Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

 that savings from biosimilars from 2021 to 2025 could total $38.4 billion, if the downward pressure biosimilars exert on reference drug prices is included, and that savings could be higher if managed care and other clinical settings increase biosimilar use.

, the sister publication of The Center for Biosimilars

“Although biosimilars have the potential to lower prices through competition, barriers to biosimilar uptake may limit these savings,” they cautioned. “Managed care organizations, payers, and policy makers have an interest in better understanding the potential for existing and future biosimilars to help control price and spending growth for biologics.”

Their assumptions for growth in biosimilar savings took into account the potential for biosimilar sales increases and market entry of new biosimilars. They assumed that $26.1 billion of estimated savings would come from new biosimilar products.

Adalimumab biosimilars are not projected to enter the US marketplace until 2023, but under the core savings projection, these biosimilars would account for $19.5 billion or a 50.8% share of savings from 2021-2025, authors of the study said.

They reasoned that $24.6 billion of estimated savings would result from the downward pressure on reference drug prices caused by biosimilar competition.

A more optimistic scenario for biosimilar growth and acceptance resulted in an estimate of $124.5 billion in potential savings during the 5-year period. This scenario “assumed greater biosimilar entry, volume shares, and price competition compared with assumptions used in the main approach.”

Biologics, made from living organisms, are among the most costly drugs, and although they accounted for just 2% of US prescriptions in 2017, they amounted to 37% of net spending on prescription drugs overall, which explains the value of biosimilar competition in lowering the amount of spending and improving affordability for patients.

There are currently 33 biosimilars approved for use in the United States, and of those, just two-thirds have been launched, or marketed, so far. These products are available mainly for treatment of cancer and cancer-related conditions. There are 7 approved adalimumab (Humira) biosimilars. 

Investigators projected biologics spending based on 60 biologics including the 7 facing biosimilar competition as of the fourth quarter of 2020 (bevacizumab, epoetin, filgrastim, infliximab, pegfilgrastim, rituximab, and trastuzumab). These biologics accounted for $724.4 billion in sales from 2014 to 2020 at manufacturer list prices.

Managed care organizations, payers, and policy makers have an interest in better understanding the potential for existing and future biosimilars to help control price and spending growth for biologics.

Data for the study were drawn from medical research company IQVIA’s MIDAS database.

Under a constant spending scenario, in which biologics spending conditions remained the same over the 5-year period, using the fourth quarter of 2020 as the baseline, spending would be $648.0 billion from 2021 to 2025, the investigators wrote.

Spending over the 5 years that included the $38.4 billion in savings from expanded biosimilar competition would be $609.6 billion, they said. That represents more than 20% of estimated spending of $2.5 trillion for all prescription drugs over the 5-year span, they wrote.

Investigators said that the bulk of biosimilar savings (68.1% or $26.1 billion) under their main growth scenario would come from new biosimilars introduced from 2021 to 2025.

Also, savings from new biosimilar insulins, which started to become available at the close of 2021, would be $4.1 billion over the 5-year period, the authors wrote. “All other biologics without current biosimilar competition accounted for savings of $2.6 billion (6.7%).”

Although the authors did account for some downward pressure on reference drug prices, “this approach omits a significant share of savings resulting from lower reference biologic prices,” they wrote.

They said their savings estimates were “modest” compared with recent studies “that estimated savings of $69 billion to $140 billion from 2020 to 2024.”

Mulcahy A, Buttorff C, Finegold K, et al. Projected US Savings From Biosimilars, 2021-2025. 

Published online January 3, 2021. www.ajmc.com/view/projected-us-savings-from-biosimilars-2021-2025

Articles

Savings from adalimumab biosimilars, which won't enter the US market until 2023, account for a significant share of the total, investigators said.

Biosimilar Savings Through 2025 Could Total $38.4 Billion

In the European Union, biosimilars are capturing an increasing share of territory from originator drugs, improving savings and patient access to critical biologics, according to a report from IQVIA, a pharmaceutical industry analyst. The 

“Biosimilar manufacturers are increasingly prepared for loss of exclusivity opportunities and creating increasingly crowded and competitive marketplaces within European countries,” IQVIA states. “Those who have the right system in place will be able to benefit most.”

The data analysis firm said that previously, it took up to 2 years for new biosimilars to capture as much as a 50% market share from reference (originator) biologics. Now, this is being accomplished in less than 1 year, IQVIA said.

Companies from the European Union used to be the dominant players bringing biosimilars to market. In the period from 2006 to 2010, they represented 67% of manufacturers gaining EU approvals for new biosimilars.

During that time, US and Indian companies each accounted for an 11% share of these approvals. But now many other countries are involved in biosimilar development and commercialization, as represented by the following shares for 2021:

This suggests a healthy competitive environment, but according to IQVIA it’s getting harder, not easier, for companies to bring new biosimilars to the European Union marketplace.

