pharmaceutical companies, insurance carriers and pharmacy benefit managers (PBMs) are more likely than patients to benefit from the expanded number of treatment options.
These financial ramifications are just one component of the biosimilar discussion. There are also clinical considerations pertaining to their safety, efficacy and interchangeability with their bio-originator reference products. The clinical trial process leading to FDA approval of biosimilars is as rigorous as it is for any drug and far more demanding than the process for generic small molecule drugs. This process has been widely documented at conferences and in peer-reviewed literature.
“You would have to be living under a rock as a rheumatologist if you are not familiar with biosimilars at this point,” Vibeke Strand, MD, adjunct clinical professor at the division of immunology and rheumatology at the Stanford University School of Medicine, said in an interview.
For patients, though, it is a different story. Whether they are familiar with biosimilars or understand the concepts at hand — for example, interchangeability and the difference between a biosimilar and a generic drug — is much less clear. In fact, for some patients, the distinction may not even matter.
“Patients just want to know two things,” Hanauer said. “Is the drug going to work the same? And will it have the same side effects?”
That said, 2023 will, in all likelihood, be the beginning of some shift in the rheumatology pharmaceutical marketplace. The size and nature of that shift will depend on several factors that are, unfortunately, largely beyond the control of both doctors and patients.
‘PBMs Will Decide on Almost Everything’
In a paper published in Current Treatment Options in Rheumatology, Brasington and Strand summed up a response to the question of whether more biosimilars would lead to lower prices for patients.
“Major changes in the operation of the U.S. health system must also occur for the full potential for cost savings to be realized with use of biosimilars as substitutes for our revolutionary, but extremely expensive, biologic medications,” they wrote.
If there is one key element of the U.S. health care system that needs to change, it is PBMs, according to Strand.
“We have no idea how they function, how they set their prices or how they are viewing these multiple biosimilars that will hit the market,” she said. “PBMs will decide on almost everything about the cost and availability of biosimilars, and we have no idea what or how they will make these decisions.”
According to Amelia Bond, PhD, of Weill Cornell Medical College, in New York, early experience with other biosimilars in the United States indicates that prices may “decline modestly” at initial entry of the cluster of adalimumab biosimilar products. Other experts have similarly pointed to the advent of generic medications as a predictor of how new biologics will perform.
“Historically, when a new generic enters the market, the cost savings for patients is typically 80% to 85% lower than the originator,” Newmark said. “The same should be true for biosimilars, but for this to happen, the insurers and PBMs have to put a crowbar in their wallet and share the savings with patients.”
Advocacy organizations like GHLF, CreakyJoints and the Alliance for Transparent and Affordable Prescriptions (ATAP) have been urging lawmakers to consider PBMs and the opacity of the U.S. health care market for years, with varying degrees of success. The message is beginning to have some impact, with legislation targeting the role of PBMs in the health care system recently being introduced in Congress. However, it remains uncertain whether that legislation will even make it to the floor for debate, given the current institutional gridlock in the legislative bodies.
In the meantime, there are some aspects of Humira, and its biosimilars, that may influence their uptake that need to be carefully considered.
A Unique Biosimilar
Humira and its biosimilars are unique for a few reasons, according to Bond.
“First, Humira is primarily a medication prescribed in the retail setting,” she said. “Patients pick it up from a traditional pharmacy and self-administer it.”
Other biosimilar launches, meanwhile, were for drugs traditionally administered by a provider in the physician office or hospital outpatient setting, Bond added. The self-administered nature of adalimumab may impact use and, consequently, pricing.
“The second point is that there are at least seven biosimilars launching, which is many more than we have seen for previous reference products,” Bond said. “Theoretically, additional biosimilars should exert more pressure to decrease prices.”
Whether this will translate into actual cost savings remains to the be seen, and will likely only be known after some time has passed with the products on the market.
The last point, according to Bond, is interchangeability. The FDA designated Cyltezo as the first interchangeable biosimilar to treat certain inflammatory diseases in 2021, allowing pharmacists to substitute it for Humira without the need for the prescriber to alter the prescription. It was, at the time, just the second interchangeable biosimilar product approved by the FDA, and the first monoclonal antibody.
Since then, the FDA has accepted applications for interchangeability from Alvotech and Pfizer for their Humira biosimilars. Meanwhile, Amgen and Organon have announced they are also seeking interchangeability status for their own Humira biosimilars.
“These will be the first launches with this designation,” Bond said. “The additional interchangeability designation allows the pharmacist to substitute the branded Humira with an interchangeable biosimilar. However, substitution can only occur in states that permit this.”
The dependence on state regulations is another unique aspect of the U.S. health care system that could significantly impact the biosimilar market.
“The only biosimilars that are broadly used in the United States are for infliximab (Remicade, Janssen), which is used primarily in the Veterans Administration and Kaiser systems,” Strand said.
