The Center for Biosimilars Staff

In an interview with The Center for Biosimilars®, Hyoung Ki Kim, vice chairman and CEO of Celltrion Healthcare, broke down the role that biobetters could play in the global biologics industry and how they differ from biosimilars.

Hyoung Ki Kim, vice chairman and CEO of Celltrion Healthcare

CfB: What are the benefits of having a biobetter version of a drug vs a biosimilar or a reference product?

Biosimilars have the potential to transform health care systems as they can reduce costs by offering a lower-cost treatment option, whilst offering the same benefits as their reference product. Cost savings from biosimilar uptake could also support patient access to other treatments or be reinvested, which is particularly important as health care systems look to recover from the impact of the pandemic. Biosimilars could pave the way for increased shared decision making, providing more treatment options for patients.

Biosimilars are just the beginning. Due to technological advances, further innovations in biologic development have resulted in medicines that offer benefits beyond those offered by the reference products or their biosimilars – known as biobetters. These advances could benefit both patients and health care systems, for example as a new drug delivery method (including making the treatment available via subcutaneous [SC] administration) that can save time, money, and improve patient quality of life, or modifications to provide clinically relevant improvements, such as improved efficacy, safety, or tolerability, or reduced immunogenicity vs the reference product. These advances not only support in addressing patient unmet need, but they offer potential savings for health care systems as in-hospital treatment time and resources are reduced.

CfB: The concept of biobetters is very new, and there is still a lot more education that is needed around biosimilars to improve adoption and acceptance. What more needs to happen to increase awareness and confidence in biobetters?

While the term ‘biobetter’ is still relatively new to both health care professionals and patients, many health care professionals with expertise are in active discussions to establish a widely accepted definition of biobetters, as these medicines could offer a multitude of benefits for patients.

According to a recent international expert consensus reached by physicians with expertise, improvements in clinical outcomes and drug pharmacology are identified as crucial elements for the definition of biobetters. Whilst efforts are being made by physicians, patients may have a limited understanding of the benefits and safety profile of biobetters.

Consequently, patients may find it helpful to understand that whilst biosimilars are biologics that have no clinically meaningful differences from their reference product, biobetters offer improvements for patients vs the reference product. Relevant improvements might be related to the efficacy or safety profile, administration method or ease of use, or could result from new indications or patient populations being targeted.

In addition, these reformulated medicines could allow dosing to be tailored to individual patients, alongside optimizing pharmacokinetics (PK) and improvements in efficacy, safety, and patient convenience and experience.

Changes in drug administration route, such as IV to SC, might generate cost savings for health care systems, as in-hospital treatment time and resources are reduced. Potential budget savings could be used to provide personalized patient care, which may lead to further cost savings.

While there is much potential for the biobetters market, there is no standardized guidance available from major regulatory agencies regarding the approval pathways for innovative biologic drugs. On this note, a globally accepted, standardized set of regulatory guidelines would avoid duplicating clinical trials and allow medicines to come to market in a more timely fashion for the benefit of those patients who need them most.

CfB: What’s interesting about Celltrion’s biobetter, Remsima SC, is that it is the only biobetter on the market that is a biobetter of a biosimilar (Remsima; infliximab biosimilar) rather than an originator product. How has Celltrion’s approach to developing and marketing biobetters been shaped by biosimilars?

 Celltrion has been regarded as a ‘first-mover’ in the biopharmaceutical industry following its development of the world’s first antibody biosimilar, Remsima. From that day onwards, the biosimilar revolution began, as Celltrion Healthcare’s sales overtook the original drug’s market share in the monopoly market.

However, as the biosimilar market gained momentum, competition also intensified and companies exploring biosimilar development needed to consider the sustainability of its product. With this in mind, Celltrion did not settle for being purely a biosimilars developer but researched innovative ways to provide value-added medicines in anticipation of these medicines becoming a ‘game changer’ in the future.

Our heritage in biosimilars puts us in a strong position to lead the way in the biobetters space, and we are committed to exploring new ways to bring biobetters to patients and health care systems.

