Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

As patents near expiration for insulin products, the newer battles over product exclusivity appear to be focusing on injectors and other delivery systems, according to Stacie Ropka, PhD, and Ted Mathias, intellectual property law partners at Axinn Veltrop & Harkrider.

In March, insulin product approvals were switched to the biologics pathways under the Biologics Price Competition and Innovation Act (BPCIA), which will bring longer periods of exclusivity for innovator products and potentially much greater difficulty for product imitator companies in understanding and challenging product patents, Ropka and Mathias said in a series of 2 interviews set to appear on The Center for Biosimilars

The potential incentive for insulin biosimilar developers under the BPCIA is the prospect for an interchangeability designation, which would make it far easier for biosimilar developers to attain automatic substitution of their products at the pharmacy counter, the attorneys said.

Until recently, insulin products were approved under pathways spelled out in the Hatch-Waxman Act. This changed in March. Insulin products must now be approved under the BPCIA. The BPCIA’s 351(k) application is one of these avenues to approval. It may be less difficult for companies to get approvals under a 351(k) pathway than under Hatch-Waxman but still time consuming and complex, Ropka said.

“Given that the BPCIA has been in effect for 10 years now, and I think we’re up to 28 [biosimilar] products that have been approved by the FDA, the FDA has been able to provide more clarity regarding the types of studies and data they need to review in order to make a decision on approval,” she said. “It can be less difficult to get the data required by the FDA for a robust 351(k) application.”

Lack of clear articulation for insulin product acceptance under Hatch-Waxman was a factor in the scarcity of generic insulin approvals under that legislation, she said.

The difficulty for insulin biosimilar approvals under BPCIA stems from the level of patent information about originator products available to biosimilar product applicants.

Under Hatch-Waxman, developers had an advantage in the Orange Book, which outlines patents that cover a reference drug. This has been useful for identifying patent issues in advance that might interfere with bringing a generic drug to market.

However, under Hatch-Waxman, answering these patent issues required preparing letters of notice that cover potential patent infringement and invalidity issues, which can be lengthy to prepare.

Under the BPCIA, the Purple Book is the Orange Book equivalent, and this is a valuable reference guide for drug developers, but the patent information component is missing. “Only the reference product sponsor is in a position to identify patents that might be part of patent litigation or some other type of patent dispute resolution,” Mathias said.

The BPCIA’s patent resolution process “requires the reference product sponsor to provide a list of patents to the follow on developer that they think can reasonably be asserted against the follow on developer in patent litigation, but this list is provided after the follow-on product developer has already made the business decision to pursue a specific biologic and provided the follow-on application to the FDA and to the reference product sponsor. In other words, they’ve already spent quite a bit of money,” Mathias said.

The bottom line is the quality and timing of patent information is not as good for the BPCIA applicant as it was for the applicant under Hatch-Waxman.

There have been recent legislative attempts to improve the situation. One would require that patent information specific to an initial biosimilar application under BPCIA would be added to the Purple Book so that it is available for other biosimilar developers. The problem with that, Ropka noted, is that the information may not be completely relevant to the patent information needs of future drug applicants, and the first applicant to provide that list would have to generate it independently, therefore not having the benefit of readily available information.

It is hoped that drug developers will pursue approvals for insulin products under the BPCIA, but the question is will they be incentivized to do so?

Mathias explained that the pathway for an interchangeable designation under the BPCIA may serve as the incentive that companies are looking for. Interchangeability means a biosimilar can be substituted for a reference product at the pharmacy counter, without the intervention of a physician. “But there's a catch, and the catch is that no biologic has yet been approved as an interchangeable,” he noted. “There are reasons to think that might change soon, but we certainly are not there yet.”

When patents expire on insulin products, biosimilar developers won’t be able to simply step into the vacuum with products of their own, Ropka and Mathias said.

“We’re seeing that reference product sponsors are really focusing on building their portfolios with patents on injectors and other delivery systems,” Mathias explained. Mathias and Ropka expect this to be the new battleground in litigation between originator companies seeking to extend exclusivity for insulin products and biosimilar developers seeking to bring their products to market.

