The Center for Biosimilars Staff

Sagent Pharmaceuticals, a division of Nichi-Iko Pharmaceutical Co Ltd, announced earlier this month that it has purchased an FDA-approved manufacturing site in Raleigh, North Carolina, from Xellia Pharmaceuticals.

The site is capable of approving both small-molecule drugs and biologics. While Sagent’s chief executive officer (CEO), Peter Kaemmerer, PhD, 

 in a statement that while it intends to continue to manufacture some products for Xellia, the acquisition of the Raleigh site “will enable production of lyophilized formulations of our future biosimilar product offerings.”

Yuichi Tamura, president and CEO of Nichi-Iko, said in a statement, “We applaud this acquisition as another big step forward for Nichi-Iko and Sagent, further strengthening our competitiveness and capabilities in the key US market. The acquisition of this manufacturing facility, our first in the [United States], will have an important role as we strive to fulfill our mission of providing value-added, high quality generic products which meet the needs of patients and their families in the global market.”

Nichi-Iko has already begun its foray into biosimilars; the company received approval for its biosimilar infliximab, NI-071, in Japan in 2017, and subsequently began a phase 3 clinical program in the United States with an eye toward eventual FDA approval. The company also 

 that it has consulted with the FDA concerning a demonstration of interchangeability for the biosimilar with the reference infliximab, Remicade.

Furthermore, in June 2018, the company announced that it had forged a 

 with Lupin for the distribution, promotion, and sale of a proposed etanercept biosimilar, YLB113, in Japan. In the Republic of Korea, Nichi-Iko’s Aprogen affiliate last year 

 construction of a biologics production facility to provide a stable supply of biosimilars for the US and Japanese markets.

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Eye on Pharma: Sagent Acquires US Site to Manufacture Nichi-Iko Biosimilars

This week, Novartis announced that Richard Francis, chief executive officer (CEO) of the company’s Sandoz division, will step down on March 31.

In a statement, Novartis’ CEO, Vas Narasimhan, thanked Francis for his work over the past 5 years, and highlighted the fact that Sandoz had become a global leader in biosimilars under Francis’ leadership.

Francis, also in a statement, said that he was particularly proud of Sandoz’s successful launch of 5 biosimilars. He signaled that his reason for resigning is personal in nature, saying, “As we announced earlier this year, Sandoz is embarking on a significant transformation. While I am excited by this, I realize that this is a multi-year journey which I cannot commit to and therefore have decided that now is the right time to step down."

Francis will be replaced by an interim CEO, Francesco Balestrieri, MBA, who is currently the region head of Sandoz in Europe. Balestrieri has spent the last 8 years heading up commercial operations related to Sandoz’s generic drugs.

"I would like to thank Francesco for stepping up to take on this role. His leadership approach and business experience will be of great importance as we continue the Sandoz transformation,” said Narasimhan.

In 2018, Novartis signaled that it would shift Sandoz’s focus; 

 reported that Narasimhan told analysts that “When you think about how we’re going to drive Sandoz moving forward, a lot of it is about executing a strategy of transformation and shifting the focus to complex generics and biosimilars.”

 rumors that it planned to spin off the Sandoz unit, saying that Sandoz would remain a pillar of the company.

This week, Novartis announced that Richard Francis, chief executive officer (CEO) of the company’s Sandoz division, will step down on March 31.
 

Sandoz's CEO Stepping Down This Month

Biosimilar developer Celltrion last year 

 that it was ready to begin a phase 3 study of its proposed bevacizumab biosimilar, CT-P16, an anti—vascular endothelial growth factor referencing Avastin. This month, researchers are 

 on a phase 1 study that showed equivalent pharmacokinetics (PK) between the proposed biosimilar and its EU- and US-licensed reference products.

In the double-blind, parallel-group trial, 144 healthy adult male volunteers were randomized to receive a single dose of CT-P16 (n = 47) at 5mg/kg, or the same dose of either EU-licensed (n = 49) or US-licensed (n = 48) reference bevacizumab.

The primary end points were area under the concentration—time curve (AUC) from time zero to infinity (AUC

), AUC from time zero to the last quantifiable concentration (AUC

PK equivalence was demonstrated if the 90% CIs of the geometric mean (GM) ratios of AUC

 fell within the prespecified bioequivalence margin of 80% to 125%.

