Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Multiple biosimilar developers have obtained FDA approval for biosimilar versions of adalimumab, an immunosuppressive drug for rheumatologic and gastrointestinal disorders, but won’t be able to bring these products to market until 2023, based on deals struck with AbbVie, which markets Humira, the blockbuster adalimumab innovator product. One question is whether these approved biosimilars will still be relevant 2 years from now.

Not only has AbbVie introduced new products to take over market share from Humira (risankizumab, Skyrizi; upadacitinib, Rinvoq), it also has introduced high-concentration versions of Humira that, according to Boehringer Ingelheim, a rival producer, are capturing market share. Humira products had global net revenues exceeding $19 billion in 2019.

“A majority of all Humira prescriptions are now for the high concentration as opposed to the original formulation,” according to Boehringer Ingelheim, which developed the yet-unmarketed original concentration adalimumab biosimilar Cyltezo. “Additionally, 2 dosage forms of the original formulation of Humira have been discontinued by AbbVie since the high-concentration version was launched in July 2018,” Boehringer Ingelheim noted in a statement issued to The Center for Biosimilars

. AbbVie began marketing its citrate-free, higher-concentration formulation of Humira in July 2018.

That’s a problem for the producers with approved adalimumab biosimilars in the original concentration that have yet to launch. In the United States, 6 biosimilar adalimumab products have been licensed by the FDA for use only in a 50-mg/mL concentration formulation. Those include Boehringer Ingelheim’s Cyltezo, which is approved for 2 strengths: 20 mg and 40 mg.

Humira was originally approved in the 40-mg strength with a 50-mg/mL concentration, but later in 10-mg and 20-mg strengths for the same concentration. It is currently approved in citrate-free, high-concentration form for all 3 strengths plus 80 mg, all in a 100-mg/mL formulation. Citrate-free adalimumab is considered to cause less pain on injection, and the higher-concentration injections can involve smaller amounts. 

AbbVie’s ability to distinguish its adalimumab offerings by concentration has created competitive obstacles for companies that now must match these high-concentration formulations in order to move in the direction that the adalimumab market appears to be going.

Celltrion of Incheon, Republic of Korea, has sought European Union marketing approval for CT-P17, a high-concentration formulation of adalimumab and in December 2020 reported a 

 for approval from the Committee for Medicinal Products for Human Use. The company is poised to be the first to bring a high-concentration, citrate-free adalimumab biosimilar to market, albeit in Europe. In November 2020, Alvotech, of Reykjavik, Iceland, announced that its high-concentration 100-mg/mL dose (AVT02) adaliumumab biosimilar candidate had been accepted for review by the FDA and European Medicines Agency.

with the FDA over its interpretation of product strength in an attempt to mitigate what the company considers a too-restrictive emphasis on concentration of formulation that it says allows “evergreening” of originator products to the disadvantage of biosimilar competition.

In a citizen’s petition, the company has requested that the FDA reinterpret the term “strength” in section 351(k) of the Public Health Service Act to mean “total drug content” regardless of concentration.

Boehringer Ingelheim’s original concentration adalimumab biosimilar (Cyltezo) was approved in August 2017 but can’t debut until July 2023, under the agreement with AbbVie.

“Under the FDA’s current interpretation of ‘strength,’ no biological product can be considered biosimilar and/or interchangeable if there has been any variation in the inactive drug volume as compared to the reference product. [The] FDA’s current definition encourages, or at least permits, manufacturers to use minor concentration changes as an anticompetitive tactic, depriving patients [of] more affordable biological products contrary to the goal of the [Biologics Price Competition and Innovation Act (BPCIA)],” the company said in its statement.

Boehringer Ingelheim said it wants its Cyltezo biosimilar to be considered to have the same strength as both the original-concentration and high-concentration versions of Humira “because they contain the same total drug content per container.”

Recent draft guidance from the FDA suggests that the agency is willing to consider a reinterpretation of “strength.” However, Boehringer Ingelheim said that bringing the issue to prominence through its citizen petition helps to provide impetus for a change. “We are hopeful that by working closely with industry peers, payors, health care providers, and patient advocates, and engaging in a transparent and public discussion of the issues we have raised, the FDA will take a positive action on our petition.”

In making its case for a reinterpretation of “strength,” Boehringer Ingelheim maintains that dropping the concentration emphasis would be more in line with the nurturing environment for biosimilars that Congress intended when it created the BPCIA, which incorporates the biosimilar approval pathway.

Asked whether the scientific decision of how “strength” should be defined should be left up to the FDA, not Congress, the company responded, “Boehringer Ingelheim believes that [the] FDA should be able to assess the clinical effects of concentration differences, if any, via the usual analytical and clinical studies required to demonstrate biosimilarity and interchangeability.

“This approach would distinguish between products that, despite minor concentration differences, have no clinically meaningful differences from the reference product and/or may be substituted for the reference product without the intervention of the prescribing physician, and those that cannot. [The] FDA can adequately address the clinical effect of concentration differences through BPCIA mechanisms other than ‘strength.' [The] FDA’s interpretation of ‘strength’ is incorrect as a matter of law,” the company said.

Articles

Product differentiation by concentration is a threat to the multiple adalimumab biosimilars approved but not yet launched.

Adalimumab Biosimilars Face Product Obsolescence Before Launch

A study of the trastuzumab biosimilar ABP 980 (Kanjinti) in Europe found strong uptake patterns, according to an abstract presentation at the 2020 San Antonio Breast Cancer Symposium.

ABP 980 is approved in Europe and the United States for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and metastatic gastric cancer. Investigators sought to understand the real-world application of this product in clinical treatment of patients with breast cancer.

