Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

 for a bevacizumab biosimilar (Hanbeitai) from Chinese regulators. The company said the National Medical Products Administration (NMPA) has approved the product for treatment of metastatic colorectal cancer (mCRC) and unresectable locally advanced recurrent or metastatic nonsquamous non–small cell lung cancer (NSCLC).

This makes the fourth Henlius biosimilar to be approved by the NMPA. The others are rituximab (Hanlikang), trastuzumab (Hanquyou), and adalimumab (Handayuan) biosimilars. The trastuzumab biosimilar is approved in the European Union and markets under the product name Zercepac.

Henlius said since the original approvals of these biosimilars, their indications have been broadened to include hematological malignancies, solid tumors, and autoimmune diseases.

Henlius is also developing a programmed death (PD) inhibitor (serplulimab) for the treatment of NSCLC and has a clinical trials program in progress to test the drug in combination with bevacizumab. The company said it believes serplulimab may have potential in the treatment of various solid tumors.

Frontline studies of Hanbeitai and the PD-1 monoclonal antibody serplulimab are being conducted in nonsquamous NSCLC (phase 3) and CRC (phase 2). 

“Lung cancer and colorectal cancer are ranked second and third with high incidence of cancers in the world, respectively. They are also ranked first and second in China, and there is a huge demand for treatment,” Jason Zhu, president of Henlius, said in a statement.

He said the clinical equivalence trials of Hanbeitai showed the agent was highly similar to the originator drug, Avastin, in terms of efficacy and safety. “It is believed that the approval of Hanbeitai will further improve the accessibility of bevacizumab and provide a high-quality option for patients with lung cancer and colorectal cancer," Zhu said.

Lung cancer and mCRC are common in China. Henlius said that 810,000 cases of lung cancer are diagnosed each year in the country, and NSCLC is the most common form, accounting for 80% to 85% of lung cancer diagnoses.

“The incidence rate of CRC ranks second among all malignant tumors in China, with over 550,000 new cases in 2020,” Henlius said.

Bevacizumab when added to chemotherapy treatment has been shown to delay disease progression and prolong survival in patients with mCRC and is a standard of care, the company said. The drug binds with vascular endothelial growth factor and inhibits the growth of blood vessels that support the growth of tumors.

Avastin is also used for treatment of eye disease, such as macular degeneration, although the ophthalmology community in the United States has expressed leeriness of using bevacizumab biosimilars for eye disease, owing to the relative lack of supportive clinical evidence.

Henlius said it is developing an ophthalmic product (HLX04-O) that has the same active ingredients as Hanbeitai for the treatment of wet age-related macular degeneration (wAMD). In the first half of this year, phase 3 clinical trials were approved for initiation in Australia, the United States, Singapore, and the EU countries Latvia, Hungary, and Spain. The company has also initiated treatments in a phase 3 trial of HLX04-O in China, also for wAMD.

The Center for Biosimilars® recently interviewed 

, vice president of Business Development for Henlius, about the company’s biosimilar development plans and, especially, its adalimumab and PD-1 inhibitor programs.

Articles

Henlius gains approval in China for Hanbeitai and officials discuss combination therapy options with experimental therapy serplulimab and ophthalmology treatment.

China Regulators Approve Henlius Bevacizumab Biosimilar Hanbeitai

Samsung Bioepis will not be able to bring its etanercept biosimilar (Eticovo) to market in the United States until 2029, based on the outcome of litigation between the company and the makers of the reference product (Enbrel), a tumor necrosis factor (TNF)–inhibitor used for treatment of inflammatory and autoimmune disease.

The US District Court for the District of New Jersey has ruled in favor of a contention by Enbrel makers Amgen, Roche, and Immunex that Samsung Bioepis would infringe 2 key patents if it attempted to produce, sell, or import to the United States its biosimilar prior to 2029, which is when the patents expire.

Enbrel is approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and pediatric plaque psoriasis.

The court decision marks the second setback in a year for biosimilar versions of etanercept. In May 2021, the US Supreme Court declined to reopen a Federal Circuit patent case between the reference product makers and Sandoz, which had unsuccessfully sought to bring the etanercept biosimilar Erelzi to market prior to 2029.

These were the only etanercept biosimilars and there are no others on the approval horizon, according to a November 2021 report by Amerisource Bergen.

Erelzi received FDA approval in August 2016, but the patent litigation had kept this product in the warehouse rather than on pharmacy shelves. Eticovo was approved in April 2019.

The court decisions mean another 7 years will pass before biosimilar versions of etanercept can enter the US market, which represents the largest etanercept market by volume of sales for Amgen. Amgen reported just under $5 billion in Enbrel revenues in 2020; of that, $4.9 billion came from the US market. 

In the European Union, Enbrel is marketed by Pfizer, and Samsung Bioepis, Sandoz, and Viatris are marketing etanercept biosimilars there.

