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WHEN CHOICE ARRIVES: Competition & Consequences

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BIOSIMILAR APPROVALS

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The top gastroenterology biosimilar news from 2024 highlight fluctuations in the adalimumab biosimilar market throughout the year, while FDA and European approvals for ustekinumab biosimilars are set to improve access and reduce costs for patients with Crohn disease and ulcerative colitis.

The Top 5 Most-Read Gastroenterology Articles of 2024

Cameron Santoro is an associate editor for The Center for Biosimilars

Videos

Here are the top 5 biosimilar articles for the week of December 16, 2024.

The Top 5 Biosimilar Articles for the Week of December 16

China's trastuzumab biosimilar market is growing but lags behind European countries, with biosimilars gradually increasing market share and reducing costs despite initial barriers.

China's Biosimilar Market: Trastuzumab Uptake and Future Trends

The FDA approved Celltrion's Steqeyma (ustekinumab-stba), making it the seventh biosimilar slated to compete against blockbuster Stelara (reference ustekinumab) in 2025.

FDA Approves Steqeyma: The Seventh Stelara Biosimilar

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Providing an overview on where the healthcare reform debate is headed, Andrew Slavitt, former head of CMS, refined the discussion to highlight the potential for biosimilars to influence the rising costs of drug products.

Federal Perspective on the Biosimilar Influence on Drug Costs

During a panel on the second day of the 2017 AAM Biosimilars Council Conference, held in Washington DC, regulatory leaders from Pfizer and Sandoz shared their experiences with the development of their biosimilar products: epoetin alfa (Epogen) and etanercept (Erelzi), respectively.

Industry Regulatory Experts Share Learnings From the Biosimilar Approval Process

The approval for adalimumab-adbm comes a year after the first adalimumab biosimilar, by Amgen, was approved in September of 2016.

Competition Strengthens for Humira Market With Approval of Second Biosimilar

Janssen Moves to Block Marketing of Renflexis in Suit Against Samsung Bioepis

Senate Confirms Scott Gottlieb as FDA Commissioner

Amgen Gains EC Approval for Biosimilar to Adalimumab 

Mylan's Settlement With Genentech and Roche Opens US Market for Trastuzumab Biosimilar

New Mexico Senate Passes Bill for Biosimilar Substitution 

How Will the Genentech-Amgen Feud Bear Down on Biosimilar Development?

The biosimilar ocrelizumab candidate (Xacrel) was found to be equivalent to the originator product (Ocrevus) in reducing the annualized relapse rate and showed comparable safety and efficacy over 96 weeks in patients with relapsing multiple sclerosis (RMS), as confirmed in a 

The randomized, 2-armed, double-blind, phase 3 study from Iran (

, was conducted to assess the equivalency of the biosimilar ocrelizumab candidate to the originator product in reducing the annualized relapse rate (ARR) in patients with RMS, highlighting the importance of increasing patient access to effective, cost-efficient treatments for a disease that significantly impacts global health.

MS is an autoimmune disease affecting around 3 million people globally, characterized by immune cells attacking the central nervous system's myelin, leading to disability.

 MS can cause cognitive impairment, fatigue, and various other symptoms. It is classified into relapsing-remitting, secondary progressive, and primary progressive forms. High-efficacy disease-modifying therapies (DMTs) are used to manage MS, with B cell-targeting treatments like ocrelizumab showing effective results in reducing relapse rates. Biosimilars offer a way to increase access to MS treatments, especially in lower-income areas.

The study was conducted between August 2019 and October 2021 across 15 centers in Iran. It involved adult patients with RMS who met specific inclusion criteria. Participants were randomly assigned (1:1) to receive either 300 mg of Xacrel or Ocrevus for the first 2 doses (administered every 2 weeks), followed by 600 mg every 24 weeks for 96 weeks.

Prior to each infusion, patients received 100 mg intravenous methylprednisolone, an antihistamine (chlorpheniramine), and an antipyretic (acetaminophen) to minimize infusion reactions.

The primary goal was to evaluate the equivalency of Xacrel to Ocrevus in reducing the ARR at week 48. Secondary outcomes included disability progression, relapse-free patients at 96 weeks, and MRI changes in brain lesions. Safety was assessed through the incidence of adverse events (AEs) and infusion reactions.

Randomization was stratified by baseline disability status (EDSS), and participants were blinded to the treatment arm. Statistical analyses included Poisson regression, Cox regression, and Kaplan-Meier methods for the primary and secondary outcomes, ensuring equivalency between the 2 treatments.

A total of 170 patients were enrolled (85 per treatment group), with a 10% dropout rate accounted for. Patients had to be 18 to 55 years of age and have a history of at least 2 documented relapses in the last 2 years or 1 documented relapse in the last year before the screening visit.

