Skylar Jeremias

Hi, I’m Skylar Jeremias for The Center for Biosimilars®, your resource for clinical, regulatory, business, and policy news in the rapidly changing world of biosimilars.

Here are the top 5 biosimilar articles for the week of January 16, 2023.

 STADA Arzneimittel and Xbrane Biopharma’s Ximluci, a ranibizumab biosimilar referencing Lucentis, for the treatment of retinal conditions.

Number 4: The China National Medical Products Administration (NMPA) approved Bio-Thera Solutions’ 

 (BAT1806) referencing Actemra for the treatment of several rheumatic conditions.

Number 3: Alvotech announced that a phase 1 pharmacokinetic study for its 

 for Celltrion Healthcare’s bevacizumab biosimilar (Vegzelma) referencing Avastin for the treatment of multiple forms of cancer.

 of biosimilars found that while the United States had significantly higher prices, the uptake in Germany and Switzerland, 2 European countries with national mechanisms for drug price negotiation, was slower.

To read all of these articles and more, visit 

Videos

The Top 5 Biosimilar Articles for the Week of January 16

Patent litigators from Fish & Richardson, an intellectual property law firm, regaled audiences during a webinar, entitled “

,” covering all the big biosimilar regulatory and legal decisions throughout 2022, including updates on patent disputes and anti-trust investigations.

Jenny Shmuel, JD, principal at Fish & Richardson, provided an overlook of the FDA approvals and US launches in the biosimilars space. During 2022, there were 7 

, including 1 for a high-concentration version of an adalimumab biosmilar (Hadlima; Organon/Samsung Bioepis), 4 launches, and 2 interchangeability designations (

). Additionally, there were 11 biologics license application (BLA) submissions for biosimilars.

Since the first quarter (Q1) of 2020, uptake of biosimilars has grown substantially for some molecules. Uptake for trastuzumab and bevacizumab biosimilars has grown from about 30% in Q1 2020 to around 80% in Q2 2022. For rituximab biosimilars, that number has grown from about 5% to 64% during the same time frame. However, uptake for pegfilgrastim, infliximab, and epoetin alfa biosimilars are still trying to catch up, only obtaining 42%, 42%, and 32% of the market share, respectively.

Shmuel highlighted the 13 big originator biologics that will lose exclusivity over the next 5 years (

), which is expected to face biosimilar competition starting in late 2023 or early 2024.

Throughout the year, there were 4 new patent lawsuits. According to Geoff Bieger, JD, principal at Fish & Richardson, this was lower than the peak of filings in 2018 (n = 12) but still up from 2021 (n = 3).

The cases ranged in how much the parties took part in the 

, a multistep process within the Biologics Price Competition and Innovation Act (BPCIA) that allows for both the originator company and the biosimilar company to exchange information relevant to the patents on the reference product that might be infringed by marketing of the proposed biosimilar.

Only 2 of the cases went through all steps of the patent dance process (Regeneron vs Mylan; Genentech vs Tanvex), 1 went through some of the steps (Biogen vs Sandoz/Polpharma Biologics), and the other went through none (Janssen vs Amgen) (

The Regeneron vs Mylan case resulted in a scheduled trial for June 12 through the 23 in 2023. The current standing of the Biogen vs Sandoz/Polpharma Biologics case is that the parties have jointly requesting for an expedited preliminary injunction proceeding. The Janssen vs Amgen case was filed in November 2022 and no patent dance steps have been taken so far. In the Genentech vs Tanvex case, the parties have demanded for a jury trial, which has not been scheduled yet.

Additionally, the Supreme Court is gearing up to weigh on the Amgen vs Sanofi case regarding Sanofi’s development of a PCSK9 antibody product. In December 2022, the Court granted certiorari, agreeing to review the 

, meaning whether a party that is “reasonably skilled” in a particular field could make or use an invention protected by a patent without “undue experimentation.”

“Although not a BPCIA decision, [this case] might have significant implications in the biosimilars context…" explained Bieger. "The question the Supreme Court has taken is whether or not section 112 requires the patent to teach how to make and use the full scope of the claim embodiments. More specifically, it requires a teaching to make and use all embodiments of the invention without substantial time and effort….The results in this one will definitely generate a lot of a lot of buzz in the coming year."

