Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Among patients who switched from originator to biosimilar infliximab (CT-P13) and then back to the originator, 73.3% benefited from the reverse switch, although investigators postulated that the nocebo effect probably played a large role in the reasons for switching and outcomes.

 enrolled 758 patients with Crohn disease or ulcerative colitis, and reverse switching occurred in 75 patients (9.9% over 52 weeks). The investigators said this occurred mostly among women patients (70.7%) and female sex was a predictor for infliximab drug discontinuation, which they said was corroborated by findings from other studies.

The authors wrote that gastrointestinal symptoms (25.5%) and dermatological adverse events (21.8%) were the most common reasons for reverse switching, but said “no clinically relevant differences were seen between the pharmacokinetics of CT-P13 and originator infliximab.”

For 9 of the 75 patients (12%), loss of response to the biosimilar was given as the reason for reverse switching, and 7 (77.8%) of those patients regained response once they resumed treatment with the originator drug 

. “Infliximab persistence was equal between patients who were reverse-switched and those who were maintained on CT-P13,” the investigators said.

The 9.9% rate of reverse switching in the study, which was retrospective and involved data collected from multiple institutions (May 2015-December 2017), was slightly lower than for other studies of the same phenomenon (12.9% and 16.5%), although in all of the studies, the “clinical motivations for reverse switching were predominantly a perceived loss of response or adverse effects,” the authors said.

Besides the nocebo effect, which involves patients whose preconceptions about the effectiveness of a drug contribute to an apparent lack of efficacy, symptoms may have been falsely attributed to the biosimilar by patients and providers, the authors theorized. The nocebo effect is well documented, and “the majority of IBD [inflammatory bowel disease] patients have doubts and concerns about the safety and effectiveness” of drugs for IBD, the authors wrote.

The rate of reverse switching may have been partly attributable to the lack of clear policies in the treatment centers on how to manage patients with negative outcomes following the initial switch from originator to biosimilar, they said. “Thus, it is likely that a physician’s willingness to reverse-switch also contributed to this variation.”

One observation that mystified investigators was the occurrence of new or worsening skin reactions among patients who were reverse-switched. The blockade of tumor necrosis factor “is the mechanism considered to induce remission and is also thought to be the main immunological pathway involved in the pathogenesis of infliximab-related skin reactions,” so how skin reactions could occur in patients who did not benefit from the infliximab biosimilar is unclear, they said.

The authors wrote that patient expectations can be tempered by communication between a patient and a provider, or the provision of “tailored information.” Prior conditioning, psychological characteristics, and “situational influences” also contribute to the nocebo effect, they wrote. They concluded that nocebo notwithstanding, switching back to the originator product “seems effective” in addressing worsening gastrointestinal symptoms or loss of response. 

Switching from the originator to infliximab biosimilar is commonplace in Europe, and it has been reported that 52 weeks after switching, the rate of patients discontinuing treatment because of loss of response, new adverse events, or a reverse-switch to the originator is from 7.5% to 29%, the authors said.

CT-P13 is distributed as Inflectra in the United States and Remsima in the European Union. The originator brand is Remicade.

Mahmmod S, Schultheiss JPD, van Bodegraven AA, et al. Outcome of reverse switching from CT-P13 to originator infliximab in patients with inflammatory bowel disease. 

Published online February 4, 2021. doi:10.1093/ibd/izaa364

Articles

Three-fourths of patients who reverse-switched to originator infliximab from CT-P13 benefited, although it wasn't clear why the biosimilar treatment "failed." 

Study: Nocebo Is Likely Cause for Reverse Switching in IBD

Biosimilar competition took a $6.34 billion bite out of international revenues for Roche in 2020. It was the biggest decline so far attributable to biosimilar competition, according to Bill Anderson, CEO of Roche Pharmaceuticals. “I think we’ve seen the worst that it can get,” he said in an investor presentation. He anticipated a smaller-but-still-painful $5.1 billion biosimilar impact in 2021.

Roche faces accelerating biosimilar competition, particularly in the United States, for 3 of its aging blockbusters: Herceptin (trastuzumab), Avastin (bevacizumab), and Rituxan/MabThera (rituximab). For those products in just the United States, Japan, and European Union in 2020, biosimilar competition eroded $5.68 billion in revenue, Roche said. 

The sales erosion for Roche is evidence of the power of biosimilars to capture market share despite the many barriers in the United States and internationally that prevent these drugs from challenging higher-priced originator products.