In their suit against Samsung Bioepis, the plaintiffs argued that 5 patents owned by Roche and Immunex faced infringement. All 5 of the patents were issued well after Enbrel was first approved by the FDA, in 1998.

The pivotal patents in the court’s ruling of infringement were both owned by Roche: US patent 8,063,182 (‘182), issued in 2011, and US patent 8,163,522 (‘522), issued in 2012.

TNF is a cell-signaling protein whose overproduction leads to autoimmune and other inflammatory diseases. Etanercept is a fusion protein that binds with TNF to inhibit inflammatory responses. Both patents concern this fusion protein (p75 TNF receptor) and its makeup.

The filing of drug patents subsequent to FDA approval has the effect of extending the product exclusivity life of an originator drug, as has happened in this case. By 2029, Enbrel will have had 31 years of exclusivity in the United States.

Under the Biologics Price Competition and Innovation Act (BPCIA) of 2009, novel biologics drugs are guaranteed 12 years of exclusivity from FDA approval, with the intention that competitors can come to market after the originator company has earned a reasonable return on its product 

development investment. But as the Enbrel case has demonstrated, manufacturers can find ways 

to extend exclusivity well beyond the BPCIA time limit.

One consequence of extended patent protection for a reference product is that manufacturers have more freedom to raise prices, sometimes well above the rate of medical inflation.

In January 2021, the Institute for Clinical and Economic Review (ICER) reported that Enbrel was among 10 prescription drugs for which the wholesale acquisition cost increases between 2018 and 2019 were more than twice as high as the rate of medical inflation. Humira (adalimumab), another reference product that so far does not have US biosimilar competition, also was on that list.

ICER reported that the 2018-2019 net price increases for these drugs were 8.9% and 2%, respectively, contributing to an increase in US drug spending of $403 million and $66 million, also respectively.

In a brief statement describing the court decision, Samsung Bioepis said it was under court injunction not to make, use, import, or sell Eticovo until the etanercept patent protection expires. "We have no comment regarding the court decision," a company spokeswoman said. 

The Center for Biosimilars® recently covered the 

In the second setback this year for etanercept biosimilars, the US District Court for the District of New Jersey has ordered Samsung Bioepis to delay marketing Eticovo until 2029. 

NJ Court Decision Means 3 Decades of Product Exclusivity for Enbrel

Price negotiations for biologics and forcing drug manufacturers to rebate CMS for drug costs that exceed rates of general inflation are options the federal government is considering to control drug spending.

But these policies “are in lieu of addressing the root cause” of drug cost increases, and programs that disallow rebates paid by manufacturers to pharmacy benefit managers (PBMs) and payer plans would be more effective, argued a biosimilars manufacturer representative at the recent GRx+Biosims conference sponsored by the Association for Accessible Medicines.

Some industry stakeholders contend “pay-for-delay” deals unfairly restrict competition whereas others contend they facilitate drug affordability and market access. GRx+Biosims panelist Sarah D’Orsie said that instead of seeking to curtail and regulate pay for delay deals between drug makers, the federal government should raise the bar on the quality of patents issued to drugmakers. D’Orsie is vice president of government affairs and policy for Fresenius Kabi.

If approved, the Build Back Better Act, President Joe Biden’s safety net spending initiative would allow drug price negotiations for a small number of high-cost Medicare Part D and Part B drugs that lack generic or biosimilar competition. Prices of up to 10 drugs could be negotiated in 2025, with the annual number of drug prices negotiated increasing to 20 by 2028. The proposal would also cap the upper limit of the negotiated price. Further, an excise tax would be levied on drug makers that don’t comply with negotiation and monetary penalties would apply to companies that don’t maintain negotiated prices.

Separately, a bill in Washington, DC, the Preserve Access to Affordable Generics and Biosimilars Act, would limit pay-for-delay deals that compensate drug manufacturers for withholding their products from market.

Patent thickets, which are clusters of patents that shield originator products from competition, and poor patent quality tend to impede biosimilar competition, D’Orsie said, explaining that patents, good or bad, can give the originator company leverage to negotiate pay-for-delay settlements, which keep biosimilars and generics off the market.

As D'Orsie described, rebates paid by manufacturers can become a vicious cycle if both the original brand manufacturer and the biosimilar company feel compelled to offer them.

“As a biosimilars company, we have to compete in some way with the brand, and the way it’s going, that means giving a rebate. In order to compete [with other companies] on bigger and bigger rebates, you raise your price in order to have more room. So the concept is that the manufacturer is breaking even every year and the PBM and the plan are getting a bigger rebate…and the Medicare patient ends up paying [more, as a percentage of costs] every single year,” she said.

The US Patent and Trade Office is just granting scores of junk patents, which is why we need to do settlements between biosimilar companies and the brand, because we cannot afford to litigate these scores of junk patents.