In August 2022, a case filed in March 2019 claiming that AbbVie, the maker of Humira (adalimumab), was engaging in anti-trust behavior by creating a 

 schemes to prevent biosimilar competition was dismissed. The court declared that “weak patents” are valid and protected under the Noerr-Pennington doctrine, rendering the patent thicket argument null and void. It also said that AbbVie allowing companies to launch their adalimumab biosimilars in Europe while holding off in the United States did not constitute as a pay-for-delay scheme.

A settlement for a case involving Pfizer’s infliximab biosimilar and Johnson & Johnson/Janssen’s patents for Remicade (reference infliximab) is in progress, with a fairness hearing scheduled for February 27, 2023.

Finally, the Federal Trade Commission (FTC) is continuing to investigate pharmacy benefit manager rebate contracts favoring reference products and whether they count as anticompetitive practices that hinder competition from biosimilars and generics.

“The FTC issued a statement on this in June 2022, and specifically identified rebates and fees that stifle competition from generics and biosimilars and increased costs,” Schmuel noted. "The FDA concluded in [a] statement that it will continue to scrutinize rebates and fees to see if antitrust laws have been violated, and will also monitor related litigation and file amicus briefs as necessary."

Articles

Patent litigators from Fish & Richardson, an intellectual property law firm, regaled audiences during a webinar covering all the big biosimilar regulatory and legal decisions throughout 2022, including updates on patent disputes and antitrust investigations.

Legal Experts Provide Updates on Biosimilar Patent Disputes in 2022

The United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) granted 

, a ranibizumab biosimilar developed as part of a partnership between STADA Arzneimittel and Xbrane Biopharma.

The approval marks the second ranibizumab biosimilar for the UK market, following the approval of Teva Pharmaceuticals’ 

Ranibizumab products are vascular endothelial growth factor inhibitors used for the treatment of retinal diseases, such as neovascular age-related macular degeneration (AMD), macular edema, diabetic retinopathy, retinal vein occlusion, and visual impairment due to choroidal neovascularization in adults. Ximluci was approved for all indications of the reference products.

“Considerable unmet need for biologic ophthalmic treatments exists in the UK and throughout Europe…. With almost 15 years’ experience of supplying biosimilars, STADA looks forward to working with Xbrane, as well as with the [National Health Service] and our commercial partners, to broaden patient access to ranibizumab and optimize use of healthcare resources in the UK,” commented Bryan Kim, MBA, head of specialty care at STADA Arzneimittel.

, nearly 1.5 million people in the United Kingdom have macular disease and it affects people of all ages, especially people older than 55 years. AMD is the most common cause of vision loss in the United Kingdom and impacts more than 600,000 people.

“We are proud to have worked with STADA to take this molecule, developed under the Xlucane name, from cell-line development to approval and manufacturing, based on our patented expression system in Europe,” said Martin Åmark, MSc, MBA, CEO of Xbrane Biopharma.

The approval for Ximluci was granted through the European Commission (EC) Decision Reliance Procedure, whereby the MHRA’s decision was based on the one made by the EC. The EC granted marketing authorization to Ximluci in 

, making it available for patients in all 27 European Union member states, Iceland, Norway, and Liechtenstein. The EC came to its decision after reviewing data establishing Ximluci’s biosimilarity to the refence product. Ximluci was the third ranibizumab biosimilar to be approved in the European Union, following the approvals for 

STADA Arzneimittel and Xbrane Biopharma entered into a 

, in which both companies share development and manufacturing responsibilities. STADA Arzneimittel, a Bad Vilbel, Germany–based company, holds the marketing authorizations and commercial rights for the biosimilars included in the deal across all territories, including Europe, the United States, and several countries in the Middle East and North Africa, as well as markets in the Asia-Pacific region.

The United Kingdom has approved STADA Arzneimittel and Xbrane Biopharma’s Ximluci, a ranibizumab biosimilar referencing Lucentis, for the treatment of retinal conditions.