Remsima SC is revolutionary in that it is the only infliximab product, including Remicade (reference infliximab), that can be delivered subcutaneously instead of intravenously [IV]. How significant is this development for patients with rheumatic conditions and for stakeholders looking to save money?

At Celltrion Health care, we are extremely proud of our innovation in Remsima SC due to the huge impact it is already having for patients and health care systems across the world. We have already been able to see what the biobetter is contributing to the health care system during the COVID-19 pandemic. The availability of Remsima SC has been particularly important as the subcutaneous administration feature of Remsima SC can reduce the risks to both patients and clinic staff by minimizing clinic visits and reducing extended contact.

In addition to reducing risk to patients and clinic staffs, Remsima SC can:

reduce treatment-related travel costs for patients and care givers

provide a patient-friendly format of infliximab – this is particularly beneficial for patients who dislike infusions; and

allow patients to manage their own treatments, providing independence.

For physicians, increasing treatment options with the availability of both an IV and a SC formulation offers the potential to tailor treatment approaches to the individual needs of the patient. For example, an IV formulation could be used to induce a rapid response in patients, whilst SC can be utilized to maintain a better drug survival rate. Remsima SC can also reduce health care system costs, by reducing infusion frequency and freeing up capacity, while delaying usage of more expensive second-line treatment.

CfB: Why did Celltrion want to invest in creating a subcutaneous infliximab product?

 Celltrion Healthcare is committed to delivering patient-centric care, pursuing innovation in areas of unmet need, and the development of Remsima SC originated from insights from clinicians, patients and thought leaders to improve treatment pathways.

When we interviewed clinicians and thought leaders about the clinical use of anti-tumor necrosis factor (TNF)-α agents, they highlighted that they are often used to treat patients with severe disease. They commented that infliximab has been used over the course of 20 years in clinical practice. However, given the intravenous route of administration, it’s mostly used as an initial anti-TNF therapy rather than during the maintenance phase.

While intravenous infliximab proved to be an effective treatment with achieving good responses, it became apparent that a subcutaneous formulation of infliximab could provide an alternative option, as the frequency of administration and the cumulative costs of intravenous infusion can impact patients’ quality of life.

Accordingly, Celltrion explored the development of a subcutaneous formulation of infliximab (Remsima SC) whilst looking to extend the treatment longevity of infliximab. As a result, this enables a rapid response with Remsima IV, consequently maintaining the treatment regimen with Remsima SC, as the subcutaneous formulation can be self-administered by patients in the comfort of their own homes.

CfB: Currently, Remsima SC is available in the Republic of Korea, the European Union, and Canada. What has been Celltrion’s experience with marketing the product in those places and how has adoption been?

Remsima SC has been steadily expanding since its launch in 2020, driving the growth of the infliximab market in Europe. According to a recent market report from health care consulting firm, IQVIA data, in Germany, the market share of Inflectra, Remsima IV & SC was 36.4% in Q1 2020, and continuing to rise this year, with the first quarter reporting 51% market share. In France, the total market share of Remsima IV and SC was 18% in Q1 2021, which drastically increased to 50% this 1st quarter.

The market share of both Remsima IV and SC have increased together across Germany, France, the United Kingdom and Spain since the launch of Remsima SC, continuing to overtake the market share of its reference drug.

In addition, patient acceptability for biobetters can be found in a patient satisfaction survey in the Royal Liverpool Hospital, where 77.3% of patients out of 88 patients preferred using SC infliximab compared to IV infliximab. We believe physicians will have more flexibility or a more tailored approach when it comes to deciding whether a patient should receive Remsima IV or SC, according to each individual patient’s condition or disease state.

CfB: Is Celltrion planning to enter Remsima SC into the United States and if so, when might we see it?

While the European Medicines Agency treats biobetters as biosimilars and allows applications for approval to follow a hybrid pathway based on data showing similar efficacy to the reference product, the US FDA advises that drug applications are based on data from new clinical trials, which could possibly hinder the entry of the innovative biologics to the US market.

We are working with the US health care system to bring Remsima SC to patients as early as possible. Remsima SC is currently expected to be approved in the United States in the second half of 2023.