They enrolled patients 18 years or older with a history of breast cancer of any disease or treatment phase, seeking primarily to understand patient demographics and disease characteristics. Exploratory end points included cardiac dysfunction, infusion-related problems, other adverse events, and other safety issues. Efficacy  was a secondary end point.

Enrollment included 135 women from Poland, Italy, the Netherlands, France, and Spain, mostly from hospital sites, both academic and public or private. The mean patient age was 58.3 years. 

The investigators said 28% of sites had policies on biosimilar use and that 36% of patients were informed they were being started on a biosimilar, with 34% being notified what brand of biosimilar would be used. Twenty-two percent, 27%, 13%, and 28% of patients had stage I, II, III, or IV disease, respectively, at the time ABP 980 was initiated. They also said 68% of patients had estrogen/progesterone receptor–positive tumors. All patients (n = 73) who had been evaluated for Eastern Cooperative Oncology Group performance  had a score of 0 or 1.

There was roughly equal use of ABP 980 across treatment settings: neoadjuvant, 39%; adjuvant 30%; and metastatic, 30%.

Among patients who received treatment for metastatic breast cancer (n = 41), 56% and 20% received it for frontline and second-line treatment, respectively. The investigators said that 40% (n = 54) of patients switched to ABP 980 from another trastuzumab product. Of those, 44% switched from the intravenous form of the originator biologic and 15% switched from the subcutaneous form. Most who switched to the subcutaneous form were receiving treatment for metastatic disease.

The investigators concluded there was ABP 980 “uptake across a mixture of institution types and breast cancer treatment settings, including those with curative potential.” The study is ongoing.

Kufel-Grabowska J, San T, Bernardo A, et al. Patterns of use of a trastuzumab biosimilar (ABP 980) in patients with HER2+ breast cancer treated in clinical practice in Europe: An interim analysis from an observational chart review study (GARDENIA). Poster presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020. PS10-50. 

Among patients treated for metastatic breast cancer, 40% switched to ABP 980. 

Investigators Chart ABP 980 Biosimilar Uptake in European Clinics

Alvotech has moved forward with expansion of its Reykjavik, Iceland, facilities for biosimilar development. The company has begun a 41,000-square-foot 

of its high-tech center, which was established in the city in 2013.

Company officials said the new building will house biosimilar development, drug refills, offices, and warehouse space. A portion of the facility will be made available to the University of Iceland Biotechnology Department for collaborative work that includes student internships with Alvotech.

"It is a great delight to end this difficult year, which was marked by the battle against [coronavirus disease 2019] and subsequent gravities, with such a positive step toward the future evolution of the company,” Robert Wessman, chairman of the board of Alvotech, said in a statement. He said the expansion would provide the foundation for the commercialization of the company’s first biosimilars.

Not including this project, Alvotech has a 140,000-square-foot manufacturing and product development facility in Reykjavik; a second production center under construction in Changchun, China; and research and development operations in Julich and Hanover, Germany; Virginia; and Zurich, Switzerland.

Alvotech is developing biosimilars for autoimmune diseases, ophthalmology, and oncology. The company does not yet have any approved biosimilars, but in November 2020 Alvotech 

 with the FDA and European Medicines Agency for approval of an adalimumab biosimilar (AVT02), referencing AbbVie’s Humira for the treatment of rheumatologic and gastrointestinal disorders.

In a recent presentation, Alvotech’s chief scientific officer 

 the company’s marketing strategy to launch biosimilars in multiple countries simultaneously. Toward this end, the company has signed numerous deals with global partners. Most recently, Alvotech signed an extended 

agreement with Fuji Pharma in Japan. This covers the commercialization of 4 biosimilar medicines in that country.

An expansion of its Reykjavik, Iceland, headquarters operation will speed the company on its way to launching its first biosimilars, officials said.

Alvotech Breaks Ground for Biosimilar Development Facility

China’s National Medical Products Administration (NMPA) has 

Innovent Biologics’ adalimumab injection biosimilar (Sulinno) for new indications: pediatric plaque psoriasis and noninfectious intermediate uveitis, posterior uveitis, and panuveitis in adults for whom corticosteroid therapy may be inappropriate or ineffective.

Sulinno was previously approved by the NMPA for rheumatoid arthritis, ankylosing spondylitis, psoriasis and polyarticular juvenile idiopathic arthritis. Those approvals were issued in September 2020.

"There remains huge unmet medical need for the treatment of psoriasis and uveitis in China,” Qian Lei, senior director of Medical Sciences and Strategies of Special Diseases for Innovent, said in a statement, explaining the value of this medicine.

Psoriasis is a skin disease characterized by accelerated growth of skin surface cells, resulting in pain and psychological burden. Uveitis is a type of eye inflammation that can increase risk for glaucoma, macular edema, and cataracts.

China's National Medical Products Administration (NMPA) has cleared Innovent Biologics' adalimumab biosimilar for more indications. 

Innovent Biologics Gains NMPA Approval for Additional Sulinno Indications

Many exciting biosimilar developments could be just around the corner in 2021, according to members of The Center for Biosimilars® Advisory Board, a panel of experts from across the clinical, business, academic, pharmacy, legal, and manufacturing spectra. The potential for the first interchangeable biosimilar designation, a fresh drug classification in ophthalmology for biosimilars, and the first official insulin biosimilar are among these potential advances, they said.

However, they said there are still many hurdles to cross to get biosimilars into the mainstream of health care in the United States and beyond. “There continue to be themes of persistent barriers to biosimilar adoption in the United States, including the payer landscape, operational challenges, knowledge gaps, and clinical hesitancy with regard to switching patients from reference biologics to biosimilars, or between biosimilars,” said Advisory Board Member 

vice president of Biosimilars for Cardinal Health.

