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The review focused on Remicade (infliximab) and Enbrel (etanercept). The annualized discontinuation rate was 21% among patients who had undergone nonmedical switching to biosimilars. However, the rates were similar to those found in separate analyses of patients on reference biologics.

A review of multiple studies of anti–tumor necrosis factor (TNF) biosimilars has found high discontinuation and switchback rates, although the authors suggest these rates are comparable to those for patients treated only with reference products.

, an associate professor at the University of Missouri-Kansas City School of Pharmacy, and colleagues, also note extreme variation in rates among the studies, a pattern which they attribute to differences in study methodology and size, among other factors.

Journal of Pharmaceutical Policy and Practice

, was limited to studies from 2012 to 2018, a period when biosimilars were not well established in the United States. Consequently, most of the referenced studies were conducted in the European Union.

Promoting Biosimilar Uptake Requires a Well-Brewed Approach

For example, Enbrel (etanercept) and Humira (adalimumab) biosimilars were first approved in Europe in 2016 and 2017, respectively. Biosimilars of these biologics are not yet available in the United States.

The authors focused their review on biosimilars of Remicade (infliximab) and Enbrel, which are used for treatment of rheumatologic and gastroenterologic conditions. Based on 62 prospective and retrospective studies, the annualized discontinuation rate was 21% among patients who had undergone nonmedical switching to biosimilars.

By therapeutic area, the discontinuation rates were 26% and 17% for rheumatology and gastroenterology, respectively. The average time to discontinuation was six months across 10 studies that reported this information.

The rate at which patients on biosimilars switched back to reference products was 14%, based on data from 29 studies. By therapeutic area, the switchback rate was 17% and 8% for patients receiving rheumatologic and gastroenterologic care, respectively.

The authors also measured the incremental discontinuation rate — the difference in discontinuation rates between patients who underwent nonmedical switching to biosimilars and those who stayed on reference products.

This rate was 18% across all therapeutic areas, “indicating a significantly higher discontinuation rate among switchers than non-switchers,” Liu and colleagues wrote.

Although results varied widely across studies included in the review, the overall findings were not markedly different when compared with discontinuation rates reported in separate analyses of patients on reference biologics alone.

These discontinuation rates (for patients on reference products) were 21%, 37%, and 52% for the 6-month, 2-year, and 4-year treatment intervals, respectively.

“Switching from a TNF inhibitor to its biosimilar for nonmedical reasons was found to be associated with a high prevalence rate of biosimilar discontinuation due to treatment failure or adverse events, and a high switchback rate, but comparable with the yearly discontinuation rate of the original TNF inhibitor,” wrote the researchers

They said strong patient education that includes discussion of the nocebo effect could be valuable in reducing discontinuation and switchbacks. The nocebo effect is like the placebo but rather than ascribing benefit from an intervention related to a belief that it works, people ascribe negative consequences because of prior beliefs about side effects and lack of efficacy.

“Healthcare providers should educate patients about the efficacy of biosimilars in layman’s terms and avoid technical jargon and ambiguous statements,” they wrote.

At the time of the study, no U.S. biosimilars had achieved the interchangeable designation, which requires clinical studies demonstrating no difference in outcomes for patients switched between reference and biosimilars multiple times.

“Some physicians believe that small changes in these patients’ overall treatment regimens, which are often established after multiple rounds of trial and error, may have unwanted negative effects,” Liu and colleagues observed.

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The review focused on Remicade (infliximab) and Enbrel (etanercept). The annualized discontinuation rate was 21% among patients who had undergone nonmedical switching to biosimilars. However, the rates were similar to those found in some separate analyses of patients on reference biologics.

Biosimilar Discontinuation Rates Are High But Comparable to Those for Reference Biologics: Review

It’s an open question whether the Inflation Reduction Act (IRA) will be good or bad for biosimilars.

Associations of manufacturers who produce both reference drugs and biosimilars contend that allowing CMS to negotiate reference drug prices for the Medicare program could undermine prices that biosimilar manufacturers count on to earn a return on their investment.