The investigators report that the 90% CIs for the GM ratios of all 3 end points fell within the prespecified bioequivalence margin, and the mean serum concentration—time profiles, secondary PK parameters, safety, and immunogenicity profiles were also comparable across all 3 groups.

According to the investigators, these data support the further development of CT-P16 as a bevacizumab biosimilar.

In addition to Celltrion, multiple biosimilar develoeprs are targeting bevacizumab, which is used to treat metastatic colorectal cancer, metastatic breast cancer, non—small cell lung cancer, and glioblastoma, and which is also increasingly used 

 to treat diseases of the eye, including diabetic retinopathy and age-related macular degeneration. 

 have all disclosed clinical programs for proposed bevacizumab biosimilars; Amgen has seen both US and EU approval for its biosimilar, Mvasi, and Pfizer has received EU approval for its biosimilar, Zirabev. To date, no biosimilars for bevacizumab have been launched.

Cho SH, Han S, Ghim JL, et al. A randomized, double-blind trial comparing the pharmacokinetics of CT-P16, a candidate bevacizumab biosimilar, with its reference product in healthy adult males [published online March 9, 2019]. 

According to the investigators, their data support the further development of CT-P16 as a bevacizumab biosimilar.

Positive Results for Celltrion's Proposed Biosimilar Bevacizumab in Phase 1 Trial

The new acting chief of the FDA, Ned Sharpless, MD, has a track record with the biotechnology industry and a friendly relationship with the man he is replacing, Scott Gottlieb, MD.

Sharpless, an oncologist, co-founded 2 clinical-stage biotech companies, which he sold his shares in before becoming head of the National Cancer Institute (NCI) in 2017. The companies, G1 Therapeutics, which has a pipeline of breast cancer and non—small cell lung cancer drugs, and Sapere Bio, which studies the science of aging, reflect his interests.

Before joining the NCI, he was director of the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center. He also received his medical degree from the UNC School of Medicine and completed his internal medicine residency at the Massachusetts General Hospital and a hematology/oncology fellowship at Dana-Farber/Partners Cancer Care, both of Harvard Medical School.

Given his interests, as well as his efforts to streamline the work of the NCI, some observers believe Sharpless will be friendly to the biotech sector.

Writing in Barron’s this week, Kevin Hrusovsky, founder and chairman of Powering Precision Health, noted his background and said, “investors in biotech should be buoyed by his nomination to be the next FDA Commissioner. Based on what we know of him, he will be as friendly to the sector as his predecessor.”

How he feels about biosimilars is a little less clear, but one stakeholder expressed optimism.

In a statement emailed to The Center for Biosimilars

, The Biosimilars Forum said it “looks forward” to working with Sharpless to strengthen the US biosimilars program, improve guidelines to combat misinformation, and optimize approval processes. These areas will improve patient access to biosimilars and help realize billions of savings to the US healthcare system, said the forum.

In a statement about his appointment to the FDA, Sharpless said he will “build on its progress toward the priorities laid out by President Trump, Secretary Azar, and Commissioner Gottlieb alongside the leadership and staff of the agency.”

Sharpless is also said to have been supportive of Gottlieb’s 2 other priorities: cracking down on teen vaping with increased regulation of e-cigarettes, as well as tobacco.

 between the FDA and NCI, including in oncology, workforce development, and pediatric cancer.

Sharpless became head of the NCI in 2017. He is also chief of the Aging Biology and Cancer Section in the National Institute on Aging’s Laboratory of Genetics and Genomics, where he continues his research on the biology of the aging process that promotes the conversion of normal self-renewing cells into dysfunctional cancer cells.

New Acting Chief of FDA Has Roots in Oncology, Biotech

Ankylosing spondylitis (AS) may be treated with anti—tumor necrosis factor (anti-TNF) agents, but primary treatment failure, loss of response over time, or adverse events can prompt discontinuation. Previous 

 has also shown that women with AS have lower anti-TNF treatment retention than men with AS. Recently, a new study sought to examine treatment patterns in US patients new to anti-TNF therapy, and it found that a majority of patients, particularly women, do not remain on their first anti-TNF after 2 years.