“The payer landscape remains one of the most-cited challenges for biosimilar adoption. Payer policies can vary by plan, region, and even time of year,” and these policy variations can complicate the job of inventory management in practices and health care institutions that may be required to stock multiple brands of a single biologic to satisfy requirements of multiple payers, she said. The difficulty increases as more biosimilars appear on market, making it necessary for providers to “decipher the economic, operational, and clinical impact of choosing one product over another."

The potential for the first interchangeable designation for a biosimilar would be a “significant milestone” for the United States, where FDA interchangeable guidance—substituting biosimilars for reference products at the prescription counter—still has not resulted in a single interchangeable approval, she said.

“The implications of interchangeability designation on various stakeholders such as payers, pharmacy benefit managers, providers, and pharmacies are yet to be known,” although there is great potential value in interchangeability for making insulin products more widely available at lower cost, Oskouei said.

In November 2020, Samsung Bioepis and Biogen announced that the FDA had accepted their application for a ranibizumab biosimilar (SB11) for the treatment of patients with retinal vascular disorders. This would constitute a new drug category for which biosimilars are available, and advisory board members this year lamented the narrow range of available biosimilars (covering just 9 reference products). “With a very dynamic market, which includes emerging treatment options and step-therapy payer strategies, biosimilars can potentially have a significant impact on the overall ophthalmology treatment landscape,” Oskouei said.

The year 2021 may bring the first “authorized biologics” to market. These would be cheaper versions of reference products produced by innovator companies to compete with biosimilars. Originator companies so far have tended to rely on lowering the prices of their brand biologics to prevent the loss of business from biosimilars, notes Advisory Board Member 

 an intellectual property attorney and partner with Venable.

“The idea in the small molecule space was to maintain pricing on the brand while using the ‘authorized generic’ to increase patient access and compete with generics made by competitors,” he said. “That still seems viable in the biologics space, but perhaps the resource requirements are somewhat prohibitive. Or it could be the fact that they’d need to gain interchangeable status to be truly an authorized generic equivalent, so perhaps as we gain more insight into acquiring that designation, we’ll see biologic companies employ this strategy.”

Currently in front of the Supreme Court is a case that could influence future and preexisting biosimilar approvals, Wong noted. 

involves a dispute whether administrative patent judges of the Patent Trial and Appeal Board (PTAB) should be appointed directly by the president of the United States or by lesser officials, which has been the norm. The case has a bearing on PTAB decisions regarding post grant reviews (PGR) and inter partes reviews (IPRs), which weigh the patentability of biologics and other products. “It’s going to be briefed and argued in front of the Supreme Court in 2021 and has potential to reverse a good number of previously decided IPRs and PGRs, if not disrupt the system entirely,” Wong said.

“We’re currently assuming that, like in oil states, the Supreme Court will find a way to not upset what has already been done and just fix the issue of PTAB judges prospectively instead of retrospectively,” he said. “But if they don’t, this could significantly impact the biologics industry, particularly in light of the increase in PGR filings that allow Section 101 (35 US Code, patentability) challenges of biologics and diagnostic-based patents.”

Unless they are available for use and actually employed, biosimilars are veritable wallflowers that serve no purpose, notes Advisory Board Member 

 director of Strategic Alliances and Patient Advocacy at Sandoz. “In 2021, I’m hopeful we’ll see growing support for policies that improve patient access to these high-quality medicines, including reducing out-of-pocket costs for biosimilars under Medicare Parts B and D when patients use a lower-cost biosimilar.” This includes the removal of prior authorization requirements for biosimilars in cases where prior authorization has already been granted for the reference biologic, he said.

Lehman anticipates biosimilar markets will continue to build on existing gains. “I’m energized by the growing progress we’ve seen for the biosimilar market in 2020. I’m optimistic this will continue into 2021 and we’ll see more patients gain access to these more affordable biologic treatments.”

 co-leader of Schiff Hardin's Intellectual Property Group and co-chair of the firm's Hatch-Waxman and Biosimilars patent litigation team, expressed confidence that bills wending their way through the legislature would contribute to biosimilar uptake. “Recent examples expected to gather traction would reduce or eliminate co-pays, give the Federal Trade Commission more antitrust power for patent thickets, and encourage Medicare coverage of biosimilars,” he said.

Further, Aly expects biosimilar sponsors and advocates to more strongly oppose anticompetitive tactics used by originator companies. “We expect more court actions, as patent landscape analysis over the past few years should finally translate into more litigations on both patent and antitrust-type claims,” he said.

In 2020, the FDA issued much fresh guidance in both final and draft form, most of which should be considered insubstantial, according to Advisory Board Member 

an adjunct professor of pharmaceutical science at the University of Illinois, although Aly predicted that something might come from this.

Final guidance was issued on user fee rates for biosimilar sponsors seeking to have their biosimilar applications reviewed by the FDA.

Draft guidance was issued on promotional labeling and advertising considerations for biosimilars and reference products.

Draft guidance was issued on interchangeability for biosimilars and licensing conditions.

“We expect more FDA movement, related to their recent question and answer guidance, both about obtaining approval and about the elusive interchangeability designation,” Aly said.

Many firsts may be in store for the biosimilar industry in 2021, although it will be dogged by ongoing difficulties, Center for Biosimilars® Advisory Board members said.

Opinion: The Year Ahead in Biosimilar Potential

“The effect of the pandemic has essentially put the biosimilar market on hold,” said 

 a professor emeritus of economics at Widener University and an advisory board member of The Center for Biosimilars®. Fuhr joined other board members who discussed the state of the biosimilars market and what to expect in 2021. “Hopefully the coming year will lead to more advancement in competition in biosimilars,” he said.

