Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Biosimilars are gaining traction at a rapid rate in the United States—they have become more numerous in their first 5 years on the US market than biosimilars were in Europe in their first half decade, according to the 

 from Amgen. The report provides a detailed breakdown of biosimilar costs versus reference product costs across drug categories.

The report counts 28 biosimilars approved and 18 biosimilars launched so far in the United States. The latter figure includes Avsola, an Amgen biosimilar for infliximab, which gained approval from the FDA in December 2019 and, according to the report, was launched in July 2020.

The report is upbeat in its assessment of the supportive structure for the US biosimilar market, noting “many competitive mechanisms are in place to support biosimilar uptake,” among them CMS’ move to establish separate codes and payment rates for biosimilars, which the report states can lead to “meaningful cost savings and a sustainable marketplace.”

The report also praises current US regulatory standards for development and approval of biosimilars “as well as for establishing interchangeability,” stating that these are “scientifically appropriate to protect patient safety and support provider and payer confidence.”

The requirement for interchangeability, an FDA determination that would allow pharmacists to substitute biosimilars without physician consent, has at times been questioned, as have the requirements for clinical efficacy testing, which has been criticized as redundant.

“The US marketplace for biosimilars is now well established and accelerating across multiple therapeutic areas,” the report says.

Stable of Reference and Biosimilar Products

Amgen produces numerous biosimilars and reference products. On the innovative side, the company owns the pegfilgrastim brand Neulasta and also reference filgrastim (Neupogen), etanercept (Enbrel), and epoetin alpha (Epogen). In the United States, biosimilar competition exists for each of these drugs except etanercept, which is protected by exclusivity status. 

On the biosimilar side, Amgen recently launched an infliximab (Avsola) and markets a trastuzumab (Kanjinti) and a bevacizumab (Mvasi). It has an approved adalimumab biosimilar (Amjevita), which has yet to launch, and it is developing additional biosimilars, including a rituximab (ABP-798). 

In the United States, just 2 biosimilars have been approved so far in 2020, but 6 biosimilars have launched; and over the first 5 years of biosimilar availability in the United States, 26 biosimilars were approved compared with just 11 in the European Union, which supports the idea that, although well behind Europe in terms of biosimilar uptake, the United States is making rapid progress. The report states that, despite the scarcity of approvals so far in 2020, the number of approved biosimilars over the past 12 months is up 65% and launches are up 157%.

Still in the wings and awaiting launch are FDA-approved biosimilars for pegfilgrastim (Nyvepria), infliximab (Ixifi), etanercept (Erelzi, Eticovo), and adalimumab (Amjevita, Cyltezo, Hyrimoz, Hadlima, Abrilada, Hulio).

Of the biosimilar products that have launched, wholesale acquisition costs (WAC, manufacturer’s list price) for biosimilars have averaged 15% to 37% lower at launch than reference products’ WACs, according to the report. In addition, biosimilars’ average sales price (ASP) at launch is typically 3% to 24% below the reference products’ ASP, Amgen said.

Filgrastim biosimilars have been on the market the longest time—5 years—and have achieved a 72% share of the market, Amgen said. Bevacizumab products now have 40% of the market; trastuzumab biosimilars, 39%; pegfilgrastim, 27%; rituximab and infliximab, 20%.

The trastuzumab biosimilar Kanjinti currently has an ASP 25% below reference Herceptin’s ASP prior to the appearance of biosimilar competition in the third quarter of 2019; Herceptin is just 3% lower by ASP, according to the report.

Bevacizumab biosimilar Mvasi is 24% lower by ASP than the reference product Avastin’s ASP prior to biosimilar competion; Avastin’s ASP has dropped just 2% since the third quarter of 2019, when bevacizumab biosimilars appeared.