One significant change under BPCIA regards patent exclusivities for insulin products. Insulins previously approved under Hatch-Waxman are not entitled to any further product exclusivity now that they have become biologics “deemed to be approved” under BPCIA.

However, Mathias said, the terms of exclusivity awarded to new products under BPCIA are longer (12 years) than under Hatch-Waxman (maximum of 7 years), so new insulin products approved under BPCIA will not see competition in the form of biosimilars for a long time to come.

In a series of interviews in May, Ropka and Mathias discussed the challenge to the Affordable Care Act (ACA) and how that might affect the future of the 

. If the ACA is fully overturned by the Supreme Court, a new biologics approval pathway would have to be developed, as the BPCIA was approved as part of the ACA.

Articles

With insulin originator product patents expiring, drug companies are seeking to extend exclusivities via patents on injectors and other delivery products.

New Battleground Shaping Up Over Insulin Deliverables

Production of the world's first halal biosimilar, which would mean a biologic permissible under Islamic law, would be a feature of expanded commercial biosimilar production in Malaysia, officials involved in the deal said.

The plans include construction of a commercial biosimilar production center in Malaysia, although an exact location for this facility has yet to be determined. The project involves a collaboration with the government-backed investment company VentureTECH, Malaysia-based Duopharma Biotech Bhd, and Republic of Korea—based PanGen Biotech. Construction would be completed by 2024, the reports from the corporate officials involved and 

Officials were quoted as saying that for Malaysia, expanding the local biologics industry is a costly undertaking, but this will be made easier by taking the biosimilar route because far less investigative development is required. 

VentureTECH would invest capital in the enterprise and biosimilars would be produced for both the export and domestic markets, the official statement said.

One of the products to be produced in the new plant would be PanGen’s epoetin alfa biosimilar (Erisa, Erysaa), and this would be halal certified, according to the statement. "DuoPharma Biotech and PanGen have successfully developed biosimilar erythropoeitin ... resulting in the establishment of the [memorandum of understanding] aimed at building local capacity to produce (Erysaa) and other biosimilar products," the statement said. This product has been certified as halal by the Korean Muslim Federation and is under review by Jabatan Kemajuan Islam Malaysia for halal certification in Malaysia, they said.

Epoetin alfa stimulates erythropoiesis, or an increase in red blood cells, and is used to treat anemia.

Duopharma Biotech manufactures, imports, and exports pharmaceutical products. The company has commercialized Erysaa and also, recently, a trastuzumab biosimilar (Zuhera). The company obtained halal certification for Erysaa from the Korean Muslim Federation to qualify for product launch in Malaysia. The company said in a recent statement that this was the first halal certification for any biosimilar anywhere in the world.

“We are motivated to grow the halal pharmaceutical segment both because of the huge business potential it presents, and because we believe in offering Muslims, and indeed all discerning consumers of all faiths, a peace of mind knowing they can avail of the best medical treatments that are halal certified,” Leonard Ariff Abdul Shatar, group managing director of Duopharma Biotech, said in a June company 

The company said 95% of its products are halal certified.

The company has a production line in its Klang, Malaysia, factory that has been approved for production of Erysaa, and that operation has been under expansion to handle higher volumne Erysaa production.

PanGen specializes in the develop of new biologics and biosimilar products.

 that it had received FDA clearance for production of insulin glargine (Semglee) at its new Malaysia plant. This came after the company received Complete Response Letters and Form 483 notices, which are FDA statements that production cannot begin until improvements are made.

As part of a project to build the first biosimilar factory in Malaysia, one of the initial products would be halal certified.

World's First Halal Biosimilar to Be Produced in Malaysia

Although it has an infliximab biosimilar being tested in the 

 trial for potential use in patients with coronavirus disease 2019 (COVID-19), Celltrion Healthcare said today it has an antiviral antibody treatment candidate in a phase 1 study for patients with COVID-19 and that is expected to be completed by the end of the third quarter of this year.

The COVID-19 drug candidate treatment has shown promise in neutralizing several coronavirus-related strains, including the mutated G-variant strain of severe acute respiratory syndrome coronavirus 2 (D614G variant), the company said in a 

. Further in-human studies across Europe are planned.