A strong biosimilar portfolio can be the equivalent of a blockbuster product for a company with marketing power and reach. For example, in its 

, Amgen reported well over $1 billion in revenue from its bevacizumab (Mvasi, $798 million) and trastuzumab (Kanjinti, $567 million) biosimilars, along with $331 million in global revenue from its adalimumab biosimilar (Amgevita), which has become the most prescribed adalimumab biosimilar in Europe, with sales up 54% in 2020, according to Amgen.

Biosimilars are costly to develop and bring to market, and for that reason, they retail for significantly more than simple molecule generics. At the same time, discounts offered for the relatively few biosimilars on the market are significantly less than for generics, which affords biosimilar developers opportunity for enormous profit. 

Roche’s 2020 results indicate that in the United States, Europe, Japan, and other countries, overall sales declines were 25% for Avastin, 31% for Rituxan/MabThera, and 34% for Herceptin.

Roche’s key revenue engines now comprise relatively new drugs, rather than bevacizumab, trastuzumab, and rituximab. At Roche, those latter products dipped from 40% of sales in 2019 to 29% of sales in 2020. The company’s new products category now represents 41% of sales vs 31% before. Overall, Roche was able to report a 1% increase in sales for the year.

The company identified Tecentriq (atezolizumab), Hemlibra (emicizumab), Ocrevus (ocrelizumab), and Actemra/RoActemra (tocilizumab) as several leading new products whose global sales advanced dramatically in 2020: 55%, 68%, 24%, and 32%, respectively. 

Tocilizumab is for the treatment of rheumatoid arthritis; ocrelizumab, multiple sclerosis; emicizumab, haemophilia A; and atezolizumab, various forms of cancer.

Biosimilar competition took a big chunk of revenue from Roche's aging blockbusters in 2020, and the company is banking on its newer medicines to drive fresh revenue growth.

Roche's 2020 Losses to Biosimilars Were "Worst It Can Get"

A patient in a hospital outpatient setting was 42% less likely to receive a filgrastim biosimilar than a patient in an office setting, but 73% more likely to receive an infliximab biosimilar, according to a new study examining the relationship between biosimilar use and practice setting and patient/physician characteristics.

Clear differences in filgrastim biosimilar administration according to practice setting were noted in the study of Medicare fee-for-service beneficiaries who received either filgrastim (n = 25,870) or infliximab (n = 14,786) products from the launch of these biosimilars through December 2018.

High prescribing volume by individual physicians was a factor associated with frequency of biosimilar administration, as was specialty. Practice characteristics that were associated with biosimilar use included setting and hospital ownership status 

. Patient characteristics were only “weakly associated” with biosimilar use, the authors said.

“Importantly, this study demonstrates that factors associated with biosimilar use may differ across drug classes, and therefore, each drug class may require different interventions to promote use,” the authors concluded. The findings also suggest that practice types play a role in steering physicians toward biosimilars.

Separate figures were provided for filgrastim vs infliximab biosimilar use.

For filgrastim, the investigators examined physician time in practice but found no major differences in terms of biosimilar prescription. The same applied for provider gender. Using primary care specialists as the reference, investigators found that hematologist/oncologist practitioners were 3 percentage points less likely to prescribe filgrastim biosimilars, and oncologists were 3.4 percentage points less likely to do so.

Using physicians in independent practices as the reference, investigators found that physicians practicing in hospital-owned practices were 3.1 percentage points less likely than their counterparts to prescribe filgrastim biosimilars.

But when it came to practice characteristics, using office-based practices as the base, investigators found that hospital outpatient departments were 16.1 percentage points less likely to prescribe filgrastim biosimilars.

Office size was also a factor. Using those with less than 5 physicians as the reference, investigators found that practices with 6 to 19 physicians were 9.4 percentage points more likely to prescribe filgrastim biosimilars; and practices with 20 to 100 physicians, 11.9 percentage points more likely.

Among hospitals, using nonprofit institutions as the reference, for-profit hospitals were 17.4 percentage points less likely to prescribe filgrastim biosimilars, and government institutions were 3 percentage points more likely to prescribe them.

Hospitals with greater than 250 beds were 9.4 percentage points more likely to prescribe filgrastim biosimilars than those with less than 50 beds. Institutions with 101 to 250 beds were 7.4 percentage points more likely to prescribe filgrastim biosimilars.