The observational, retrospective, cross-sectional 

 was based on data from the IBM MarketScan Research database, which includes deidentified data for more than 50 million covered lives. Adults with AS who had at least 1 claim for an anti-TNF between 2009 and 2013 were included in the cohort.

In total, 1374 patients met the inclusion criteria; 61.7% were male, and the mean age was 43.8 years. Most patients (91.3%) had commercial insurance.

The patients started treatment with adalimumab (44.1%), etanercept (40.9%), infliximab (10.6%), golimumab (4.3%), and certolizumab pegol (0.1%). During the 2-year followup period, only 33.1% of patients were still using their first anti-TNF, whereas 40.7% had discontinued and did not start another anti-TNF and 26.1% switched to a second anti-TNF. Among those who switched, 20.1% went on to switch to a third anti-TNF.

In total, during the 2-year follow-up, 32.6% of men persisted on their first anti-TNF versus 22.8% of women.

Patients who were prescribed conventional disease-modifying antirheumatic drugs were more likely to be persistent on their first anti-TNF. Women and patients treated with opioids were less likely to be persistent on their first anti-TNF and were also more likely to switch to another.

The investigators note that, during the study period, interleukin-17 inhibitors were not available, so it is not possible to know whether switching to such options would have impacted the observed treatment patterns.

More research is needed, they write, to understand the reasons for nonpersistence and the increasing trend of second-line anti-TNF use among patients with AS.

Hunter T, Schroeder K, Sandoval D, Deodhar A. Persistence, discontinuation, and switching patterns of newly initiated TNF inhibitor therapy in ankylosing spondylitis patients in the United States [published online March 5, 2019]. 

Recently, a new study sought to examine treatment patterns in US patients new to anti–tumor necrosis factor (anti-TNF) therapy, and it found that a majority of patients, particularly women, do not remain on their first anti-TNF after 2 years.

Most Patients With AS Stop Their First Anti-TNF Therapy by Year 2, Study Finds

The Trump administration has released its proposed budget for the fiscal year 2020, and contained within it are a variety of proposals that impact biosimilars.

The fact that the House of Representatives is under Democratic control means that it is highly unlikely that the budget will be approved, but the document does give signals as to the administration’s developing position on biosimilars.

 of the budget hails the FDA’s record-breaking number of biosimilar approvals in 2018, and credits the FDA with helping to promote efficient, predictable, and science-based regulatory requirements that will help to reduce the time it takes to develop biosimilars.

It goes on to put forth the following proposals for advancing the Biosimilar Action Plan and promoting competition in the coming year:

Creating disincentives for pay-for-delay agreements. 

 agreements are those in which in which brand-name drug makers compensate generic or biosimilar developers if they agree to keep their competitive products off the market for a certain period of time. The budget proposes reducing the payment for innovator drugs from average sales price (ASP) plus 6% to ASP minus 33% in cases in which a pay-for-delay agreement is made or in which a manufacturer “takes another anti-competitive action” after exclusivity expires. Once biosimilars become available for innovator biologics, CMS would pay ASP plus 6% for both the innovator and biosimilar products.

Amending the Public Health Service Act to state that biologics do not have to meet the same United States Pharmacopeia standards as non-biologic drugs.

 According to the budget, this revision will make it easier for biosimilars to enter the market.

Reducing the Medicare payment for single-source Part B drugs.

 This proposal, which applies to single-source biosimilars and other products in cases in which ASPs are not available, would lower the payment for single-source products from 106% of wholesale acquisition cost (WAC) to 103% of WAC. The budget also requires Part B drug makers to report ASP data.

 Under this policy, biosimilars as well as other biologics and drugs would no longer be eligible for pass-through payments, but they would be eligible for reduced 340B payment or immediate bundling under the Medicare Outpatient Prospective Payment System. According to the budget document, such a change will give manufacturers less incentive to make small changes to products in order to qualify for higher pass-through payments.

Restructuring the coverage gap discount program.

 This change to the program would exclude manufacturer discounts from calculations of patients’ true out-of-pocket-costs for branded drugs and biosimilars.

Eliminating cost sharing for generic drugs and biosimilars for low-income subsidy (LIS) beneficiaries. 

This proposal, says the budget document, encourages the use of high-value products among LIS beneficiaries by reducing their cost sharing to $0, producing $930 million in savings over 10 years.