Rituximab biosimilars have managed to pull down the ASP of reference Rituxan by just 1% since the late 2019 launch of the first rituximab biosimilar, Truxima. Currently, Truxima’s ASP is 5% lower than the reference product’s ASP was at Truxima’s launch. However, Ruxience was launched at an ASP 20% below the reference product’s ASP and remains at that lower level, according to the report

In the category of nephrology/oncology supportive care, the epoetin alfa biosimilar Retacrit was launched at 33% below Epogen’s WAC and 5% below Epogen’s ASP. Retacrit was launched 57% below Procrit’s WAC and 5% below its ASP. Epogen and Procrit are identical drugs but are marketed by separate companies in different therapeutic areas. Retacrit now has a 25% share of the market for epoetin alpha vs 18% for Procrit and 57% for Epogen.

In the US infliximab market, 3 biosimilars have been marketed, including Avsola (July 2020). The ASP for reference Remicade has dropped to 33% below its pre-biosimilar cost, and the ASPs for Renflexis and Inflectra currently stand at 40% and 43%, respectively, below the reference product’s ASP cost before biosimilar competition, according to the report.

Articles

Amgen's 2020 biosimilar report goes into detail on market share and costs for biosimilars across the therapeutic spectrum in the United States.

Amgen 2020 Biosimilar Report Provides Market Share, ASP Info

Alexion receives positive regulatory news in its bid to stay ahead of biosimilar competition, and Celltrion Group announces a phase 3 trial for its coronavirus disease 2019 (COVID-19) prophylactic drug candidate. 

Seeking to fend off biosimilar competition for its eculizumab originator product (Soliris), Alexion has received some aid in the form of FDA 

for a 100 mg/mL formulation of follow-on product ravulizumab (Ultomiris), for the treatment of nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. The drug allows for reduced annual infusion times by roughly 60% vs Ultomiris 10 mg/mL.

Alexion said it plans an immediate product launch. The FDA decision comes less than a month after Alexion 

 a positive opinion from Europe’s Committee for Medicinal Products for Human Use in the same intravenous formulation.

Multiple biosimilar developers are working on competitor versions of eculizumab, including Samsung Bioepis, Epirus Biopharmaceuticals, and Amgen. Generium received Russian regulatory approval for an eculizumab biosimilar last year.

advanced by biosimilar developer Celltrion Group as a preventative for  COVID-19 has entered a phase 3 clinical trial. Celltrion aims to enroll 1000 patients to evaluate the prophylaxis capability of CT-P59 in patients exposed to SARS-CoV-2. Trial end points are prophylactic effect, safety, and whether CT-P59 can stimulate a sufficient antibody response to fight off SARS-CoV-2.

“We hope anti-COVID-19 monoclonal antibodies such as CT-P59 can provide high-risk individuals with effective protection against COVID-19 and help prevent further spread in the community,” said Dr Sang Joon Lee, senior executive vice president of Celltrion. “We look forward to continued data generation as this trial proceeds.”

The trial’s launch follows a go-ahead received from the Republic of Korea Ministry of Food and Drug Safety on October 8, 2020.

Alexion and Celltrion separately announce advances in their drug development and marketing efforts.

Alexion, Celltrion Notch Product Development Gains

The marketing of programmed death (PD) inhibitors in the treatment of cancer got off the ground in 2014 with the launches of pembrolizumab (Keytruda) and nivolumab (Opdivo), first indicated for patients with melanoma and then expanded to multiple indications, including non–small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, and esophageal carcinoma.

The first biosimilars for these products may be years off, as exclusivity protections remain in force for the originator products, but a handful of companies have announced interest in developing biosimilars for these agents, most recently NeuClone of Redfern, Australia, which in an interview with The Center for Biosimilars® said the groundwork for these biosimilars is well underway.

“We’re feeling quite confident about these molecules and feeling pretty positive about the outlook moving forward,” said company strategic analyst Thomas Wakim.

Pembrolizumab and nivolumab are both PD-1 inhibitors. PD-1 is a "checkpoint" protein on immune cells that alerts them not to attack cells that express PD-L1. Some cancer cells express PD-L1, which enables them to “switch off” an immune system response. Monoclonal antibodies such as pembrolizumab and nivolumab block this signaling between PD-1 and PD-L1 and thereby reinforce the immune system response to tumor cells.