UK Authorizes New Lucentis Biosimilar, Ximluci

Health Canada has granted approval for Celltrion Healthcare’s bevacizumab biosimilar, Vegzelma, for the treatment of multiple forms of cancer, according to a 

The biosimilar represents the fifth bevacizumab biosimilar and fiftieth biosimilar approval in Canada. The other bevacizumab biosimilars include Abevmy, Aybintio, Bambevi, Mvasi, and Zirabev. It is also the second Canadian approval in 2023, following the approval of Samsung Bioepis and Organon’s high-concentration, citrate-free formulation of 

, an adalimumab biosimilar referencing Humira.

Vegzelma, also known as CT-P16, referencing Genentech’s Avastin. Bevacizumab products are inhibitors for vascular endothelial growth factor receptors. The drug is used in the treatment of metastatic colorectal cancer, non-small cell lung cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and glioblastoma. Vegzelma was approved for all the same indications as the reference product.

 Vegzelma as the United States’ fourth bevacizumab biosimilar in September 2022. In August 2022, the European Commission gave its decision 

granting Vegzelma marketing authorization

 throughout the European Union. Overall, Vegzelma is approved in 35 countries, including the Republic of Kora, the United Kingdom, and Japan.

“We hope that Vegzelma, the third anti-cancer antibody biosimilar after Truxima and Herzuma, will settle quickly in the Canadian market…. We will do our best to supply high-quality biopharmaceuticals at reasonable prices to provide various treatment options to patients at home and abroad,” a Celltrion representative said.

In January 2023, Celltrion signed an agreement with Hikma Pharmaceuticals for the commercialization of Vagzelma in 17 countries throughout the Middle East and North African region., including Jordan and Morocco, according to 

. It would be the sixth drug developed by Celltrion to be distributed by Hikma in the region, a list which includes Truxima (rituximab biosimilar), Remsima (infliximab biosimilar), and Herzuma (trastuzumab biosimilar).

Prior to the approval, Celltrion announced the submission of a biologics license application for the American approval of its infliximab biobetter, 

. The biobetter references the company’s infliximab biosimilar (Remsima), which references Remicade, and is the only infliximab product in the world that allows for subcutaneous administration.

Additionally, KoreaBioMed reported that in early 

, Celltrion signed an development deal with Rani Therapeutics over an oral formulation of the former’s ustekinumab (CT-P43) biosimilar for the treatment of psoriasis, plaque psoriasis, psoriatic arthritis, Crohn disease, and ulcerative colitis. The development would leverage Rani Therapeutics’ 

, which could allow for the oral administration of any drug, including large molecules.

Health Canada has granted approval for Celltrion Healthcare’s bevacizumab biosimilar (Vegzelma) referencing Avastin for the treatment of multiple forms of cancer.

Canada Approves Celltrion Bevacizumab Biosimilar

The China National Medical Products Administration (NMPA) approved Bio-Thera Solutions’ tocilizumab biosimilar (BAT1806) referencing Actemra for the treatment of several rheumatic conditions.

The drug will be used in patients with rheumatoid arthritis (RA), systemic juvenile idiopathic arthritis, and cytokine release syndrome (CRS). BAT1806 is the third biosimilar developed by Bio-Thera to receive regulatory approval in China, following the approvals of Qletli (adalimumab biosimilar) and Pobevcy (bevacizumab biosimilar).

“We are delighted that BAT1806 has been approved as the world’s first tocilizumab biosimilar. This is a very important step for Bio-Thera in the field of rheumatology, and it is more important to patients as its approval provides a new treatment option to many patients with autoimmune conditions…. China is currently facing an unprecedented spread of the COVID-19 infections, and BAT1806 provides a treatment option to many hospitalized COVID-19 patients with severe lung conditions,” commented Shengfeng Li, PhD, founder and CEO of Bio-Thera Solutions, in a 

Tocilizumab products are recombinant humanized monoclonal antibodies that target interleukin (IL)-6 receptors, which bind to soluble and membrane-bound IL-6 receptors and inhibit signaling. Actemra is approved for the treatment of RA, giant cell arthritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, CRS, and COVID-19.