“The high upfront investment and production costs, coupled with pricing pressures and limited access, are raising the bar for biosimilar developers. An increasing number of pharmaceutical companies decided to not launch biosimilars or continue their development plans, putting sustainability of the biosimilars marketplace as a critical issue for all stakeholders,” authors of the report wrote.

In the European Union, biologics represent 34% of medicine spending based on list prices, and this is growing at a 10.5% annual rate. This is more than double the past of growth (5.1%) for the total market, which includes small molecule drugs plus biologics and biosimilars, IQVIA said.

The firm identified the pandemic as a challenge for some elements of the biologics market, but said that in the European Union, at least, it has not held up the approvals of new biosimilars. “From a regulatory standpoint, the European Medicines Agency continued to perform well on approving innovative medicines and biosimilars alike. There were at least 7 new biosimilars approved in the European Union during 2021, vs 9 approved in 2020, IQVIA said.

Pandemic-related factors impeding the growth of medicine sales in 2021 included the difficulty of conducting face-to-face patient/physician consultations and difficulty switching prescriptions to biosimilars or starting patients on them.

As measured by list prices and volume of prescriptions, biosimilar savings in 2020 amounted to $6.5 billion, although manufacturer rebates and discounts obscure the real value, IQVIA said. This compares with slightly over $4 billion in savings in 2019.

Much of the 2020 savings was attributed to adalimumab and infliximab biosimilars.

The core proposition of biosimilar medicines is to generate savings in the system, but also increase access to the high cost, complex biologic molecules from which they are based.

“The core proposition of biosimilar medicines is to generate savings in the system, but also increase access to the high cost, complex biologic molecules from which they are based,” but this is not happening evenly from country to country, IQVIA said.

“Despite significant list price reductions, subsequent confidential rebates, and increasing competition, not all European countries have been either willing or able to increase access to biologic medicines in the available therapy classes,” authors of the report said.

Over the next 10 years, reference drugs in the European Union are expected to lose patent exclusivity predominantly in the oncology (29%), endocrine (11%), and blood and lymphoma (21%) categories. However, IQVIA predicted there will be challenges in getting manufacturers to produce biosimilars for some disease types for which reference drugs are losing exclusivity.

 spoke with experts from Medicines for Europe, a trade association of biosimilars and generics producers, about a market survey conducted by the association that elucidated trends affecting biosimilars in the European Union. 

Commenting on the IQVIA report, Isabell Remus, chair of the biosimilar medicines sector group of Medicines for Europe, stated: “Patients should have equitable access to the therapy they need irrespective of where they live. However, in Europe we still see unacceptable inequalities. 

"Biosimilars are part of the solution, and they will only deliver their full potential with the continuous and strong support of the European Commission and every member state implementing the suitable policy interventions in support of uptake," Remus said.

Biosimilars have produced more than $20 billion of savings in Europe, but more use of these agents is needed. 

Report: Biosimilar Competition in Europe

 regarding their dispute over etanercept (Enbrel) patents, with a ruling in favor of the reference drug companies, which included Immunex, Amgen, and Roche.

Enbrel is indicated for the treatment of autoimmune disease, specifically rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and juvenile idiopathic arthritis.

The upshot was that Samsung Bioepis effectively will not be able to bring its etanercept biosimilar (Eticovo) to the US market until 2029.

Samsung Bioepis was permanently enjoined from “making, using, offering to sell, or selling within the United States, or importing into the United States any product containing etanercept,” according to the ruling.

The mandate will end when 2 key patents for etanercept expire on April 24, 2029, meaning another 7 years before biosimilars can offer competition for Enbrel and potentially bring down prices. According to a 

 in 2019, the cost of a month’s supply of Enbrel was $4945, putting this drug third from the top of the 10 most costly drugs in the United States. The others were Afinitor (everolimus; cancer) and Humira (adalimumab; inflammation).

The reference product earned $5 billion for Amgen in revenues in 2020, most of it from the US market.

There is one other FDA approved biosimilar for etanercept, and that is a Sandoz product (Erelzi). This has also been warehoused owing to unsuccessful patent litigation. In May 2021, in another setback for Enbrel biosimilars, the US Supreme Court declined to reopen a Federal Circuit case concerning an etanercept patent dispute between Sandoz and the reference companies.

“We are disappointed the Supreme Court decided not to review our case,” said Keren Haruvi, president of Sandoz US and head of the company’s North America operations.

Separately, multiple court actions were playing out between AbbVie, maker of Humira, and Alvotech, a Reykjavik, Iceland, company that hopes to bring an adalimumab biosimilar (AVT02) to market by 2023.