Even in late-stage cancers, these drugs have demonstrated effectiveness across tumor types. Recently, pembrolizumab was granted FDA 

for unresectable or metastatic solid tumors with high tumor mutational burden in patients who have exhausted other options for treatment. The FDA decision was based on an overall response rate of 29% (95% CI, 21%-39%), which included a 4% complete response rate and a 25% partial response rate. More than half of patients (57%) had response durations of 12 months or longer.

Besides their many indications for use as monotherapy, pembrolizumab and nivolumab have also shown promise in combination therapy, which extends their utility as cancer-fighting tools. In May 2020, nivolumab was 

in combination with ipilimumab and platinum chemotherapy as a frontline treatment for patients with metastatic or recurrent non–small cell lung cancer. The combination therapy demonstrated superior overall survival (OS) vs chemotherapy alone. Median OS was 14.1 months in the combination arm vs 10.7 months for chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; 

The increasing utility of these agents across cancer settings and their effectiveness have contributed to increasing market value for the originator companies.

Pembrolizumab, a Merck product, had worldwide sales of $11.1 billion in 2019, up 55% from $7.2 billion the year before. A glance at quarterly sales revenue indicates that earnings continue to grow strongly for this product. Pembrolizumab sales were $3.4 billion in the second quarter of 2020, up 29% from $2.6 billion in the comparable year-ago quarter.

Nivolumab had $7.2 billion in 2019 worldwide revenues, up 7% from $6.7 billion the prior year. The second-quarter 2020 sales total was $1.7 billion, up 9% from the previous year.

Such numbers help to explain the attraction companies such as NeuClone have for developing biosimilars of these products. “From a really commercial standpoint, they seem like quite good opportunities for developing biosimilars and trying to capture a share of the market they represent,” Wakim said. Because the cost of these originator drugs has been going up, there is tremendous value potential for patients in the downward effect on pricing that biosimilars can exert, he added. Although drug regimens may differ, estimates of the cost of a year’s course of pembrolizumab or nivolumab range as high as $150,000.

“We see from a biosimilar standpoint that there’s a great opportunity to introduce cheaper, more affordable versions of these drugs to really bring down that health care expenditure and allow many more patients around the world to gain access to what are incredibly effective and beneficial oncology treatments,” he said.

Multiple patents for nivolumab exist, but one 

suggests that patent exclusivity in the United States for this product could end in 2027. Neuclone is positioning itself for market launch of both products by the end of this decade. “We envision that probably toward the late 2020s—at least, that’s what the originator companies have reported publicly. And that gives us ample time to conclude our preclinical work on these biosimilars and, in the coming years, enter phase 1 and possibly phase 3 clinical trials,” Wakim said.

As for target markets, NeuClone aims to obtain regulatory approvals for its pembrolizumab and nivolumab biosimilars in both the United States and the European Union. Not only are patients and providers more accepting of biosimilars in these markets, but also the strength of regulatory approvals from the FDA and European Medicines Agency (EMA) can give NeuClone “leverage” to obtain marketing approvals in other regions of the world, Wakim said. “We envision that with an approval, say, in Europe from the EMA, it would allow us to relatively smoothly bring our products into the Australian market through the [Therapeutic Goods Administration].”

Among companies with announced intent to bring PD-1 inhibitors to market is 

of Taizhou, China, which has indicated it has the nivolumab biosimilar candidate CMAB819 approved for clinical trials.

In addition, Celltrion of Incheon, Republic of Korea, has reportedly 

 on a biosimilar version of pembrolizumab.

Years ahead of patent expirations for programmed death-1 (PD-1) inhibitors, biosimilar companies have begun focusing on these targeted drugs.

Interview: Understanding the Attraction for PD-1 Inhibitor Biosimilars

The US Public Interest Research Group (PIRG) has filed an 

 in support of a 7th Circuit Court of Appeals case against AbbVie alleging anticompetitive practices over the company’s blockbuster product Humira (adalimumab).

UFCW Local 1500 Welfare Fund v AbbVie Inc 

allege AbbVie’s numerous patent filings have effectively blocked biosimilars from entering the market, allowing the company to charge more for adalimumab than if the competitive marketplace were untrammeled by this “patent thicket.”