The year 2020 saw just 3 biosimilar approvals from the FDA, which brings the total to 29 since the first US biosimilar approval in 2015. “Although 2020 brought many fewer FDA biosimilar approvals (most recently, the rituximab Riabni), the pandemic has created additional financial pressures for providers, and of course patients, which has resulted in heightened attention to biosimilars as potential cost savings opportunities,” said Advisory Board Member 

Indeed, many companies across the globe saw significant value in biosimilars in 2020 and have pushed forward with clinical trials, factory construction, and partnerships with other companies to establish a market presence wherever markets for biologics are robust.

“It is a positive that we have continued to see uptake of biosimilars, even with the pandemic continuing,” said Advisory Board Member 

 senior principal for the Center for Pharmacy Practice Excellence at Vizient. “Through the third and fourth quarter, we saw substantial growth in market share for biosimilars, particularly in the oncology monoclonal antibody space where additional competing products were approved and launched.”

 an adjunct professor of pharmaceutical science at the University of Illinois, described the slow pace of new biosimilar approvals in 2020 as disappointing, noting the sharp upward trend in previous years: 10 approvals in 2019, 7 in 2018, and 5 in 2017, and 2 in 2016. “More disappointing was the observation that no new molecule joined the list of previous molecules: filgrastim, rituximab, pegfilgrastim, adalimumab, trastuzumab, infliximab, etanercept, bevacizumab, and epoetin alfa. The European Medicines Agency had more activity, approving 9 products, including pegfilgrastim, bevacizumab (2), trastuzumab, insulin aspart, etanercept, rituximab, and adalimumab. Again, no new molecules were in the authorized category of the European Medicines Agency either,” Niazi said.

The year was significant on the regulatory level for biosimilar diversity, he said, because on March 23—the 10-year anniversary of the enactment of the Biologics Price Competition and Innovation Act (BPCIA), which created the pathway for biosimilar approvals—insulins and various other biologics were added to the drug categories that could be approved by this means. These may include treatments for respiratory distress syndrome, fertility conditions, Cushing syndrome, deep vein thrombosis, Gaucher disease, and many more. Niazi said this increases the likelihood that an interchangeable biosimilar may soon be approved, which would allow automatic substitution with brand prescriptions at the pharmacy counter. “As of today, no biosimilar insulin has been approved by the FDA, but I foresee many coming soon.”

Lucio echoed the concern that the number of biologics for which biosimilars exist in the United States is limited to 9. “It is great to have additional competition for the same molecules. However, it would be even better if the number of biologics for which biosimilar competition exists would grow. Whether this takes the form of true biosimilars for insulins or competition for a biologic like ranibizumab, we need to move beyond the 9 biologic targets currently approved,” he said.

Lucio also said that while an “interchangeable” designation is a much-talked-about objective, it has yet to be demonstrated that such an appellation for a biosimilar will make a difference for patient access and cost reduction. “It would be interesting to see if someone breaks through the interchangeability hurdle so we can truly discern the relevance of this designation.”

The year 2020 witnessed a challenge to the Affordable Care Act (ACA) that put one of its constituent elements, the BPCIA, in jeopardy. Many observers believe the individual mandate will be found severable from the ACA, and therefore the rest of the statute will remain empowered, but the outcome is not 100% certain as long as the issue is deliberated by the Supreme Court. “I hope that the most recent challenge to the ACA does not negatively impact the 351(k) pathway so we can move beyond this existential threat to biosimilar licensing for good,” Lucio said.

an intellectual property attorney and partner with Venable, said the loss of the BPCIA via the ACA review would be devastating for the stability of the biosimilar approval structure. “We’ve had concerns that if the BPCIA were to disappear, legal and regulatory frameworks for biosimilars would need to be recreated, which could cause lots of issues with respect to already approved abbreviated Biologics License Applications (aBLAs), pending aBLAs, and biosimilar litigation, which could significantly impact patient access,” he said. “Our current read on the oral arguments is that the Supreme Court will do what we expected and remove the individual mandate while severing the remainder of the ACA and thus sparing the BPCIA.”

The combination of the pandemic and general preference for innovator biologics, for whatever reasons, amounts to lost savings for the health care community and patients in particular, said Advisory Board Member 

 director of Strategic Alliances and Patient Advocacy at Sandoz. “Based on the most recent prices for the 9 biologic drug classes with FDA approved biosimilars, as of December 2020, estimated patient out-of-pocket, lost savings is greater than $270 million and increasing day-by-day. Similarly, between 2018 and 2020 the estimated year-to-date lost savings to the health care system is greater than $24 billion.”

Not only is the near-term savings potential from biosimilars huge, but also “an estimated 1.2 million US patients could gain access to biologics by 2025 as the result of increasing biosimiar availability,” Lehman said. This is based on an estimated $100 billion in potential savings for the 5-year period ending in 2024, he said.

Potential savings from biosimilars for all self-insured US employers could have reached $1.4 billion in 2018 had they made sufficient use of biosimilars, according to an ERISA Industry Committee study Lehman cited. But employers are moving in this direction. “I anticipate the adoption of more biosimilars will have a positive impact for the industry going forward. The more we see employer-sponsored health plans include biosimilars, the more we can expect to see cost savings for employers and employees alike, as well as increased medicine access for patients, resulting in healthier and more productive employees.”

Incremental gains in the number of approved biosimilars and no new biologic categories were the low points, but uptake and improved patient access were highlights of 2020.

CfB Board Members Reflect on Year in Biosimilars

The final 6 months of 2020 fueled many headlines of interest to the readership at The Center for Biosimilars

. For a summary of the most popular stories and related issues, read on.

 from The Center for Biosimilars® in July 2020 was with Byoungseo Choi, head of marketing for Celltrion Healthcare, a rising force in the world of biosimilar development. He discussed the company’s infliximab biosimilar (Inflectra, Remsima) and its value in the treatment of coronavirus disease 2019 (COVID-19). He also talked about Celltrion’s ambitious plans to launch multiple biosimilars over the next decade.

