The Center for Biosimilars Staff

Our latest infographic provides 3 key takeaways from the 

American Society of Hematology's (ASH) 59th Annual Meeting and Exposition.

Articles

Our latest infographic provides 3 key takeaways from the American Society of Hematology's (ASH) 59th Annual Meeting and Exposition.

Infographic: 3 Takeaways About Biosimilar Filgrastim from the 2017 ASH Meeting

Hi, I’m Kelly Davio 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 biosimilars articles for the week of December 4.

modeling and simulation may allow for better decision making

 that can increase the likelihood of successful outcomes in biosimilar development.

Number 4: At the American Society of Hematology’s 59th Annual Meeting and Exposition in Atlanta, Georgia, a research team will present findings that community-based lymphoma care is 

associated with guideline-discordant use of rituximab.

Number 3: Rival insulin makers Novo Nordisk and Sanofi both 

announced positive data on their products

 that could help them to stave off biosimilar and follow-on competition.

savings generated from the use of biosimilar filgrastim

Number 1: A new report from the National Academy of Sciences, Engineering, and Medicine 

calls for big changes in how US pharmaceuticals are priced, promoted, and sold

, so that treatments are more affordable and equally available to all Americans.

Finally, last week, our e-newsletter asked whether you think prescribers, patients, or payers are the key drivers of biosimilar uptake. To see results of the poll, visit us on 

To read all of these articles and more, visit centerforbiosimilars.com.

The Center for Biosimilars recaps the top 5 articles for the week of December 4. 

The Top 5 Biosimilars Articles for the Week of December 4

USV has announced that the European Medicines Agency (EMA) has accepted for review its application for a proposed pegfilgrastim biosimilar.

 that the Mumbai-based USV hopes to market the pre-filled syringe presentation of its pegfilgrastim biosimilar under the brand name Grasustek.

Prashant Tewari, MD, managing director of USV, told Express Pharma that “We are happy with the acceptance of our [application] by the EMA. USV has achieved a very significant milestone in the development program of Grasustek. We intend to provide high quality, affordable therapy options for cancer patients. We believe that Grasustek has potential life as well as cost-saving benefits for these patients.”

Filing of the application follows USV’s September 2017 

 that it had successfully completed phase 1 and phase 3 studies on the proposed therapy. The phase 1 study compared the pharmacokinetics and pharmacodynamics of the biosimilar with the reference Neulasta at both a therapeutic dose and a low dose, and the phase 3 study followed 254 patients with breast cancer who were scheduled to undergo chemotherapy.

 that, in addition to its clinical program to support submission of its application to the EMA, the company has begun planning for phase 1 development in the United States, and has held relevant meetings with the FDA. In India, USV has received approval to initiate phase 3 clinical studies for the proposed product.

USV joins fellow Indian drug maker Biocon in 

 to receive the first European authorization for a pegfilgrastim biosimilar; Biocon announced in November 2017 that the EMA had accepted its resubmitted marketing authorization applications for a pegfilgrastim and a trastuzumab candidate (the recently FDA-approved 

). Biocon had previously withdrawn its applications from the EMA to allow for a re-inspection of its manufacturing facility.  

 biosimilars for somatropin, teriparatide, platelet-derived growth factor, filgrastim, glucagon, and epidermal growth factor.

European Medicines Agency to Review USV's Proposed Pegfilgrastim Biosimilar

Neutropenia, a primary cause of delays, interruptions, and dose reduction to chemotherapy, can compromise both patient survival and complete response rates. Granulocyte colony-stimulating factors (G-CSFs), including tbo-filgrastim (Granix), can reduce the incidence, duration, and severity of febrile neutropenia in patients who are receiving chemotherapy. However, drugs like tbo-filgrastim (a follow-on filgrastim product that was approved before the United States had instituted a regulatory pathway for the approval of biosimilar products under the Biologics Price Competition and Innovation Act) can cause serious immune reactions. 

The production of anti-drug antibodies (ADAs) can have negative consequences for patients, including such reactions as anaphylaxis, reduced efficacy, and the neutralization of endogenous counterparts by cross-reactive neutralizing antibodies. A new study, conducted by Linglong Zou, PhD, and colleagues, evaluates the immunogenicity of tbo-filgrastim in patients receiving chemotherapy for solid and hematologic malignancies.

 The research team’s data will be presented at the American Society of Hematology’s 59th Annual Meeting and Exposition in Atlanta, Georgia, on Sunday, December 10, 2017.