Giving the FDA more authority to address abuses of citizen petitions.

 The budget proposes to give FDA the authority to summarily deny citizen petitions and eliminate the 150-day response timeframe for addressing such petitions. Citizen petitions have 

 as methods used to delay generic or biosimilar competition.

Other proposals put forward in the budget include allowing some Part B drugs to be moved to Part D to allow HHS to leverage Part D plans’ negotiating power, clarifying how manufacturers who sell authorized generics of their own products can calculate their average prices, capping the growth of the ASP payment of Part B drugs at the Consumer Price Index for all Urban Consumers quarterly, and capping beneficiary out-of-pocket spending in the Part D catastrophic phase, among others.

White House Budget Contains a Raft of Biosimilar Proposals

The FDA has approved Pfizer’s trastuzumab-qyyp (Trazimera), a biosimilar referencing Herceptin.

"This is an important milestone in the [United States] which both adds to our growing portfolio of oncology treatments and has the potential to improve access to cancer care,” said Andy Schmeltz, global president of Pfizer Oncology, in a statement. “We are proud to be able to offer treatment options that can help address the diverse needs of patients.”

Pfizer’s data package for the biosimilar included findings from the comparative clinical trial for the biosimilar, REFLECTIONS B327-02. The study 

 that, in patients receiving trastuzumab and paclitaxel as first-line treatment for 

positive metastatic breast cancer, the biosimilar showed similar efficacy, safety, immunogenicity, and pharmacokinetics (PK) to the EU-licensed reference drug. The study met its primary objective for equivalence in the objective response rate (ORR) for the biosimilar versus the reference, with the risk ratio of ORR of 0.940 (95% CI, 0.842-1.049) falling within the prespecified equivalence margin of 0.8 to 1.25.

 of the biosimilar as neoadjuvant therapy in combination with docetaxel and carboplatin, REFLECTIONS B327-04, found no clinically meaningful differences between the biosimilar and the EU-licensed reference in terms of efficacy, safety, immunogenicity, and noninferiority in terms of PK.

The approval for Trazimera, which also earned 

 a Complete Response Letter from the FDA in April 2018. The company said at the time that the FDA had asked for “additional technical information,” but did not request additional clinical information or safety data.

Trazimera is the fourth trastuzumab biosimilar, following the FDA’s approval of 

, none of which have launched in the United States.

FDA Approves Pfizer's Trastuzumab Biosimilar, Trazimera

Biosimilars have been making substantial inroads in Europe, where their use is associated with increased patient access to treatment, particularly in nations with lower healthcare resources. Even so, biosimilars may be unfamiliar to stakeholders, and prescribers, pharmacists, and patients have lingering concerns about these products.

 was conducted among Polish pharmacists in general hospitals, and sought to assess attitudes toward and use of biosimilars in practice, and the results have been newly published in 

The investigators distributed a paper-based, self-administered questionnaire to Polish hospital pharmacists and found that 77% of surveyed hospitals used biosimilars, while 90% used originator biologics.

The survey found that biosimilars comprise less than one-third of all biological therapy used in Polish hospitals, and 88% of surveyed pharmacists say that they are concerned that biosimilars are not identical to their reference products. Similarly, 48% of respondents are concerned about potential immunogenicity of biosimilars, and 44% have concerns about pharmacokinetic properties of these drugs.

The study’s authors conclude that, given the many concerns that stakeholders still have about biosimilar products, introducing these therapies into patient care requires special consideration. The authors call for improved legal regulation for biosimilars to help stakeholders feel more comfortable with understanding when and how biosimilars can be substituted for their reference products (Poland 

 for unrestricted pharmacy-level substitution of biosimilars), improved communication between prescribers and pharmacists, and educational efforts to help improve the safe and effective use of biosimilars.

Improved use of biosimilars could have a positive impact on the Polish health system, which, like many healthcare systems in Eastern Europe, faces challenges related to its financial constraints. Last year, a paper published in 

reported that, in Eastern Europe, numerous barriers stand between patients and biologic therapy. Among those barriers are volume limits on the number of patients who can be treated with biologics under public reimbursement, waiting lists for treatment (even in oncology indications), limited-duration biologic treatment, nonreimbursement of complementary diagnostics, and restricted reimbursement.