The PIRG brief states that a 1-year supply of Humira in the United States, where there is no biosimilar competition for Humira currently, increased 144% from 2012 to 2018. Costs of a year-long supply have been as much as $48,612, the brief states. Meanwhile, biosimilar competition for adalimumab in Europe has led to discounts as 

“Neither inflation nor higher manufacturing costs explain these price increases. As the record demonstrates, most of Humira’s US patents were set to expire in 2016, but AbbVie engaged in a patent thicket strategy that allowed the company to prolong its Humira monopoly for years beyond what Congress intended,” PIRG states.

Numerous companies have reached agreements with AbbVie to launch their adalimumab biosimilars in 2023 on a staggered schedule.

In June 2020, the US District Court for the Northern District of Illinois, Eastern Division, 

 a class action suit against AbbVie with a finding of insufficient merit to the claims of misconduct and antitrust violations alleged by the plaintiffs.

An element of PIRG’s argument is the alleged influence AbbVie’s product protection tactics may have on other originator companies looking to extend exclusivity for their drugs, too. The group contends this will lead to excessive patent fillings by other manufacturers. “Make no mistake, the district court’s decision with respect to AbbVie’s conduct will have huge ramifications going forward,” PIRG said.

“Pay for delay” is a label that has been attached to the multiple agreements AbbVie has reached with biosimilar developers to postpone their adalimumab marketing until 2023. Until now, the Federal Trade Commission (FTC), which has authority to enforce antitrust laws, has not brought a public enforcement action involving biosimilars. But the allegations lodged in the contention between originator and biosimilar drug developers have attracted its notice.

The AbbVie class action suit ruled on in June is among 2 prominent cases that the FTC has been watching closely, according to 

, acting director for the FTC’s Bureau of Competition. The other case is 

 (J&J). Pfizer has alleged that J&J unfairly employed rebate payments to discourage use of the company’s infliximab biosimilar (Inflectra). The biosimilar has been available for use in the US since 2016 but has achieved just a 10.5% share of the market.

“What’s interesting is that Pfizer is one of the largest drug companies in the world and yet it’s having problems, so maybe there’s really something going on here,” Meier said at the American Conference Institute’s 11th Summit on Biosimilars & Innovator Biologics.

The US Public Interest Research Group (PIRG) contends AbbVie's patent thicket for Humira (adalimumab) will encourage anticompetitive practices by other manufacturers.

PIRG Files Amicus Brief in Support of Humira Plaintiffs

Celltrion Healthcare will initiate a phase 3 trial of its omalizumab biosimilar 

candidate for the treatment of chronic idiopathic urticaria, a form of hives, based on a regulatory green light from the Republic of Korea’s Ministry of Food and Drug Safety.

CT-P39 references the Genentech and Novartis product Xolair, an injectable prescription drug that targets and blocks immunoglobulin E. It is approved in the United States, the European Union, and Japan for the treatment of adults and children with moderate-to-severe asthma and chronic hives. The drug had worldwide sales of $1.17 billion in 2019, a 13% increase from the year before.

, the CT-P39 trial would be conducted at 65 sites in 7 countries, with a target enrollment of 600 patients with chronic idiopathic urticaria. The end points are efficacy and safety demonstrated via comparison of CT-P39 and Xolair. Trial completion is anticipated by the 2023 half-year point.

The product would target the lucrative, billion-dollar worldwide market for Xolair.

Celltrion Healthcare Advances Trials for Omalizumab Biosimilar

Responding to increasing calls to do away with comparative clinical efficacy trials for biosimilar candidates, based on the contention these studies are largely unnecessary, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) has issued 

 for a reduction in such data requirements.

In most cases, a comparative efficacy trial would not be needed; however, such a determination must be supported by robust evidence and would be made only after consideration of all other elements of an application for biosimilar approval, the draft guidance states.

The draft document follows a recent position 

 from members of the MHRA arguing that, except in rare cases, biosimilarity to a reference product (RP) can be demonstrated by analytical testing and a pharmacokinetic (PK) trial. Under the system they propose, comparative efficacy trials would be “reserved for exceptional circumstances.” 