The phase 1 study follows a new drug application approval from the Republic of Korea Ministry of Food and Drug Safety. Celltrion officials also said they expect the agent will be tested as a form of preventive therapy for COVID-19.

The phase 1 trial will enroll 32 healthy volunteers who have not had a COVID-19 diagnosis and evaluate safety of the antiviral antibody treatment. Following a further in-human phase 1 trial in Europe, Celltrion anticipates expanding the investigation through phase 2/3 trials in patients with mild and moderate COVID-19.

Additional investigation is planned in use of the antiviral as a preventive measure in individuals who come into proximity with patients with COVID-19, such as health care workers.

“The initiation of this in-human clinical trial is a key milestone in the development of our antiviral antibody treatment,” said Sang Joon Lee, PhD, senior executive vice president of Celltrion. “We were encouraged by the positive safety and efficacy results in our preclinical studies, and we are now ready to move into in-human clinical trials as we originally planned. We remain committed to carrying out local and global clinical studies with the goal of commencing mass production of the therapeutic antibody treatment in the latter half of this year.”

Celltrion Healthcare said an antiviral drug candidate is moving along in trials as a potential treatment for coronavirus 2019 (COVID-19).

Celltrion Antiviral Treatment for COVID-19 Makes Progress

Developing biosimilars is not an easy process. Exact details of the manufacturing process are typically not available from the reference manufacturer. Further, minute variations in product quality can be magnified as biosimilar production moves through its various stages. For these reasons, biosimilar developers often run into complications when seeking approval from regulatory authorities.

A recent study of failed applications for biosimilar approval points out the various reasons why attempts to get biosimilars approved in the United States and Europe have broken down. “Most regulator rejections can be attributed to gaps in the manufacturer’s understanding of what is expected from a comparability exercise and also Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP) implementation,” the authors said.

In this article, The Center for Biosimilars

 discusses findings from the report, and in the coming days, we will post a video interview with lead author Anurag S. Rathore, PhD, about the group’s conclusions and general observations about biosimilar development and regulator review.

Prior to the arrival of epoetin alfa biosimilars, Amgen had difficulty with variability in outcomes for its originator product. During its first decade, the product was associated with a relatively small number of cases of pure red blood cell aplasia (PRCA), which is associated with oxygen-poor blood concentrations. From 1998 to 2004, however, there was an “epidemic” of PRCA related to this product. This increased immunogenicity was eventually attributed to a formulation change, and preventive measures were successful in reducing the incidence of PRCA to normal levels.

This case illustrates the difficulty of maintaining consistency in product quality even for originator companies, according to the authors.

For the pegfilgrastim biosimilar Fulphila, the journey to acceptance by the European Medicines Agency (EMA) was a bumpy one. As a candidate biosimilar, it did not fit within acceptable ranges for purity and impurity to demonstrate biosimilarity with the reference product, Neulasta.

Another issue with Fulphila centered around poor control for sterility of the finished product, which raised questions about the quality of the manufacturing plant. The product applicant, Mylan, withdrew its application to the EMA, adjusted the manufacturing and control processes, and resubmitted. Approval was granted in 2018.

“For receiving approval for a biosimilar application, it is necessary to demonstrate similarity between the proposed product and the reference molecule with respect to safety, efficacy, and quality. This comparability exercise serves as the basis for approval and hence it is not a surprise this also happens to be the most common reason for denying approval to a biosimilar application,” the authors wrote.

Regulatory guidelines typically recommend that biosimilar equivalence be demonstrated by analytical studies, which establish comparability to the reference product, and preclinical and clinical studies, which demonstrate that safety and efficacy fall within acceptable boundaries.

During process validation, different human insulin products from Marvel LifeSciences have been flagged by the EMA for insufficient data on fermentation, harvesting, and purification processes, for example. Similarly, for the candidate Herzuma biosimilar trastuzumab, the FDA had concerns about the processes for lyophilization, or low-temperature dehydration, and vial filling.

“Manufacturing biosimilars is a complex process involving many steps such as choosing appropriate cell line, cell culture, harvest, purification, formulation, and packaging,” the authors wrote. For this reason, manufacturers need to understand the factors that affect safety and efficacy and establish controls that provide for consistency in product quality, they said.