She added that uptake of rituximab (Rituxan, Genentech) biosimilars has also increased beyond the VA and Kaiser systems.
“But it is hard to know what is being used, and where, and how payers are determining the preferences for which biologics are used for rituximab,” she said.
Rheumatologists, then, will be at the mercy of not only PBMs and insurance formularies, but of regulations in their individual state. Understanding physician attitudes and knowledge about biosimilars could also influence prescriptions and use moving forward.
Comfort and Concerns
In a paper published in Rheumatology (Oxford), Gibofsky and McCabe aimed to assess perceptions surrounding biosimilar products among U.S. physicians. Specifically, they surveyed rheumatologists who are familiar with TNF-alpha inhibitors and rituximab biosimilars.
The analysis included responses to a 19-question survey from 320 U.S. rheumatologists. Results showed high familiarity with the FDA definition of a biosimilar product. Respondents also knew that an infliximab biosimilar was already on the market. However, there was less familiarity with the status of the FDA approval of adalimumab, etanercept (Enbrel, Amgen) and rituximab biosimilars.
There was understanding among 84% of the group that the FDA did not automatically deem a biosimilar as interchangeable. Additionally, 73% said they were more likely to initiate a biosimilar in a biologic-naïve patient. However, just 35% reported that they would switch to a biosimilar in a patient with RA who was meeting treatment goals on the bio-originator.
“We have heard that some health care providers, including rheumatologists, have concerns with prescribing biosimilars, while others are completely comfortable with using FDA-approved biosimilars,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the FDA, told Healio Rheumatology.
Consistent with the findings from Gibofsky and McCabe, Yim noted that most of the concerns she hears are related to switching stable patients from a reference product to a biosimilar or interchangeable drug.
“However, all FDA-approved biological products, including reference products and biosimilar products, undergo a thorough evaluation and meet FDA’s rigorous standards so that health care providers and their patients can be assured of the efficacy, safety and quality of these products,” she said.
That said, it is critical that insurance companies do not insist on switching a patient to a biosimilar simply to protect or increase profit, according to Newmark.
“If someone is doing well on their biologic, switching medications could be disruptive and lead to unintended health consequences,” he said. “The decision to switch should be one made between a rheumatologist and their patient in relation to each person’s individual medical needs and treatment preferences.”
According to Yim, much of the hesitancy regarding biosimilars in general is “simply expected” due to the fact that these are relatively new products in the United States.
“There is a lack of experience with prescribing these products,” she added.
However, that experience is growing. Biosimilars have been used in the United States since 2015 with no major safety or efficacy issues.
“They have been used in Europe for more than 15 years with great success,” Yim added.
Patience may be the most essential factor when considering the impact that biosimilars will ultimately have in rheumatology.
“If you take the field of cancer as an example, hematologists and oncologists do not pay much attention to biosimilars anymore because they have been accepted as part of the system for many years,” Hanauer said. “The newness is to the field of immune disease.”
Both rheumatologists and their patients may eventually reach a point where biosimilars are as accepted as they are in the cancer field. In the meantime, it may be useful to explore patient attitudes surrounding biosimilars to predict how they may be perceived, and used, in the coming years.
The Promise of Real-World Data
According to Hanauer, there is a psychological component to a non-brand name medication that plays a significant role in how it is perceived. And a significant part of that perception is wrapped up in a drug’s price tag.
Although the cost of the adalimumab biosimilars coming to market is not yet known, it is likely that they will carry cheaper sticker prices than Humira.
“The idea of a new product that is perceived as generic can lead to cognitive dissonance,” Hanauer said. “If something costs more, it can be perceived as better, even if it is not better, or if it has been proven in clinical trials to be exactly the same.”
Like many other experts, Newmark reiterated that biosimilars are carefully evaluated by the FDA.
“But rheumatologists and patients were very happy with the originator drugs because these drugs took people out of wheelchairs, and gave them back into their social, personal, and professional lives,” he said. “Who would want to risk losing this personal and economic freedom?”
This is just one patient consideration, but there may be many others, according to Strand. “Since there has not been a broad penetration of biosimilars in this country as yet, I do not think we have any real idea what patients are thinking about them,” she said.
Fortunately, data on this topic are beginning to accrue, particularly in Europe. It may be possible to look to the European experience to see how patient attitudes could evolve in the United States.
In a prospective observational analysis published in the European Journal of Hospital Pharmacy, Barbosa and colleagues queried 134 patients about their experience with an etanercept biosimilar. Results demonstrated that the majority of patients were satisfied with the administration method of the biosimilar product. Overall satisfaction was also high.
Another reason patients under the rheumatic and autoimmune umbrella may ultimately accept biosimilars pertains to the chronic nature of their conditions.