The draft guidance follows a transition under which the MHRA would become a regulator in its own right with complete 

 over evaluation and approval of all medicinal products for use in the United Kingdom. This change takes effect on January 1, 2021.

The MHRA transition is related to the United Kingdom's exit from the European Union. Until now, the United Kingdom has followed guidelines on medicine approvals from the European Union's 

Committee for Medicinal Products for Human Use. According to the MHRA, the waiver of comparative clinical efficacy trials has already been "

allowed for certain biosimilar products in the [European Union] but has not yet been applied to complex biosimilar products, such as monoclonal antibodies."

Part of this transition of authority in the United Kingdom involves creation of a streamlined pathway for the approval of innovative drugs that incorporates ongoing, postmarketing analysis of outcomes based on real-world evidence and novel clinical trial designs.

Whereas the United States and European Union do currently require the use of comparative clinical efficacy trials for biosimilar approvals, members of the MHRA, in their position paper, contend that these studies add little to the quality of evidence garnered by analytical testing, in-human PK, and pharmacodynamic studies. Technological advances over the past 10 years have made efficacy trials largely redundant, they contend.

Recently the International Generic and Biosimilar Medicines Association (IGBA) concurred with this opinion, also 

 global regulatory authorities to simplify the biosimilars approvals process in order to do away with redundancies and avoid unnecessary use of time and resources. IGBA is a trade association representing biosimilar producers.

According to the MHRA draft guidance, comparative efficacy trials are “not considered necessary,” but “a well-argued justification for the absence of an efficacy trial” must be included with an application for biosimilar approval. “The efficacy of the RP can usually be derived from its [mechanisms of action],” the guidance states.

The draft guidance also notes that a biosimilar will be considered interchangeable with a RP once the biosimilar is authorized by the MHRA, but only with the prescriber’s approval in consultation with the patient. Pharmacy level substation without prescriber approval would not be allowed for biosimilars, under the guidance.

In the United States, interchangeable status, which allows free use of either a biosimilar or RP for a given indication, is not automatically granted, but requires additional evidence.

“Switching patients from one product to another (RP or biosimilar) has become clinical practice,” the UK regulators state. “The decision rests with the prescriber in consultation with the patient….No safety signal has been detected in more than a decade of experience with switching.”

Simplified standards for biosimilar approvals in the United Kingdom may open the door to broader changes.

UK Regulators Seek Response on Waiving Comparative Efficacy Testing

The sudden influx of coronavirus disease 2019 (COVID-19)–related trials work at the FDA has required judiciously pulling resources from various departments at the agency to support those efforts, according to Peter P. Stein, MD, director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research (CDER).

“We certainly had to prioritize, and we did provide very early internal guidelines on how to most appropriately prioritize what work had to be considered key, and most importantly, what work might be delayed if it had to be,” Stein said in a discussion on COVID-19 at the DIA 2020 Biosimilars Conference. CDER is charged with regulation of OTC and prescription drugs, including biologics and generics.

In late August, the FDA reported it had 270 clinical trials underway specifically related to potential COVID-19 treatments, and it said more than twice that number were in the planning stages. Concurrent with those concerns, the FDA’s Office of Therapeutic Biologics and Biosimilars 

 that it is tracking 90 biosimilar development projects. The pace of biosimilar approvals is off sharply from last year, currently standing at 2 for 2020 vs 10 for 2019.

“We have had to make sure that we were able to work across silos to move staff across divisions,” Stein said. “We have lots of folks in divisions that weren’t directly affected by COVID-19 therapeutic work moving to divisions to support the…regulatory review work.”

The FDA has established interdisciplinary groups to work across departmental lines to address critical needs and track the effects of COVID-19 on clinical trials, and during the pandemic, the agency has “been working virtually, and we’re getting used to it, and we’re pretty productive,” Stein said. “I think we’ve learned how to work in this environment.” Improvisations to keep the FDA well integrated and effective have included “town hall” meetings, staff meetings, and similar virtual interactions.

