Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Samsung Biologics has decided to abandon efforts to develop SAIT101, a rituximab biosimilar for the treatment of follicular lymphoma, according to a report in the 

The report cited a corporate financial disclosure and official statement this week that stated Samsung Biologics and AstraZeneca had decided to suspend long-running research and development activities by a jointly owned subsidiary, Archigen Biotech, which was solely engaged in development of the rituximab candidate. Samsung Biologics said the subsidiary would be dissolved.

There was a conflict of interest in that a member of the Samsung Group, Samsung Bioepis, was in business collaboration with Biogen, the original developer of Rituxan, the reference brand of rituximab, the report said.

The report estimated that Samsung Biologics had invested $126 million in Archigen Biotech since its founding in 2016. A global phase 3 trial of SAIT101 in patients with follicular lymphoma was completed in August 2020 and demonstrated similar therapeutic effects to the reference product, with an objective response rate of 66.3% vs 70.6% for the Republic of Korea–marketed version of rituximab, MabThera.

Phase 1 trial results of the biosimilar candidate vs MabThera in patients with rheumatoid arthritis demonstrated therapeutic equivalence.

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Their rituximab biosimilar candidate was advancing in clinical trials for equivalence but represented a business conflict.

Samsung Biologics and AstraZeneca Dissolve Rituximab Partnership

Two biosimilars were approved by the FDA in mid-2020, well down from the total of 10 approved last year, but this drop-off does not give a true account of the federal government’s commitment to expanding biosimilar options for patients, according to 

, JD, MBA, formerly a senior advisor to HHS and principal deputy director of the Center for Medicare at CMS.

At the Association for Accessible Medicines 2020 GRx+Biosims conference, Brooks, currently a consultant with South Capitol, discussed the federal policy and regulatory infrastructure for biosimilars that has been constructed over the past few years and pending changes that could pick up the pace of biosimilar adoption.

“Regardless of administration, regardless of party, everybody agrees that encouraging biosimilar uptake, encouraging more competition, is the direction we should be headed. That’s for a pretty obvious reason,” he said giving the oft-cited statistic that biologics, costly by nature, now represent 3% of prescriptions written and 40% or more of total drug costs. “Everyone agrees that the biosimilar market is critical to making sure patients are adequately cared for and we get a good return on our health care investment.”

Politicians may be prodded by public sentiment to beef up biosimilar adoption, but the commitment to getting this done extends deep into the professional ranks of the FDA, CMS, and other federal departments, Brooks said. Such consensus led to the FDA’s Biosimilar Action Plan in July 2018, which was supported by President Donald Trump’s drug price reduction “blueprint,” issued in May 2018.

“Encouraging biosimilar competition was one of the primary planks identified as important for reducing costs and improving quality,” he said. “We saw a lot of actions from both the FDA/regulatory side in terms of governing the supply of biosimilars coming into the marketplace, as well as on the CMS side in terms of how we reimburse.”

for the interchangeable biosimilar pathway. This would take the doctor decision out of whether biosimilars or originator drugs are issued at the pharmacy counter. Interchangeability qualification is a stringent pathway for these agents and that’s because the FDA is very concerned about maintaining safety standards, Brooks said. But there are companies that are moving insulins through the pipeline, which could be the first interchangeable biosimilars, supported by recent FDA “patch” guidance that facilitates the process. This included modification of the requirements for immunogenicity studies leading to biosimilar approval. Interchangeable insulins could become a reality within a 24- or 36-month timeframe, “which would be a tremendous win for a lot of patients as well as for our overall health care system,” he said.

An example of a building block that levels the playing field for biosimilars is the 

, which was signed into law in December 2019 and targeted anticompetitive practices that make it difficult for biosimilar companies to obtain reference product samples they need for development of biosimilars.

Revisions to guidance on naming biosimilars (March 2019) have relaxed but not eliminated requirements for 4-letter random suffixes on biosimilar names, which critics say differentiate biosimilars from reference products in patients’ minds and make it harder for these drugs to achieve acceptance. “That guidance does not come as far as some stakeholders in the industry would like, but the FDA has also engaged in a pretty comprehensive education campaign to reassure people around the safety of biosimilars,” Brooks said. “As we saw with generics, where it took 5, 10, 15 years to get everybody on board with assurances around the safety of those products, there’ll be a journey here.”

On the payment side, CMS has assigned separate codes for each biosimilar “so that each company entering the biosimilar space can control a little bit more of their destiny in terms of what their [average sales price] is going to look like, what their pricing strategy is going to be,” he said.