Regulators have held up applications on the grounds of shelf life and product quality concerns. The FDA raised such concerns over stress studies for trastuzumab biosimilar (Trazimera) and epoetin alfa (Retacrit) biosimilar applications, because the stress studies were not representative of how products would hold up under real-time commercial shipping conditions.

Many biosimilar applications have stalled over regulatory concerns about compliance with GMP. In early 2018, Celltrion Healthcare, for example, was asked to make manufacturing facility 

 in order to move forward with its rituximab (CT-P10) and trastuzumab (CT-P6) applications.

The importance of getting the manufacturing formula right on biosimilar development is highlighted by the growth in the market for biologics and the sheer cost of originator products.

Biotherapeutics represented a $4.4-billion market in 1990 and now represent about $275 billion, an increase of more than 6000%. This class of drugs now represents 25% of the total pharmaceutical market. By comparison, biosimilars account for a very small proportion of these revenues, just 2% to 3% of the US biologicals marketplace, according to the study authors.

“It is now widely accepted that continued adoption of biosimilars will result in significant savings to the cost-bearer, the government, or the patients, or both, and that this will dramatically improve the accessibility toward this effective but unaffordable class of products, not only for those living in emerging economies but also significant portions of those living in developed economies,” the authors wrote.

Still, they predict a rapid increase in the number of biosimilars in coming years due to the pending expiration of patents on originator drugs. As of September 2019, there were 83 biosimilar development programs registered with the FDA for 38 biologic drugs. And biosimilars for at least 23 originator biologics were in late-stage development in the United States, according to the authors.

Regulatory policies are working to shape the development of biosimilars. Regulatory diligence is critical to avoid substandard products and elevated patient risk. The EMA has “shown significant success in maintaining this balance, with the US FDA and others (regulators) gradually progressing toward this goal,” the authors said.

Manufacturers are on the early side of a learning curve, regulators can be expected to clarify and improve guidance, and the rejection ratio will diminish over time, thereby driving down the cost of biosimilar development and improving access and affordability of these agents, the authors said. “Indeed, the coming decade will witness the success of biosimilars.”

Rathore AS, Chhabra H, Bhargava A. Approval of biosimilars: a review of unsuccessful regulatory filings, expert opinion on biological therapy. &lrm;

. Published online July 7, 2020. doi:10.1080/14712598.2020.1793954

Investigators found that process complexities have created numerous difficulties for biosimilar developers in regulatory filings, but they anticipate that the success rate will improve with experience and improved guidance.

 

Why Biosimilar Approval Applications Break Down

More biosimilars are being launched, but numerous factors affect whether they become available in the clinic. On Monday, July 20, 2020, from 5 to 6 pm EST, MJH Life Sciences™ 

 about how biosimilar rebates shape payer policies and provider options.

The program features a panel of leading experts on oncology practice and payment who will provide perspectives on how the structuring of biosimilar payment contracts at the payer level is affecting biosimilar access and cost at the provider level.

With more biosimilars, the expectation is that costs will decline and providers will have more freedom to choose the most appropriate medications for their patients. However, marketplace dynamics have made that ideal a more complicated objective than anticipated.

Providers who want to use biosimilars find their choices of these medicines often are determined not by clinical concerns but by regional payer-by-payer contracts that necessitate careful pharmacy planning, staff training, and sometimes, compromise.

Hear what our panelists have to say about these issues and how they deal with them. They are Kathy W. Oubre, MS, chief operating officer of the Pontchartrain Cancer Center in Louisiana; Ali McBride, PharmD, MS, BCOP, FASHP, FAzPA, clinical coordinator of Hematology/Oncology for The University of Arizona Cancer Center; and Timothy Chiu, PharmD, BCPS, pharmacist evidence analyst and strategist for Kaiser Permanente.

An upcoming webinar from MJH Life Sciences™ will address the payer rebate deals that limit provider choice of biosimilars and complicate clinical pharmacy operations.

Webinar: How Biosimilar Rebates Shape Payer Policies, Provider Behavior

The transition from reference to biosimilar etanercept was safe and effective in patients with stable rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA), according to updated findings from the BENEFIT study, based on observed declines in disease activity.