In 2020, visitors to The Center for Biosimilars® also paid close attention to stories about biosimilar launches by Cadila Pharmaceuticals of Ahmedabad, India. One such 

 in July 2020 was a rituximab biosimilar (Ritucad) for the Indian market. A second Cadila launch the same month involved bevacizumab biosimilar Bevaro, for the treatment of ovarian cancer, glioblastoma multiforme, colorectal cancer, breast cancer, lung cancer, cervical cancer, and kidney cancer.

Although Alzumab (itolizumab) is not a biosimilar, the biosimilar developer Biocon Biologics attracted attention in 2020 when it announced that this anti-CD6 IgG1 monoclonal antibody had been 

 for COVID-19–related illness by the Drugs Controller General of India. The drug was indicated for the emergency treatment of acute respiratory distress syndrome (ARDS) in patients with COVID-19. Biocon said the drug was of value in treating cytokine release syndrome, which is common among patients with moderate-to-severe ARDS. The drug is ordinarily used for treating chronic plaque psoriasis.

As pharmaceutical companies began to share promising news in the development of COVID-19–related treatments, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infection Diseases, stated in a town hall meeting that early-stage treatments such as monoclonal antibodies (mAbs) and direct-acting antivirals (DAAs) had contributed to impressive trial findings. At the time, the mAb infliximab (Remsima) was undergoing evaluation in the CATALYST study of COVID-19–related inflammation.

In addition to DAAs, which target specific virus proteins and disrupt viral replication and infection, convalescent plasma and hyperimmune globulin therapies, which involve the use of antibody-laden blood from patients who have recovered from COVID-19, also were candidates for potential use in the pandemic struggle, 

The month of August 2020 saw Cadila put another biosimilar on the market in India, this time a teriparatide biosimilar (NuPTH), which is indicated for the treatment of osteoporosis and increased risk of bone fracture. The drug could be an important tool in providers’ armamentarium, Cadila said, calling India “the osteoporosis capital of the world.” The 

By this time in the pandemic, many biosimilar developers had joined the fight to find treatments for COVID-19. In some cases, biosimilars were under the microscope as candidates for effective management of the disease; in others, originator biologics became the focus, offering the potential for a role for biosimilars if the innovator products proved successful. In the latter group is Roche’s bevacizumab (Avastin), which was hypothesized to offer value in the treatment of pulmonary edema–related acute lung injury and ARDS. Pulmonary edema involves fluid buildup in the lungs, a condition that bevacizumab can suppress. The Center for Biosimilars® did a popular 

 of these efforts to address the COVID-19 problem.

Related to this, Celltrion Healthcare’s mAb CT-P59 demonstrated positive results in the phase 1 CATALYST 

 for management of COVID-19–related inflammation. Also, a commentary published in

called for priority attention to developing anti–tumor necrosis factor (TNF) therapies for the treatment of COVID-19, saying that these agents, which include biosimilars, have been overlooked. “The potential of anti-TNF therapy as a treatment for COVID-19 is supported by both biological plausibility and observational clinical data,” 

. "Few current treatments under investigation have this level of supportive evidence."

During the month of September, a published paper brought to prominence 

 among UK regulators about the relatively weak evidence provided by comparative biosimilar efficacy trials. Investigators have long contended that pharmacokinetic and pharmacodynamic studies can produce more exact comparative data to demonstrate biosimilar equivalency to reference products and that in-human efficacy trials lack a strong scientific basis for performing this task. With Brexit, the United Kingdom’s exit from the European Union, the country is assuming control for authorizing medicines, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency issued guidance stating that comparative efficacy/safety trials generally would not be necessary.

A well-read story in October 2020 concerned Amgen’s 

 on market share and pricing discounts achieved by biosimilars. Biosimilars introduce discounts to the market and capture share from originator products, but they also induce originator companies to drop their prices for reference products in order to maintain market share. The Amgen report demonstrated that both dynamics have been in play in recent years. Biosimilars, Amgen said, have been gaining traction, although it depends on the type of biosimilars and the length of time they have been available in the market.

Similarly, a report from IQVIA Institute for Human Data Science stated that concerns about limited biosimilar uptake in the United States appear to be overblown. “Some commonly held assumptions about patient and provider acceptance and comfort with biosimilars appear to be more conservative than data demonstrate,” said the authors of the report. They 

 that drugs accounting for 51% of the spending on biologics would face biosimilar competition over the next 10 years.

The renewed concerns about the value of comparative clinical efficacy trials prompted Center for Biosimilars® Advisory Board Member Sarfaraz K. Niazi, PhD, to write a column about reasons why these trials add little to the weight of evidence for biosimilar approvals. “Comparative efficacy testing of biosimilars is redundant at best,” he wrote in this 

Canadian provinces have made huge strides in establishing biosimilar use via mandatory switching. A November 2020 

 in this regard saw high traffic from Center for Biosimilars® readers. Having begun its program in 2019, Alberta saw 16% of patients switched to biosimilars from use of 7 reference products, according to a presentation at the Terrapinn Festival of Biologics Basel 2020. The province is hoping to have 100% of patients switched by January 15, 2021. From the US standpoint, these are an enviable achievement and goal. British Columbia began a similar initiative 6 months earlier than Alberta and also has reported good results. Officials reported being able to funnel millions of dollars in savings back into medical programs to expand access for residents of the province. Other Canadian provinces reportedly are considering switching programs to achieve similar results. In August, biosimilars had an 

 relative to reference drugs in Canada, vs rates of 50% to 95% for countries that have fully embraced these alternative biologics.