One provision of the Build Back Better Act would require drug manufacturers to rebate the federal government if their prices for biologics covered under Medicare Part B and Part D increase faster than the rate of inflation. “Everybody’s worried about the inflationary penalties,” D'Orsie said.

She said pay-for-delay settlements actually help biosimilar companies to bring their products to market. Although these agreements appear to delay biosimilar competition, the “root cause” of delayed competition is an excess of patent approvals that are granted on a weak basis of evidence of product improvement or innovation, she said.

“The US Patent and Trademark Office is just granting scores of junk patents, which is why we need to do settlements between biosimilar companies and the brand, because we cannot afford to litigate these scores of junk patents,” D’Orsie said. “The settlements actually get us closer; [they] allow us to launch, sooner than if we were just going to wait for the patent to expire.”

Panelist John Brooks, a partner with health policy consulting firm South Capitol, said reforms are needed to Medicare Part D, which he said was designed for an era when generic drugs were a significantly smaller proportion of prescriptions written and biosimilars didn’t exist.

“It’s really exciting to see the potential for significant changes here that could improve the program but also provide additional opportunities to level the playing field for products and manufacturers,” he said.

The current design of Medicare coverage, along with manufacturer rebates, “creates a series of incentives for [payer] plans that can drive them toward using higher-cost products,” Brooks said.

He suggested that policy makers level the playing field, in part, by putting biosimilars, such as adalimumab, on specialty tiers. “We’ve seen just in the past year that CMS has given plans additional flexibility to create a second specialty tier. That should improve the negotiating leverage of biosimilars.”

Specialty tiers for biosimilars and reforms that address the proliferation of poor-quality patents would help lower costs and improve access, biosimilar industry veterans said.

Biosimilar Industry Critiques Biden's Drug Pricing Reforms

Ontario in early 2020 became the third Canadian province to begin switching patients on reference (originator) drugs to biosimilars; however, the move did not mandate switching all patients to biosimilars if they were already started on reference products. In a 

, investigators estimated potential savings from stronger substitution policies.

Using pharmacy claims data for biologics reimbursed under provincial drug insurance, investigators modeled spending and patient utilization according to mandatory nonmedical biosimilar substitution and substitution for new users only. They also considered the availability of adalimumab and insulin glargine biosimilars based on price discounts as low as 25% of the reference product price, which they said was achievable based on studies of biosimilar adoption in other regions.

Their analysis covered the 2-year period from January 2018 to December 2019 and also forecast trends to December 31, 2020.

A mandatory nonmedical biosimilar substitution policy for inflammatory diseases would have affected 7209 patients during the 3-year period and saved $238.6 million. Had the substitution policy applied only to new users, 757 patients would have been affected and the savings would have been limited to $34.2 million. With the hypothetical availability of an adalimumab biosimilar, the 3-year savings under mandatory switching would have increased to $645.9 million, and 12,928 patients would have been affected, based on all biosimilars being priced at 25% of the reference product price.

Not including adalimumab biosimilar savings, the expansion of nonmedical mandatory switching to include an insulin glargine biosimilar would have saved $288.7 million, investigators said.

The importance of biosimilars—equally effective and safe as reference drugs—for savings and access to health care has long been recognized, but in Canadian provinces uptake of these agents has been tepid, and so in recent years British Columbia and Alberta, and now Ontario, have begun mandating that patients use biosimilars. The growth of use of biologics, among the most costly of drugs, also has driven this trend.

In 2018 biologics accounted for 1.5% of claims in Canadian public health programs, but 27.3% of drug costs. In Ontario, use of biologics increased 462% from 2010 to 2019, and public spending on biologics in the province was forecast to reach $1.4 billion by 2021.

“Although biologics are improving outcomes for patients, their increasing use and high costs threaten the financial sustainability of public drug programs,” authors of the study wrote.

The study included publicly funded prescriptions for infliximab, etanercept, and adalimumab for rheumatic conditions or inflammatory bowel disease (IBD). In their analysis of 2018 claims information, investigators found that 84.1% of users of etanercept and 86.7% of users of infliximab were treated with a reference product vs a biosimilar.

When it came to starting treatment for patients with rheumatic conditions or IBD, reference products still retained traction: 39.5% of patients starting etanercept and 59.8% of patients starting infliximab began with a reference product rather than a biosimilar.

International research suggests that policies requiring nonmedical switches or automatic substitutions with biosimilars generally lead to rapid shifts in dispensing patterns and large cost reductions for public payers, but potentially increased costs related to health services utilization

“Overall, the considerable cost savings and number of patients affected by the biosimilar policy changes examined in this study are within the range of estimates found in other jurisdictions, both nationally and internationally,” authors of the study wrote.