Investigators evaluated clinical records of adult patients in France, Germany, Italy, and Spain. The real-world study employed Samsung Bioepis’ etanercept biosimilar, SB4, which is approved in multiple markets and distributed under the names Benepali, Brenzys, and Eticovo. It received FDA approval in 2019 but is not expected to come to market until 2029.

The investigators enrolled 358 patients with RA and 199 patients with axSpA. They used the Disease Activity Score 28 (DAS28) to measure changes in RA and the Bath Ankylosing Spondylitis Disease Activity Index (

DAS28 assigns a score from 1 to 10 based on tenderness and swelling in 28 bodily joints, with higher scores being more disease severity. In the study, the mean individual DAS28 change following transition from reference (Enbrel) was —0.02 (95% CI, –0.11 to 0.08) at 3 months and 0.01 (95% CI, –0.09 to 0.11) at 6 months.

BASDAI assigns a score of 1 to 10 based on fatigue, spinal pain, joint pain and swelling, tenderness, and stiffness. Among patients with axSpA, the 3- and 6-month values for BASDAI were —0.01 (95% CI, –0.24 to 0.21) and –0.11 (95% CI, –0.31 to 0.10), respectively.

Among patients with RA, 19 (5.3%) experienced adverse events and 5 (1.4%), serious adverse events (SAEs). The respective numbers for patients in the axSpA cohort were 12 (6%) and 2 (1%). Investigators said an SAE of pneumonia in the RA cohort was considered SB4 related.

At 6 months, 90.8% of patients remained on SB4, compared with 92.4% in the axSpA group.

The updated findings correlate with data 

 from BENEFIT last year at the European League Against Rheumatism (EULAR) Annual European Congress of Rheumatology.

Selmi C, Krüger K, Cantagrel A, et al. BENEFIT: real-world effectiveness of SB4 after transition from reference etanercept in rheumatoid arthritis and axial spondyloarthritis. 

https://pubmed.ncbi.nlm.nih.gov/32662409/

The transition from reference to biosimilar etanercept was safe and effective in patients with stable rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA), according to updated findings from the BENEFIT study.

Samsung Bioepis' SB4 Performs Well in RA, axSpA Transition Study

The House Appropriations Committee has asked for policy action by CMS that will support access to, use of, and competition from lower-cost biosimilars to provide savings for seniors, patients, and taxpayers.

The request came as the committee approved the fiscal year 2021 Labor, Health and Human Services, Education, and Related Agencies bill.

In a statement, the committee said it “is concerned about the underutilization of lower-cost biosimilars, particularly those in Medicare Part B, and encourages CMS to support development and implementation of new policies that may help increase biosimilar uptake when clinically appropriate, such as reducing patient copays or other mechanisms.”

During The Hill’s “Health Reimagined: The Future of Healthcare” 

, which featured keynote speakers Anthony Fauci, MD, and HHS Secretary Alex Azar, experts said there is a need for healthy competition from biosimilars and policies in Congress that can lower costs for seniors, employers, and the health care system at large.

Juliana Reed, president of the Biosimilars Forum, outlined the cost-savings potential of biosimilars amid increased spending during the coronavirus disease 2019 (COVID-19) crisis. “As the United States battles the COVID-19 pandemic and Congress has authorized more than $3 trillion in critical funding to fight off the virus and help our economy, our health care system also needs to look forward to lowering drug costs. Estimates show that biosimilars could save the US health care system as much as $250 billion over the next 10 years. As we begin to rebuild the economy in a way that reduces the financial burden on patients, employees, and the health care system at large, biosimilars will play a key part in that solution.”

Annette Guarisco Fildes, president and CEO of the Erisa Industry Committee, identified the obstacles in place to ensure that patients consistently receive biosimilars.

“I think there is a misunderstanding about what biosimilars are and there’s a particularly unfortunate one in that people think that the FDA needs to designate a biosimilar somehow as interchangeable before it can be prescribed to a patient,” she said. “And that’s simply not the case. From large employers, where I sit, they do try to design their plans to align the incentives correctly, but the other systems in place create cross-purposes so that the most affordable drug isn’t necessarily prescribed to the patient each and every time. We need to do better as a country, and Congress and the FDA and CMS have important roles to play in all this. There are answers—and Congress and the administration just need to act.”