But backer of the legislation, which President Joe Biden signed into law on Aug. 16, say that biosimilar market will be well protected and even fostered. They point to the provisions that are designed to incentivize doctors to prescribe biosimilars by paying them an add-on fee of 8% of the average sales price (ASP) of the reference drug in addition to the cost of the biosimilar, a 2-percentage point increase from the current 6% add-on. The change becomes effective October 1, 2022.

Also, CMS doesn’t have free rein to negotiate drug prices. The IRA limits negotiation to drugs for which there are no biosimilars currently on the market and none expected to come on the market in the next two years

Furthemore if manufacturers of reference drugs manage to delay biosimilar entry beyond that two-year window, they won’t be allowed to delay price negotiations and they may have to pay money back to Medicare.

These provisions of the IRA are intended to ensure that biosimilars work their free-market magic by competing on price with expensive biologics.

Based on the terms of the IRA, Humira (adalimumab), a drug for rheumatoid arthritis and other autoimmune diseases, will not see forced negotiation with Medicare because biosimilars are anticipated to reach market starting about three and a half months from now, in January of next year

Amgen’s Enbrel (etanercept), another top-selling autoimmune product, could see Medicare price negotiation and other restrictions under the IRA. Enbrel will have had roughly 30 years of exclusivity by the time its key patents expire in 2029 and FDA-approved biosimilars can enter the US market.

Any biologics that have been on the market for at least 13 years will be subject to negotiation, starting in 2026 for Medicare Part D drugs and 2028 for Part B drugs. Enbrel is covered under Part D.

Starting in 2023, however, the IRA imposes inflation caps that could also affect Enbrel. Amgen has long faced criticism for raising the price of this drug well in excess of inflation. This also has been the case in 2022, when Amgen raised the price of Enbrel 9.4%, above the 9.1% rate of inflation. From 2019 to 2020, half of drugs reimbursed by Medicare had price increases that 

The IRA will penalize manufacturers who raise the price of their drugs above the inflation rate by forcing them to rebate that excess cost.

The IRA will phase in negotiation slowly, so Medicare will go after just the top-selling drugs at first to maximize potential savings. Despite that slow pace, Medicare is anticipating savings of 25% to 65% on drugs selected for negotiation.

Eylea (aflibercept) is a top-selling Part B drug for macular degeneration that has yet to face biosimilar competition, so it could become a target for negotiation. Eylea’s 2022 estimated sales top $6 billion.

So far in the United States, there are biosimilars marketed for just nine types of biologics, so in the biologics category is wide open for reference drug negotiations.

Several provisions in the law are designed to protect and foster the biosimilar market. But some representatives of the sector see CMS drug price negotiation as a threat to profit margins.

How the Inflation Reduction Act May Affect Biosimilars

Just how similar are biosimilars to their brand-name “originators”? That is a question that continues to hang over biosimilars and impede their acceptance into everyday healthcare. Congress and the FDA may have unwittingly fed the doubts by creating the interchangeable designation. Some manufacturers contend there is a perception, encouraged by the makers of interchangeable biosimilars and their marketing tactics, that interchangeables are somehow “better biosimilars.”

Biosimilars are certified by drug regulators, such as the FDA in the U.S. and the European Medicines Agency in Europe, to be as safe and effective as their reference products. Interchangeable biosimilars are no different from biosimilars, except that when a physician prescribes an originator biologic, pharmacists can give the patient an interchangeable biosimilar without having to consult the physician, subject to individual state laws.

Adding to the confusion is that interchangeable biosimilars undergo switching studies to ensure that patients who go back and forth between the originator agent and the interchangeable agent won’t experience any difference in outcomes.

Companies such as Alvotech and Biocon Biologics are using the interchangeable designation as a marketing ploy to set their biosimilars apart from others. The tactic is a concern for manufacturers such as Samsung Bioepis that opted to create plain-Jane biosimilars without the interchangeable designation.