A well-read article in December concerned 

, whose market share and use have seen some erosion due to the availability of on-body injectors (OBIs), which are marketed only for the originator brand, Neulasta. OBIs offer convenience but they are not 100% reliable, and providers and patients may prefer to use pegfilgrastim biosimilars instead, even though they require that patients return to the clinic for injections that the OBIs would perform automatically at the patient’s home. Studies presented at the American Society of Hematology Annual Meeting and Exposition demonstrated that the failure rate of OBIs adds to hospitalization costs. The savings from pegfilgrastim biosimilars, the authors argued, could significantly expand access to this medicine, which is used to reduce the incidence of febrile neutropenia in patients receiving chemotherapy.

During the month of December, Boehringer Ingelheim (BI) attracted attention with the filing of a 

 that asked the FDA to reconsider its interpretation of “strength of formulation” for biosimilars under the Public Health Service Act. The company wants the FDA to interpret strength to mean “total drug content” regardless of concentration or total volume. BI contends that originator companies that want to block biosimilars from challenging their market share may place undue stress on the FDA’s current interpretation of strength, which might delegitimize a biosimilar that is in fact equivalent to a reference product.

Finally, fresh guidance from the FDA on licensing procedures for biosimilars when it comes to interchangeability generated a large number of clicks from Center for Biosimilars® readers. The FDA asked applicants to be clear during the applications process whether they were seeking interchangeable status for their biosimilar candidates. The guidance was only in draft form and the FDA is 

In part 2 of this year-end feature, we look at the most-read biosimilar stories of the second half of 2020. 

A Review of the Most-Read Biosimilar Stories of 2020: Part 2

For Bengaluru, Karnataka, India–based Biocon Biologics, the pandemic has interrupted the  FDA review process for its planned bevacizumab biosimilar. 

by the FDA that a decision on its biologics license application (BLA) for the bevacizumab biosimilar candidate MYL-14020, referencing Avastin, has been deferred while the agency awaits an opportunity to inspect the company’s manufacturing facility.

Biocon announced in March 2020 that the FDA had 

its BLA for MYL-14020. The anticipated decision date at the time was December 27, 2020. A European application for approval also has been filed, but Biocon did not provide an update on that progress.

Biocon is developing MYL-14020 for marketing in conjunction with 

, which was formed through the recent merger of Mylan and the Upjohn division of Pfizer.

“To complete the application, the [FDA] noted that an inspection of the manufacturing facility is required as a part of the standard review process,” Biocon said in an investors statement. “However, due to restrictions on travel related to [coronavirus disease 2019], the agency is unable to conduct an inspection during the current review cycle.”

Biocon said it would await an opportunity for an inspection from the FDA. The agency in March 2020 

most inspections outside the United States. “We are aware of how this action may impact other FDA responsibilities, including product application reviews,” the FDA said at the time.

The agency said it would consider “mission-critical” inspections on a case-by-case basis, rely more heavily on border inspections of incoming products, and place some trust in companies with a history of positive compliance. Some sharing of information and cooperation with foreign governments was incorporated into the strategy.

Mylan prior to the Upjohn merger had 20 biosimilars and insulins in its portfolio of marketed and pipeline products. Upjohn was spun off from Pfizer, which retained its biosimilar portfolio. Mylan and Biocon have jointly distributed trastuzumab (Ogivri) and pegfilgrastim (Fulphila) biosimilars. They are also working to obtain biosimilar status for the insulin glargine product Semglee, which was approved in the United States in June 2020.

MYL-14020 could have been the fourth US biosimilar approved by the end of 2020, but the FDA hasn't been able to complete a necessary foreign inspection, owing to the pandemic.

Pandemic Delays FDA Decision on Biocon's Bevacizumab Application

The year 2020 saw just 3 FDA approvals for biosimilars: Pfizer’s pegfilgrastim (Nyvepria) and Mylan/Fujifilm’s adalimumab (Hulio), in June and July, respectively, and Amgen's rituximab (Riabni), in December. That was hardly a stellar rate of approvals, considering the 10 biosimilars approved in 2019; however, 2020 in biosimilars was eventful, nonetheless.

A review of the most popular stories published on The Center for Biosimilars

 website shows the breadth of topics that captured readers’ attention. As the stories reveal, it was a year in which many events were shaped by the unfolding coronavirus 2019 pandemic (COVID-19). Despite this, biosimilars continued their upward march, capturing market share from reference products and gaining new regulatory support.

 of Pfizer’s bevacizumab biosimilar Zirabev at a 23% discount to the wholesale acquisition cost of Avastin. This biosimilar was indicated for the treatment of metastatic colorectal cancer, recurrent or metastatic nonsquamous non–small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma, and persistent, recurrent, or metastatic cervical cancer.

 “authorized” generic versions of its insulin products NovoLog and NovoLog mix at a 50% discount to its brand name reference products. The launch came prior to the March 23 transition under the Biologics Price Competition and Innovation Act (BPCIA), which was intended to create a new regulatory approval pathway for competitor insulin products that could break the dominance of originator brands.

 of an insulin glargine contender (Semglee), by Biocon Biologics and Mylan, although this was approved under the 505(b)(2) New Drug Application pathway for generic medicines and was not technically a biosimilar. Analysts speculated that insulin biosimilars will start to appear in 2021 as a result of the BPCIA transition.

 its biosimilars business to focus on sales of its oncology drug pembrolizumab (Keytruda), a programmed cell death protein 1 (PD-1)  inhibitor that thwarts cancer cells’ ability to switch off the immune system response. The biosimilars Merck sought to divest from included infliximab (Renflexis), trastuzumab (Ontruzant), and etanercept (Brenzys). Entrepreneurial forays into biosimilars may no longer hold interest for Merck, but the company is likely to see biosimilar competition for Keytruda in coming years. NeuClone of Sydney, Australia, announced in September 2020 it is developing biosimilar versions of the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab. These could start to reach market in 2027.

 biosimilar (Trazimera) for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Other biosimilar versions of trastuzumab already were on the market. These included Ogivri (Mylan/Biocon Biologics) and Kanjinti (Amgen).