Alex Brill, founder of economic consulting firm Matrix Global Advisors and a resident fellow at the American Enterprise Institute, discussed a solution that Congress or the administration could approve that aligns the incentives of physicians and taxpayers to mitigate the rising costs of biologic spending.

“One of the ways to align these incentives would be for CMS, in particular the Center for Medicare & Medicaid Innovation, to launch a demonstration project, a shared savings program in Medicare Part B for biosimilars. This would reward physicians for increasing their utilization of biosimilars, which would both

create that incentive for physicians and align that incentive with the desire of taxpayers to lower overall costs in the biologic spend category,” he said.

A few weeks ago, Senators John Cornyn, R-Texas, and Michael Bennet, D-Colorado, introduced bipartisan 

 to lower health costs by supporting biosimilars.

The House Appropriations Committee has called upon CMS to increase access to biosimilars.

House Committee Calls for CMS Action on Biosimilars

More new drugs tend to be biologics, approximately 1 in 4, which is a concern because biologics tend to command higher prices and enjoy longer market exclusivity, thereby fending off competitors such as biosimilars that would bring prices down and improve access, authors of a new study wrote.

They studied exclusivity periods for a range of generic and biologic products to understand the changes that are occurring and spot important trends.

“High drug prices charged during exclusivity periods allow drug manufacturers to recoup returns on earlier investment in drug development. However, unnecessarily lengthy exclusivity periods contribute to excess health care spending, and it is not clear whether the current system is financially incentivizing clinically important innovations,” investigators wrote.

Current marketing exclusivity periods for drugs range from 13 to 17 years, although biologics tend to have longer exclusivity, they found. “Policymakers should consider options to encourage timely competition, particularly among biologic drugs.”

The authors used claims data to estimate market exclusivity for 264 small molecule and 4 biologic drugs that faced new generic or biosimilar competition from 2012 to 2018. The exclusivity periods for biologics averaged 21.5 years versus 14.4 years for small molecule drugs (

Investigators also found that drugs with lower annual revenues tended to have longer exclusivity periods:

Investigators found that versions of existing drugs that had been modified (eg, administration route, therapeutic area) or gained approval via use of expedited approval pathways had shorter exclusivities than new drugs (9.9 vs 14.5 years; 

Periods of exclusivity make it possible for manufacturers to charge high prices for their innovator drugs, which is partly why brand-name products account for 80% of US prescription drug spending. Once competitor products enter the market, prices may drop substantially, leading to lower-out-of-pocket spending, improved medication adherence, and patient outcomes, authors said.

Therefore, market exclusivity periods are an important factor to consider in the patient-access equation, they said.

The study drew upon records from 17 million commercial and Medicare Advantage patients in 50 states, as well as FDA lists of generic and biosimilar approvals from 2012 to 2018. The study encompassed 109 new products and 159 modified products.

Modified drugs approved under an expedited FDA pathway had longer exclusivity than regular pathway drugs (15.1 vs 9.7 years; 

Therapeutic area and route of administration also correlated with exclusivity length, with longer periods for new products in the hematology/oncology (14.3 years), infectious disease (16.1), and dermatology (17.0) arenas, and longer periods also for topical (27.6), inhaled or intranasal (17.1 [modified drugs only]) or injected products (15.4).

Authors of the study said they did not find evidence that exclusivity periods lengthened for new small molecule drugs between 2012 and 2018. But longer exclusivity periods were noted “among the first 4 biologic drugs to face biosimilar competition, which is notable because biologics account for a rising proportion of new drug approvals.”

The lack of automatic substitution of biosimilars at the pharmacy counter has the potential to limit competition for innovator drugs, but biosimilars can still make an important difference via their lower prices, the authors said. “Since biosimilar competition can still lead to modestly lower prices even without automatic substitution, timely biosimilar competition is still important for improving patient access to lower-cost treatments and limiting unnecessary spending on these expensive products.”