According to the study, no significant differences in infliximab biosimilar use were noted between various types of practitioner, such as dermatologists, gastroenterologists, and rheumatologists. Similarly, no large differences were seen in infliximab use between independent and hospital-owned practices. HOPDs were 3 percentage points more likely to prescribe infliximab biosimilars than office-based practices. And for-profit hospitals were 10.8 percentage points more likely to prescribe infliximab than nonprofits.

“As this work demonstrates, adoption of biosimilars in Medicare has been uneven across different products. The uptake of filgrastim has risen consistently over time, reaching 52% of the market by December 2018. However, the uptake of infliximab biosimilars has been significantly slower, reaching 10% of the market by December 2018,” the authors wrote.

The authors speculated that the reasons for slower uptake of infliximab biosimilars could be an unwillingness among physicians to switch patients to biosimilars who are doing well on the originator brand. They said that financial incentives for infliximab and its biosimilars may be different than for the originator brand. “The unique contracting mechanisms used by the manufacturer of originator infliximab (eg, Johnson & Johnson) have included exclusionary contracts and purchasing bundles with health care professionals, health care systems, and insurers to allegedly block biosimilar competition,” they wrote.

A shortcoming of the study was that it examined only Medicare patients and left out those who have commercial coverage, “for whom uptake patterns could be different,” the authors said. The study also was not designed to establish causal links between the various characteristics of institutions, patients, and physicians that might affect biosimilar use.

“Surprisingly, the direction of the associations between practice setting and uptake was opposite for the 2 drug classes,” the authors concluded. They recommended more investigation to understand the differences in use patterns more clearly.

Dean EB, Johnson P, Bond AM. Physician, practice, and patient characteristics associated with biosimilar use in Medicare recipients. 

. Published online January 27, 2021. doi:10.1001/jamanetworkopen.2020.34776

Physician specialty and practice setting each play a significant role in whether biosimilars are administered vs originators, according to a large, cross-sectional study.

Study: Biosimilar Use Varies by Type of Institution and Physician Characteristics

Celltrion Healthcare has received Canadian authorization to market a subcutaneous formulation of the infliximab biosimilar Remsima (Remsima SC; CT-P13), which was indicated for the treatment of rheumatoid arthritis (RA).

The company noted that 374,000 Canadians over the age of 16 have RA, the most common form of chronic inflammatory joint disease. Some Canadian provinces and territories are aggressively switching patients to biosimilars or contemplating doing so to improve savings over more-costly reference products.

Remsima SC was approved for use in combination with methotrexate to ease symptoms of moderate-to-severe RA and inhibit progression of structural damage and improve physical function in adult patients.

Celltrion said Canadian regulators issued the “notice of compliance” allowing marketing to commence after weighing evidence demonstrating that the clinical response to Remsima SC was comparable to CT-P13 intravenous up to 1 year. Switching studies also demonstrated both products were comparable.

“Remsima SC may also enhance treatment options for the use of infliximab by providing high consistency in drug level and exposure,” said Edward Keystone, professor of medicine, University of Toronto, Canada. “The approval of Remsima SC in Canada provides patients the opportunity to (self) administer the treatment at home, giving physicians and patients more control over their treatment.”

 in the European Union in late 2019. At that time, the product was the first subcutaneous infliximab product to achieve regulatory approval anywhere. In July 2027, the product 

 for the treatment of adults with ankylosing spondylitis, Crohn disease, ulcerative colitis, psoriatic arthritis, and psoriasis.

Celltrion said sales and marketing of the product in Canada would be handled via the establishment of a Celltrion entity based in Canada. “We are proud that Remsima SC will be the first product to enter the Canadian market under our new direct sales marketing strategy. We plan to strengthen our presence in Canada and support the company’s growth,” said Jovan Antunovic, senior vice president and commercial director at Celltrion Healthcare Canada.

The company added that it “has applied for patent protection, until 2038, for Remsima SC in approximately 100 countries throughout North America, Europe and Asia.”

Celltrion aims to try a direct marketing approach in Canada to streamline sales of its subcutaneous form of Remsima. 

Celltrion Gains Canadian Nod for Subcutaneous Infliximab

Biosimilars worked for and against Amgen in the year just ended, according to the company’s 

. Amgen saw competitors’ biosimilars continue to erode sales and profits for the company’s originator products, such as Enbrel (etanercept) and Neulasta (pegfilgrastim); however, Amgen’s bevacizumab (Mvasi) and trastuzumab (Kanjinti) biosimliars delivered strong results, prompting the company to cite them as key revenue drivers.