Progress with all non–COVID-19 trials has been "hugely" affected by the pandemic, he said. In guidance, the FDA has allowed that modifications to trials necessitated by COVID-19 would be acceptable, but convincing evidence will be required for the FDA to reach drug approval decisions. 

 imposed by COVID-19 have included patient inability to participate in trials and the potential for COVID-19 infections to compromise trial results.

Stein said the FDA has seen fruit from its recent emphasis on “master protocols,” which are trials that evaluate multiple investigational drugs simultaneously. “I think we’ve learned that master protocols are an incredibly important way that we can be able to evaluate therapies more efficiently and effectively.”

“We’ve also had to think about how to evaluate a pack of trials where there is more missing data that we’d like to have—how do we evaluate those to make sure we get as much information from them as we possibly can. I think we’ve also learned more about how real-world evidence can be used particularly as it relates to practice patterns, disease characteristics and drug utilization. I think we’ve learned a tremendous amount.”

From the private sector standpoint, utilization of biosimilars and other specialty products dipped between 10% and 30% as the pandemic unfolded owing to factors such as patients delaying care and temporary clinic shutdowns, according to Sean McGowan, senior director of Biosimilars at AmerisourceBergen, a drug wholesaler. “There was absolutely an impact on utilization, and especially in the biosimilar space,” he said.

“But we have seen a very good and solid recovery in these clinic and health system spaces, and utilization picking back up, not only for the biosimilar products but also for the specialty product market,” he said.

Whereas the approvals process was challenged at the FDA and the wholesale trade saw dips in utilization of specialty drugs, provider-based administration of these agents, including biosimilars, has fallen markedly during the pandemic, according to Juliana M. Reed, MS, vice president of Corporate Affairs, Global Immunology and Inflammation, and Biosimilars for Pfizer.

In the categories of Crohn disease, multiple sclerosis, rheumatoid arthritis, and retinopathy, drug administrations dropped 17%, 30%, 34%, and 45%, respectively, she said, citing IQVIA data.

COVID-19 has made it clear that biosimilars can play an important role in saving money on health care, Reed said. “COVID-19 is opening everybody’s eyes to that. As stakeholders, we are leaving money on the table, and that is something that we need now, especially as we’re seeing how COVID-19 has affected the economy.” She said office-based practices had patient visit reductions of 60% in the first months of the COVID-19 outbreak and said an early projection suggested hospitals stand to lose $323.1 billion in 2020.

On the plus side, the pandemic has changed how health care is administered in such a way that improves access for patients, Reed said. Patients can be classified as homebound and receive infusions at home, and physicians are able to direct infusions via digital links as they are performed by clinic or hospital staff or contracted health workers.

The FDA has had to rely on triaging to address its most critical priorities during the unfolding coronavirus disease 2019 (COVID-19) pandemic, according to Peter P. Stein, MD. 

FDA Reshuffles Priorities to Meet COVID-19 Trial Demand

The European Medicines Agency has initiated review of a proposed ranibizumab biosimilar (SB11) from Samsung Bioepis. The product candidate references Roche’s Lucentis and would treat retinal vascular disorders, a leading cause of blindness.

Samsung Bioepis developed the product and under a commercialization agreement announced in November 2019, Biogen will handle the marketing of both SB11 and an aflibercept biosimilar (SB15), which is an ophthalmology agent referencing Eylea, a Regeneron Pharmaceuticals/Bayer product. Biogen would manage sales of both products in the United States, Japan, Europe, Canada, and Australia.

“We believe SB11 has the potential to be a meaningful new offering for patients with retinal vascular disorders, and we look forward to continued engagement with the EMA throughout the review process,” Hee Kyung Kim, senior vice president for the Clinical Sciences and Regulatory Affairs Division at Samsung Bioepis, said in a 

Ranibizumab is an anti–vascular endothelial growth factor (VEGF) therapy that is used to block the excess development of blood vessels in the eye, which can contribute to the development of disease and tumor formation.

Aflibercept is used to treat wet macular degeneration and metastatic colorectal cancer. It is also an anti-VEGF product.

Samsung Bioepis is based in Incheon, Republic of Korea, and Biogen is in Cambridge, Massachusetts.

The European Medicines Agency (EMA) regulatory review advances a pact between Samsung Bioepis and Biogen announced last year.