Proposed changes to Medicare Part D would lower cost sharing for patients who use drugs on a 

designed to incentivize manufacturers to compete to get their drugs on this tier by offering lower prices. “It hasn’t been finalized yet; we’re still anxiously keeping our eyes on the Federal Register to see if CMS will finalize that policy—hopefully, sometime this fall—but it is a particularly good step forward, and it’s also an indication of how the agency is looking at this issue. They see biosimilars as a really important tool in terms of improving the cost piece,” Brooks said.

This tier might also encourage more biosimilar developers to enter the market, thereby enhancing competition, he said.

Several further ideas under consideration at CMS also could make a difference, Brooks said. One is the creation of a demonstration model for shared savings from biosimilars, under which providers would be “nudged” to use biosimilars in place of reference products because of the additional revenue they might earn.

He also expressed faith in the potential value of a Star Ratings system of measures that would grade Medicare Advantage plans on their biosimilar uptake and incentivize a greater shift in that direction. “There are a lot of exciting policy ideas out there. This an extremely dynamic marketplace,” Brooks concluded.

Prior to the turmoil of the pandemic, the FDA and CMS were at work on shoring up the biosimilars market, and this work continues on various fronts, a regulatory/policy expert explains.

Fed Expert Describes Improving Regulatory, Policy Structure for Biosimilars

Celltrion Healthcare has unveiled plans to build a $453.3 million biopharmaceutical plant and research center near its base of operations in Incheon, Republic of Korea. The company said the buildout is supported by rapidly increasing biopharmaceutical demand across the globe.

The biosimilar developer aims to build a 60,000-liter biopharmaceutical plant for diverse types of production needs and also a research center employing 2000 professional biodevelopment personnel for high-level activities related to expanding the company’s pipeline of medicines, including biosimilars, according to a 

. The plans were announced during a biopharmaceutical industry forum this week in Korea.

Celltrion aims to complete the research center and the factory by July 2022 and May 2023, respectively, with the factory starting operations by June 2024. The additional plant will give Celltrion a total production capacity of 250,000 liters annually, up from 190,000 at its 2 existing plants.

Eight 7500-liter incubators will shorten the time between manufacture of drug batches, the company said. A fourth plant also is in the planning stages, although further details were not provided, according to the press report.

 plans for $2 billion in spending on what it called the world's largest factory and biopharmaceutical production center, also in Incheon. The company aims to begin production at the site by the second half of 2022. 

Plans for a $453.3 million high volume plant and research center were unveiled during an industry forum this week in Republic of Korea.

Celltrion to Break Ground on Massive New Biopharmaceutical Plant

Samsung Bioepis and Biogen said the FDA has accepted for review their biologics license application for a ranibizumab biosimilar candidate (SB11), referencing Lucentis, a Genentech product. The drug is an anti–vascular endothelial growth factor treatment for retinal vascular disorders, a leading cause of blindness.

SB11 was developed by Samsung Bioepis and Biogen is the commercialization partner, according to an agreement the companies signed in November 2019.

“The FDA filing acceptance for SB11 brings us a step closer to our goal of being able to offer affordable treatment options for people with retinal vascular disorders,” said Hee Kyung Kim, senior vice president and Clinical Sciences Division and Regulatory Affairs team leader for Samsung Bioepis.

The European Medicines Agency accepted the marketing application for SB11 in October 2020. The corporate partners already market several biosimilars on the European market, including an etanercept (Benepali), adalimumab (Imraldi), and infliximab (Flixabi).

Samsung Bioepis and Biogen also plan to bring an aflibercept biosimilar (SB15) to market in the United States, Canada, Europe, Japan, and Australia. In the United States, aflibercept (Eylea) is indicated for the treatment of macular degeneration, macular edema, and diabetic retinopathy.

The FDA's acceptance of the biologics license application (BLA) moves the companies one step closer to entering the US ophthalmology treatment sphere with a biosimilar.

FDA Accepts Ranibizumab BLA From Samsung Bioepis and Biogen

Several legislative initiatives supporting biosimilar use are active in Congress, and the encouraging part is that many have bipartisan backing, said Molly Burich, associate director for Public Policy at Boehringer Ingelheim Pharmaceuticals, who provided her take on the health of the biosimilars market at the Association for Accessible Medicines GRx+Biosims 2020 conference.

“We’re definitely seeing some good tailwinds on biosimilars, but I would caution everyone that we aren’t there yet. This is still a very nascent market, and while the oncology market is certainly showing us reasons to be optimistic, the immunology market is still trailing,” Burich said in her discussion.

“We have to make sure that we’re setting up a system—whether that’s a combination of regulatory administration activities and potential legislative goals—that is not only moving across all therapeutic areas, but also creating a sustainable, long-term biosimilar market,” she said.

