The Center for Biosimilars Staff

Sandoz announced today that the European Commission has granted a marketing authorization for its pegfilgrastim biosimilar, Ziextenzo, referencing Neulasta. 

The biosimilar has gained authorization for the same indications as the reference drug: reducing the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy.

"Despite advancements in cancer treatment, febrile neutropenia remains one of the most significant complications of chemotherapy and is a major cause of morbidity," Stefan Hendriks, global head of biopharmaceuticals at Sandoz, 

. "With the approval of Ziextenzo…we look forward to providing a treatment option that delivers the possibility of further reducing both the personal and financial burden of cancer."

Paul Cornes, MD, oncologist and member of the continuing medical education program of the European Association of Hospital Pharmacists and core lecturer for the European School of Oncology in the United Kingdom added that “Pegfilgrastim biosimilars, such as Ziextenzo, mark a true advancement for people with cancer. These medicines help deliver optimized long-acting dosing and patient convenience while creating savings for our hard-pressed health systems.”

The authorization of Ziextenzo follows a September 2018 positive opinion from the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP). The opinion was granted on the basis of data including positive 

 presented at the December 2017 San Antonio Breast Cancer Symposium. The molecule has also been studied in phase 3 clinical 

 in patients undergoing chemotherapy. Sandoz had previously put the molecule forward for EMA review, but withdrew its application in October 2017 after CHMP 

 that Sandoz was not able to resolve in the timeframe permitted by the regulator. 

The authorization of the biosimilar brings the number of EU-approved pegfilgrastim biosimilars to 4. A fifth pegfilgrastim product, Mylan’s Fulphila, is awaiting the European Commission’s decision on its own positive CHMP opinion, also rendered in September. 

Articles

Sandoz announced today that the European Commission has granted a marketing authorization for its pegfilgrastim biosimilar, Ziextenzo, referencing Neulasta. 
 

Sandoz Gains European Authorization for Pegfilgrastim Biosimilar, Ziextenzo

The European Commission has granted a marketing authorization to Cinfa Biotech and Mundipharma’s biosimilar pegfilgrastim, Pelmeg, for all indications of the reference product, Neulasta.

The authorization of the drug indicated to reduce the duration and incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy follows a positive recommendation from the Committee for Medicinal Products for Human Use in September 2018. The biosimilar gained a positive recommendation on the basis of a comprehensive package of data including a 

 of pharmacodynamics and immunogenicity that was presented at the American Society of Hematology’s annual meeting in December 2017. 

“We hope this approval will significantly improve the lives of people who are affected by chemotherapy induced neutropenia and febrile neutropenia," Phillippe Bastide, head of biosimilars at Mundipharma, 

 in a statement. "The availability of this biosimilar represents an important opportunity to reduce healthcare costs while increasing access to an effective treatment option.”

Pelmeg will be the fourth biosimilar commercialized in Europe by Mundipharma, a network of companies that operates in 120 countries worldwide, which 

 Cinfa Biotech October 2018; the company is engaged in an ongoing partnership with Korean drug maker Celltrion to commercialize Remsima (biosimilar infliximab), Truxima (biosimilar rituximab), and Herzuma (biosimilar trastuzumab) in Europe. In addition to access to the biosimilar pegfilgrastim, acquisition of Cinfa Biotech provides Mundipharma with additional research and development capacity for future biosimilar products. 

When it enters the European market, Pelmeg will become the third biosimilar pegfilgrastim product available; 2018 saw a 

 of approvals in the pegfilgrastim space, with Coherus Biosciences’ Udenyca and Accord Healthcare’s Pelgraz authorized in September (Udenyca also earned FDA approval in November). Another biosimilar pegfilgrastim, Mylan and Biocon’s Fulphila, is currently 

 EU authorization (the product has been FDA approved and launched in the United States).

The biosimilar will also compete with a range of EU-approved short-acting granulocyte colony-stimulating factor biosimilars and follow-ons, including Zarzio/Filgrastim Hexal, Accofil, Grastofil, Nivestim, and Ratiograstim/Tevagrastim.

The European Commission has granted a marketing authorization to Cinfa Biotech and Mundipharma’s biosimilar pegfilgrastim, Pelmeg, for all indications of the reference product, Neulasta.
 

European Commission Authorizes Pegfilgrastim Biosimilar, Pelmeg

Nielsen, a global measurement and data analytics company, recently revealed that direct-to-consumer (DTC) healthcare advertising has reached 75% of US cancer survivors on television. 