Apart from the litigation, Alvotech has good story to tell its investors. The company has developed a high concentration, citrate-free version of adalimumab, which could improve patient adherence and potentially make this more competitive than some other adalimumab biosimilars already approved, and in the United States it could be earlier to market than most adalimumab biosimilars. It has also obtained European Commission approval (November 2021) for commercialization in EU countries.

However, in the United States, Alvotech must free its biosimilar candidate from entangling litigation, which mars the good business proposition of the high concentration biosimilar. The company is headlocked in a yearlong litigation process with AbbVie over patents that may be infringed if AVT02 comes to market, and this court review will likely stretch to at least October 2022.

 underway in the court system, and that involves allegations from AbbVie that Alvotech had help it shouldn’t have had in developing the manufacturing process for AVT02; namely, that an employee of AbbVie’s Singapore offices stole confidential manufacturing information and went to work for Alvotech in setting up an adalimumab production line for that company. Alvotech contends that didn't happen, and the case is now before the US International Trade Commission.

Although Alvotech has approval to launch in the European Union, the company has not announced a launch date and it remains unclear whether AbbVie is attempting to prevent an EU launch from happening.

Meanwhile, for Alvotech, the stakes in this contest with the reference drug manufacturer are high. Alvotech recently lined up a 

 from a consortium of companies and announced plans to go public. AVT02 is the nearest drug to commercialization in its pipeline and potentially the most lucrative, so a major letdown in the legal arena could have consequences for the success of these other business dealings.

There is one other high concentration, citrate-free adalimumab biosimilar approved in Europe: Celltrion Healthcare’s Yuflyma, which has already begun commercialization.

 that has implications for biosimilars, the state of Mississippi filed suit against the 3 top incumbent insulin producers: Eli Lilly, Novo Nordisk, and Sanofi-Aventis, as well as pharmacy benefit managers that contract with those producers.

Despite a century of insulin availability, the price of treatment remains stubbornly high, and in Mississippi the cost of treating state residents is $3.5 billion annually, according to state Attorney General Lynn Fitch. “As a mother of a diabetic, I know the emotional, physical, and financial toll the unacceptable price of insulin has on families,” she stated in a recent interview with the Mississippi Center for Investigative Reporting.

The civil suit was filed in Hinds County Chancery Court in Jackson, Mississippi, and contends that the defendants are running an “insulin pricing scheme” with the aim of gouging patients and payers for the sake of profits.

The first insulin biosimilar (Semglee, insulin glargine) was approved in 2021, and this could have a downward effect on pricing in 2022. Indeed, regulators in the United States are hoping that a newly opened regulatory pathway for insulin biosimilars could help to spur insulin discounting and broaden access and affordability for patients. That pathway opened in 2020 via the Biologics Price Competition and Innovation Act.

The top legal stories in biosimilars over the past year concerned etanercept and adalimumab biosimilars and access to insulin.  

The Top 5 Biosimilars Legal Stories of 2021

Episode 1. California’s “Pay-for-Delay” Law

Episode 2. The FDA Reaches Out to the US Patent and Trademark Office

Episode 3. The Build Back Better Act and Biosimilars

Episode 4. Defining Interchangeable Biosimilars More Clearly

Videos

The Center for Biosimilars® spoke recently with Chad Landmon, chair of the Intellectual Property and Food and Drug Administration Practice Groups at Axinn, a New York–based antitrust, intellectual property, and litigation law firm.

Biosimilar Legal and Business Developments in 2021

Although regulatory reviews for biosimilar approval may take a year or longer, companies are often more confident of their prospects for receiving approval than they would be for novel drug candidates. A series of corporate announcements in recent weeks gives credence to this perspective: In advance of regulatory approvals for ustekinumab, ranibizumab, denosumab, and trastuzumab biosimilars, companies are signing deals for commercialization of these product candidates around the globe. 

that the relative probabilities of success for developmental generics, biosimilars, and novel drugs are 90%, 78%, and 10%, respectively.

Hyphens Pharma, a Singapore-based pharmaceutical supplier, recently signed an agreement to commercialize Icelandic company Alvotech’s ustekinumab biosimilar candidate if and when it is approved, according to 

. Hyphens Pharma would have sales jurisdiction in Singapore, Malaysia, and the Philippines.

Ustekinumab (Stelara) is used for the treatment of immune-mediated disorders such as plaque psoriasis, psoriatic arthritis, and Crohn disease. Alvotech is a development-stage company that also has adalimumab and other biosimilars under development.

With no products on the market or with regulatory approval so far, the company is confident in the potential of its adalimumab and ustekinumab biosimilar candidates. Alvotech recently 

 that it has lined up $450 million in investor capital and aims to take the company public at an unnamed future date.