Investigators found that a generic pathway created via the Hatch-Waxman Act appears to have succeeded in incentivizing earlier generic competition. Hatch-Waxman was designed to encourage generic competition by allowing 180 days of exclusivity to the first generic product to gain tentative FDA approval and go to market against an established brand-name drug. Shorter exclusivity periods resulted from this policy, but for almost 50% of new drugs, the first generics did not qualify for the 180-day exclusivity period, investigators found.

They said it remains to be seen whether the FDA’s 2017 Drug Competition Action Plan is able to encourage generic competition and increase generic approvals. “It will be critical to examine whether exclusivity length eventually shortens,” they said.

 emphasized the importance of improving access to biosimilars as a way to generate better outcomes and lower costs for medicine.

Rome BN, Lee CC, Kesselheim AS. Market exclusivity length for drugs with new generic or biosimilar competition, 2012-2018. 

The rise of biologics as a class of prescription spending is fueling a trend toward longer exclusivity periods, which ultimately makes access more remote, authors of a new study said.

New Biologics Are Skewing Exclusivity Periods Longer, Study Says

Following a court decision earlier this month, it’s very possible that Amgen will continue to enjoy exclusivity for its etanercept originator product until 2029. That would be a very lucrative outcome for the company, which pulled in $5 billion in sales for the rheumatology drug last year.

Meanwhile, 2 would-be competitors sit on the sidelines: Sandoz, which owns the etanercept biosimilar Erelzi, approved in 2016, and Samsung Bioepis, which has the drug Eticovo, approved by the FDA in 2019.

Enbrel is listed as one of the most expensive drugs in the United States, at $67,000 for a year’s supply, according to the blog 

, and the drug has had the etanercept market to itself since it was launched in 1998.

To Kashyap Patel, MD, vice president of the Community Oncology Alliance and president of Carolina Blood and Cancer Care Associates in Rock Hill, South Carolina, Sandoz’s latest failed bid to crack open the market for a biosimilar etanercept is “a huge blow to the perceived success for biosimilars as a class and their promise to address drug prices in the United States.”

“Even in developed, high-income countries, the costs of delivering care—especially in chronic diseases like autoimmune disorders and cancer care&mdash;are becoming an increasing burden on national budgets, and the ability to maintain this level of spending on health care is a growing concern. Biosimilars offer the promise of addressing costs of care, improving access, and providing affordability,” Patel said.

“Even though biologics account for approximately 2% of all US prescriptions, they represent almost 40% ($120 billion) of prescription drug spending in the United States and are responsible for increasing drug spending by 70% from 2010 to 2015,” he said.

In August of 2019, a District Court of New Jersey judge 

 Sandoz’s attempts to invalidate patents related to Enbrel’s manufacture and active ingredient, and on July 1, a Federal Circuit panel 

 that ruling, although with some dissent.

The main argument was whether Sandoz had demonstrated the existence of obviousness-type double patenting (OTDP). OTDP was developed as a legal means to prohibit a company from inappropriately extending patent protection by patenting the same invention twice.

In the case of Enbrel, Sandoz was unable to convince the court that this was the case. However, a dissenting judge argued against the majority that owing to subtle language in a contract between Roche and Immunex, which Amgen acquired, Sandoz did have a valid claim for OTDP.

that expressed its frustration with the outcome, Sandoz said it was reviewing its options, including a possible appeal to the Supreme Court.

By this time, Sandoz is in deep in terms of investment in development and its legal defense of Erelzi, and the market for etanercept is large and remains tempting. Ha Kung Wong, an intellectual property law attorney with Venable of New York, said a Supreme Court appeal is likely, although he said it’s also possible that Sandoz will try for an en banc rehearing involving Federal Circuit judges. En banc rehearings are generally granted only to exceptionally weighty issues.

“The fact that there was a dissent could lead to further discussion over what the right [OTDP] analysis should be,” Wong said. This is where Sandoz appears to have the most likely grounds for appeal, he said. The drug maker also argued “written description,” meaning the claimed invention was not properly described in the patent application, and “obviousness,” essentially meaning that there was lack of true innovation in the product; however, these issues were more fact dependent in the case and are thus less likely to interest the Supreme Court, Wong said.