Zou and his team collected blood samples during 3 different phase 3 clinical studies that compared the efficacy and safety of tbo-filgrastim with filgrastim and/or placebo administered 1 day after chemotherapy for a duration of 5 to 14 days. The team implemented a 3-tier approach—including screening, confirmation, and a titer assay&mdash;to evaluate binding ADAs for tbo-filgrastim using a validated homogeneous enzyme-linked immunosorbent assay. Neutralizing activity was assessed for confirmed-positive ADA test samples using a validated cell-based proliferation assay. Clinical measures were examined for all patients who had confirmed ADAs in order to assess a possible correlation between ADAs and the potential clinical impact of immunogenicity.

In total, 436 patients who had been diagnosed with cancer and who had received tbo-filgrastim were assessed for immunogenicity of the follow-on filgrastim product. These patients had breast cancer (n = 213), lung cancer (n = 160), and non-Hodgkin’s lymphoma (n = 63).

Only 3 patients with breast cancer developed ADAs at a low titer, and none of the samples showed cross-reactivity to endogenous G-CSF or neutralizing antibody activity. Three patients with lung cancer developed ADAs at a low titer, but none of the ADA-positive samples cross-reacted with endogenous G-CSF, and 1 pre-dose sample showed neutralizing antibody activity in cycle 1 prior to tbo-filgrastim treatment. Among the patients with non-Hodgkin’s lymphoma, 1 patient developed ADAs at a titer too low to be determined. No cross-reactivity or neutralizing antibody activity were associated with this patient’s blood sample. Overall, immunogenicity incidence was 1.6% among all of the patients tested, and none of the patients with positive ADA samples showed evidence of hypersensitivity, anaphylaxis, or a loss of treatment efficacy.

The researchers concluded that the incidence of immunogenicity or treatment-emergent ADAs in patients receiving chemotherapy and tbo-filgrastim was low across the 3 cancer populations tested, and that all positive samples had low-titer ADAs. None of the positive samples had cross-reactive ADAs to endogenous G-CSF, and none of the patients with positive ADA samples had clinically relevant immunogenicity-related symptoms during the study period.

1. Zou L, Buchner A, Field J, Barash S, Liu P. Immunogenicity assessment of tbo-filgrastim in cancer patients receiving chemotherapy. Presented at the American Society of Hematology 59th Annual Meeting and Exposition, December 10, 2017; Atlanta, Georgia. Abstract 2274. 

https://ash.confex.com/ash/2017/webprogram/Paper99985.html

A new study, conducted by Linglong Zou, PhD, and colleagues, evaluates the immunogenicity of tbo-filgrastim in patients receiving chemotherapy for solid and hematologic malignancies.

Study Shows Low Incidence of Immunogenicity With Tbo-Filgrastim

Lucentis (ranibizumab) faces oncoming competition from 4 companies that are developing proposed biosimilars. 

Infographic: Which Companies are Developing Ranibizumab Biosimilars?

Hi, I’m Kelly Davio 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 biosimilars articles for the week of November 27.

Number 5: The World Health Organization has a released a new report that estimates that 

1 in 10 drugs worldwide is either falsified or substandard

, leading to unnecessary deaths and increased costs to patients and health systems. 

Number 4: German drug maker Formycon projects that its biosimilar challenger to Lucentis will be 

 devoid of meaning, to the nonproprietary names of newly approved biologics.

explains the potential impact of CMS’ proposed rule

 that would treat biosimilars as generic drugs for the purpose of cost-sharing under Medicare Part D.  

The FDA has approved Mylan and Biocon’s trastuzumab biosimilar,

Finally, last week, our e-newsletter asked whether you think that innovative device design will play a role in reference product sponsors’ defense strategies against biosimilar competition. To see results of the poll, visit us on 

The Center for Biosimilars recaps the top 5 articles for the week of November 27.

The Top 5 Biosimilars Articles for the Week of November 27

The European Union has swiftly outpaced the United States in the number of biosimilar therapies that it has approved for marketing; the FDA has only approved 7 biosimilars to date, though many additional molecules are being developed with the US market in mind. Because biosimilars are relatively new to the United States, drug makers pursuing FDA approval for biosimilars seek additional information about the kinds and quantities of evidence that the agency uses to approve these therapies.

Journal of Managed Care and Specialty Pharmacy

, assesses the evidence that was used in the first 5 biosimilar approvals: filgrastim-sndz (Zarxio), infliximab-dybb (Inflectra), adalimumab-atto (Amjevita), etanercept-szzs (Erelzi), and infliximab-abda (Renflexis). The review draws on data derived from drug-specific FDA approval documents, webcasts, and advisory committee votes; reference product information; evidence used for the extrapolation of indications; and evidence used to demonstrate similarity in terms of analytic and functional characteristics, pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety, and immunogenicity.