EMA Begins Review of Samsung Bioepis' Ranibizumab

Medicure said it has entered an agreement with Reliance Life Sciences (RLS) to market an unnamed cardiovascular biosimilar. Medicure, a Canadian company based in Winnipeg, Alberta, referred to the biosimilar candidate only as “the product.”

 has no FDA biosimilar approvals for the US market. 

RLS is a diverse pharmaceuticals company with a focus on biotherapeutics, including biosimilars, regenerative medicine, pharmaceuticals, clinical research services, and molecular medicine.

Building Up Medicure's Cardiovascular Portfolio

The agreement gives Medicure exclusive rights to market the agent in the United States, Canada, and the European Union.

"We are very pleased with the agreement we have reached with RLS. The product fits well with Medicure's mission of being a significant cardiovascular company focused on the US market," Albert Friesen, CEO of Medicure, said in a 

 by IQVIA, RLS had 14 biosimilars in its pipeline, making it one of the leading biosimilar developers at the time. The Medicure statement described RLS as a company with $86 billion in annual revenues.

Medicure specializes in the development and commercialization of cardiovascular therapies. Two of the products in its portfolio are tirofiban hydrochloride (Aggrastat), an anticoagulant, and pitavastatin (Zypitamag), a cholesterol-lowering statin. Both of these products are marketed in the United States.

No further details of the biosimilar agreement or marketing plan were provided.

The agreement enables Reliance Life Sciences to springboard into the US market using Medicure's commercial reach.

Medicure and Reliance Team Up for Cardiovascular Biosimilar

A group of researchers from the biosimilar industry and academia have recommended in a 

that the FDA widen the scope of acceptable studies for determining interchangeable status for biosimilars.

Interchangeability is a status that would enable pharmacists to make an automatic switch from reference product to biosimilar at the prescription counter without doctor consultation. No biosimilars have yet met the requirements for this designation, although interchangeability is considered important for the uptake of biosimilars and potential savings.

For biosimilars to meet the requirements for interchangeability, they must be shown to produce the same clinical result as the reference product and pose no greater risks of diminished efficacy than if patients remained on the reference product.

The authors, who include Pfizer employees, argue that use of pharmacokinetic (PK) parameters for evaluating potential differences in immunogenicity between reference and biosimilar products is challenging and that interchangeability should be “assessed on a case by case basis, considering the ‘totality of the evidence’ and biologic plausibility.

“Alternative approaches to statistical analysis (eg, use of asymmetric rather than symmetric margins to test equivalence) and study designs that meet the FDA’s expectations for demonstration of interchangeability should be considered,” they wrote.

The authors contend that interchangeability studies as required by the FDA are complicated and are not required by European regulatory authorities. “Without requiring additional clinical studies, individual national authorities in the European Union may endorse the switching from 1 reference or biosimilar product to another at the pharmacy level without consent of the prescriber,” they said.

“By definition, the biosimilar has already been deemed by the FDA not to be clinically different from the reference product. As such, there is little reason to expect altered PK, heightened immunogenicity response, increased safety risk, or improved or diminished efficacy in patients who switch back and forth from a reference product to the corresponding biosimilar.”

One reason the FDA has given for requiring immunogenicity studies is to demonstrate, beyond the existing body of evidence on biosimilar efficacy and safety, that multiple switches between reference and biosimilar drugs would not result in a different outcome; however, the authors contend that the “perceived drawback of multiple switching…is based on theoretical concerns and experience with switches between one biologic product and another that is different, and not its biosimilar.”

“There is a low likelihood that the incidence, titers, or specificity of antidrug antibodies will increase or change as a result of multiple switches between a reference product and its biosimilar,” the authors wrote.

Alvarez DF, Wolbink G, Cronenberger C, Orazem J, Kay J. Interchangeability of biosimilars: what level of clinical evidence is needed to support the interchangeability designation in the United States? 

. Published online September 29, 2020. doi:10.1007/s40259-020-00446-7

Researchers contend the "totality of evidence" for biosimilar approval may be sufficient to demonstrate interchangeability. 