Alvotech’s key biosimilar candidate is AVT02, a high-concentration, citrate-free version of adalimumab, which the company anticipates will have strong competitive standing based on the sales trend for a similar version of the originator company’s product (Humira). Alvotech also hopes to gain “interchangeable” status in the United States for AVT02, which would allow pharmacists more flexibility to dispense this product without first gaining approval from the prescribing physician.

In recent weeks, MS Pharma and Bioeq, both Switzerland-based, signed an agreement to commercialize a ranibizumab (Lucentis) biosimilar candidate, for the treatment of eye disease, in the Middle East and North Africa. The biologic copy (FYB201) was developed by Bioeq and Formycon, of Germany.

Ranibizumab is used for the treatment of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization.

A biologics license application for FYB201 was submitted to the FDA in August 2021 and an approval decision is anticipated in August 2022. In June 2021 and July 2021, Formycon and Bioeq submitted an application for approval for FYB201 to the European Medicines Agency and the United Kingdom’s Medicines and Healthcare products Regulatory Agency, respectively. Based on anticipated approvals, Bioeq and Formycon expect marketing to begin in both the United States and European Union in 2022.

In July 2021, Bioeq signed with Teva Pharmaceutical Industries to 

 the ranibizumab biosimilar candidate in the European Union, Canada, Israel, and New Zealand.

Gedeon Richter and Hikma Pharmaceuticals said they have agreed on a US commercialization deal for Richter’s denosumab (Prolia, Xgeva) biosimilar candidate. Denosumab is used for the treatment of osteoporosis and bone fractures caused by the advancement of cancer.

Gedeon Richter is based in Hungary and Hikma is based in London, England.

Patients with multiple myeloma and solid tumors that have metastasized often develop bone problems, such as giant cell tumor of the bone and hypercalcemia. Denosumab helps to increase bone mass in patients. By binding to a protein called RANKL, denosumab prevents RANKL from binding to another protein, RANK, on the surfaces of bone cells, and this is believed to prevent bones from breaking down and cancer cells from growing. It is also thought to aid in bone retention of calcium.

The denosumab biosimilar candidate is currently in phase 1 and 3 clinical studies. Richter would complete the clinical studies and market the biosimilar in the United States, and Hikma would handle the US regulatory approval process.

Lastly, Prestige BioPharma and Dr. Reddy’s said they have reached an agreement for the sale of a trastuzumab biosimilar candidate in select countries in Latin America and Southeast Asia. The proposed biosimilar (HD201) would reference Herceptin, which is used for the treatment of human epidermal growth factor 2 (HER2)–positive breast and metastatic gastric cancer.

With fewer of the risks associated with novel drug development, biosimilar candidates allow manufacturers to plan far into the future for marketing needs.

Highly Confident, Biosimilar Companies Notch Global Commercialization Deals

The Northwest Territories has become the fifth Canadian jurisdiction to mandate switching to biosimilars for patients in the public health system. The Northwest Territories is a sparsely populated (41,000) wilderness area that is known for its native settlements, European immigration, fur trade and gold prospecting history (Yellowknife).

Public officials said in a statement that the biosimilar switching policy will be consistent with those already established in British Columbia, New Brunswick, Alberta, and Quebec. Canada has begun imposing mandatory biosimilar switching programs following lackluster voluntary biosimilar uptake. Biosimilars are highly similar to the original brand drugs they reference and just as safe and efficacious. They enter the market at discounts to the originator drugs and help to bring down the costs of health care and improve patient access to critical medicines.

The Canadian Rheumatology Association strongly recommends that access to citrate-free Humira be made available for Canadian children requiring treatment with Humira.

A statement by Biosimilars Canada, a trade association of biosimilars producers, explained that in the Northwest Territories switching will become mandatory for patients on 10 biologic reference drugs for which biosimilars are available, within the following therapeutic areas: arthritis, diabetes, inflammatory bowel disease, and psoriasis. The transition to biosimilars must occur by June 20, 2022.

“The full benefits of biosimilars cannot be realized unless drug plans adopt policies that support their expanded use with the implementation of successful biosimilar transitioning or “switching” policy,” the group said.

In Canada, a new jurisdiction inaugurates mandatory switching to biosimilars.

In Canada, More Mandatory Switching 

Editor's note: After the writing of this story, the FDA 

another biosimilar, an insulin glargine product from Eli Lilly called Rezvoglar. 

Technically, the FDA has approved just 2 biosimilars in 2021, a substandard performance compared with recent years (for example, 10 biosimilars in 2019 and 3 biosimilars in 2020).

Headline readers might say, “Hold on! Weren’t there 4 approvals in 2021, including 1 this week?” Yes and no.

the adalimumab biosimilar Yusimry, which became the seventh adalimumab biosimilar that won’t enter the marketplace until 2023. Still, it’s not the FDA’s business to actually get biosimilars onto market.