“International research suggests that policies requiring nonmedical switches or automatic substitutions with biosimilars generally lead to rapid shifts in dispensing patterns and large cost reductions for public payers, but potentially increased costs related to health services utilization,” they said.

An important factor when contemplating a switching policy is that manufacturers of reference products often provide funding for some patient care and medication administration costs, as well as co-payment assistance, investigators said. “Therefore, any policies introducing mandatory changes in therapy need to allow for scaling up of these services for the corresponding biosimilars,” they wrote.

Although Ontario public drug programs require that new users of infliximab and etanercept start on biosimilars, the reality is this policy is subverted by a hospital practice of starting patients on reference products that are obtained for relatively low cost.

“As our model indicates, considerable additional savings could be achieved if the intended new-user biosimilar policy was fully enforceable,” the authors wrote.

Adalimumab biosimilars became available in Ontario in February 2021.

, investigators shed light on helpful practices and considerations for pharmacists when switching patients to rheumatology biosimilars. 

Authors of a new study estimated significant savings from biosimilars in Ontario based on deep price discounts and mandatory switching programs.

Study Models Biosimilar Savings in Ontario From Mandatory Switching

Investigators have reported significant improvement in progression-free survival (PFS) for patients with nonsquamous non–small cell lung cancer (NSCLC) treated with sintilimab and Byvasda, a bevacizumab biosimilar, in combination with chemotherapy.

 at the European Society for Medical Oncology Virtual Plenary meeting this month. In the phase 3 ORIENT-31 trial, patients who progressed on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy were treated with sintilimab (a programmed death inhibitor), a bevacizumab (which inhibits tumor vascularization) biosimilar, pemetrexed, and cisplatin.

Sintilimab, marketed as Tyvyt, and Byvasda are approved in China, and the EGFR-mutated nonquamous NSCLC study was conducted at multiple sites in China. Tyvyt was developed by Innovent Biologics and Eli Lilly, and Byvasda was developed by Innovent Biologics.

Investigators said that in the intent-to-treat patient population, those who received sintilimab plus the bevacizumab biosimilar in combination with chemotherapy demonstrated a statistically significant improvement in PFS compared with patients who received just chemotherapy (HR, 0.46; 95% CI, 0.337-0.639; 

 < .0001). The median PFS was 6.9 vs 4.3 months, respectively.

They said a third cohort of patients was administered sintilimab and chemotherapy, but findings did not achieve statistical significance in comparison with the sintilimab-plus-bevacizumab- biosimilar-and-chemotherapy cohort.

The investigators said key secondary end points for objective response rate and duration of response showed improvement in the sintilimab-plus-bevacizumab-biosimilar arm vs chemotherapy alone. Safety results were consistent with those previously reported for sintilimab and Byvasda.

Innovent said that it will file an investigational new drug application with China’s National Medical Products Administration based on the findings from ORIENT-31.

The results are important because the prognosis for advanced EGFR-mutated NSCLC is very poor, investigators said.

“Despite initial clinical response to EGFR-TKI therapy, virtually all advanced EGFR-mutated NSCLC [cancers] inevitably acquire resistance mechanisms and progress after treatment with an EGFR-TKI,” said Shun Lu, MD, PhD, principal investigator from the Oncology Department of Shanghai Chest Hospital.

The current standard of care for EGFR-mutated advanced nonsquamous NSCLC is platinum-based chemotherapy, although this offers little benefit. “New treatment options are imperative for this unmet medical need,” Lu said.

Investigators said ORIENT-31 was the first prospective, double blind, phase 3 study to demonstrate an improvement in this patient population with sintilimab and bevacizumab in combination with chemotherapy.

"Lung cancer is one of the most prevalent cancers and remains the leading cause of cancer-related mortality both in China and worldwide. EGFR-mutated NSCLC is the most prevalent molecular subtype in Chinese lung cancer patients, accounting for 40% to 50% of nonsquamous NSCLC,” said Hui Zhou, PhD, senior vice president of Innovent.

“While immunotherapy has greatly changed the treatment paradigm for many malignancies, it has not yet conquered driver genes–mutated cancers. Drug resistance is unavoidable for patients with EGFR-mutated advanced NSCLC after first-, second-, and third-generation EGFR-TKI treatments, with limited treatment options, representing a large unmet medical need. The ORIENT-31 data at this year's ESMO indicate the potential of combination therapy to prolong the lives of these patients,” he said.

Innovent was founded in 2011 and has offices in Suzhou, China, and San Francisco, California.

Progression-free survival (PFS) was improved for patients with epidermal growth factor receptor–mutated nonsquamous non–small cell lung cancer who were treated with PD-1 and antivascularization therapy.

Sintilimab and Bevacizumab Biosimilar Improve PFS in Advanced Lung Cancer

 from Samsung Bioepis and Organon takes aim at misconceptions about biosimilars and industry practices that hinder their adoption. The companies held 3 virtual panel sessions with doctors, nurses, pharmacists, policy experts, and patient advocates.