But more trastuzumab biosimilar launches were in store. Herzuma (Celltrion/Teva) and Ontruzant (Samsung Bioepis) were launched in March and April, respectively.

The arrival of COVID-19 in the early portion of the year was as disruptive for biosimilar development as for all other aspects of medical care. Clinical treatment programs—both patient visits and clinical trials—were delayed or cancelled. The FDA issued special guidance for the continuance of clinical studies to minimize the damage to data collection and medicinal product applications that COVID-19–related issues would cause. 

One of the most-read Center for Biosimilars

 COVID-19 injected into the drug supply chain. US pharmaceuticals were thought to be at risk for shortages owing to the country’s heavy reliance on internationally sourced materials. While these concerns were developing, the FDA announced that it would have to suspend on-site inspections of international facilities where drugs bound for the United States were manufactured.

Related to the COVID-19 crisis, pharmaceutical companies found themselves challenged to get the word out about their newer products, which encountered headwinds in the form of shifting priorities in the health care sector and struggles getting sales personnel into the field for product pitching. Quarantines made that difficult, if not impossible. A transition toward digital marketing that had begun previously was 

Similarly, the FDA’s resources shifted toward managing hundreds of trials and reviews for COVID-19 vaccine candidates and related therapies, and agency officials restated throughout 2020 the singular focus required to get this job accomplished. For companies with product candidates considered less essential, it was possible that a delay in FDA consideration could be anticipated.

The pandemic forced Celltrion, of Incheon, Republic of Korea, to suspend construction of a $514 million biopharmaceutical manufacturing plant in Wuhan, the epicenter of the outbreak, but the company saw opportunity in the crisis and moved forward to develop therapeutic antibodies capable of 

 SARS-CoV-2, the virus responsible for COVID-19. The company reported encouraging results of development work and clinical trials throughout 2020, and in December, its COVID-19 antibody treatment CT-P59 was 

 for patients with life-threatening conditions by the Republic of Korea Ministry of Food and Drug Safety, according to a Reuters report.

Among the leading biosimilar stories from May 2020 was a report about Celltrion’s efforts to gain European Union approval for its adalimumab biosimilar candidate CT-P17. The potential biosimilar was designed as a high-concentration formulation that Celltrion hoped would give it an edge against competitor products. In early December 2020, the company gained a 

 for CT-P17 from the European Medicines Agency Committee for Medicinal Products for Human Use, and a final decision by the European Commission is anticipated in the early part of 2021. Adalimumab biosimilars in Europe have made progress against the reference product, Humira, but in the United States, the originator company, AbbVie, has managed to negotiate deals that will keep these biosimilars off the market until 2023.

 that Gedeon Richter, of Hungary, would buy a tocilizimab biosimilar candidate (LusiNEX) from Mycenax, a pharmaceutical contract development and manufacturing organization in Taiwan. The biosimilar was thought to be useful in managing COVID-19–related pneumonia. Meanwhile, the reference product, Roche’s Actemra, received FDA approval for a phase 3 trial to evaluate safety and efficacy in adult patients hospitalized with pneumonia as a complication of COVID-19.

Biosimilar competition for Johnson & Johnson’s Stelara (ustekinumab) may be years off, and yet interleukin-23 (IL-23) inhibitors such as this are an important new class of drugs for the treatment of Crohn disease and ulcerative colitis. Other companies developing these products are AbbVie and Allergan, whose merger in 2020 was approved by the Federal Trade Commission, giving rise to 

 that this would limit competition in the IL-23 inhibitor market.

However, biosimilars are in development for IL-23 inhibitors. In 2020, NeuClone completed a phase 1 clinical trial for its ustekinumab biosimilar candidate NeuLara, and Formycon, of Martinsried-Planegg, Germany, is developing FYB202, another potential competitor for Stelara, which had global sales of $6.6 billion in 2019.

In June 2020, the World Health Organization (WHO) 

 the rituximab biosimilar Truxima to provide a more affordable treatment option for blood cancers in lower-income countries. Riutuximab is used for the treatment of diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and follicular lymphoma. This was the second biosimilar prequalification for the WHO. In December 2020, the WHO prequalified 

, a Samsung Bioepis trastuzumab biosimilar (Ontruzant).

Also this month, the FDA approved the Pfizer pegfilgrastim biosimilar Nyvepria, making this the fourth pegfilgrastim approved for use in the United States, with the others being Ziextenzo, Udenyca, and Fulphila. These products reference Amgen’s Neulasta. The FDA clearance brought Pfizer’s total approved biosimilars for the US market to 6. During the first half of 2020, Pfizer brought 2 biosimilars to market: the rituximab biosimilar Ruxience and Trazimera.

The top stories in biosimilars for 2020 encompassed biosimilar approvals and launches, the coronavirus disease 2019 pandemic, and the FDA's challenge to stay on top of the rapidly changing health care landscape. 

A Review of the Most-Read Biosimilar Stories in 2020: Part 1

The FDA’s approval of Amgen’s rituximab biosimilar (Riabni) this month brings to 29 the number of approved biosimilars in the United States since 2015, and if Amgen launches on schedule in January 2021, there will be 19 marketed biosimilars in total. Amgen has 4 other biosimilars with FDA approvals: adalimumab (Amjevita), infliximab (Avsola), trastuzumab (Kanjinti), and bevacizumab (Mvasi). All are launched except Amjevita (scheduled for 2023).