In September, the FDA approved a ranibizumab biosimilar (Byooviz), which constituted the first ophthalmology biosimilar and a new category of therapeutics for biosimilars at that. That was clearly a new biosimilar approval, too. (Byooviz will launch in mid-2022.)

In October, the FDA also approved Cyltezo (adalimumab) as an interchangeable biosimilar, but Cyltezo was actually approved in August 2017 as a regular biosimilar, and the interchangeable designation merely represents a license for pharmacists to dispense the biosimilar instead of the reference product (Humira) without having to first consult the prescribing physician. So, not a new biosimilar approval.

In July 2021, the FDA also approved another drug as a biosimilar and an interchangeable (Semglee, insulin glargine), but this drug was previously approved (June 2020) under the 505(b)(2) new drug application regulatory pathway. So, it went from being a “new drug” to a biosimilar of a reference brand. The reclassification was thought by its maker, Viatris, to improve its marketability.

Although not a fresh biosimilar approval, that shift in status did mean that an insulin product became a biosimilar product for the first time; and, these Cyltezo and Semglee approvals were firsts in that there weren’t any interchangeables before. Regardless of their status, these agents have tremendous potential for lowering costs for patients and improving access.

related to biosimilars, though. It moved further along a round of biosimilar user fee reauthorization, potentially bringing fees for biosimilar applications up to date and improving the resources at the FDA’s disposal for developing the biosimilar program.

It initiated a guidance development program for interchangeable biosimilars, with the purpose of clarifying how this designation will be used and interpreted going forward. This is a relief to manufacturers who anticipated much confusion as the interchangeable designation becomes more commonplace.

It also issued final guidance for its Biosimilars Action Plan for a more efficient and predictable biosimilar development and review process.

Last but not least, the FDA reached out to the US Patent and Trademark Office (USPTO) with an offer to help it sort through patent applications to weed out the ones that are of little merit. One big problem in the biologics marketplace is the proliferation of patents that often appear to have been filed solely to block attempts by competitors to bring biosimilars to market. The FDA’s offer of assistance constitutes an effort to help the USPTO improve the “quality” of patents.

All these things add up to both a disappointing year for biosimilar approvals and a positive year for policy improvements, said Sarfaraz K. Niazi, PhD, a biosimilars entrepreneur and biopharmaceuticals consultant and adjunct professor who also serves on the Advisory Board of The Center for Biosimilars

“On the regulatory side, the FDA has issued addendums to its guidelines, along with question-and-answer sessions, that provide more clarity for biosimilar developers,” he said.

This clarification includes the possibility that developers may count on less costly and less wasteful methods of biosimilar development and evaluation, he said, noting that the FDA has indicated that biosimilar developers may be allowed to use reference product samples for testing that have been sourced in the European Union rather than in the United States.

“I also foresee that the FDA and European Union will develop guidance to the effect that there is no longer any requirement for animal studies and likely more concessions on the requirements for clinical efficacy testing,” he added. Both types of tests have been considered imprecise tools in the biosimilar development armamentarium and often of no value at all compared with other available tools. “So far, the FDA has licensed a couple of products without efficacy testing, and I see more such exemptions happening,” Niazi said.

He also anticipates a “significant revision” of regulatory guidelines that will facilitate the US marketplace entry of smaller biosimilar companies “that is essential to ensure that biosimilars meet the expectation of value to patients.” Mylan, an Indian company that became Viatris through a merger in 2020, is one such example of this, he said.

The biosimilar pipeline going forward includes various types of potential insulin products, immunosuppressants, and bone health and growth hormone products. That combined with some of the pivotal events described above makes 2021 an “inflection year” for biosimilars, according to Sonia T. Oskouei, PharmD, BCMAS, DPLA, vice president of Biosimilars for Cardinal Health and an Advisory Board member for The Center for Biosimilars

“The next year will bring more promise and opportunities of biosimilars to an expanded patient population across multiple therapeutic areas including diabetes and ophthalmology,” she said. “For example, following the approval and launch of the first interchangeable biosimilar for Lantus, we will now be able to witness how pharmacy benefit biosimilars will perform in the market, and understand drivers influencing adoption patterns.”

The year ahead will provide valuable insight into how well the interchangeable designation works to make biosimilars accessible to patients with diabetes, Oskouei said.

Although an insulin glargine (long acting) biosimilar was approved in 2021, the coming year is expected to see the approval of a short-acting interchangeable insulin biosimilar (insulin aspart), she said.

Also, the approval of a ranibizumab biosimilar in 2021 represents a landmark development for patients with age-related macular degeneration, with the potential to significantly reduce the financial and treatment burden associated with retinal conditions.