“We've played a lot of defense in biosimilars, and now as we're on offense, we're able to have a high quality of execution,” said Peter Griffith, Amgen’s executive vice president and chief financial officer, in an 

“We continue to see biosimilars as an extremely strong allocation of capital for us. The margins continue to be very competitive, and we're very confident in terms of allocating capital that category, and we'll continue to do that, and we think we've got some strong expertise there,” he said.

The company reported $541 million in fourth-quarter 2020 biosimilar sales, which were boosted by higher sales volume and offset by lower selling prices—partly the result of competition. Total revenues were up 7% to $6.6 billion for the fourth quarter vs the comparable 2019 quarter, and up 9%, to $25.4 billion, for the full year.

Although Enbrel (etanercept) does not face biosimilar competition in the United States, where it was initially approved in 1998 for the treatment of rheumatoid arthritis, it does have multiple overseas competitors, including 3 in Europe: Erelzi (Sandoz), Benepali (Samsung Bioepis), and Nepexto (Viatris). 

Global Enbrel sales totaled $5 billion in 2020 ($4.86 billion in the United States), down 4% from 2019. Lower selling prices and the coronavirus 2019 (COVID-19) pandemic contributed to sales declines, Amgen said.

Sales of Neulasta (pegfilgrastim), an originator product, were down 19% in the fourth quarter and dropped 29% for the full year, owing to lower selling prices and increased biosimilar competition, the company said. Total Neulasta sales were $2.3 billion in 2020 (US sales, $2 billion) vs $3.2 billion in 2019. Those figures include sales of Neulasta Onpro, a wearable pegfilgrastim injector kit which Amgen said “continues to be the preferred choice for physicians and patients with a volume share of 54% in the (fourth) quarter.” The prophylactic quality of Onpro has contributed to its popularity during the COVID-19 pandemic. 

Amgen said the average selling price for Neulasta in the United States was down 28% in the fourth quarter vs the fourth quarter of 2019. “In 2021, we expect the pricing and volume dynamics to continue as biosimilar competition increases,” the company said. In the United States, Amgen faces Neulasta competition from 4 brands: Fulphila (Viatris), Udenyca (Coherus Biosciences), Ziextenzo (Sandoz), and Nyvepria (Pfizer).

Other maturing Amgen originator products facing heavy biosimilar competition in the United States and abroad are Neupogen (filgrastim) and Epogen (epoetin alfa) which saw full year sales declines of 15% and 31%, respectively.

In terms of Amgen’s biosimilar offense, Mvasi generated $280 million in fourth quarter 2020 sales and $798 million for the full year. “In the United States, Mvasi became the leader of the bevacizumab segment in the fourth quarter, with an average share of $48%,” the company said. Sales were up 21% in the fourth quarter of 2020 vs the comparable 2019 quarter. Amgen predicted more launches of this product in international markets. Mvasi so far has little competition in the United States. It is 1 of 2 approved and launched bevacizumab biosimilars.

Kanjinti generated $158 million in fourth quarter 2020 sales and $567 million for all of 2020. By year’s end, the product held a 41% average share of the trastuzumab market; however, total sales of this product were down as gains in sales volume were offset by price declines caused by competition, among other factors. There are 4 other trastuzumab biosimilars on the United States market.

"Bevacizumab as a molecule is actually growing [in sales], whereas trastuzumab as a molecule is flat to declining," said Murdo Gordon, executive vice president of Amgen's Global Commercial Operations. "So, one thing that we're seeing in Mvasi is actually the number of [treatment] cycles of bevacizumab overall are growing. So [market] share in that molecule actually holds up quite well. We also have less competition. That's the other factor. So there is less competition for now in the bevacizumab molecule whereas with trastuzumab we have more competitors. And so I think going forward, you would see competitive dynamics shaping those 2 brands a little bit differently."

Another performer in Amgen’s biosimilar portfolio was Amgevita (adalimumab), which saw full year 2020 sales of $331 million, up 54% from $215 million in 2019, although lower selling prices offset the sales increase. Launched in 2018, “Amgevita continues to be the most-prescribed adalimumab biosimilar in Europe,” Amgen said. There are 7 other adalimumab biosimilars authorized for sale in the European Union. No adalimumab biosimilars are yet marketed in the United States.