Authors of the paper hold up Cleveland Clinic as a model of a health system that has achieved success in converting patients to biosimilars from reference products.

Key to the success of Cleveland Clinic's program, the authors explain, was educating stakeholders and setting up direct communications so that patients and providers could learn what they needed to know about biosimilars.

Some of those stakeholders were nurses, who were given specific training so that they could “reassure patients about the quality of care they would be receiving and answer any questions patients might have.”

In the broader health care community, “many physicians still lack confidence in biosimilars,” the authors wrote. In oncology, biosimilars have been embraced by physicians and patients, but in gastroenterology, there are lingering concerns about whether these agents will serve patients as well as their reference products.

“Many gastroenterologists who prescribe biologics for their patients with inflammatory bowel disease are concerned about biosimilar safety, immunogenicity, and indication extrapolation,” the authors wrote.

Another health care institution that has successfully transitioned patients to biosimilars is Kaiser Permanente, authors of the whitepaper said.

“Kaiser’s approach starts with a rigorous review of available biosimilar evidence, including data from manufacturers, FDA approvals, and real-world data from countries where biosimilars have already launched,” they wrote.

Kaiser Permanente got biosimilars into circulation by building physician confidence, a strategy that 

Having these data on hand is critical to informing physicians and other stakeholders so they can more readily embrace biosimilars, the authors wrote.

However, those informational materials need to be digestible. “A gastroenterologist participating on the panel who has published on the merits of biosimilars in treating inflammatory conditions shared that many physicians are too busy to study in-depth clinical trial data and would prefer to receive easily digestible educational materials demonstrating a biosimilar’s safety, equivalence, and cost savings,” the authors wrote.

Samsung Bioepis has developed and gained regulatory approval for multiple biosimilar versions of reference products, and it relies on Organon for assistance with marketing these products. Some of Samsung Bioepis’ biosimilars include etanercept (autoimmune), infliximab (immunosuppressive), adalimumab (autoimmune), and other products. The company has a robust pipeline of biosimilars in development, including aflibercept (ophthalmology), denosumab (endocrinology), ustekinumab (immunology), and eculizumab (hematology) candidates.

Stakeholder education programs and robust data on clinical studies are key to building patient and provider support for biosimilars, according to a new whitepaper. 

Samsung Bioepis White Paper Describes Biosimilar Barriers to Adoption

The Center for Biosimilars® spoke with Martin Perry, MBChB, BSc, MMEd, FRCP, Clinical Medical Director for the National Health Service (NHS) in the Greater Glasgow and Clyde region of Scotland about biosimilar savings and access during COVID-19. Perry was a presenter on the topic during the recent Terrapinn Festival of Biologics meeting in Basel, Switzerland. 

Perry oversaw a COVID-19 ward and during this talk with The Center for Biosimilars® Senior Editor Tony Hagen, he explains the challenges of providing treatment for patients. He also sheds light on the United Kingdom's unique system of biosimilar choice and pricing. Access to biosimilars has broadened in the United Kingdom, partly due to the lower cost of these agents; but overall spending on biologics and specialty drugs is on the increase there, as in the United States. 

Perry also addresses switching patients from reference products to biosimilars and patient acceptance. Nocebo, or the potential for patients with poor attitudes toward biosimilars to influence their own outcomes, is a very real concern, Perry explains, underscoring the need for strong educational efforts to support biosimilar use. 

Brexit, or the United Kingdom's separation from the economic apron strings of the European Union, is well along since the beginning of 2021, and this has resulted in "no notable difference" in biosimilar supply, Perry reports. 

The UK continues to get a handle on the COVID-19 pandemic, and its most recent spike in cases is on the wane; and in the Glasgow/Clyde area the infection rate hasn't been as serious as in the Southeast (London), partly because residents have been more adherent to mask mandates, Perry speculates. Overall, the United Kingdom has seen 1 in 7 residents infected with COVID-19, according to an ongoing 

Perry says many UK residents are now coping with lingering complications of COVID-19, and the NHS is working to address these issues while seeking to reestablish normal services across the health care spectrum. "Currently, we're in a quieter phase in comparison with other stages" of the pandemic, he says. 

Martin Perry, MBChB, BSc, MMEd, FRCP, clinical medical director for the National Health Service in Greater Glasgow and Clyde, Scotland, explains frontline care with biosimilars during COVID-19. 

A UK Clinician Discusses Biosimilars in the Time of COVID-19

Biosimilars in the United States have seen perhaps the greatest uptake in oncology, but the use of biosimilars in oncology has also broadened access, meaning that competitive pricing of these agents, relative to reference products, has enabled more patients to receive treatment, according to a recent study of biosimilar administration at 122 practices by the Community Oncology Alliance (COA).