“2022 is particularly exciting for ophthalmology, given that in parallel to the market entrance of biosimilars, we will also see market entrance of innovative treatment options (including the impact of the recently approval Susvimo, a novel port delivery system with ranibizumab, on the market),” Oskouei said. She noted that getting Byooviz into circulation will depend heavily on patient and physician education efforts, payer coverage, and the availability of supportive clinical data.

There’s more work to be done to get biosimilars into wider circulation, but the underlying message is one of hope for patients “across immunology, oncology, gastroenterology, endocrinology, and other underserved therapy areas,” said Brian Lehman, MBA, MHA, RPh, director of Patient Advocacy and Strategic Alliances for Sandoz and an Advisory Board member for The Center for Biosimilars

. “I’m hopeful that the availability of additional biosimilars will help millions of patients,” he said.

He also said self-insured employers are showing a stronger interest in the savings afforded by biosimilars. “Considering that millions of Americans receive health coverage through their employer, employers have a vested interest in finding solutions to curb health care spending, reducing monthly premiums and out-of-pocket costs for employees.”

The year 2021 brought several firsts in biosimilars and set the stage for expansion across therapeutic areas including diabetes and ophthalmology. 

2021 Was an "Inflection Year" for Biosimilars

The FDA has approved a seventh adalimumab biosimilar, Yusimry (CHS-1420) developed by Coherus BioSciences. The product references Humira, a tumor necrosis factor blocker, and was approved as a 40 mg subcutaneous formulation. It is indicated for plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Crohn disease, and ulcerative colitis.

The Redwood City, California, company said that by arrangement with AbbVie, the maker of reference adalimumab (Humira), the product would not be launched until July 2023.

The 6 other makers of FDA-approved adalimumab biosimilars also have settled with AbbVie and also will delay launch until 2023. Two of these biosimilars also are launching in July 2023, another 2 adalimumab biosimilars in January and June 2023, and 2 after that, in September and November 2023.

Until now, Coherus’ sole product has been a pegfilgrastim (Udenyca), a colony stimulating factor that promotes white blood cell growth and is used in the treatment of  neutropenia caused by cancer medications. Including Udenyca, there are 4 pegfilgrastim biosimilars on the US market.

“We are excited that Coherus has received FDA approval for Yusimry, our second approved product, and we are grateful to the patients and investigators who participated in our clinical trials and for the dedication of employees across all functions at Coherus,” said Denny Lanfear, CEO of Coherus.

Coherus said approval of the product was based on a randomized control study (N = 545) comparing efficacy and safety of Yusimry vs Humira in patients with moderate-to-severe chronic plaque psoriasis and also a double-blind randomized study to confirm pharmacokinetic similarity in 200 healthy subjects.

"The approval of Yusimry brings a new offering to health care practitioners and their patients with certain inflammatory diseases,” said Barbara Finck, MD, chief medical officer of Coherus.

The company touted the sales potential of Yusimry, given that Humira is the world’s top selling drug and so far in the United States has no biosimilar competition. Humira had 2020 sales of roughly $20 billion globally and $16 billion in the United States.

Coherus also has an ophthalmology biosimilar under review with the FDA. This is CHS-201, which references Lucentis. The company is anticipating an FDA decision for CHS-201 in August 2022. An additional biosimilar candidate under development at Coherus is CHS-305, which references Avastin (bevacizumab).

Coherus reported 2020 sales of $476 million (mainly from Udenyca) and at the time said its pegfilgrastim biosimilar had a strong, 21% share of the overall pegfilgrastim market and a 50% share of the prefilled syringe segment. Coherus said that Udenyca together with the adalimumab and bevacizumab biosimilars would serve as the core of an immune-oncology portfolio.

The company also aims to commercialize a toripalimab product. This is a programmed death receptor-1 monoclonal antibody that prevents cancer cells from “switching off” the immune system response. This product was developed by Shanghai Junshi Bioscience of China, and Coherus is partnering with them on sales in the United States and Canada.

The FDA has granted breakthrough therapy designation to toripalimab for third-line treatment of nasopharyngeal carcinoma.

Coherus BioSciences said the 40 mg subcutaneous formulation of adalimumab would be launched on or after July 1, 2023, in agreement with AbbVie, maker of Humira, the reference product.

FDA Approves Yusimry, the Seventh Adalimumab Biosimilar

After having its adalimumab (Humira) trade secrets case against Alvotech dismissed by a court for lack of jurisdiction, AbbVie is trying again with a filing with the US International Trade Commission (ITC).

AbbVie maintains that Alvotech’s biosimilar candidate for adalimumab (AVT02), which has yet to receive US FDA approval, was developed with trade secrets solen by employees who once worked for AbbVie and then went to work for Alvotech.