“It is increasingly urgent that semantics are clarified,” lead authors Joseph P. Park, Ph.D., senior manager of regulatory affairs for Samsung Bioepis, and Gillian Woollett, M.A., vice president and head of regulatory strategy and policy at the company, wrote in an opinion piece published in 

 in June. Their central argument is that interchangeability “is a legal distinction, not a clinical one.”

The other authors of the piece also work for Samsung Bioepis, which has a major stake in the interchangeable debate. The South Korean company has developed a biosimilar to Humira (adalimumab) called Hadlima (adalimumab-bwwd) that is not designated as interchangeable.

The interchangeable issue will come to a head next year when the Humira market will be flooded with biosimilars, both interchangeable and regular. As many as 11 Humira biosimilars may enter the market in 2023.

Although interchangeables can be substituted more freely at the pharmacy counter, doctors (not pharmacists) still can substitute regular biosimilars as they wish and use them as indicated by the FDA or off label. “For every FDA-licensed biosimilar, physicians and their patients can have as much confidence as they historically have had with the originator product,” Park and Woollett wrote in 

Interchangeables have not been around that long. Semglee (insulin glargine-yfgn) was approved as the first interchangeable biosimilar in July 2021. Biocon Biologics specifically sought that designation so it could rebrand Semglee and strengthen its marketing appeal.

Boehringer Ingelheim’s Humira biosimilar, Cyltezo (adalimumab-adbm), received an interchangeable designation in October 2021, and Alvotech, an Icelandic company, may get one for its Humira biosimilar, named AVTO2 for now. The FDA is currently reviewing the company’s application for AVTO2, and the biosimilar could hit the market mid-2023. That would pit two interchangeable Humira biosimilars against the rest of the Humira biosimilar field, although Pfizer, Amgen and Samsung Bioepis have said they also intend to seek interchangeable status for their biosimilars. Because they are coming on the market during the same year, the Humira biosimilar market in 2023 and beyond will be a good test whether the interchangeable designation will be an advantage for biosimilars.

Interchangeability in other countries is not an added regulatory distinction, according to Park, Woollett and their colleagues. “European Union regulators have stated that they consider all their approved biosimilars to be interchangeable as a clinical matter,” they wrote.

Public health authorities in Canada, impatient with the slow pace of biosimilar adoption, have forcibly switched patients to biosimilars unless their doctors obtain medical exemptions. Canadian officials consider biosimilars to be equal to reference products, period, and therefore the issue of interchangeably is moot.

As Canadian experience has shown, physicians can be hesitant about adopting biosimilars, and many tend to hold out for as much clinical data as they can get. This tendency gives an edge to companies that invest in additional switching studies so their biosimilar can qualify for an interchangeable designation.

However, many biosimilar experts argue that biosimilar comparability to reference products is demonstrated best by analytical testing, such as laboratory pharmacokinetic and pharmacodynamic studies. Clinical studies conducted with human subjects are less precise, they say. Occasionally, biosimilar studies conclude that biosimilars are not always close copies of reference products. Sometimes these differences are chalked up to the nocebo effect — when people experience adverse effects and other negative consequences from a medication (or a placebo) that they believe is inferior or possibly harmful.

 in late 2021 will not help the case for those arguing for biosimilars. The results showed that patients who switched to the Humira biosimilar Amjevita (adalimumab-atto) were more likely to have exacerbated symptoms of psoriasis. The authors wrote that 30% of patients receiving Amjevita had increased psoriasis severity and lower quality of life. They said outcomes returned to normal when patients restarted Humira.

However, the study was retrospective, conducted at a single center and unblinded, all of which cast some doubt on the validity of the findings. Amjevita, an Amgen product, is scheduled to be the first Humira biosimilar to come on the U.S. market in 2023. It does not have the interchangeable designation.