“Survivors will look to many sources to increase their knowledge about the disease, become more informed about treatment options and learn about ways to reduce future risk of recurrence,” 

 to Neilsen.  The report also states that the sources individuals value most are linked with how long they have had their diagnoses. 

Those who have been diagnosed for 1 to 2 years are more alert to healthcare advertising, according to Nielsen, than average cancer survivors. This group is 28% more likely than the average survivor to report having seen advertising at a pharmacy, 23% more likely to report having seen ads on the internet, and 15% more likely to report having seen ads in direct mail. They are also 35% more likely to value information that they read in newspaper advertising than in other media. 

Nielsen also indicates that this group of survivors is more likely than the average cancer survivor to ask their physicians to prescribe a specific drug as a result of having seen healthcare advertising. 

Such numbers are of particular interest given the Trump administration’s 

 to require DTC television advertisements for drugs to contain drug pricing information. The proposal, which is part of the administration’s focus on curbing the increasing price of drugs, has been met with resistance from drug makers; According to Stephen Ubl, president and CEO of the trade group Pharmaceutical Research and Manufacturers of America, disclosing the list price in TV advertisements may discourage patients from seeking needed medical care. Ubl also noted that if a requirement was implemented to disclose such information it would “raise significant legal issues, including First Amendment concerns.”

Nielsen, a global measurement and data analytics company, recently revealed that direct-to-consumer healthcare advertising has reached 75% of US cancer survivors on television. 
 

Patients Diagnosed With Cancer for 1 to 2 Years Are More Alert to Healthcare Ads

The European Crohn’s and Colitis Organisation (ECCO) has surveyed its members in 2013 and 2015 concerning their knowledge of and views on biosimilars, and in 2017, researchers from Asia adopted the same survey questions to gather information on the views of members of the Asian Organization of Crohn’s and Colitis (AOCC). Results of the survey, 

demonstrate that Asian physicians are less confident in using biosimilars than their European peers are. 

The 17-question, multiple-choice, anonymous web survey gathered responses from 151 physicians from Korea, Japan, China, Hong Kong, Malaysia, Taiwan, Singapore, and India. Most participants were gastroenterologists (96.6%), and most (77.5%) had cared for patients with inflammatory bowel disease (IBD) for more than 5 years. 

The survey found that 49.6% of respondents had access to biosimilars and had already prescribed them, while 26.4% had access to biosimilars but had not prescribed them, and 19% had no access to biosimilars (in 2015, the corresponding percentages among ECCO members were 60%, 22%, and 18%, respectively). 

In terms of provider education, most respondents (66.2%) were aware that a biosimilar is not identical to the originator. Some (8%) thought that a biosimilar was a different agent altogether (comparable to the difference between adalimumab and infliximab). Furthermore, 19.9% believed that biosimilars have different activities than the originator, while 38.4% thought that biosimilars would have different immunogenicity than the originator. While these patterns of education are similar to ECCO members’ responses, a lower percentage of AOCC respondents (77.5%) than ECCO members (92.4% in 2015) considered cost savings as a main advantage of biosimilars.

Like ECCO members (85% in 2015), most AOCC respondents (87.8%) disagreed with automatic substitution of a biosimilar by a pharmacist, but unlike ECCO members (44.4% in 2015), only 19.2% of AOCC respondents believed that biosimilars could be used interchangeably with their references. Similarly, fewer AOCC respondents (39.1%) than ECCO members (50.8% in 2015) were comfortable with the extrapolation of indications.

Finally, only 6.0% of the survey respondents said they would be confident prescribing a biosimilar, compared with 28.8% of ECCO members in the 2015 survey.

“Asian gastroenterologists are generally well informed about biosimilars,” write the paper’s authors. “However, compared with ECCO members in 2015, Asian gastroenterologists had more concerns and less confidence about the use of biosimilars clinical practice. Thus, IBD-specific data on comparison of efficacy, safety, and immunogenicity in Asian patients are needed.”

Park SK, Hisamatsu T, Ran Z, Wei SC, Park DI. Knowledge and viewpoints on biosimilar monoclonal antibodies from members of the Asian Organization of Crohn’s and Colitis: comparison with European Crohn’s and Colitis members [published online November 12, 2018]. 

Results of a recent survey demonstrate that Asian physicians are less confident in using biosimilars than their European peers are. 

Asian Gastroenterologists Are Less Confident in Biosimilars Than Their European Peers

Samsung BioLogics, parent company of the biosimilar development business Samsung Bioepis, has been fined by the Republic of Korea’s financial regulatory body, The Securities and Futures Commission, after the commission ruled that Samsung had committed fraud.

 by Nikkei Asian Review, the commission found that, in 2015, Samsung BioLogics used accounting methods that inflated the value of Samsung Bioepis ahead of an initial public offering in 2016. 