“AVT02 will undercut Humira significantly on price and unfairly compete, leading to lower revenue, lower profits, reduced return on investment and, as a result, significant injury to the industry that AbbVie has invested in significantly to develop in the United States,” AbbVie writes in the complaint. The ITC has the authority to investigate and rule on alleged acts of product infringement.

Alvotech has stated it is innocent of any wrongful taking or use of AbbVie's trade secrets regarding the manufacture of adalimumab. 

“This action by AbbVie–which repackages the meritless allegations from a case that was thrown out of court earlier this year–is a sign of AbbVie’s weakness and concern that Alvotech’s efforts to bring a lower-cost offering to market will expose AbbVie’s longstanding abuse of the patent/legal system," Alvotech said. "AbbVie’s abuse has improperly extended its monopoly.”

The employees AbbVie alleges to have stolen the manufacturing information are Rongzan Ho, Yi Li Tan, and Zhi Sheng Sheah. All three began working with Alvotech after resigning from AbbVie, the manufacturer alleges. AbbVie alleges that Ho, Tan, and Seah, were “were involved in setting up AbbVie’s Humira manufacturing plant in Singapore from the ground up” and so became intimately familiar with the company's secret processes for manufacturing adalimumab.

“These employees not only learned and had access to documents describing
AbbVie’s knowhow for running a high-quality manufacturing process for commercial -scale production of adalimumab, but also learned and had access to documents describing AbbVie’s knowhow for bringing a new adalimumab facility online and obtaining GMP certification of a new adalimumab facility,” the AbbVie complaint said.

In October 2021, Judge Harry D. Leinenweber of the US District Court for the Northern District of Illinois, 

 in the case because the alleged trade secret theft occurred abroad. Ho, for example, was based in Singapore and working at an AbbVie facility there when he allegedly took secrets, resigned, and went to work for Alvotech in Iceland. AbbVie claims he interviewed with Alvotech in late 2017 and began working there in January 2018.

AbbVie claims it has documented several attempts, including a successful one, by Ho to send large Excel spreadsheets of information about AbbVie’s confidential manufacturing processes to his personal email address. “With these documents, a competitor would have the necessary knowhow to manufacture an adalimumab drug substance,” AbbVie wrote.

Ho has not responded to a request for comment from The Center for Biosimilars®.

These employees not only learned and had access to documents describing
AbbVie’s know how for running a high-quality manufacturing process for commercial -scale production of adalimumab, but also learned and had access to documents describing AbbVie’s knowhow for bringing a new adalimumab facility online and obtaining GMP certification of a new adalimumab facility.

According to AbbVie, Ho was contacted about the alleged theft and acknowledged the taking of the Excel information in a declaration that was included in the ITC filing but fully redacted from public access. Ho’s current resume was also included in the documents and states that he worked for Alvotech for 2 years and 5 months and later went to work for Merck Life Science in Shanghai, China.

The case is important for Abbvie because Alvotech plans to bring an increasingly popular form of adalimumab (high concentration, citrate free) to market in the United States and potentially could bring it to market sooner than other biosimilar competitors. There is no adalimumab competition on the market in the United States so far.

“Alvotech...continues to state publicly that it will manufacture, import, and have marketed by Alvotech’s marketing partner Teva AVT02 manufactured in Iceland and foreign jurisdictions and imported to the United States,” Alvotech wrote in the ITC complaint.

As part of its application to the FDA for approval of AVT02, Alvotech has “imported” AVT02 into the United States, AbbVie alleged, although some manufacturing of a rival's product is permitted for the purposes of developing a product rather than selling it.

The FDA began its review of AVT02 in November 2020 and has delayed an approval decision so it can complete manufacturing facilities inspections. In November 2021, Alvotech received approval from the European Commission for the marketing of AVT02 under the product names Libmyris and Hukyndra.

AbbVie has requested that the ITC open an immediate investigation into the alleged trade secret theft and bar Alvotech from importing AVT02 into or selling it in the United states

Alvotech and AbbVie are at odds over AVT02 in a 

. The District Court for the Northern District of Illinois his hearing a patent infringement dispute between the two companies, which is expected to resolve in October 2022, if the proceedings go according to the court scheduling order.

After an unsuccessful attempt to get an Illinois court to block the distribution of Alvotech's adalimumab candidate, AbbVie has tried again in a new forum. 

AbbVie Returns to Court in Effort to Block Alvotech Adalimumab Biosimilar Candidate

There were several firsts in 2021 for biosimilars, including the first interchangeable biosimilars and the first ophthalmology biosimilar, but under the surface an “identity crisis” has developed, said Eva Temkin, JD, a former regulator who moved recently to private law practice, in a panel discussion at the 2021 GRx+Biosims conference.