The review’s authors identified 6 key issues from their data:

The types of evidence that the FDA evaluated when approving each product ranged from many analytical studies to few clinical studies. The researchers note that this finding is reflective of the agency’s “totality of the evidence” approach to demonstrating biosimilarity.

All manufacturers used 3-way bridging studies (which allow a biosimilar developer to use data from a product licensed in another locality to indirectly demonstrate similarity between the proposed molecule and a US-licensed drug) when seeking the FDA’s approval.

Many indications of the approved biosimilars were granted on the basis of extrapolation, the scientific justification for which often includes the mechanism of action in each indication for which licensure is sought. PK and immunogenicity in different patient populations, as well as the toxicity profile for each indication and patient population, are also often included in the scientific justification.

The majority of formulations of approved biosimilars were the same (or nearly the same) as those of their references, a finding that may bear a relationship to the FDA’s position that biosimilars with formulations not identical to those of the reference may not be granted interchangeable status. Some discrepancies existed, however, such as Amjevita’s auto-injector device that contrasted with the reference Humira’s pre-filled pen, and the presence of a needle guard for Erelzi.

The biosimilars were not always approved for all indications of their reference products for 2 reasons: first, some reference drugs were granted new indications after biosimilar approval, and second, some reference product indications were protected by marketing exclusivity.

None of the approved biosimilars were granted an interchangeable status, since the FDA has not yet finalized its process for demonstrating interchangeability.

Finally, the authors note that FDA advisory committee meetings may be slowing the process of biosimilar approval, and suggest that only those biosimilars that have “specific issues” that would warrant convening a committee be subject to such proceedings. The review identifies a second challenge specific to US biosimilar uptake: the long interval between product approval and market availability, which is a phenomenon largely tied to lengthy patent litigation between reference product sponsors and biosimilar developers.  

Because biosimilars are relatively new to the United States, drug makers pursuing FDA approval for biosimilars seek additional information about the kinds and quantities of evidence that the agency uses to approve these therapies.

Systematic Review Identifies 6 Trends in US Biosimilar Approvals

This week, the Supreme Court of the United States heard oral 

Oil States Energy Services, LLC v Greene’s Energy Group, LLC, 

a case that asks the court to decide whether inter partes review (IPR), a proceeding before the US Patent Trial and Appeal Board that provides for the review of 1 or more claims of a patent, is constitutional.

 from a dispute over a patent held by an oilfield service company on equipment used in hydraulic fracturing, the court’s decision will have far-reaching implications for biosimilar stakeholders; the IPR process is 

 used by biosimilar developers to challenge patents for reference biologics, especially such blockbuster drugs as Rituxan (rituximab) and Herceptin (trastuzumab).

argued that patents can only be revoked by a federal court decision, and that IPR proceedings, which were 

 by Congress as part of the America Invents Act as a means to address patent reviews, violate an entity’s constitutional right to have challenges heard before a federal jury.

Arguing for Greene’s Energy Group, Christopher Kise argued that IPRs simply reexamine whether a patent should have been issued initially, and that IPRs do not involve the exercise of judicial power.

 that the outcome of the case is difficult to predict (some justices asked numerous questions while others asked none at all), and suggested that Justice Kennedy’s vote in the matter may be significant to the eventual decision.

Biosimilars stakeholders will be watching the case closely in the coming days; in a recent interview, attorney Robert Cerwinski 

 that “IPRs have been one of the main tools in the tool kit of biosimilar applicants to try to clear a path for biosimilars to market.” He added, “The upshot is, if in fact the law that created IPRs is governed to be unconstitutional, Congress is going to have to take another shot at either modifying or redoing the statute that created IPRs. So, the potential impact on biosimilar applicants from having the IPR scheme eliminated entirely will be quite significant…there is a risk that the IPR world as we know it could change in the near term.”

This week, the Supreme Court of the United States heard oral arguments in Oil States Energy Services, LLC v Greene’s Energy Group, LLC, a case that asks the court to decide whether inter partes review (IPR) is constitutional.

SCOTUS Hears Case That Could End IPRs for Biosimilar Developers

German drug maker Formycon released its third quarter financial 

 on Monday, and reported that it plans to launch its biosimilar ranibizumab candidate, FYB201, in the United States in 2020.