In addition to imposing a fine of approximately $7.05 million and suspending Samsung BioLogics’ trading, the commission could also recommend that the company be delisted from the Korean stock exchange. Such a delisting would have major impacts on the company; currently, 

, Samsung Biologics is Korea’s fifth largest firm in terms of market capitalization.  

 to shareholders, Samsung BioLogics defended itself, saying, “Samsung BioLogics would like to sincerely apologize to our clients and shareholders for the confusion caused by the recent accounting issue. However, the SFC's announcement today is very unfortunate as it is our firm belief that Samsung BioLogics has not breached any accounting rules at all.”

The company went on to indicate that it sought the advice of multiple accounting firms, all of whom deemed its accounting practices acceptable. Furthermore, the company said that it plans to file a lawsuit to “clearly prove the legality of Samsung BioLogics’ actions.”

News of the scandal and its repercussions come shortly on the heels of reports that Biogen has 

 its stake in Samsung Bioepis. Earlier this month, Samsung BioLogics confirmed that it will conclude a transfer of shares to Biogen that has been pending since June of this year. Under the deal, Biogen will receive more than 9 million shares of the joint venture for a payment of approximately $677 million.

Samsung BioLogics Could Be Delisted From the Stock Market Over Fraud

AbbVie has struck agreements with multiple developers over biosimilar adalimumab, forestalling US market entry until 2023. Here's when each product could reach US patients.

AbbVie has struck agreements with multiple developers over biosimilar adalimumab, forestalling US market entry until 2023. Here's when each product could potentially reach US patients.

A Timeline of US Biosimilar Adalimumab Launch Dates

The Canadian Agency for Drugs and Technologies in Health (CADTH), the Canadian entity responsible for health technology assessments, has released a new 

 related to biosimilar and the factors that facilitate their use. 

According to CADTH, during 2016, the 30 top-selling biologics in Canada accounted for 24% of all pharmaceutical sales in the country, but 13 biologics could face biosimilar competition in Canada within the next 3 years, with a potential to generate substantial savings. “However, for a health care system to realize these cost savings, successful market uptake of biosimilars will depend on various factors, such as number and timing of entrants into the market, patient and health care provider’s understanding and acceptance of biosimilars versus biologics, cost of biosimilars, pricing policies, payer coverage and utilization policies, and policies around interchangeability and substitution,” wrote CADTH, and the report seeks to identify the international policies best suited to providing a context favorable to biosimilar use.

The report’s authors relied on literature in Medline, Embase, PubMed, and the Cochrane Library, and present findings on 4 postmarket-related policies for the United States, Australia, New Zealand, Finland, France, Germany, the Netherlands, Norway, and the United Kingdom. 

Interchangeability, Switching, and Substitution

While the United States is the only nation to hold a legal definition of interchangeability that guides pharmacy-level substitution, a variety of other policies exist worldwide. In the United Kingdom, switching is managed at the providers’ discretion, and substitution at the pharmacy level is not recommended. In Germany, prescriber-led switching is encouraged. In France, patients can be switched at any time, but pharmacy-level substitution can only take place for treatment-naïve patients and with notification to the prescriber. The Netherlands permits new patients to receive biosimilars immediately, but leaves the decision to switch to prescribers. Norway similarly leaves the decision to switch to prescribers, but considers switching among reference products and biosimilars safe at any time in treatment. While automatic substitution is not permitted in Finland, switching among biosimilars and the reference at any time is permitted so long as documentation is provided. In Australia, the government actively encourages the use of biosimilars for treatment-naïve patients, and physicians may choose to switch established patients. Pharmacy-level substitution is permitted for 

. No substitution is permitted in New Zealand, where the decision to switch remains with the clinician.

Free pricing policies are in place for biosimilars in the United States and United Kingdom, but UK policies subject biosimilars to the Pharmaceutical Price Regulation Scheme, which sets price ceilings. The UK system also makes use of tendering procedures in both the outpatient and hospital pharmacy contexts.

, the costs for biosimilars cannot exceed the cost of the reference biologic, and insurance plans can negotiate prices through tenders. German patients also must pay the difference between the retail price and the reference reimbursement price, incentivizing patients to choose cheaper products. 