The FDA has worked to educate the public on the differences between biosimilars and interchangeable biosimilars, and more guidance is on the way. Sarah Yim, M.D., director of the Office of Therapeutic Biologics and Biosimilars at the FDA’s Center for Drug Evaluation and Research, outlined some of the agency’s plans in a talk in late 2021. She said manufacturers also need help understanding what happens to interchangeable designations when the method of administration changes. Such changes could raise questions about whether interchangeable biosimilars are still interchangeable with reference products if reference products are delivered another way.

Tony Hagen is a medical, business and environmental editor and writer in Florence, New Jersey.

Some companies are using the interchangeability designation as a marketing ploy.

Are Interchangeable Biosimilars Better? 

Insulin prices, once only known to patients, families and a few insiders, have entered the political arena in a big way and are not going to leave any time soon.

A $35 cap on monthly out-of-pocket expenditures for insulin is a signature part of the Inflation Reduction Act that President Joe Biden signed on this week and a talking point that Democratic supports of the legislation believe will serve them well.

But the cap only applies to people covered by Medicare. Many advocacy groups, patients and their clinicians see the measure as half a loaf for insulin affordability: a good deal better than nothing but only partial.

“The removal of the $35 per month cap for commercial plans by the Senate leaves millions of Americans, including more than 1.6 million people with type 1 diabetes, facing inflated prices of a drug they need every day to stay alive,” said JDRF, a research and advocacy organization for Type 1 diabetes, which used to be referred to as juvenile diabetes. The organization heaped blame on the Senate because a legislative maneuver in the upper house that would extended to the cap to commercial plans failed. 

Before insulin cap for Medicare beneficiaries was subsumed into the Inflation Reduction Act, it was one of the main features of 

 that had passed the House in late March and had been introduced in the Senate. It’s possible that legislation will be revived this fall.

In the meantime, there have been assorted effort to put cheaper insulin into the hands by manufacturing and marketing biosimilars. Whether those efforts will lose steam if the cap for Medicare beneficiaries gets extended to those with private insurance remains to be seen.

California has firmed up plans to manufacture its own insulin biosimilar by earmarking $100.7 million for the purpose in its 2023-2024 budget. The plan includes construction of a biosimilar manufacturing plant. It’s possible California may license an existing FDA-approved biosimilar, otherwise it could take up to nine years to develop a biosimilar insulin, according to industry estimates. Regulatory review and legal opposition from reference product companies could add to that time.

California “has the potential to become a producer of last resort, remedying drug shortages and addressing what researchers have described as oligopolistic market structures and other market failures that plague the pharmaceutical industry,” state officials explained in a project brief.

Maine and Michigan are also investigating becoming insulin manufacturers, according to the FDA.

And in March, various payers, including Blue Cross of California and Kaiser Permanente, announced they were joining an initiative by the nonprofit Civica to manufacture insulin biosimilars. Civica aims to ensure that through this production patient costs for insulin do not exceed $30 per vial or $55 for a box of 5 prefilled pens. Intermountain Healthcare, a healthcare system headquartered in Salt Lake City, and Trinity Health, a Catholic healthcare system headquartered in Livonia, Michigan, are participating in Civica’s efforts

The three biggest manufacturers in the U.S. insulin market are Eli Lilly, Novo Nordisk, and Sanofi. They have been accused of monopolizing sales of insulin products and gouging patients. The issue is politically charged, as 37.3 million Americans, or 11.3% of the population, have diabetes, according to the CDC. Many Americans believe that prescription drug prices are too high. A 2019 study by Data for Progress said 44% of all voters “strongly support” allowing governments to produce their own copycat prescription drugs if the price is too high.

Part of the rebuttal from Lilly, Novo Nordisk, and Sanofi has been that the rebates they pay to insurers — and prescription benefit managers, more specifically —are a big part of the problem because payers do not necessarily share them with patients.

 said that average one-year insulin OOP costs were $474 for all patients and $1,288 for uninsured patients, based on 2014-2017 data. A March 2022 

 by KFF suggested 75% of patients with private insurance would save between $19 and $42 a month if insulin OOP rates were capped at $35.

 from CharityRx, a discount card provider, said a very high percentage of insulin users have financial difficulty as a result of the cost of insulin; 4 out of 5 people it surveyed said they had taken on credit card debt to pay for insulin.