“A few years ago, when biosimilars were entering the market, several COA practices started using these, and we started to see savings anecdotally within our own organizations,” said Kathy Oubre, MS, CEO of the Pontchartrain Cancer Center in Louisiana and a cochair of the biosimilars committee at COA.

“We as an organization decided to take this a step further and look at this from a broader perspective, with a working hypothesis that biosimilars were going to play an integral part in bringing down health care costs,” she said in a presentation at the COA 2021 Payer Exchange Summit.

For the study of biosimilar use, participating practices submitted data for over 2 million administrations of reference and biosimilar products, and in the analysis, COA focused on rates of biosimilar adoption, administrations, and access to care.

In 2019 there were 68,000 administrations of Rituxan, the originator product for rituximab. The first rituximab biosimilar was Truxima, launched in November 2019, and this accounted for 19% of administrations in the first quarter of 2020.

Biosimilar rituximabs achieved a greater presence in the market with the launch of Ruxience in January 2020, and by the fourth quarter of 2020, rituximab biosimilars accounted for 55% of all rituximab administrations, Oubre said.

There were 112,000 administrations of rituximab in 2020, and 66,000 of those involved the reference product and the remaining 46,000, biosimilars. Oubre said this amounted to an increase of 44,000 administrations from 2019 to 2020, so access to care had sharply improved within the practices included in the study.

In 2019 there were about 23,000 administrations of both reference (Remicade) and biosimilar infliximab, and of those, 20,000 were reference product administrations. At that time, biosimilars accounted for a small percentage of administrations, but the presence of infliximab biosimilars began to grow. In 2020, Remicade administrations added up to 21,000—a 5% increase—but biosimilar administrations were significantly higher, 5000, reflecting growth in biosimilar share of administrations and also an increase in access to care with infliximab, Oubre said.

In 2019, there were about 120,000 administrations of pegfilgrastim, and 100,000 of those represented reference product (Neulasta) administrations. But in 2020, the number of administrations climbed to 139,000 in total, with 98,000 (a decline) being reference drug administrations and 41,000 being biosimilar administrations. “So, quite a large increase,” Oubre said.

“Within our organization [Pontchartrain], biosimilars have offered us a lower-cost alternative without sacrificing any quality for our patients. Therefore, we continue to see increases in access to care,” she said.

The first pegfilgrastim biosimilar entered the market in July 2018 and by the fourth quarter of that year had a 2% share of the market. By the end of 2020, pegfilgrastim biosimilars had a 31% share, Oubre said. There were 4 available biosimilar pegfilgrastims by that point.

The first trastuzumab biosimilar (Kanjinti) was launched in July 2019. In the fourth quarter of 2019, there were roughly 24,000 administrations of trastuzumab, and about 16,000 of those were the reference product (Herceptin), and 8000 were biosimilar administrations.

In 2020, the quarterly administrations overall were about the same, 24,000, but “we noticed tremendous biosimilar uptake, with 65,000 administrations of biosimilars and a significant drop to 29,000 administrations of the originator product,” Oubre said.

“To put a finer point on it, biosimilars accounted for 35% of all the trastuzumab administrations in the fourth quarter of 2019, and that quickly grew to 79% of all administrations by the fourth quarter of 2020,” she said.

It's our working hypothesis that these market shifts are likely a combination of patient acceptance, physician confidence, and a growing demand from patients as well as physicians to find ways to bring down health care costs.

Bevacizumab biosimilars entered the market in July 2019 and in the fourth quarter accounted for 8000 of the overall administrations of this product, vs 21,000 for the reference product (Avastin). In 2020, there were roughly 31,000 administrations of bevacizumab per quarter, which breaks down to roughly 13,000 reference product administrations vs 18,000 biosimilar administrations.

Bevacizumab biosimilars achieved a 29% overall share of administrations in the fourth quarter of 2019 and by the end of 2020 they accounted for a 72% share, Oubre said.

“These market shifts are likely a combination of patient acceptance, physician confidence, and a growing demand from patients as well as physicians to find ways to bring down health care costs,” Oubre said. “Biosimilars offer quality without compromise, and at a cost savings to the patient, physician practice, and the overall health care ecosystem.”

Oubre said that these findings run counter to assertions that biosimilars haven’t delivered on their promise. “Earlier this year there was an 

 in which the author argued that we should throw in the towel on biosimilars. As I hope we have shown you today, that argument is premature.”

Kathy Oubre, MS, a cochair of the biosimilars committee of the Community Oncology Alliance (COA), explains findings from a broad study of biosimilar use in oncology practices.  

COA Study: Biosimilars Have Broadened Patient Access in Oncology 

Organon, a Merck spinoff that officially started life in June 2021, reported $140 million in biosimilars revenue for the just-ended quarter, up 41% from the comparable 2020 third quarter. During the spinoff, Organon assumed Merck’s biosimilars portfolio and women’s health brand products, along with various other established brands.