Temkin and Rachel Turow, JD, MPH, a private industry general counsel representing Teva Pharmaceuticals, agreed that many policy questions are coming to a head, such as labeling practices and defining the interchangeable designation. Interchangeable biosimilars are ones that pharmacists can dispense in place of reference brands without obtaining authorization from the prescribing physicians.

Looking from the outside in, Turow said that for regulators, this may be a time of intrigue and creative problem solving, but for the biosimilars industry, “it does seem to feel like you’re running around trying to put out many fires at once,” including legislative, regulatory, and patient and physician education problems.

The FDA is developing a regulatory science program with the goal of improving regulatory decision making and making it possible for stronger science-based recommendations in the development of applications under the Public Health Service Act 351(k) licensing process for biosimilars, said Alison Falb, JD, the sole regulatory panelist, who is counsel for the FDA's Office of Therapeutic Biologics and Biosimilars (OTBB).

The OTBB oversees regulatory policy for biosimilars, interchangeables, and other therapeutic biologic products.

Falb said a pilot program is scheduled for 2023 with the stated purpose of advancing the development of interchangeable biosimilars and improving the efficiency of biosimilar product development. The program will also help to determine what real-world evidence might be needed to establish the safety standards for interchangeable status. There will also be stakeholder meetings to review the progress made on these initiatives and determine future priorities.

The practice of “skinny labeling” (labeling carve-outs) worries Turow, who heads up regulatory law and policy divisions for Teva.

I really hope we’ll see skinny labeling addressed, coming out of [

GlaxoSmithKline v. Teva Pharmaceuticals USA, Inc]

, but I think the implications for biosimilars are really just as severe, if not more worrisome, in terms of the liability for induced patent infringement with a skinny label.

Labeling carve-outs involve marketing generics and biosimilars for a narrower range of medical indications than the brand products as a means of avoiding infringement of patents that concern only specific indications. The generic or biosimilar company may include only limited indications on its product label, which the FDA approves, but if the physician or patient assumes that the product is safe for all indications of the reference product and uses it for a patent-protected use, the question may arise whether the generic or biosimilar manufacturer “induced” the physician or patient to use the product for that indication.

GlaxoSmithKline (GSK) and Teva have battled over this issue in court, with GSK alleging induced infringement of Coreg (carvedilol) and Teva emerging as the victor. “I really hope we’ll see skinny labeling addressed, coming out of [

, but I think the implications for biosimilars are really just as severe, if not more worrisome, in terms of the liability for induced patent infringement with a skinny label,” Turow said.

There are signs that federal policy makers are going to continue to support labeling carve-outs, said Temkin, a partner in the FDA and Life Sciences practice of King and Spalding and a former director of policy in the OTBB. She said this was clear from the text of a recent HHS report on drug competition and drug pricing. “Who knows what that will mean in practice and whether it will translate into congressional action, but it does seem to be a focus, and I think it’s an important thing to consider,” she said.

In September 2021, HHS issued its Comprehensive Plan for Addressing High Drug Prices to the White House, and in this, HHS emphasized that it considers the pathway for labeling carve-outs to be an important means of lowering costs for patients and the federal government via Medicare and Medicaid spending.

The FDA has also promised to provide more clarity on the handling of the interchangeable designation. Turow said there’s a lot of ground to cover in providing the desired level of detail for stakeholders in the biosimilar sphere. Aspects of the interchangeable designation requiring clarification range from basic comparability of the biosimilar and the reference product to labeling and any product application devices used. So far, 2 biosimilars have been issued the interchangeable designation in the United States.

“I do have my favorite interchangeability question,” Turow said, “which is if biosimilar A is interchangeable to the reference product and biosimilar B is interchangeable to the reference product, are they interchangeable with each other? And I don’t think the FDA has answered that question.”

Turow said she’s encouraged that pharmacy benefit managers recently have been moving interchangeable biosimilars onto their preferred formularies, but she said that, in the health care community, there’s still a lot of basic education required about biosimilars to generate more confidence in their use.

Under the Biosimilar User Fee Act (BsUFA) reauthorization for 2023 to 2027, the FDA spells out product developer fees and goals for developing the biosimilar approvals process, and the reauthorized plan includes addressing product labeling, interchangeability, and advertising for biosimilars, Falb said. With regard to the interchangeable designation for biosimilars, this includes paying attention to postapproval manufacturing changes to products and addressing differences between drug application products. “I think it’s definitely something we consider a high priority area for guidance,” she said.

As for labeling differences between biosimilars and interchangeable biosimilars, Falb said, the FDA has previously stated that “the principles from the biosimilar labeling guidance would also apply to interchangeable biosimilar labeling,” although the interchangeable designation is somewhat different from the biosimilar definition and those standards also are relevant to how these agents should be regarded, Falb said.

A trio of regulatory experts discuss the current standing of biosimilar policy in the United States and expectations going forward. 