No sales data were provided for Avsola (infliximab), which Amgen launched in the United States relatively recently, in July 2020. The company has hopes for another biosimilar, Riabni (rituximab), which launched in the United States in January 2021, and in an update on product development, Amgen said a phase 3 efficacy and safety trial was underway for its eculizumab biosimilar candidate (ABP 959). ABP 959 references Soliris, a blockbuster drug for paroxysmal nocturnal hemoglobinuria and atypical haemolytic uremic syndrome that garnered $4.06 billion in global 2020 sales, up from $3.95 billion the year before. Biosimilar competition for eculizumab in Europe is anticipated in 2022.

Amgen, in a settlement with Soliris manufacturer Alexion, has agreed to 

Amgen described how a double-edged biosimilars sword has worked for and against the company's profit margin. 

Amgen Profits Get a Ride on Biosimilar Growth

 strong biosimilar revenue growth for the fourth quarter of 2020. The company said biosimilar operating income of $525 million for the quarter was up 86% compared with the fourth quarter of 2019. Operating income is what’s left after deducting employee pay, depreciation, cost of goods sold, and other standard expenses.

Pfizer launched 3 biosimilars in the United States last year: rituximab (Ruxience), bevacizumab (Zirabev), and trastuzumab (Trazimera) biosimilars. The company singled these out as major drivers of fourth-quarter revenues.

Average annual expenditures on just the reference drugs for these 3 oncology drugs were $8.6 billion from 2011 to 2016, 

 of its membership by Vizient, a pharmaceutical network manager, ranked rituximab as the third highest drug by amount of spending among its membership. 

And recent IQVIA information cited by Vizient in its report suggested that Pfizer has a lot of room for profit growth, given the respective market shares of Ruxience and Trazimera, which are relatively small compared with the remaining market shares held by the originator products 

Pfizer faces biosimilar competition for its etanercept originator product (Enbrel), but not in the United States, where competing biosimilars are not anticipated until 2029. However, Pfizer noted that overseas biosimilar competition is eroding Enbrel revenues, which were down 18%, “primarily reflecting continued biosimilar competition in most developed Europe markets as well as in Brazil and Japan.”

The Vizient report predicted that Pfizer would significantly 

 of etanercept in the United States in the coming years as it nears the end of its patent protection. 

For all of 2020, Pfizer reported biopharmaceutical revenues of $41.9 billion, up 8% operationally. Primary growth engines, in addition to biosimilars, were Vyndamax (tafamidis) and Vyndaqel (tafamidis meglumine), both oral formulations for the treatment of rare forms of cardiovascular disease.

Pfizer spun off its Upjohn division in November 2020 but retained its biosimilars unit. Upjohn combined with Mylan to form Viatris, which through the Mylan portfolio of products and partnerships is also a 

Pfizer's investment in biosimilars is starting to pay off, as it now ranks these agents among its top revenue drivers. 

Pfizer Biosimilar Revenues Top $525 Million in Fourth Quarter 2020

Using a combination of step therapy and parity reimbursement, pharmacy benefit manager (PBM) Magellan Rx Management has achieved a 

 in biosimilar authorizations for the period from July 2019 to May 2020. Magellan Rx, a division of Magellan Health, manages specialty drug benefits for health plans, employers, and trade unions.

Oncology biosimilars emerged on the US market in July 2019 with the launch of Kanjinti (trastuzumab; Amgen) and Mvasi (bevacizumab; Avastin). Now, there are 10 oncology biosimilars available in the United States.

Magellan defined the 90% utilization rate as the number of authorizations for biosimilars compared with authorizations for reference products 

. “Due to the cost differential between oncology biosimilars and their reference brands, savings are expected to be at least 15%,” Magellan said in a statement.

Oncology therapeutic biosimilars have been approved for not only bevacizumab (Avastin) and trastuzumab (Herceptin) but also rituximab (Rituxan). There also are multiple approved oncology support biosimilars. Bevacizumab, rituximab, and trastuzumab “were the highest-spend drugs in the United States from 2011 to 2016,” according to Rebecca Borgert, PharmD, BCOP, senior director of Oncology Clinical Strategies and Innovation for Magellan. During that period, average annual expenditures on the reference products for bevacizumab, rituximab, and trastuzumab were $8.6 billion in the United States.