Burich highlighted various pieces of legislation that she said would incentivize the use of biosimilars by stimulating providers, patients, and payers to push these lower-cost products into centerfield.

, also known as the ACCESS for Biosimilars Act, would eliminate patient cost shares for biosimilars provided under Medicare Part B and drive biosimilar uptake from the patient direction. “It could serve as an incentive to get patients talking to their physician about these options,” Burich said. “While the majority of beneficiaries of Medicare Part B do have wraparound coverage that helps with the 20% coinsurance, there are a chunk of patients who do not, and so this bill would either lower their cost shares significantly or zero [the cost shares] out if, in fact, they’re given the biosimilar.”

 would increase provider payments for use of biosimilars to average sales price plus 8%, up from plus 6%, Burich noted. Under the wording of the bill, this increased payment opportunity would extend for 5 years.

Another potentially useful stimulus for biosimilar circulation is 

, Burich said. This bill would augment the Star Rating measures used to grade Medicare Advantage coverage plans. Star Ratings guide patients in their choice of plans, and the higher the ratings, presumably, the more patients select these plans. The measures under consideration for biosimilar stimulus include the following assessments:

whether a biosimilar is included on plan formulary in lieu of or in addition to its reference biologic

tier placement or cost sharing for a biosimilar vs reference product

how and whether tools for utilization management are used for a biosimilar vs reference product

the percentage of plan enrollees who are prescribed a biosimilar vs its reference product

, the Purple Book Continuity Act, is a piece of legislation that would raise the Purple Book of patent information to a more practical level so that biosimilar developers are better equipped to anticipate the obstacles they’ll encounter in trying to bring their products to market, Burich noted.

“There has been a lot of talk that the Purple Book isn’t set up exactly the same way as the Orange Book [for generic medicines], so is there a way to take some of the provisions in the Orange Book around patents and other really important information that impacts a developer’s decision around that product and put that in the Purple Book?” 

 is a federal appropriations bill that contains language encouraging greater utilization of biosimilars in Medicare Part B, she said. Related to this, the House Appropriations Committee has encouraged the administration to support new policies for reducing patient co-pays and developing cost-sharing models to spur biosimilar uptake.

 would require HHS to maintain a website and perform other activities to educate providers, patients, and other stakeholders about the value and importance of biosimilars.

“There’s definitely progress being made, and I don’t want to undersell that progress. But the reality is, we still have a ways to go, and we need to be looking at the incentives that will get us a little closer to biosimilar success,” Burich said.

The good news is the bipartisan consensus that these drugs can contribute to broader access and health care system savings and deserve a fighting chance, Burich said. “The focus on drug pricing, the focus on patient affordability, government spending—all of these things—they’re not going to go away.”

Despite a rocky power transition at the federal level, the compass heading for biosimilars is unchanged, said policy expert Molly Burich.  

Burich: Saving Grace for Biosimilars in 2021 Will Be Bipartisan Support 

Genentech has filed suit attempting to block the anticipated sale in the United States of a bevacizumab biosimilar by Centus Biotherapeutics, a joint venture between Fujifilm Kyowa Kirin Biologics and AstraZenenca. The reference product is Avastin, which already faces biosimilar competition in the United States. Centus has a biologics license application (BLA) under review with the FDA for the bevacizumab biosimilar candidate FKB238, and the company has filed a notice of intent to commercialize the agent.

Genentech alleges that Centus and its constituent corporate owners and partners failed to disclose sufficient information about the proposed biosimilar to enable Genentech to do a sufficient analysis of potential patent infringements. However, the suit claims potential infringement of at least 10 patents related to the manufacture of bevacizumab reference product.

The suit was filed in the US District Court for the Eastern District of Texas. The US drug candidate was 

 for marketing this fall in Europe, under the name of Equidacent.

According to the suit, the FDA accepted the BLA for FKB238 on November 18, 2019. The drug is a genetically engineered antibody that inhibits the growth of blood vessels that promote the development of tumors. Avastin, the reference product, was first approved in 2004 and is currently indicated for colon cancer, lung cancer, glioblastoma, ovarian cancer, and cervical cancer.

Genentech and its parent company, Roche, have much to lose from another bevacizumab biosimilar. 

of approximately $900 million in the first 9 months of 2020, according to Roche.

The first bevacizumab biosimilar to appear on the US market was Amgen’s Mvasi. This launched in July 2019 and was followed by Pfizer’s Zirabev in January 2020. These 2 biosimilars have gained a 40% share of the US market for bevacizumab, 

Genentech asserts that Centus has unfairly abridged its rights to conduct a review of the biosimilar candidate by having access to the BLA and information about the manufacturing processes involved in making the product. The company asserts that Centus provided only partial information and “only conclusory assertions that the patents identified by Genentech…were invalid.”