The NMPA’s approval was based on positive data from comprehensive analytical similarity studies, nonclinical similarity studies, and clinical studies, which have confirmed that the safety, efficacy, and immunogenicity profiled between the biosimilar and the reference product are “highly similar."

According to Bio-Thera, BAT1806 was created in accordance with the biosimilar guidelines laid out by the NMPA, the FDA, and the European Medicines Agency (EMA). Regulatory approval applications for the biosimilars are currently under review with the FDA and EMA.

The FDA is also reviewing biologics license applications for tocilizumab candidates developed by 

 have tocilizumab biosimilars in development.

In addition to BAT1806, Bio-Thera is developing several other biosimilar products, including biosimilar candidates referencing Simponi (golimumab), Stelara (ustekinumab), and Cosentyx (secukinumab). All 3 of these biosimilars are being evaluated in global phase 3 analyses. A proposed biosimilar for Nucala (mepolizumab) is under investigation in a phase 1 study.

China's NMPA Approves Tocilizumab Biosimilar

Finding the right people to research ophthalmology biosimilars will be critical for the National Eye Institute (NEI) to help address hesitency and mistrust in these products among ophthalmologists, said Michael Chiang, MD, director of the NEI.

What is the NEI approach to newly emerging ophthalmology biosimilars, especially as we begin to see hesitancy among retinal specialists to use biosimilars despite potential cost savings?

This is an important question. At the National Eye Institute, our role is, basically, to identify important research studies and to support them. And hopefully, these are going to be the things that lead to advances in clinical care. With biosimilars, some of the fundamental questions are, of course, are they safe? Are they clinically effective? And are they cost-effective? And those are not exactly the same questio, and you don't study them the same way.

So, what I see as our role is, basically, we have to work with people in the community who want to study these questions, identify exactly how we're going to do them, and get the data to really answer the questions that ophthalmologists need.

Michael Chiang, MD, director of the National Eye Institute, discusses how his team is working to instill greater confidence in ophthalmology biosimilars among wary ophthalmologists.

Dr Michael Chiang: How the National Eye Institute Is Building Confidence in Ophthalmology Biosimilars

Here are the top 5 biosimilar articles for the week of January 9, 2023.

Number 5: IQVIA’s eighth edition of its Impact of Biosimilar Competition in Europe report 

 in many countries throughout the region. However, not every country has great adoption rates and companies may have a harder time choosing which molecules to invest in for biosimilar development.

Number 4: Ivo Abraham, PhD, chief scientist of Matrix45 and a professor at the University of Arizona, demonstrated why regulatory bodies in the United States 

 economic evaluations when reviewing regulatory data for biosimilars in his latest column.

Number 3: Celltrion Healthcare submitted a biologics license application (BLA) to the FDA for its 

 allowing for subcutaneous administration (Remsima SC).

Number 2: The authors of a retrospective real-world study of patients with hidradenitis suppurativa treated with adalimumab concluded that switching patients between adalimumab products risked a greater likelihood of

Number 1: Alvotech, an Iceland-based company, announced that the 

 its biologics license application (BLA) for its proposed ustekinumab biosimilar referencing Stelara. The company said it expects the FDA’s decision in the second half of 2023.

The Top 5 Biosimilar Articles for the Week of January 9

, researchers found stark differences in the uptake and pricing patterns for biosimilars between the United States and 2 European countries that have national mechanisms for drug price negotiations, suggesting that more policies targeting anticompetitive practices are needed to boost biosimilar utilization.

“Policies for drug pricing negotiations in the US against anticompetitive practices of exclusionary contracts could allow biosimilars to enter the market sooner and at lower costs, which could result in lower health care costs and improved patient access. Awareness of biosimilars should be promoted to increase the uptake of biosimilars in all three countries,” the authors explained.

In the United States, biologics only make up 2% of prescriptions but account for 37% of net drug spending. 

, the federal government was not able to negotiate drug prices with companies. Although the Inflation Reduction Act will enable Medicare plans to negotiate as of January 2023, this will not apply to commercial plans. Additionally, 

 have postponed many companies’ launch dates for biosimilars, resulting in patients waiting for 

 that are FDA-approved to enter the market.