“Oncology and oncology support drugs continue to be the largest driver of specialty pharmacy spend on the medical benefit—43% of total medical drug spend for both the commercial and Medicaid populations and 55% in Medicare—and given the billions of dollars that are spent on these treatments, significant additional savings are anticipated with full results expected in early 2021,” Magellan said.

The first bevacizumab and trastuzumab biosimilars launched at a 15% wholesale average cost discount to the reference products, and the first rituximab biosimilar launched at a 10% discount to the reference product, according to a 

Prior to the launch of the first oncology therapeutic biosimilars, Magellan worked to prepare its client network to incorporate these agents into therapeutic plans. The PBM developed a provider education program and targeted key oncology providers. Drug utilization management policies were drawn up and reviewed with clients prior to biosimilar launches. Health plans were given the option to use step therapy for patients who had not previously received the reference product, or they could manage oncology biosimilars at parity with the reference products.

From September 1, 2019 to January 31, 2020, patients received biosimilars (Mvasi, Kanjinti) 15.3% of the time under the parity strategy and 49% of the time under step therapy. “Payers equipped with proactive utilization management strategies for oncology biosimilars were able to capitalize on early utilization shifts to the less expensive biosimilar products,” investigators concluded. They said some providers switched patients to oncology biosimilars “even without” step therapy requirements.

, Magellan reported similar success among its payer clients in increasing use of infliximab biosimilars vs the reference product. Beginning in the third quarter of 2017 and ending in the third quarter of 2018, infliximab biosimilar use rose from 0% to 86% vs 100% to 14% for the reference product after Magellan established a policy of transitioning all patients to a biosimilar agent.

These figures apply to Magellan health plan customers (physician offices and hospitals) that accepted a management approach to utilization that involved working closely with Magellan pharmacists to follow the clinical policy. “Even when utilizing a softer approach that mandates only new patients use the biosimilar version, health plans have experienced an uptake in biosimilar utilization as high as 75%,” the company said.

The pharmacy benefit manager reported 90% biosimilar uptake among its health plans that adopted clinical management policies that included step therapy or parity usage.

Magellan Rx Reports Step Therapy Is Workhorse in Biosimilar Utilization

The FDA has accepted a biologics license application (BLA) for the review of 

, a proposed biosimilar to bevacizumab, referencing Avastin. If approved, the Bio-Thera Solutions biosimilar candidate would become the third bevacizumab biosimilar on the US market. The others are Mvasi and Zirabev.

In the United States, Mvasi (Amgen) was launched in July 2019 and Zirabev (Pfizer) in January 2020. By June, 2020, these biosimilars had achieved a 40% share of the US market for bevacizumab, according to 

Zirabev and Mvasi were launched at average sales prices (ASPs) 19% and 12% below the ASP of Avastin, respectively. By the end of the second quarter of 2020, they had contributed to a 2% decline in the ASP of Avastin. 

Bio-Thera is a Guangzhou, China-based company with offices in Beijing and Cambridge, Massachusetts. The FDA has established a

Bio-Thera is seeking approval for use of BAT1706 in the treatment of metastatic colorectal cancer in combination with fluorouracil-based chemotherapy, first-line treatment of nonsquamous non–small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma in combination with interferon alfa, and persistent, recurrent, or metastatic cervical cancer.

The company said it has also filed for regulatory approval in China and the European Union, thereby “demonstrating Bio-Thera’s commitment to developing BAT1706 to global standards so that BAT1706 can be made available to the global cancer patient community.”

Bio-Thera said the BLA submission is based on positive data from preclinical comparison studies, pharmacokinetic studies, and an international, multicenter, phase 3 clinical comparison study. These provided evidence that BAT1706 is highly similar to the reference product in terms of clinical efficacy, safety, and immunogenicity, the company said.

The company has commercialized 1 biosimilar so far, to adalimumab, a rheumatologic and gastrointestinal therapy. The product is Qletli, which references AbbVie’s Humira and is marketed in China. The company is also developing biosimilar versions of tocilizumab, golimumab, ustekinumab, and secukinumab, which are all immunosuppressants and indicated for such conditions as arthritis and plaque psoriasis. The company is also developing a mepolizumab biosimilar, an anti-inflamatory for the treatment of asthma, eosinophilic granulomatosis, and hyperosinophilic syndrome.