Quoting from statute, Genentech declared, “Centus was required to provide Genentech with a ‘detailed statement that describes, on a claim by claim basis, the factural and legal basis of [its] opinion…that [the patents identified by Genentech are] invalid, unenforceable, or will not be infringed by the commercial marketing’ of Centus' FKB238 product.”

Commercial notice of marketing must be issued 180 days before the date of the launch of the product. Centus indicated to Genentech via this notice that it would begin marketing FKB238 as soon as October 21, 2020. Marketing cannot begin, however, unless and until the FDA approves the biosimilar candidate, and Genentech said that Centus has asserted, in recent exchanges, that it has complied with all information requests from Genentech as required under the Biologics Price Competition and Innovation Act (BPCIA), which spells out the biosimilar approval pathway, including the “patent dance” exchange of information concerning potential exclusivity infringements.

“Genentech seeks an order declaring that Centus’ actions are contrary to the BPCIA and that the manufacture, use, offer for sale, sale, and/or importation of Centus’ proposed biologic product infringes Genentech’s intellectual property rights,” Genentech said.

The reference product rights holder contends that Centus has not provided complete information about its manufacturing processes related to FKB238, the proposed biosimilar.

Genentech Files to Block Marketing of Centus' Bevacizumab Biosimilar

A study of multiple biosimilar switches for patients with a variety of rheumatic musculoskeletal diseases (RMDs) demonstrated a high rate of patient retention (89%) and no major changes in disease activity or function, investigators reported at the American College of Rheumatology Convergence 2020 meeting. 

Sufficient information is available to elucidate the safety and efficacy of a single switch from an originator to a biosimilar product in the treatment of RMDs, but “The effect of multiple switching between biosimilars of the same reference product has not been thoroughly investigated to date,” investigators said.

Biosimilars are available at significant discounts to reference products, and the more biosimilars that are available, the more attractive multiple switching becomes, as providers and patients look for the most affordable treatment; hence, the significance of the study, investigators said.

The retrospective study enrolled 100 patients with rheumatoid arthritis (n = 54), axial spondyloarthritis (n = 27), and psoriatic arthritis (n = 19) who switched to 2 etanercept biosimilars for economic reasons over a 21.1-month average follow-up period. The switches (first, Benepali, SB4; second, Erelzi, GP2015) included in the study began in 2017, and the end of the observation period was October 2019.

Disease activity, function, and adverse events (AEs) were assessed regularly, and the primary end point was scores documented at week 12 after the second switch. The composite Disease Activity Score-28 and the Stanford Health Assessment Questionnaire Disability Index were used to measure changes in rheumatoid arthritis and psoriatic arthritis. Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, and Ankylosing Spondylitis Disease Activity Score were used for axial spondyloarthritis.

The 89% retention rate was observed about 6 months after the second switch. Seven patients discontinued due to inefficacy or AEs, 2 were lost to follow-up, and 1 patient died (cardiac arrest).

Investigators said 14 AEs were reported in 8 patients; and among those patients, 4 resumed treatment with reference etanercept in month 6; one patient was successfully retreated with Erelzi in month 3 after experiencing mucosal erosions; and 3 patients were switched to other forms of medication. Week 12 scores for disease activity and function were unchanged.

Investigators said their study is valuable because biosimilar switching is likely to increase for economic reasons. 

High Patient Retention Observed for Multiple Etanercept Switches

The International Generic and Biosimilar Medicines Association (IGBA) has launched the first Global Biosimilars Week, an attempt to raise awareness of the value of biosimilars and provide resources for interested persons to find out more about these lower-cost agents

 for Global Biosimilars Week contains patient testimonials, an introductory overview of biosimilars, and various other resources designed to explain the global reach biosimilars have achieved and their importance for extending treatment options.

“Enhanced knowledge of biosimilar medicines will support improved access to life-saving biological treatments and support healthcare systems, which are under increasing pressure due to the rising costs of innovative treatments and the new fiscal demands created by the Covid-19 global public health crisis,” said Hanan Sboul, chair of the IGBA.

IGBA is based in Geneva and is a trade association of companies that develop and market biosimilar medicines, which are often sold at significant discounts to innovator biologics and help to increase access to treatment for patients.

Global Biosimilars Week will continue through Friday, November 20. “Enhanced knowledge of biosimilar medicines will support improved access to life-saving biological treatments and support health care systems, which are under increasing pressure due to the rising costs of innovative treatments and the new fiscal demands created by the Covid-19 global public health crisis,” said Erika Satterwhite, chair of the IGBA biosimilars Committee. 