CfB: Does Celltrion have any future plans for developing more biobetters in the future?

Due to technological advances, the development of improved versions of previously approved biologics, beyond that of biosimilars, has become possible.

It is Celltrion’s aim to pioneer uncharted areas of innovative therapies, incorporating unique and successful next-generational approaches that promote health and welfare globally.

We are dedicated to advancing the field of biosimilars and biobetters, and will be exploring possibilities to expand our pipeline in the future. Apart from biosimilars and biobetters, we are focused on securing new drug development platforms, such as antibody-drug conjugates as well.

CfB: What is something that you wish more people understood about biobetters?

The concept of biobetters is new for both patients and health care systems. Therefore, education is key to improve access and consequently outcomes. Differentiating between biosimilars and biobetters will be crucial, highlighting the fact that biobetters are patient-centric alternatives offering benefits beyond the reference product, such as improved clinical outcomes and pharmacokinetic benefits, without impacting the original benefits of the treatment.

Biobetters and the innovation they offer are backed by extensive research to optimize the treatment and further relieve disease burden from both the patient’s and health care provider’s perspectives.

CfB: There have been some concerns that biobetters are just a way for companies to improve an existing product to extend patent exclusivity and avoid spending money on new innovative products. What would you say to people who are worried about that?

Countries like the United States, Canada, and Japan consider these biobetters as a new drug requiring pivotal clinical trials in each indication and therefore, the development can be more time consuming and costly compared to abbreviated biosimilar approval pathways.

Biobetters provide numerous benefits for different stakeholders, offering improved clinical outcomes for physicians and improved quality of life for patients. Improved cost-saving metrics for payers provide opportunities to treat additional patients, to expand eligibility criteria (such as to patients earlier in the disease course), or to reinvest in the health care system, which could provide additional services for patients or increase capacity.

At Celltrion Healthcare, we are united in the belief that biobetters could transform health care systems and patient outcomes. This motivation is what drives our commitment to continue to innovate in the field of biobetters. As with anything new, there may be some concerns and gaps in knowledge that exist, and it is our mission to tackle these through education, awareness and evidence.

How do you think that biobetters will shape the biopharmaceutical space going forward?

Biobetters could be transformative for the biopharmaceutical space going forward—in the same way that the introduction of biologic therapies and biosimilars were. The introduction of biologic therapies led to a paradigm shift in the treatment of many immune-mediated inflammatory diseases, with the subsequent availability of biosimilars facilitating reductions in treatment costs without compromising efficacy or safety.

Ensuing cost savings provided opportunities to treat additional patients, to expand eligibility criteria (such as to patients earlier in the disease course) as is the case in the United Kingdom, where the National Institute for Health and Care Excellence published a guideline. The initiative expanded the treatment options for patients by recommending that these biological treatments can be used to treat moderate as well as severe rheumatoid arthritis, or to reinvest in the health care system which could provide additional services for patients or increased capacity.

In light of advancing technologies and innovative approaches, biobetters could allow for improved patient and health care professional choice, and ready-to-use formulations such as Remsima SC could reduce the handling burden for clinicians, especially in light of the coronavirus pandemic.

Articles

In an interview with The Center for Biosimilars®, Hyoung Ki Kim, vice chairman and CEO of Celltrion Healthcare, breaks down the benefits of biobetters, how they differ from biosimilars, and how they could alter the future landscape of the biologics industry.

Q&A: How Will Biobetters Fit Into the Growing Biologics Market? Celltrion Executive Explains

Biosimilars revenues grew by 28% year over year for Biocon Biologics Ltd in the third quarter, which ended December 31, 2021, and is up 32% quarter over quarter.

During the quarter, the insulin glargine biosimilar (Semglee) launched in the United States with Biocon’s partner Viatris. In July 2021, Semglee was approved as the 

. The interchangeable designation means that Semglee can be substituted for the reference product (Lantus) automatically by pharmacists without physicians' permission

“Biocon Biologics achieved a key milestone with the commercialization of the world's first interchangeable biosimilar, our Insulin Glargine, in the US,” Kiran Mazumdar-Shaw, executive chair at Biocon said in a statement. “Approvals for several of our generics and biosimilars in global markets, and renewal of key long-term research service agreements at Syngene, position us for a strong close to this fiscal [year]."