In December 2020, Bio-Thera announced it had formed a partnership with Brazil-based Biomm for the commercialization of BAT1706 in Brazil. Biomm will file the regulatory application.

Guangzhou, China-based Bio-Thera has filed a biologics license application (BLA) with the FDA for the approval of bevacizumab biosimilar candidate BAT1706.

FDA Accepts Bio-Thera's BLA for Bevacizumab Biosimilar

In various therapeutic areas, biosimilars have gained significant ground on reference products, providing greater access to medicine and savings for health care in general, "yet the feeling that we have not fully realized the value of these medications persists,” says a new 

The report identifies the adalimumab market as the most important potential growth area for biosimilars, given that in the United States, there are no biosimilars available for this product (Humira) and the originator company, AbbVie, could soon reap $24 billion in US annual sales from adalimumab, up from 

“The target of greatest interest remains adalimumab, for which biosimilars will be launched in 2023,” the report says.

Vizient, in its new report, predicts an adalimumab price increase of 7.5% before adalimumab biosimilars have a chance to enter the US market, as AbbVie capitalizes on the long-running domestic monopoly it still enjoys with this product for rheumatologic and gastrointestinal disorders.

In general, Vizient’s drug market price predictions tend to be 1 or 2 percentage points above the actual increases, although in recent years it has been accurate in forecasting large upward swings in pharmaceutical prices.

“These trends, compounded by [the coronavirus disease 2019] pandemic, have created even greater need for cost savings for patients and health care organizations. Therefore, providers must press forward with adoption of biosimilars,” the report said.

Vizient is anticipating FDA approval of individual biosimilar products in 2021 for pegfilgrastim (referencing Neulasta), ranibizumab (Lucentis), and adalimumab 

. Biologics license applications for each of these products were filed in 2020.

Of the 29 biosimilars approved by the FDA so far, 9 are not being marketed because of patent settlements or other business reasons. The biosimilars launched so far saved roughly $18 billion between 2010 and 2014 and $19 billion between 2015 and 2019, Vizient said. However, “the greatest savings” are expected to occur in the 5-year span ending in 2024, the company noted, citing IQVIA data projecting up to $104 billion in biosimilar savings between 2020 to 2024, “driven largely by biosimilars for adalimumab that are expected in 2023.” 

Trastuzumab biosimilars accounted for an overall 24% market share from October 2019 to September 2020, but the national market share for trastuzumab biosimilars had expanded to 39% by September 2020, as by that point, 5 were on the market and competing with the originator product, Herceptin.

“This finding suggests that as the number of competitors continues to grow, biosimilars are gaining greater acceptance. The same trends hold for other products such as biosimilars for rituximab and bevacizumab,” Vizient said.

The company urged health care providers to improve their understanding of biosimilars in order to position themselves for successful uptake of these products. “It is also important to engage clinicians whose acceptance of biosimilars has been limited (such as gastroenterologists) and those who will soon have the option available to them for the first time (eg, endocrinologists).”

Vizient also noted that payer formulary decisions continue to be a trouble spot in securing access to biosimilars and urged pharmacy organizations to work closely with finance departments and others to combat coverage denials and better coordinate coverage for biosimilars. “Pharmacy departments at several Vizient member organizations have begun to provide their financial colleagues with language to include in payer negotiations to secure biosimilar coverage at parity with the originator drug or with other biosimilars.”

Vizient predicted an overall 2.67% drug price increase over the year ending June 30, 2022. Among drugs ranked highest in total amount spent by Vizient’s health organization network, adalimumab was in the top spot, and rituximab and infliximab in third and fourth.; biosimilars are available for the 2 latter drugs. In second, fifth, and sixth places are pembrolizumab (Keytruda), ustekinumab (Stelara), and nivolumab (Opdivo), for which biosimilars are being developed and not yet approved.

In the new report, adalimumab ranks No. 1 on Vizient’s list of drugs by highest projected price increase. Ustekinumab is third, and etanercept (Enbrel), for which biosimilars are approved but not launched, ranks fourth. Pembrolizumab is fifth.

Interestingly, vasopressin (Vasostrict), a low blood pressure medication, is second on that list. Vizient noted that this drug has been on the market for decades but because of a regulatory fluke, the manufacturer, Par Pharmaceutical Companies, was able to obtain exclusivity and raise the price of this product. The FDA’s Unapproved Drugs Initiative (UDI)  allowed manufacturers of legacy medications to seek formal approval and rewarded them with 3 to 5 years of market exclusivity. The emergence of a new formulation of vasopressin, however, enabled Par Pharmaceutical Companies to gain patent exclusivity until 2035. Realizing the problem, HHS terminated UDI, but the die was cast and vasopressin soared in price.