A number of states have instituted “safety net” programs that provide temporary relief from insulin OOP costs, but such relief will not eliminate the problems identified by the CharityRx study.

Lilly, Novo Nordisk, and Sanofi have each instituted caps on insulin costs for some patients. At the start of the pandemic, in 2020, Eli Lilly announced that it would allow anyone with commercial insurance or no insurance at all to obtain insulin for a $35 monthly copay.

Meanwhile, there are price competitive alternatives to the top brand insulins on the market. Semglee, a biosimilar to Lantus (insulin glargine; Sanofi) was rebranded and relaunched this year by Biocon Biologics/Viatris and has since made its way on to formulary as a preferred agent by Express Scripts and Prime Therapeutics, both pharmacy benefit managers. An unbranded version of Semglee was launched at a 65% discount to Lantus, based on list price. 

Also, Basaglar (Lilly), which is a highly similar copy of Lantus but not officially a biosimilar, was launched in 2016 and has been credited with capturing market share and significantly reducing the cost of Lantus.

The Inflation Reduction Act puts a $35 cap on monthly out-of-pocket expenses for insulin. The catch: It applies only to people covered by Medicare. Some states, including California, and Civica Rx, the generic drugmaker, are gearing up to make biosimilar versions of brand-name insulin products. The competition could drive down prices.

  The Holy Grail Search for Affordable Insulin: The Quest Continues

Concerned about potential neonatal immune suppression, the American College of Rheumatology recommends against using biological disease modifying anti-rheumatic drugs (bDMARDs) during pregnancy, but in a retrospective 

, Rebecca Scott, BM BCh, MA, PhD, MRCP, and her co-researchers conclude that the evidence goes contrary to this guidance.

Scott, the lead author, and her colleagues at University College London Hospital looked at tumor necrosis factor inhibitor (TNFi) biosimilar use in 18 pregnant women at a tertiary medical center. They observed no harmful outcomes for infants from biosimilar therapy use by their mothers and said disease flareups caused by biosimilar cessation are the bigger concern.

“Not only should women on biosimilar therapies feel confident to conceive while using these drugs, but it would appear prudent that continuation of biosimilar TNFi therapy throughout pregnancy should be the norm rather than the exception to prevent later disease flares,” Scott wrote in the 

This was the first study of biosimilar bDMARDs in pregnant women and was undertaken because there are minute differences between biosimilars and their reference products whose significance needs to be elucidated, Scott wrote. The findings were consistent with outcomes reported in studies of TNFi reference products in pregnant women.

Women in Scott’s study underwent treatment with biosimilars of Humira (adalimumab), Enbrel (etanercept), and Remicade (infliximab). Humira biosimilars launch in the U.S. market in 2023 and Enbrel biosimilars are expected in 2029. Nine of the women enrolled in the study had inflammatory rheumatic disease and six had inflammatory bowel disease.

The study evaluated outcomes for women who had been on bDMARDs for an average of five years prior to conception. Two women discontinued biosimilar use in the first trimester, eight in second, and one in the third. Disease flareups occurred in seven women who stopped biosimilar treatment and two who continued without stopping. Six women restarted biosimilar therapy as a result of flareups.

Scott wrote that all pregnancies resulted in live births. She and her researchers identified a significant risk for earlier delivery in women who stopped treatment with biosimilars (38 weeks and 5 days vs 39 weeks and 5 days).

However, no newborns required admission to the neonatal unit and no congenital abnormalities were observed. One child was born with “floppy larynx,” which is loose tissue that impairs breathing and feeding and is correctable with surgery. One birth was preterm (36 weeks and 6 days). The average birth weight was 7.1 lbs.

Scott said 16 women were breastfeeding at discharge and 13 were on biosimilars at three months postpartum.