In France, biosimilar prices are negotiated between pharmaceutical companies and the government, with a compulsory discount on biosimilars that ranges from 10% to 20%. The Netherlands uses a reference pricing system for biosimilars, setting the price of the biosimilar at the same price as the reference. However, tenders are used to generate further discounts. In Norway, the price of a biosimilar cannot exceed that of the reference, and mandatory discounts increase with time and the number of market entrants. Finland caps the price of the first reimbursable biosimilar at a 30% discount to the reference, and the prices of the reference biologics are renegotiated once a biosimilar has launched. 

Beginning in October 2018, Australia put in place a mandatory discount of 25% on the price of the reference when a biosimilar is introduced. As an incentive to prescribe cheaper drugs, pharmacists are currently allowed to keep the difference when dispensing medicines that are cheaper than the government’s reimbursement price.

While no prescribing incentives are in place in the United States, new Medicare Part B reimbursement rules could provide an indirect incentive to physicians to prescribe biosimilars. Meanwhile, in the United Kingdom, providers and clinical commissioners have entered into 

 agreements that allow health systems to keep a portion of cost savings from using biosimilars. Germany uses a similar approach, and also sets national, regional, and local prescribing quotas for some biosimilars. Additionally, German physicians who exceed their pharmaceutical budget substantially must repay the amount about 115% if no justification can be provided.

France is expected to implement a new framework to promote biosimilars by setting up new contracts with hospitals, but currently, no specific policies are in place. By contrast, Finland and Norway compel physicians to choose the least expensive products. 

Australia offers a faster and simpler preapproval process for biosimilars while maintaining higher requirements for reference biologics, although prescribers remain in control of which drugs are prescribed.

In the United States, both the FDA and industry are engaged in efforts to educate stakeholders, and likewise, the European Medicines Agency has published a 

The United Kingdom has also produced a commissioning framework for biologic medicines, and drug-specific clinical practice guidelines also facilitate the use of biosimilars. In Germany, France, Norway, and the Netherlands, specific educational programs focus on physician awareness. In Australia, the government has launched an awareness initiative that targets both providers and patients. 

While the report identified a number of policy options for the Canadian healthcare system, wrote CADTH, “Whether similar policy mechanisms can be applied in the Canadian setting will depend on a complex interplay of factors and the coordinated engagement of a number of stakeholders.”

The Canadian Agency for Drugs and Technologies in Health, the Canadian entity responsible for health technology assessments (HTAs), has released a new report that explores international policies related to biosimilars and the factors that facilitate their use.

Canada's HTA Body Releases Report on International Biosimilar Policies

Asian news media are reporting that Republic of Korea—based Celltrion has won a court decision that declared patents on Roche’s Herceptin invalid in Japan. The decision, 

Pulse, clears the way for Celltrion to market its trastuzumab biosimilar, Herzuma, for breast cancer in Japan.

Celltrion and its Japanese distribution partner Nippon Kayaku 

 the biosimilar in the Japanese market in August 2018, but only for the indications of HER2-positive gastric cancers, for which it was approved by Japan’s Ministry of Health. 

 that Celltrion will now seek an indication for the treatment of breast cancer, and that the company believes it can obtain approval for this indication by early 2019. 

 in the European Union in February 2018, where it is also marketed under the brand name Herzuma. The product is not yet authorized in the United States, however, as Celltrion received a Complete Response Letter (CRL) for the drug in April 2018 from the FDA.

The CRL came after Celltrion had received the FDA’s 

 in 2017. Then, in February 2018, Celltrion received a 

 from the agency related to its manufacturing processes. The drug maker has since 

 the product to the FDA for approval, and a regulatory decision is expected by the end of 2018.

However, despite the resubmission, Celltrion continues to face legal battles over the biosimilar in the United States. In January 2018, Celltrion and its partner Teva sought a declaratory judgment of noninfringement against Roche’s Genentech. In May 2018, Genentech was successful in its own request for the court to 

Also in January, Genentech filed its own complaint against Celltrion and Teva, alleging that the partnership had infringed 40 patents. In June, Genentech moved to dismiss certain counterclaims, and in July, it filed a 

 that alleged infringement of the same 40 patents covering Herceptin.

Republic of Korea-based Celltrion has won a court decision that declared patents on Roche’s Herceptin invalid in Japan.

Eye on Pharma: Celltrion Wins Japanese Trastuzumab Case

While US patients with HER2-positive cancers do not have an available subcutaneous (SC) trastuzumab option, Brazil, Canada, and the European Union have an approved product that has been shown in a phase 3 trial to be noninferior to intravenous (IV) trastuzumab. 