1. Paw&#322;owski I, Paw&#322;owski L, Krzy&#380;aniak N, Koci&#263; I. Perspectives of hospital pharmacists towards biosimilar medicines: practice in general hospitals [published online March 4, 2019]. 

2. Inotai A, Csandi M, Petrova G, et al. Patient access, unmet medical need, expected benefits, and concerns related to the utilisation of biosimilars in Eastern European countries: a survey of experts [published online January 10, 2018]. 

Biosimilars have been making substantial inroads in Europe, where their use is associated with increased patient access to treatment, particularly in nations with lower healthcare resources. Even so, biosimilars may be unfamiliar to stakeholders, and prescribers, pharmacists, and patients have lingering concerns about these products.
 

Most Polish Pharmacists Have Concerns About Biosimilars, Survey Finds

The launch of biosimilar adalimumab products in the European Union in October 2018 was an important moment for health systems in serious need of cost savings on one of their top drugs for spending: Humira. Now, early data reported by 

 show that adalimumab biosimilars are off to a strong start in the EU market.

According to IQVIA’s data, 14 countries had biosimilar adalimumab available as of November 2018: the United Kingdom, Germany, France, Spain, Italy, the Netherlands, Belgium, Sweden, Ireland, Austria, Finland, Denmark, the Czech Republic, and Slovenia. Among these nations, Germany had the most biosimilar options available, with launches of Samsung Bioepis’ Imraldi, Amgen’s 

. Austria and Finland, by contrast, each had just 1 biosimilar available: Amgevita.

In Germany, the number of patients taking the brand-name Humira fell in November versus the year before biosimilars launched. While some patients were switched to other agents, such as the interleukin inhibitors sekukinumab (Cosentyx) or ustekinumab (Stelara) that are often used as alternatives for patients who lose response to anti—tumor necrosis factor therapies, the greatest percentages of patients who switched away from Humira were transitioned to Imraldi (37%), Hyrimoz (15%), and Amgevita (12%).

In the United Kingdom, which was responsible for the most consumption of brand-name Humira in the European Union as of September 2018, a centralized tender broke the adalimumab market into 11 regions, and awarded shares of the market to multiple bidders. 

 took the greatest share, with nearly 45% of the English market. Amgevita and Sandoz were each awarded roughly one-fourth of the market, and Hulio was awarded approximately 5% of the market.

According to IQVIA, “It is Samsung with Imraldi that has won out so far in the 2 markets that matter the most: Samsung has the largest potential market in the United Kingdom and has shown the most success in acquiring Humira patients in Germany.”

The launch of biosimilar adalimumab products in the European Union in October 2018 was an important moment for health systems in serious need of cost savings on one of their top drugs for spending: Humira. Now, early data show that adalimumab biosimilars are off to a strong start in the EU market.

Early EU Experience Shows Positive Results for Samsung Bioepis' Biosimilar Adalimumab

Napp Pharmaceuticals has announced the UK launch of Pelmeg, a biosimilar pegfilgrastim developed by Cinfa Biotech and subsequently acquired by Mundipharma.

The biosimilar, which is indicated to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults undergoing cytotoxic chemotherapy, and which is self-administered, is Napp’s first launch of a product developed by Cinfa.

Paul Clark, director of biosimilars at Napp Pharmaceuticals, said in a statement 

 the launch, “We are proud to be delivering treatments that address patient need in the oncology treatment pathway and that could potentially improve patient experience at such a critical time. We hope that Pelmeg will not only help to alleviate some of the resource pressures on the [National Health Service] by providing a more affordable long-acting treatment option, but that it may also help improve patient access to these vital medicines.”

Pelmeg was authorized by the European Commission in November 2018 following 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 (PD) and immunogenicity that was presented at the American Society of Hematology’s annual meeting in December 2017. 

The UK launch of Pelmeg follows a February launch of the biosimilar in Germany, the Netherlands, and Irleand, by Mundipharma, a network of companies that operates in 120 countries worldwide, and that is also engaged in an ongoing partnership with Republic of Korea-based drug maker Celltrion. Mundipharma is responsible for commercializing Celltrion’s Remsima (biosimilar infliximab), Truxima (biosimilar rituximab), and Herzuma (biosimilar trastuzumab) across Europe. 