“About 75% of our therapies are for diseases that are chronic,” Strand said. “For example, in RA, once they get past methotrexate, they are going to be taking a biologic forever after.”
The long-term nature of treatment breeds a familiarity with the treatment landscape and a more intimate understanding of the relationship between the benefits and adverse events of any drug, Strand added. Rheumatology patients are keenly in tune with their pain and functional limitations on a day-to-day basis, as well as how the drugs they take impact that pain and function.
It is for this reason that Bond is anxiously awaiting the first wave of data from the adalimumab biosimilars in real-world settings, as opposed to clinical trials.
“This will determine whether these medications are taken up at a faster rate and whether prices decline more than modestly as in early biosimilar launches,” she said.
For Strand, a companion point about the patient experience in rheumatology is that they are adapt at — or at least familiar with — navigating the health care system.
“If you are using a biologic, you are accustomed to dealing with a specialty pharmacy, there are often patient assistance programs from pharma involved,” she said. “They are FedExing the drug, there is prior authorization required. It is already a much bigger and more detailed procedure than it is for patients taking other types of medications.”
That said, not every rheumatology patient is going to be as savvy about drug acquisition and use as, for example, a patient with RA who has been on biologics for a decade.
“Many new patients are still unfamiliar with biosimilars and confused by the many terms that come along with biosimilars, like interchangeability or extrapolation,” Newmark said. “Further, we know patients go through trial and error to find the right medication, which carries an emotional and physical burden.”
With that in mind, being switched to a biosimilar may be intimidating for patients, according to Newmark.
“That is why our organization is publishing educational content to inform patients about biosimilars and alleviate stress, so when the time comes that they are faced with a biosimilar option, they can have an informed conversation with their doctor and care team,” he said.
Signaling for a ‘Sea Change’
Hanauer noted that, after some initial uncertainty, societies like the American College of Rheumatology have been on board with biosimilar uptake, creating patient-facing materials as well as informational sessions at conferences and meetings. The same is true for other organizations.
“I have done a number of presentations for the American Gastroenterological Association and other organizations to educate people about biosimilars,” he added. “One of the concepts I discuss is that they will lower costs.”
However, Hanauer stressed that the issue keeps coming back to one fundamental problem — how long it will take for patients to benefit.
“It does not seem likely that they will lower the cost for the patient immediately,” he said. “It may take 10 years because most patients do not pay for their drugs.”
Organizations like the Arthritis Foundation and the GHLF are engaged in similar efforts at patient and provider education.
“The Global Healthy Living Foundation recently launched a new podcast called Breaking Down Biosimilars, to help patients and providers become more comfortable with biosimilars,” Newmark said. “The podcast features a range of experts, including physicians, a pharmacist, researchers and patients living with rheumatic disease, who share their story of starting on a biosimilar. Our goal is to educate patients on what biosimilars are, how they get approved, their potential savings, and what promise they hold.”
GHLF also has published the free, downloadable “Patient Guide to Biosimilars,” while CreakyJoints regularly publishes articles that deal with all aspects of the topic, from health insurance to specialty pharmacies.
“Much of our ArthritisPower research also explores how patients make decisions about their treatment, based on the preferences and concerns,” Newmark said.
It seems encouraging that the FDA, societies like the ACR and advocacy organizations are all on the same page when it comes to making biosimilar products available for patients with rheumatic diseases. The main question, then, is when.
“With so many biosimilars coming on to the market, we hope it signals a sea change that biosimilars will finally live up to their intended purpose of providing effective, safe treatment at a more affordable cost in the coming years,” Newmark said. “If so, this could lead to large savings for both patients, and in the case of Medicare, the national health care system.”
- References:
- Barbosa CMM, et al. Eur J Hosp Pharm. 2021;doi:10.1136/ejhpharm-2019-001999.
- Brasington R, Strand V. Curr Treat Options in Rheum. 2020;doi:10.1007/s40674-020-00159-6.
- Gibofsky A, McCabe D. Rheumatology (Oxford). 2021;doi: 10.1093/rheumatology/keaa502.
- For more information:
- Amelia Bond, PhD, can be reached at 402 E. 67th St., Room LA 220 | New York, NY 10065; email: amb2036@med.cornell.edu.
- Stephen B. Hanauer, MD, can be reached at 16th Floor, Clinic: 259 E. Erie St., Chicago, Illinois 60611; email: shanauer@northwestern.edu.
- Steven Newmark can be reached at 15 N. Midland Ave., Nyack, NY 10960; email: jdaitch@ghlf.org.
- Vibeke Strand, MD, can be reached at 306 Ramona Rd., Portola Valley, CA 94028; email: vibekestrand@me.com.
- Sarah Yim, MD, can be reached at 10903 New Hampshire Ave., Silver Spring, MD 20993-0002; email: cdertradepress@fda.hhs.gov.
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