In Europe, studies have shown that there are varying policies and biosimilar uptake between countries. On the other hand, the perceived levels of uptake and competition have not reached the level that was expected by 2022 in the United States. Policymakers in both regions have considered implementing legislation and regulatory reforms to promote biosimilar competition.

, looked at reference biologics and biosimilars that were approved in the United States, Germany, and Switzerland through August 2020 and analyzed prices and sales data from January 1, 2011, to December 31, 2020. The data was collected from public and commercial databases and the researchers conducted their analysis from August 1, 2021 to February 28, 2022.

By number of biologics, the United States had 15 biosimilars for 6 reference products, Germany has 52 biosimilars for 15 reference products, and Switzerland had 28 biosimilars for 13 reference products. Some substances were exclude from the US sample because they were either approved before a biosimilar approval pathway existed or the had entered the market yet.

Biosimilar uptake increased in all 3 countries over time, but differences in uptake were observed. In the United States, uptake at 1 year post market entry was highest for bevacizumab biosimilars (36%) and lowest for infliximab biosimilars (3%). In Germany, uptake was highest for adalimumab biosimilars (48%) and lowest for insulin lispro biosimilars (2%). In Switzerland, rituximab biosimilars has the most successful uptake (25%) and insulin glargine biosimilars had the worst (1%).

Between the countries, uptake across biosimilars was the best in Germany followed by the United States and Switzerland. However, uptake rates grew the fastest in the United States during the first year after market launch.

The relative prices of biosimilars compared to their reference products was the highest in the United States. In the United States, the median monthly treatment costs for the biosimilars and their reference products as of October 2020 were $8987 and $11,503, respectively. In Germany, the median monthly costs were $932 for biosimilars and $1285 for reference products. In Switzerland they were $1351 and $1801 for biosimilars and reference products, respectively.

“This difference might be explained by the fact that European countries have more comprehensive mechanisms for drug price assessment and negotiation than the fragmented system in the US,” the researchers said.

Additionally, the authors noted that limited biosimilar availability has led to skepticism about the safety and efficacy of biosimilars. 

 found that over half of US physicians did not believe that biosimilars were appropriate for use in patients. The authors of the present analysis attributed the increased uptake over time as proof that biosimilar awareness is increasing.

The study had some limitations, including sales data may have been limited or underreported, the sample size was small, and that the authors did not account for rebates when analyzing the United States.

Carl DL, Laube Y, Serra-Burriel M, et al. Comparison of uptake and prices of biosimilars in the US, Germany, and Switzerland. 

. 2022;5(12):e2244670. doi:10.1001/jamanetworkopen.2022.44670

A study assessing uptake rates and prices of biosimilars found that while the United States had significantly higher prices, the uptake in Germany and Switzerland, 2 European countries with national mechanisms for drug price negotiation, was slower.

Study Compares Uptake, Prices of Biosimilars in US vs 2 European Countries

 healthy participants with its golimumab biosimilar candidate (AVT05) as part of its phase 1 study evaluating the drug’s safety, pharmacokinetics, and tolerability.

“We are delighted with the progress of the AVT05 development program…. As we enter our fifth biosimilar candidate into clinical studies, we reaffirm our commitment to improving patient lives by expanding access to affordable biologics,” said Joseph McClellan, PhD, chief scientific officer at Alvotech, in a statement.

AVT05 was developed to reference Simoni and Simponi Aria, which are used to treat rheumatoid arthritis in combination with methotrexate, psoriatic arthritis, ankylosing spondylitis, and polyarticular juvenile idiopathic arthritis. Simponi is administrated subcutaneously and Simponi Aria is administered intravenously. Simponi can be used in adult patients and Simponi Ara can be prescribed for adult and pediatric patients 2 years or older.

From October 2021 to October 2022, global combined net revenues for Simponi and Simponi Aria reached over $2.2 billion, according to reported sales data from Johnson & Johnson, the manufacturer of the reference products.