In total, Organon had revenues of $1.6 billion in the quarter just ended, down 1% from the comparable year-ago quarter. Of that amount, net income from continuing operations was $323 million.

The company said results were in line with expectations. The double-digit growth in biosimilar revenue was driven by increased sales of the company’s infliximab product (Renflexis), which launched in 2017 and has seen sales growth in Canada in particular, Organon reported.

Ongoing sales of the trastuzumab biosimilar Ontruzant in the United States (launched July 2020) and Brazil were offset by sales declines in the European Union, which the company said were the result of competitive pressure and failure to maintain “tenders,” or contracts with health authorities in the European Union. Tenders are generally awarded through a competitive bidding process.

Organon, based in Jersey City, New Jersey, has a portfolio of more than 60 medicines and products. Eighty percent of its sales is derived from non-US sources. The company prefers to partner with originator drug companies to market their products, rather than developing its own. Organon has partnered with Samsung Bioepis (Republic of Korea) for the marketing of Renflexis, etanercept (Brenzys, Eticovo), bevacizumab (Aybintio), trastuzumab (Ontruzant), and adalimumab (Hadlima) 

Although when it started life in June, Organon said it was not a research and development company, in tandem with its earnings announcement this week the company reported the acquisition of Forendo, a clinical-stage drug development company with a focus on novel medications for women’s health. “Forendo is pioneering the science of intracrinology, addressing disease through a novel, tissue-specific approach,” Organon said.

The company’s lead pipeline product is a treatment for endometriosis, a chronic condition that affects 1 out of 10 women of reproductive age, causing abdominal pain. The disease is associated with infertility.

Another potential spinoff is in the works. Novartis announced late last month that it was considering its options related to the Sandoz brand, which encompasses a broad generic medicines portfolio, a number of launched biosimilars, and a pipeline of new biosimilars under development.

The announcement came with the third-quarter earnings report for Novartis, which revealed continuing earnings pressure for Sandoz. Novartis reported net sales of $13 billion, up 6%, for the third quarter of 2021, vs $2.4 billion for Sandoz, down 1%. With that announcement, Novartis said it had commenced a “strategic review” of its Sandoz holdings.

“We had stated that we wanted to create a more autonomous Sandoz within Novartis that would give us the optionality to ultimately determine whether Sandoz is best owned by Novartis or by our shareholders or another party,” Vas Narasimhan, CEO, stated in the company’s third quarter earnings call.

“We think Sandoz is well placed to capitalize on its growth drivers over the next decade, and we think Sandoz is also well placed to really be a leader in the next wave of biosimilars launches,” Narasimhan said.

He touted the division’s biosimilars pipeline of 15 product candidates, which he said could potentially achieve $3 billion in sales by 2025 and $5 billion by 2030. A completion of the strategic review is anticipated prior to the end of 2022.

Sandoz has 8 biosimilars launched globally: Omnitrope (somatropin; endocrinology), Erelzi (etanercept; rheumatology, dermatology), binocrit (epoetin alfa; oncology), Zarzio (filgrastim; oncology), Ziextenzo (pegfilgrastim; oncology), Rixathon (rituximab; oncology), Hyrimoz (adalimumab; rheumatology, gastroenterology, dermatology), and Zessly (infliximab; rheumatology, gastroenterology, dermatology).

In its earnings presentation, Novartis predicted a compound annual growth rate of 9% for its biosimilars portfolio and boasted that its biosimilars held global leadership shares. The company expects to launch 6 biosimilars in the United States and European Union “over the next few years,” which Richard Saynor, CEO of Sandoz, said would “start rapidly accelerating our business.”

Narasimhan said he believes that increasing interest in biosimilars in the United States will put a tail wind on Sandoz’ attempts to launch these products. “I think it’s a tremendous opportunity for the Sandoz business,” he said.

In its first quarter of independence from Pfizer, Organon saw growth in biosimilars revenue; Sandoz' biosimilar portfolio has been touted as a growth driver amid talk of a spinoff from Novartis.

Biosimilar Spinoffs: Organon Earnings and Sandoz' "Strategic Review"

With the COVID-19 pandemic more under control and the FDA settling back into its normal routines, the federal agency has had more to say lately about its efforts to develop the biosimilar market and usher more of these drugs to market.

At the GRx+Biosims 2021 meeting of the Association for Accessible Medicines this week, multiple FDA representatives, including Acting Commissioner 

, delivered addresses intended to update the biosimilar development community on the FDA’s efforts to work the bugs out of the biosimilar development review process.

This included a talk by Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the FDA’s Center for Drug Evaluation and Research, who focused on efforts to clarify how the interchangeable designation will be applied and how the FDA is improving manufacturer communication and timelines for biosimilar application review processes.