For biologics in general, Vizient is anticipating a 3.96% price increase in the year from July 1, 2021 to June 30, 2022.

In its annual drug price guide, Vizient predicts that US annual adalimumab (Humira) revenues could reach $24 billion before biosimilars enter the marketplace.

Vizient Predicts 7.5% Humira Price Increase Before Biosimilars Arrive

A study of the nocebo effect (NE) in biosimilar use has demonstrated nurses can play an important role in building patient confidence in these drugs and improving the retention rate (RR). NE involves an adverse event (AE) that cannot be attributed to the therapy and may be psychosomatic.

Investigators enrolled 45 patients who were switched for nonmedical reasons from originator  infliximab (OI) to biosimilar infliximab (SB2, Renflexis) between May 2018 and August 2019. The patients all had chronic inflammatory rheumatoid disease (rheumatoid arthritis, 17; spondylarthritis, 28).

A historical cohort of 52 patients from multiple previous studies was compiled to serve as the comparator. At 34 weeks, the SB2 RR was 91.2%, which was comparable to the historical cohort RR of 96.2% (

 = .41). At 12 months, the SB2 RR was 84.4% vs 88.5% for the historical cohort (

 = .52). The nvestigators said the SB2 discontinuation rate owing to possible NE was 6.6% at the 12-month point.

Historical double-blind, randomized control trials (RCTs) have shown comparable discontinuation rates between originator products and biosimilars, but these rates were higher in open-label RCTs (11%-36%) and higher still for real-life, observational cohorts (up to 30%), the authors wrote.

“Reducing the NE during switches could enable better biosimilar acceptance, with advantages from an individual and public health point of view,” the authors wrote.

In preliminary interviews with enrolled patients, the investigators found low knowledge of biosimilar efficacy and tolerance, fear of AEs, unwillingness to change from OI, patient need for support, and the desire to decide for themselves whether to switch. To prepare for the study, doctors and nurses involved in switches received biosimilar and NE training.

Prior to receipt of SB2, patients received an oral explanation from nurses along with written information to answer typical questions. The same information was provided during medical consultation. “If needed, an interview was proposed with a doctor trained in motivational communication,” the authors said.

NE leading to biosimilar withdrawal was defined as a lack of efficacy with no objective criteria for increased inflammation, such as disease flare or swollen joints, or nonspecific AEs, such as headache, fatigue, or anxiety.

Investigators said the SB2 RR at 34 weeks was significantly better than the average RR for 3 European real-life studies included in the historical cohort. No significant difference in RR was observed between the SB2 cohort and a historical OI-only cohort.

The authors wrote that no previous investigations have been done to evaluate nurses’ roles in the success of drug switches. “Our interpretation is that patients were used to meeting the same nurses for their infusions. Conversely, doctors in the day-care unit change over time, and consultations with the rheumatologist are few. Therefore, patients develop close interactions with nurses, who may not be the same during the switch of subcutaneous biologics.” They added that “nurses might be easier to talk to” than other health care professionals.

The authors concluded that nurses can be of value as the “first point of contact” for patients to facilitate switching and acceptance.

European studies have shown possible reasons for the NE. A French survey found that patients feared biosimilars would not be as effective (60%) or tolerated (75%) as originator drugs. “Reduced costs generated by the switch would be an incentive in only 20% in this study,” the authors wrote, adding that these findings were consistent with what patients told them in the preliminary interviews for the switching/NE study.

“In conclusion, a tailored communication strategy focusing on a trustful relationship between patients and nurses and the implication of a multidisciplinary team showed improvement in outcomes after a switch from infliximab to a biosimilar, by reducing the nocebo effect. The intervention we describe may be useful for future switches of other intravenous biologic drugs,” the authors wrote.

Petit J, Antignac M, Poilverd RM, et al. Multidisciplinary team intervention to reduce the nocebo effect when switching from the originator infliximab to a biosimilar. 

. Published online January 2021. doi:10.1136/rmdopen-2020-001396

The study of originator infliximab and SB2 used nurses as the first point of contact when educating patients, relying partly on patient trust in these health care professionals.