Alvotech’s biosimilar portfolio contains 8 products that can be used to treat autoimmune diseases, retinal disorders, osteoporosis, respiratory diseases, and several cancers. 

, an adalimumab candidate referencing Humira, is currently under review with the FDA and is expected to launch on the US market in July 2023. The company and its partner STADA Arzneimittel have launched AVT04 in 

In addition, Alvotech submitted a biologics license application for an 

 referencing Stelara to the FDA. A phase 1 trial is in progress for a 

 candidate referencing Xgeva/Prolia. In July 2022, Alvotech initiated a phase 3 trial for an 

In February 2022, Alvotech entered into a licensing agreement with BiosanaPharma for the development of a 

 (omalizumab). AVT16 and AVT33 are the other products in development; however, the molecules they are referencing have not been disclosed publicly.

 on the Nasdaq stock market, making it the first dual-listed Islandic company to be on both a US and Icelandic stock exchange.

 is working on its own golimumab biosimilar candidate (BAT2506). The biosimilar is currently being evaluated in a phase 3 trial of 480 patients with psoriatic arthritis.

Alvotech announced that a phase 1 pharmacokinetic study for its golimumab biosimilar referencing Simponi has commenced.

Phase 1 Trial for Alvotech Golimumab Biosimilar Begins

Coherus Biosciences has acquired the US commercial rights for an aflibercept biosimilar, the FDA has sent Biocon Biologics a complete response letter (CRL) regarding its insulin biosimilar, and Lannett provides an update on the development of its insulin glargine and insulin aspart biosimilars.

Coherus Acquisition of Aflibercept Biosimilar

Coherus has announced that it would acquire the exclusive 

 to FYB203, an aflibercept biosimilar referencing Eylea, from Klinge Biopharma.

The companies anticipate the transaction to complete during the first quarter of 2023, and Coherus will be responsible for filing a biologics license application (BLA) for the biosimilar to the FDA for approval. If approved, Coherus said that it intends to launch the product in 2025.

Aflibercept is used to treat neovascular age-related macular degeneration (wet AMD), macular edema, diabetic macular edema, and myopic choroidal neovascularization. Klinge Biophama had in-licensed FYB203 from Formycon. FYB203 is currently being investigated in a phase 3 randomized, double-blind, multicenter study comparing the safety and efficacy profiles between the biosimilar and the reference product.

The researchers recruited 434 patients with wet AMD. The participants will receive 1 intravitreal injection of the biosimilar every 4 weeks for the first 3 doses followed by 1 injection every 8 weeks through study completion.

Biocon, the parent company of the Bengaluru, India–based Biocon Biologics, shared that the company 

 from the FDA conserving its recombinant insulin biosimilar.

The CRL called for additional data to be submitted and an “expectation of a satisfactory implementation of a [Corrective and Preventive Actions] plan pertaining to the pre-approval inspection” of their manufacturing facilities in August 2022.

A company spokesperson at Biocon Biologics said that the company is in the process of addressing the letter.

Lannett Updates on Insulin Biosimilar Development

 on the clinical development of 2 insulin biosimilars: an insulin glargine and an insulin aspart. The company is developing the biosimilar candidates as part of a partnership with the HEC Group of companies.

The updates from a preclinical study comparing the biosimilar insulin aspart with the US version of the reference product (NovoLog) demonstrated that the products were highly comparable. The data will be submitted to the FDA as part of Lannett’s request for approval, which it expects to file during the end of 2024, with a potential launch in 2025.

Comments from Tim Crew, CEO of Lannett, claimed that studies for the biosimilar insulin glargine are ongoing, and results are expected to be available by the end of February 2023. The need for equipment maintenance and recalibration led to a 2 month delay in the study, and researchers were able to complete it by the UK-based lab’s planned end-of-year shutdown. Crew said that Lannett anticipated filing a BLA in midyear 2023 and aims to launch the product during the first half of 2024.

Coherus Biosciences has acquired an aflibercept biosimilar; the FDA has sent Biocon Biologics a complete response letter (CRL) regarding its insulin biosimilar; Lannett provides an update on the development of its insulin glargine and insulin aspart biosimilars.