The Center for Biosimilars® (CfB) interviewed Christophe Bourdon, senior vice president and general manager of US Oncology for Amgen, about the Riabni approval and marketing plan. The product is approved for all indications of the reference product, Rituxan, which in the United States is marketed by Biogen and Genentech and in Europe by Roche. Those indications are non-Hodgkin lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis, and microscopic polyangiitis.

 at a wholesale acquisition cost (WAC) 23.7% less than the reference product, 15.2% less than the WAC for the rituximab biosimilar Truxima, and on par with the WAC for the other rituximab biosimilar, Ruxience. Riabni will be marketed at an average selling price (ASP) 16.7% below the current Rituxan ASP. Ruxience sells for an ASP 20% below Rituxan.

CfB: How long did it take from initial application filing to product approval in the FDA process?

 It’s usually 12 months between submission and release, and the good news is we were actually able to get approval 2 days ahead of plan, so we were expecting the Riabni approval on December 19, 2020, and we got it on the 17th.

CfB: What hurdles and challenges did you encounter in terms of gaining approval?

 It was a very smooth process. We had some very constructive dialogue—we received feedback and advice from the FDA on the data package, and we’re very pleased to now have the possibility to serve more patients starting early next year.

CfB: Amgen decided to do a comparative clinical efficacy study for Riabni. There’s a lot of debate about whether those are necessary. Was it the FDA that asked you to do that, or was there another reason?

 We believe that, for biosimilar approval, generating very solid data is paramount for the safety of patients and also to increase the level of confidence and trust for providers. Riabni was approved here in the United States with a total body of evidence. We submitted comparative analytical, nonclinical, and also clinical data, and at the end we were pleased to see that there were no clinically meaningful differences, both in safety and effectiveness, between Riabni and the rituximab originator.

CfB: So, just to clarify, you feel that having a comparative clinical efficacy study is a big win for gaining confidence of providers and patients?

 Exactly. Any data that we can generate to ensure the safety and effectiveness of our product is really something very critical to enhance the trust of providers and also of patients.

CfB: Sometimes biosimilar developers encounter difficulty obtaining originator product samples to facilitate the development work. Did you have any difficulty here?

 No, that was not the case. We were really able to obtain sufficient product samples for our needs.

CfB: Have you encountered any litigation with Roche or Genentech over this product, or are you launching “at risk” of litigation?

 Amgen has settled all outstanding issues with Genentech and Roche, and we have acquired the license that allows Riabni to be launched within the time frame that we have communicated.

CfB: How much did you have to spend to bring Riabni through the development and approval process to the point of marketing?

 Beyond money, we invested time. The Amgen biosimilar journey started 10 years ago, at which time Amgen committed to invest $2 billion in 10 different biosimilar products, so roughly to answer your question, $200 million per biosimilar.

CfB: And $200 million is what you spent on Riabni?

CfB: Are there any particular sales channels you’re aiming for as you roll this product out in the United States?

 Our responsibility is to serve every cancer patient here in the United States, so we will make Riabni available for specialty and wholesale distribution as quickly as possible in January—all channels.

CfB: Can you comment on the importance of getting this product placed on formulary—getting both payers and pharmacy benefit managers [PBMs] on board?

 Especially in the middle of the pandemic, the financial pressure on the system is really there—it’s tangible. And every stakeholder, whether it’s PBMs, payers, providers, has gained experience over the last 2 to 3 years on how to quickly adopt biosimilars. We have seen, now, payers being very nimble and agile in adopting biosimilars, so we have the experience and we believe we will be able to repeat that success.

CfB: How else will you support the rollout of this product, by educating providers?

 We should not forget that, at the end of the day, we’re talking about severely ill cancer patients, and so beyond the economic dimension, providers have a responsibility to have the answers to certain questions. Is it safe to inject or infuse a product? Is the manufacturer a reliable and long-term supplier of the product, ie, guaranteeing there will be no disruption in supply? And certainly, with co-pays and out-of-pocket payments, how can the manufacturer support the patient? This is where we’re really investing a lot of effort, reassuring and informing providers about the role Amgen can play in delivering biosimilars for patients, and I feel very good about this.

 noted that rituximab biosimilars have a 20% share of the market relative to Rituxan’s 80%. Do you feel that that 20% share is adequate progress for rituximab biosimilars?

  It’s a very fast-moving environment, and if you look at other classes of drugs, we’ve seen fast uptake of biosimilars, so I’m very optimistic and we’re optimistic at Amgen that Riabni will introduce additional benefits.

CfB: Although the first rituximab biosimilar entered market in 2019, Biogen and Genentech have not lowered the price for the originator. Do you feel that the arrival of a third rituximab biosimilar, Riabni, is going to put pressure on them to finally bring down the price on their side?

 If you look back 10 years ago, you know that the introduction of biosimilars was really a social compact here in the United States, which was continuing to deliver the best innovative medicines for patients at a lower price, and what we are seeing with the successive launch of biosimilars is 2 things are happening: First, biosimilars are usually introduced at a lower price than originators, bringing short-term savings; and, over time, you see also the originator price (ASP) trending down. These are 2 ways that savings are generated, and we are seeing this across all biosimilars that have been launched so far in the United States. I cannot comment on or predict the future, but Amgen is convinced that the efficiency of the market right now is bringing a lot of savings through price decreases of biosimilars and originators.

CfB: The biosimilar Ruxience is cheaper than Truxima, but Truxima has a higher market share [17% vs 3%]. Would you say this is because Truxima was on the market earlier [November 2019 vs January 2020] or are there other issues here?

Christophe Bourdon, senior vice president and general manager of US Oncology for Amgen, discussed the development and marketing plan for the company's newly approved rituximab biosimilar. 