In addition, Biocon noted that Semglee received preferred status in 2 national formularies: Prime Therapeutics and Express Scripts. It will also be offered through the Walgreens Prescription Savings Club.

Semglee, which launched in the United States in November 2021, is available in vial and prefilled pen presentations. Arun Chandavarkar, PhD, managing director of Biocon, noted that following the approval and launch of Semglee in the United States, and robust demand in the United States and globally, the company has initiated an investment to expand the insulin manufacturing facility in Malaysia.

In Canada, Biocon’s bevacizumab biosimilar received approval during the third quarter. According to the financial report, market share for biosimilar trastuzumab (Ogivri) in the United States and biosimilar pegfilgrastim (Fulphila) in the United States and key European Union countries remained steady.

Biosimilar trastuzumab is the leading biosimilar in several countries and has close to half the market share in Brazil, Indonesia, and Algeria.

“The development of our next wave of biosimilars continues to progress well, with some of them poised to enter the clinic this quarter,” according to the report.

In the third quarter, ending December 31, 2021, biosimilars revenues were up 28% year over year for Biocon Biologics Ltd.

Biocon Posts 28% Growth in Biosimilars Revenues Year Over Year

Biocon said this week it received a Form 483 letter from the FDA related to an inspection at its insulin manufacturing plant in Malaysia, where the company will produce its insulin glargine product, referencing Sanofi’s Lantus.

, Biocon said the FDA conducted a pre-approval inspection of the facility between February 10 and February 21. The notice includes “3 observations, which we believe are procedural in nature,” the company wrote.

The follow-on product is already authorized in the European and Australian markets, where the product is regulated as a biosimilar and is sold under the brand name Semglee.

In the United States, the product has a target action date set for June; Biocon said in its announcement it does not “believe the outcome of this inspection does not in any way impact the commercialization plans."

However, Biocon’s Malaysian plant has been the subject of numerous regulatory challenges in 2018 and 2019. The company received a Form 483 from the FDA, inclusive of 6 observations, in 2018, and another inspection of the site in June and July 2019 yielded another Form 483 with 12 observations. 

In August 2019, it received a certificate of good manufacturing practice from the European Medicines Agency’s Irish inspection authority. 

With the latest notice, Biocon said it is confident of addressing the observations "expeditiously" and said it is committed to "global standards of Quality and Compliance."

This is the third Form 483 Biocon has received for the insulin plant in 3 years. 

Biocon Says FDA Issues Form 483 to Insulin Plant in Malaysia

The FDA said Monday it launched the first phase of its improvement to the Purple Book by moving from a list format to a 

, so the public can more easily search biosimilar and biologic products.

; the FDA said; while the update to the new database continues, the FDA said the static PDF will continue to house information on all FDA-licensed biological products. The initial Purple Book version contains a limited data set that includes all approved biosimilar products and their related reference products, with a simple search and advanced search function.

The FDA said it will also publish a Federal Register notice and open a docket to gather public comment on the database to inform the next phases of development; they will also take user testing and stakeholder input into consideration as additional functionality and improvements are developed and implemented in subsequent phases.

Ultimately, the Purple Book is supposed to include all Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) regulated products, 

Once the new database update is completed, the list/PDF format version will cease updates. The updated database is “intended to improve transparency and functionality for stakeholders by providing a complete view of biological product options, including biosimilar and interchangeable products, and to advance public awareness about licensed biological products,” the FDA said.

“Providing stakeholders with more information about biological products through a modernized platform should better facilitate the acceptance and use of existing biosimilar products and the development of new ones, potentially leading to lower costs for patients and improved access to safe, effective, high-quality medications,” FDA Commissioner Stephen M. Hahn, MD, 

The new database includes information about FDA-licensed biological products, such as the product’s proprietary and proper names, the full product label, dosage form, route of administration, strength, marketing status, and more. The enhancements also include more information about approved biological products (such as including information pertaining to exclusivity, and whether a product has demonstrated that it is biosimilar to, or interchangeable with, a reference product), intended to help patients and industry track the licensure statuses of biosimilar and interchangeable biological products, and to aid prescribers and pharmacies in identifying life-saving, and potentially cost-effective medications.