Formycon says that FYB201, referenced on Roche’s Lucentis, is the world’s only biosimilar candidate for ranibizumab that has progressed to a phase 3 clinical trial, and that “an innovative application system underpinned by the company’s own patent applications” puts the drug maker in a “highly promising position” to capture a share of the market for anti—vascular endothelial growth factor (anti-VEGF) therapy for eye disorders.

If approved in the US marketplace, Formycon’s drug will compete with Lucentis, which is approved to treat neovascular age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization. Lucentis has already faced significant 

 from another anti-VEGF therapy, Regeneron’s Eylea (aflibercept), which some investors 

 could earn up to $5 billion in sales by 2023.

Formycon is also taking aim at Eylea; the biosimilar developer 

 that it is in the preclinical development phase with FYB203, a biosimilar aflibercept candidate. Formycon says that it is currently completing measures to establish its manufacturing process for the drug, and predicts that it is on track to launch a biosimilar in the US marketplace when Eylea reaches US patent expiry in 2023.

The company is also undertaking development of biosimilars to treat other conditions; Formycon is currently developing FYB202, a proposed ustekinumab biosimilar. The molecule, referencing Stelara, is a human interleukin-12 and -23 antagonist that, if approved for all indications of the reference product, will treat moderate to severe plaque psoriasis in adults and adolescents, active psoriatic arthritis, and moderately to severely active Crohn’s disease. Formycon is developing its biosimilar candidate under a partnership with Santo Holding GmbH; under the companies’ agreement, Formycon is contributing 30% of development costs to this project.

German drug maker Formycon released its third quarter financial results on Monday, and reported that it plans to launch its biosimilar ranibizumab candidate, FYB201, in the United States in 2020.

Formycon Projects US Biosimilar Ranibizumab Launch in 2020

Biologics are increasingly used in the treatment of inflammatory bowel disease (IBD), but real-world data quantifying the costs of these therapies have been lacking. A new study, 

Alimentary Pharmacology and Therapeutics, 

sought to determine trends in costs and relative market share of IBD therapies in the United States over the past 9 years.

Drawing from de-identified outpatient, inpatient, and pharmaceutical claims for approximately 40 million to 50 million patients in the Truven MarketScan Commercial Claims and Encounters database for the years 2007 to 2015, the researchers included patients with IBD diagnoses and at least 1 pharmaceutical claim during the study period.

The study cohort comprised 415,405 patients; 188,842 patients had Crohn’s disease (CD), 195,183 patients had ulcerative colitis (UC), and 31,380 patients had indeterminate colitis (ID). During the 9-year period, among patients with CD:

The proportion of patients who used biologics increased from 21.8% to 43.8%

The proportion of patients who used immunomodulators decreased from 27.2% to 18.0%

The proportion of patients who used 5-aminosalicylic acid (5-ASA) therapies decreased from 34.1% to 21.6%

The proportion of patients using biologics increased from 5.1% to 16.2%

Immunomodulator use decreased slightly, from 17.1% to 13.7%

5-ASA use also decreased slightly, from 59.0% to 53.7%

Patients who used corticosteroids only remained largely stable in both populations (CD: 16.9% versus 16.6%; UC: 18.8% versus 16.2%).

Utilization trends show a consistent rise in biologics’ market share; from 2007 to 2015, use of biologic therapies increased from 13.7% to 30.1%. A pediatric subgroup analysis showed an even sharper rise in biologics use, from 19.1% in 2007 to 45.9% in 2015.

The cost of biologic therapy also rose over the study period; in 2007, the average patient taking biologic therapy accounted for $25,275 in per-member per-year costs (a value comprising the costs paid by a patient's health plan plus the patients’ copay and deductible amounts). In 2015, that amount rose to $36,051. Pediatric patients’ costs grew even more, from an average $23,616 to $41,109. These cost trends for biologics “greatly exceed” the cost trends for other drugs that treat IBD, including immunomodulators, 5-ASAs, or corticosteroids.

“From a clinician perspective, corticosteroid-sparing therapy plans are evidence-based and necessary to optimize long-term health outcomes, maximize quality of life, and minimize opportunity loss,” the authors write. However, the increases in cost associated with biologic therapies are only expected to continue for US patients with IBD. “The findings from our study further reiterate the ongoing need to develop patient-centered, cost-effective pharmacotherapy strategies by judiciously incorporating biologics in individualized therapy plans.

Biologics are increasingly used in the treatment of inflammatory bowel disease (IBD), but real-world data quantifying the costs of these therapies have been lacking. A new study, published in Alimentary Pharmacology and Therapeutics, sought to determine trends in costs and relative market share of IBD therapies in the United States over the past 9 years.