It’s also possible that Samsung Bioepis may invlaidate certain related patents, he noted. “There is an ongoing case on the same patents between Amgen and Samsung Bioepis. It's possible that Samsung could try to invalidate the patents.  It's a little unclear what the status of this case is because it's administratively stayed based on a confidential stipulation, so we don't really know what the stay is for or what would lift it.  The stay does allow for discovery to proceed, though.”

 by the Rand Corporation predicted the potential for $54 billion in biosimilar savings over 10 years, but actual utilization doesn’t appear to be keeping up, largely because of patent walls that keep biosimilars out of the market, Patel said.

“Despite the efficacy and safety of biosimilars, the level of utilization is still less than expected in the United States due to multiple factors, including discounts and rebates to pharmacy benefits managers, patent litigation, physician and patient concerns of comparable efficacy and safety to the reference product. These prevent optimum utilization of biosimilars and the latest ruling by the US court has not helped at all,” he said.

A victory for Amgen and a defeat for Sandoz pushes biosimilar competition in the etanercept market out to 2029 unless Sandoz or Samsung Bioepis can eke out headway against Enbrel's patent wall.

Legal Opinion: Fresh Attack on Enbrel Patents Is Likely

An anti-CD6 IgG1 monoclonal antibody from Biocon Biologics of Bengaluru, India, has been 

 by the Drugs Controller General of India for the emergency treatment of acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19).

Biocon said in a statement that itolizumab (Alzumab), long used for treatment of acute psoriasis, was approved in injectable form, 25 mg/5 mL, for use in India for the treatment of cytokine release syndrome in patients with moderate-to-severe ARDS. The repurposed drug was originally launched in India in 2013 for treating chronic plaque psoriasis.

Itolizumab “has proven to be an efficacious intervention in treating the serious hyper-immune response seen with COVID-19,” said Kiran Mazumdar-Shaw, executive chairperson of Biocon, in a company statement. Mazumdar-Shaw said the results came from a randomized controlled study of Itolizumab that focused on safety and efficacy in preventing CRS in patients with ARDS due to COVID-19.

“It is the world’s first anti-CD6 novel biologic therapy to be approved for treating patients with moderate-to-severe COVID-19 complications,” Biocon said.

The company said the primary end points of reduced mortality were met, as were secondary end points for efficacy and biomarkers. “The data are compelling and I am confident that this ‘first-in-class’ biologic will save lives and help reduce the mortality rate in our country,” Mazmundar-Shaw said.

COVID-19 has been observed to stimulate a strong immune response leading to CRS, which is a “storm” of cytokines that can damage the lungs and other organs. In worst-case scenarios, the outcomes can be multiple organ failure and death.

In the trial, all patients treated with itolizumab responded positively and recovered. There were deaths in the control arm that did not involve treatment with itolizumab. A 1-month mortality rate was measured.

Sandeep Athalyze, chief medical officer for Biocon, said that the drug succeeded in increasing oxygen saturation (absorption) in patients without requiring the increase of oxygen flow (artificial source oxygen). “All the patients on the Itolizumab arm were weaned off oxygen by day 30, and none needed ventilator support, unlike the control arm,” he said.

Inflammation markers such as IL-6, umor necrosis factor—alpha, serum ferritin, d-dimer, lactate dehydrogenase, and C-reactive protein showed clinically significant suppression after dosing and correlated well with symptom improvement and chest x-ray findings. “Itolizumab was overall well tolerated and was found to be safe. Itolizumab when administered to patients with moderate to severe ARDS due to COVID-19 prevents morbidity and mortality due to cytokine storm,” Athalyze said.

The company statement included testimonials from doctors in hospitals in India who said that comparable treatments for COVID-19—related CRS do not exist and that the results in patients treated with itolizumab had been impressive.

“Patients who were with initial oxygen saturation of less than 80%, and would have been put on ventilator support with little chance of survival, recovered completely when treated with Itolizumab and got discharged,” said Suresh Kumar, medical director of Lok Nayak Hospital in Delhi.

Biocon recently announced plans to take its biosimilar unit 

India's medical authorities approve Biocon Biologics' itolizumab, an anti-CD6 IgG1 monoclonal antibody, for emergency treatment of cytokine release syndrome in patients with coronavirus disease 2019 (COVID-19).