Ultimately, the Purple Book is supposed to include all Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) regulated products, including transition biological products.

FDA Launches Searchable Database Intended to Replace Static Purple Book Lists

Pfizer's trastuzumab biosimilar to Herceptin, Trazimera, launched Wednesday in the United States.

Trazimera is available for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

The company said last month that Trazimera will have a wholesale acquisition cost (WAC) of $80.74 per 10 mg, a 22% discount to the WAC of Herceptin. In January, Pfizer launched its rituximab product, Ruxience (referencing Rituxan), and its biosimilar bevacizumab Zirabev (referencing Avastin).

With Trazimera in place, Herceptin now has 3 biosimilar competitiors. Besides Trazimera, the other 2 are the Mylan and Biocon biosimilar trastuzumab, 

This is the sixth biosimilar to launch within 120 days, making for 15 biosimilars launched in the U.S. The launch of Trazimera officially makes the Herceptin market one of the most competitive therapeutic markets in the U.S. (now having three biosimilars competing with one reference product) and the Herceptin market could have as many as five biosimilars competing in it by the end of 2020

With Trazimera in place, Herceptin now has 3 biosimilar competitiors.

Pfizer Launches Trastuzumab Biosimilar

 today that it has received a positive opinion on its pegfilgrastim biosimilar, CHS-1701, from the European Medicines Agency’s Committee for Human Use (CHMP). Coherus plans to sell the drug, referencing Neulasta, under the name Udenyca.

Coherus indicated that its data package for the drug included analytical similarity data, a 3-arm, triple-crossover pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers, as well as an immunogenicity package including a dedicated immunogenicity study in more than 300 patients.

"The positive opinion issued by the CHMP today is a significant milestone for Coherus, as it validates both our Udenyca biosimilarity package as well as our development platform as a whole," said Denny Lanfear, president and CEO of Coherus BioSciences, in a 

The opinion is welcome news for the biosimilar developer; in 2017, Coherus experienced a setback for CHS-1701 when received a Complete Response Letter (CRL) from the FDA. The CRL cited a need for a reanalysis of a subset of samples with a revised immunogenicity assay, as well as for additional manufacturing information. In May 2018, Coherus resubmitted its Biologics License Application in May 2018.  

Also today, Accord Healthcare received a positive CHMP 

 for its own pegfilgrastim biosimilar, which it plans to market as Pelgraz.

The opinion was based on a phase 1 PK and PD study in healthy volunteers as well as a phase 3 study in patients with breast cancer who were receiving docetaxel, doxorubicin, and cyclophosphamide chemotherapy.

Accord has long-standing experience in the European biosimilars space with its filgrastim biosimilar, Accofil, which was approved in 2014. “Since then the product has been used over 2 million times,” said Binish Chudgar, vice chairman and managing director of Intas Group, Accord’s parent company. “Accord has gained valuable experience in bringing biosimilar medicines to market. Our continued focus on bringing biopharmaceuticals to Europe has enabled us to be a first to launch a pegfilgrastim, and as a first mover we expect to gain an even bigger market share with Pelgraz,” he added.

Both products will now await final clearance by the European Commission before they will be authorized for marketing in the European Union and European Economic Area.

Drug maker Coherus announced today that it has received a positive opinion on its pegfilgrastim biosimilar, CHS-1701, from the European Medicines Agency’s Committee for Human Use (CHMP). Coherus plans to sell the drug under the name Udenyca. Separately, Accord Healthcare received a positive opinion for its own pegfilgrastim biosimilar, which it plans to market as Pelgraz.
 

Coherus, Accord Both Receive Positive CHMP Opinions for Pegfilgrastim Biosimilars

A recent survey of US rheumatologists found that there is room for improvement in clinicians' awareness of biosimilar therapies. 