“Within our cohort, 64% of those women who stopped their biosimilar therapy had a flare in their inflammatory disease in late pregnancy or in the postpartum period….

“Our data suggest that the risk of inflammatory disease flare persists even if the biological therapy is continued into the middle of pregnancy before being stopped.”

Disease flareups occurred in seven women who stopped biosimilar treatment and two who continued without stopping, according to findings published in the journal Obstetric Medicine.

Biosimilars Are Safe for Pregnant Women: Study

There are biosimilars on the market in the United States for nine different types and biosimilars have been approved by the FDA in two additional categories.  

In July, the first ophthalmologic biosimilar, Byooviz (ranibizumab) began competing with the blockbuster originator Lucentis. The next category that is poised to see more biosimilars is immunology, where multiple biosimilars of Humira (adalimumab) are set to enter the U.S. market in 2023.

Humira competition is certain because FDA approvals have been issued and launch dates have been announced. Moreover, the makerters of the Humira  biosimilar makers have signed agreements with AbbVie, Humira’s maker, that preclude the possibility of legal opposition.

Beyond 2023 and the Humira biosimilars are new categories of biosimilars whose launch timelines can be only be estimated based on pieces of information here and there. These launches are by no means certain and might drift well out into the future.

 said that more than 40 additional reference biologics are potential targets for biosimilar development. The company also made some projections about which biosimilars would come on the market by 2030.

In the near term, Cardinal is predicting that a biosimilar for immunology drug Actemra (tocilizumab) will come on th emarket this year or next. Actemra, whic is used to treat rheumatoid arthritis and related conditions, had sales of $3.26 billion in 2021.

A biosimilar to Stelara (ustekinumab), a treatment for plaque psoriasis and psoriatic arthritis, could make its way on to market by 2024. Stelara had  $9.1 billion in sales last year..

Also anticipated by 2024 is the launch of an Eylea (aflibercept) biosimilar. Eylea is used for the treatment of age-related macular degeneration, macular edema and diabetic retinopathy. The drug reaped $9.24 billion in sales in 2021.

 Simponi (golimumab), which is used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis, is another candidate for biosimilar competitoin in 2024. Simponi brought in $2.28 billion in sales in 2021.

Further out, Cardinal Health is predicting that biosimilars of immunosuppressive drug Soliris (eculizumab) and bone strengthener Prolia (denosumab) will emerge in 2025. Soliris and Prolia had 2021 sales of $1.87 billion and $3.25 billion, respectively.

The next most likely biosimilar launch will not occur until 2029, when biosimilars for Enbrel (etanercept) that are already approved by FDA are likely to launch, according to Cardina's report. Enbrel is used to treat plaque psoriasis, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Enbrel had sales of $4.47 billion in 2021. By the time 2029 rolls around, the drug (and its owner, Amgen) will have enjoyed roughly 30 years of market exclusivity.

Existing categories of biosimilars may also see new launches soon.

Kashiv Biosciences and Amneal Pharmaceuticals have FDA approval for Releuko, a Neupogen (filgrastim) iosimilar approved earlier this year. The same companies have FDA approval for Flynetra, a biosimilar to Neulasta (pegfilgrastim). Neupogen and Neulasta boost the body’s white blood cell count.

Amneal and mAxbience have FDA approval for Alymsys, a biosimilar to Avastin (bevacizumab), which is used in the treatment of a number of different types of cancer, including lung, colon, and kidney cancer. 

 Eli Lilly has FDA approval for Rezvoglar, a biosimilar to Lantus (insulin glargine).

Biosimilars launched in the past three years have achieved an average market share of 74%, which is far better than the 3-year average of 38% measured in 2019, according to 

. This signifies growing acceptance of of biosimilars and potential for savings, although uptake in rheumatology has been sluggish and could be challenging in ophthalmology, according to Cardinal Health.

When it comes to patient access to important biologic medicines, much depends on the successful and timely launch of the biosimilars anticipated for the remainder of this decade.

Humira may face competition from multiple generics next year.  An octet of biologics may see competition this decade.