This product has substantial benefits related to 

, but it also has benefits for trastuzumab’s sponsor, Roche, as there are no approved biosimilars of the SC formulation to compete with this product.

the SC trastuzumab contains the same monoclonal antibody as the intravenous formulation at a dose of 600 mg per 5-mL vial, plus a recombinant human hyaluronidase, to be used every 3 weeks. The hyaluronidase is used to increase the permeability of the extracellular matrix, allowing for administration of higher volumes and enhanced absorption. 

The SC formulation had a similar safety profile to the IV formulation in the phase 3 HannaH study, but serious adverse events (AEs) were more common with the SC trastuzumab than the IV product (21.0% vs 12.0%; 

 value not reported). Antidrug antibodies (ADAs) were reported in 7.1% of patients receiving the IV product and 14.6% of those receiving the SC product, but the elicited ADAs were deemed to have no clinical relevance as they were non-neutralizing and did not impact the pharmacokinetic profile of trastuzumab.

However, one of the main concerns with trastuzumab’s biological activity is its interaction with pertuzumab to treat HER2-positive cancer, and interactions among HER2 receptor, pertuzumab, and trastuzumab—ADA complexes have not yet been fully evaluated. The phase 3 SAPPHIRE study did evaluate the safety, tolerability, and efficacy of IV pertuzumab plus SC trastuzumab and a taxane, but the small population enrolled in the study made it difficult to draw conclusions. 

According to the paper’s authors, it also remains unclear whether, in the case of a tumor recurrence, patients who had received the SC product would have more long-lasting memory ADAs, or whether this would impact the safety and efficacy of a subsequent line of treatment using IV trastuzumab and pertuzumab. 

Pimentel FF, Morgan G, Tiezzi DG, de Andrade JM. Development of new formulations of biologics: expectations, immunogenicity, and safety for subcutaneous trastuzumab. 

. 2018;32(5):319-325. doi: 10.1007/s40290-018-0247-5.

While US patients with HER2-positive cancers do not have an available subcutaneous trastuzumab option, Brazil, Canada, and the European Union have an approved product that has been shown in a phase 3 trial to be noninferior to intravenous trastuzumab. 

Paper Raises Unanswered Questions About Subcutaneous Trastuzumab

After previous US regulatory setbacks, Coherus Biosciences has gained FDA 

 for its pegfilgrastim biosimilar, Udenyca (pegfilgrastim-cbqv). 

The biosimilar, referencing Neulasta, has been approved to decrease the incidence of infection, as manifested by febrile neutropenia, in patients receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia.

“We are excited to announce that Coherus has received FDA approval for Udenyca. I want to thank the Coherus team, our strategic partners, and the [FDA] for this extraordinary achievement,” said Denny Lanfear, chairman, CEO and president of Coherus BioSciences. “The list price of Neulasta has nearly tripled since approval in 2002 and now represents a $4 billion annual cost burden in the US. We believe that competition is essential in controlling burdensome price increases, and Udenyca will play an important role in curbing that spend when launched,” he added. 

The company will provide more details on pricing and a launch date on its November 8 earnings call. 

Udenyca was also authorized for marketing in the European Union in September of this year after having received a positive 

 from the European Medicines Agency’s Committee for Human Use in July 2018. 

Today’s news marks a major milestone for Coherus and for Udenyca, which has had a difficult road to approval. After its first filing of a Biologics License Application for the biosimilar, Coherus revealed in June 2017 that the FDA had issued a Complete Response Letter (CRL) for the drug, requesting that the company provide additional manufacturing information as well as a reanalysis of a subset of samples with a revised immunogenicity assay. 

The company was hit hard by the CRL, terminating 30% of its workforce in a bid to shave $10 million from its operating costs as it worked to meet the FDA’s requests. Having completed its reanalysis of the immunogenicity assay—and having raised new funds through a private placement 

 with Temasek—Coherus resubmitted its BLA in May 2018. 

While Coherus worked toward resubmission, it also 

 a key legal battle in its bid to bring its biosimilar to market; in March 2018, a Delaware court judge granted Coherus’ motion to dismiss a lawsuit brought by Amgen over alleged infringement of US patent 8,273,707 (which covers the reference Neulasta), helping to clear the way for the product to launch in the United States. 

Udenyca joins 1 other pegfilgrastim biosimilar in the ranks of United States approvals; Mylan's Fulphila is also approved, and 

After previous US regulatory setbacks, Coherus Biosciences has gained FDA approval for its pegfilgrastim biosimilar, Udenyca (pegfilgrastim-cbqv).