The group is inviting interested members of the public to join an online discussion about biosimilars on social media this week using the hashtag #GlobalBiosimilarsWeek.

The International Generic and Biosimilar Medicines Association (IGBA) hopes to build momentum for the use of biosimilars. 

IGBA Launches Global Biosimilars Week

In a study of use of infliximab biosimilars among patients with gastrointestinal and rheumatologic conditions, investigators found high adherence.

The retrospective study, presented at the American College of Rheumatology (ACR) annual meeting, involved 533 patients in the IBM MarketScan commercial insurance database who were treated with infliximab from 2014 to 2018. Investigators characterized those who initiated use of infliximab biosimilars after treatment with the reference product or no prior infliximab treatment.

Patients were divided according to never having used infliximab reference product, early switchers with less than 2 years of reference product use, and late switchers with greater than 2 years of reference product use.

Investigators said 41.6% to 47.4% of patients had inflammatory bowel disease and 34.2% to 48.7% had rheumatoid arthritis. Psoriasis patients accounted for 8.8% to 14.2% of the population.

Roughly half of patients were highly adherent to infliximab biosimilars at 12 months of treatment with these alternative agents. Among those with ≥ 12 months of follow-up care, 53.6% of naïve users, 44.3% of early switchers, and 56.1% of late switchers remained highly adherent at 12 months.

High adherence among patients with at least 18 months of follow-up amounted to 59.3% for naïve infliximab biosimilar users, 50% for early switchers, and 40.7% for late switchers.

Investigators found that there was no significant difference in adherence among those who initiated biosimilar infliximab.

Investigators divided comorbidity rates according to patient type. Among infliximab naïve users, 14.3% had diabetes; 42.9%, hypertension; 17.3%, depression; chronic obstructive pulmonary disease, 19.4%; and cancer, 11.2%.

The respective percentages for early switchers were 17.5%, 37.7%, 21.1%, 7%, and 3.5%; and for late switchers, 15.9%, 38.1%, 10.6%, 15.9%, and 11.5%.

The adjusted odds ratio for high adherence among naïve infliximab biosimilar users was 1.68 (

 = .35), meaning the former group was far more likely to adhere to infliximab biosimilar than the latter group.

Sarvesh S, Alanaeme JC, Curtis JR, Yun H. Utilization and adherence among infliximab biosimilar initiators in a U.S. national commercial insurance database. Presented at: ACR Convergence 2020; November 5-9, 2020. Poster 0555.

Investigators looked at adherence in patients who switched from reference infliximab during treatment for rheumatologic and gastrointestinal treatment. 

High Adherence Noted Among Infliximab Biosimilar Users

One-year results of a phase 3 study of a proposed ranibizumab biosimilar (SB11) in patients with neovascular age-related macular degeneration have shown equivalence in efficacy and pharmacokinetics (PK), as well as comparable safety and immunogenicity to the reference product, according to Samsung Bioepis.

Results of the study will be presented at the American Academy of Ophthalmology 2020 Virtual meeting from November 13 to 15, 2020.

Investigators enrolled 705 patients and said that 634 patients completed the study up to week 52. They said that clinical end points, defined as changes from baseline in best corrected visual acuity (BCVA) at week 8 and central subfield thickness (CST) at week 4, were met.

Long-term efficacy, safety, PK, and immunogenicity were secondary end points, and findings were comparable between SB11 and the reference product (Lucentis).

In the randomized, double-blind, multicenter study, the 8-week mean change in eye chart letters read correctly from baseline in BCVA at week 8 was –0.8 letters (90% CI, –1.8 to 0.2) between SB11 and reference ranibizumab. The mean change from CST baseline at week 4 was an adjusted treatment difference of −8 mcm (95% CI, −19 to 3 mcm) between SB11 and the reference agent.

The mean change from baseline in BCVA by week 52 was 9.79 letters for SB11 vs 10.41 letters for reference ranibizumab (difference: –0.62 [90% CI, −2.092 to 0.857]).

The mean change in CST was −139.55 mcm for SB11 compared with −124.46 mcm for reference ranibizumab (difference: −15.09 [95% CI, −25.617 to −4.563 mcm]).

Investigators said that PK, safety, and immunogenicity between the biosimilar candidate and reference product were comparable at all time points up to week 52.

In May 2020, Samsung Bioepis reported 24-week interim 

Results up to week 52 in the phase 3 study show that primary end points were met for best corrected visual acuity and central subfield thickness.