Interchangeability is granted for biosimilars whose developers have completed patient-switching studies involving multiple changes from reference product to biosimilar and back again. In the patient sense, it means that their pharmacist can give them the biosimilar instead of the reference brand without having to consult with the physician. 

But in the manufacturing and policy community, questions have arisen that focus on whether interchangeability will apply across reference product indications and what happens if the method of biosimilar administration evolves, such as from prefilled syringe to wearable applicator, or if something changes with the reference product. Answers to these questions were not spelled out in the FDA’s original guidance on interchangeables.

“We’re going to do some things to help advance the development of interchangeable biosimilar biological products,” Yim said at GRx+Biosims. This will include development of a supportive regulatory science program and issuance of “foundational guidelines on container closure systems and device constituent parts for proposed interchangeable combination products,” she said.

Additional product support will involve development of guidelines for the labeling of interchangeable products, promotional labeling, and advertising considerations. Also in the works is guidance on supporting “postapproval manufacturing changes for different reporting categories for interchangeables,” Yim said.

“With this, we’re also going to be shooting for doing a scientific workshop on developing interchangeable products no later than October 2025,” she added.

In her presentation, Yim provided a brief timeline of recent biosimilar-related activities of significance to the commercial development sector:

In November 2020, the FDA initiated renegotiations for biosimilar user fee amendments (BsUFA), which was meant to insure that FDA fees charged of manufacturers for reviewing biosimilar approval applications are sufficient to pay for the work involved.

In December 2020, the Biologic Product Patent Transparency Act was signed into law as part of the Consolidated Appropriations Act, and this required the listing of patent information in the FDA’s Purple Book, which the biosimilar legal community has said makes the information available to biologics license applicants (biosimilar developers) much more useful.

In January 2021, the FDA initiated an interim assessment of the BsUFA program to evaluate biosimilar application review performance under Section 351(k) of the Public Health Service Act.

In April 2021, Congress passed the Advancing Education on Biosimilars Act, which called upon the FDA to continue with efforts to promote and support the use of biosimilars through a

In June 2021, the FDA was able to complete the BsUFA user fee negotiations and the patent information inclusion requirement for the Purple Book became effective.

In July 2021, the FDA approved the first interchangeable biosimilar,which happened to be the first insulin biosimilar (insuline glargine, Semglee).

In September 2021, the FDA published fresh guidance for biosimilar developers, approved the first ophthalmology biosimilar (ranibizumab, Byooviz), and conducted a workshop on pharmacodynamic biomarkers for biosimilar development and approval.

With regard to the Purple Book enhancements, one of the chief improvements FDA officials touted at GRx+Biosims was the inclusion of a search engine function, Yim said. The book is now fully electronic and provides information on biosimilars that are on the market. Not only is it searchable, but data also can be sorted by fields selected by the user, FDA officials have said.

Yim also noted that FDA biosimilar educational materials have been improved. “If you Google 'biosimilars,' you can actually bring up a link to our landing page, and this is full of 

These resources include calendar listings of upcoming events the FDA is organizing or participating in. “This year we have more than 2 dozen events with different stakeholders, ranging from health care professionals, patient groups, payers, health care policymakers, developers, and academics. In fact, being virtual probably made it a little easier for us to attend these different meeting events,” she said.

The FDA also has plans for provider and patient videos and a modular curriculum for health care professional development.

There’s a lot of changes coming up next, and we’re looking forward to continuing to work with stakeholders in terms of education, outreach, and regulatory science, as well as advancing the development of interchangeable rules.

As part of the BsUFA reviews, the FDA worked to establish timelines for labeling change approvals. These include safety information updates, added indications, and indication removals or deletions. Also, for meetings with developers that are narrowly focused on just a few key application elements, the FDA shortened the timelines for conducting these, providing a 60-day window.

The FDA also decided to reduce the background data, or “preliminary comparative analytical data,” that biosimilar applicants must bring to these meetings. “We’re also working on promoting best practices in communication during application reviews,” Yim said.

She said the FDA also is working toward issuing draft guidance on the use of alternative tools for factory inspections. Alternative tools would include means of reviewing manufacturer worthiness and quality preparations in lieu of actual site inspections, many of which were suspended during the COVID-19 pandemic because of potential COVID-19 exposure risk. 

With the start of BsUFA III in 2023, the FDA will initiate demonstration projects, one of which will advance the development of interchangeable products and another that will address the efficiency of biosimilar product development. “The details of how these are going to be operated, operationalized, and implemented are still being worked out, but we hope to have everything up and running by the start [in 2023],” Yim said.

Sarah Yim, MD, provided a point-by-point overview of the FDA's efforts to clarify the role of the interchangeable biosimilar designation, improve communication with manufacturers, and pay for biosimilar regulatory reviews.