The primary efficacy measure, the ARR at 48 weeks, showed similar results between the 2 groups. In the per-protocol (PP) set, the ARR for Xacrel was 0.067 (95% CI, 0.029-0.155), and for Ocrevus, it was 0.070 (95% CI, 0.031-0.158), with no significant difference (95% CI, −0.080 to 0.075; 

 = .95). The results were consistent in the intent-to-treat (ITT) set, where the ARR was 0.065 for Xacrel (95% CI, 0.028-0.149) and 0.068 for Ocrevus (95% CI, 0.030-0.153), again showing no significant difference (95% CI, −0.078 to 0.072; 

Over the 96-week period, the confirmed disability progression rate at 12 weeks was 7.06% for Xacrel and 5.90% for Ocrevus (

 = .71), and at 24 weeks, it was 7.06% for Xacrel and 2.35% for Ocrevus (

 = .16). Regarding relapse-free rates at 96 weeks, 89.41% of patients in the Xacrel group and 87.10% in the Ocrevus group remained relapse-free (

 = .63). In MRI assessments, the mean number of new or enlarging T2 hyperintense lesions was 0.16 for Xacrel (95% CI, 0.08-0.33) and 0.08 for Ocrevus (95% CI, 0.03-0.20), with no significant difference (

 = .21). The volume of T2 lesions decreased similarly in both groups (Xacrel, −0.60; Ocrevus, −0.70; 

Regarding safety, 97.65% of patients in both groups experienced at least 1 adverse event (AE), with infusion-related reactions being the most common. In total, 24 serious AEs (SAEs) were reported, with 6 in the Xacrel group and 15 in the Ocrevus group. There was no significant difference in the incidence of SAEs between the 2 groups. Serious infections occurred in both groups, including cases of coronavirus, pharyngitis, urinary tract infection, and appendicitis.

No positive samples for anti-ocrelizumab antibodies were found in the immunogenicity assessment, indicating no immunogenic response to Ocrevus. A post hoc analysis of ARR at 96 weeks revealed no significant difference (Xacrel, 0.122; Ocrevus, 0.124; 

 = .82), and the proportion of patients with CD19 levels below 1% at least once was similar between the 2 groups (Xacrel, 64.71%; Ocrevus, 63.53%; 

The study had limitations. The COVID-19 pandemic affected patient adherence and attendance at scheduled visits, potentially influencing results. Variability in MRI instruments between study centers could also have introduced inconsistencies in the MRI data. Despite these limitations, the results suggest that Xacrel is a viable alternative to Ocrevus in treating RMS.

1. Sahraian MA, Abolfazli R, Shaygannejad V, et al. Evaluating efficacy and safety of ocrelizumab biosimilar (Xacrel) compared to the originator (Ocrevus) in relapsing multiple sclerosis: a phase III, randomized, equivalency, clinical trial. 

. 2024;14(1):24921. doi:10.1038/s41598-024-75745-y

2. Global Regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the global burden of Disease Study 2021. 

2024;23(4):344-381. doi:10.1016/s1474-4422(24)00038-3

The phase 3 trial (NCT04966338) found that a biosimilar ocrelizumab candidate (Xacrel) was equivalent to Ocrevus in reducing the annualized relapse rate and showed comparable safety and efficacy in treating relapsing multiple sclerosis over 96 weeks.

Clinical

Business & Practice

Ocrelizumab Biosimilar Shows Equivalent Efficacy as Multiple Sclerosis Treatment

Here are the top 5 biosimilar articles for the week of December 2, 2024. 

 of affordable biosimilars, with varying impacts across different jurisdictions.

 that the aflibercept biosimilar MYL-1701P is as effective and safe as the reference aflibercept in treating diabetic macular edema (DME), offering a promising option for reducing treatment costs and improving global access to care for patients with DME.

 (NCT04966338) found that a biosimilar ocrelizumab candidate (Xacrel) was equivalent to Ocrevus in reducing the annualized relapse rate and showed comparable safety and efficacy in treating relapsing multiple sclerosis over 96 weeks.

 have multiple biosimilar competitors, but originator biologics respond quickly to competition by increasing rebates and lowering net prices, despite short approval-to-launch timelines for biosimilars.

Veterans with inflammatory bowel disease (IBD)

 prioritize shared decision-making, transparency, and individualized care in biosimilar switching, favoring delayed switching for severe cases and greater patient control.

To read all of these articles and more, visit 

Video Series

The Top 5 Biosimilar Articles for the Week of December 2

Biosimilars offer critical savings and increased access to treatments, but they face substantial barriers before reaching patients. This series for Global Biosimilars Week, a worldwide online biosimilar advocacy event hosted by the International Generics and Biosimilars Association, focuses on 3 major areas where obstacles limit access in the US:

Payer and pharmacy benefit managers (PBMs) policies

 is a media partner for Global Biosimilars Week 2024. Each article in this series will shed light on these barriers and suggest steps to enhance biosimilar access, affordability, and equity.

Dancing With the Companies: The Patent Dance and Biosimilars

The "patent dance" is a structured legal process unique to the biosimilar landscape in the US, designed to help streamline patent disputes between biosimilar manufacturers and reference product sponsors.

 Created as part of the Biologics Price Competition and Innovation Act (BPCIA) in 2010, the patent dance aims to expedite biosimilar entry into the market while balancing the interests of innovators who initially developed these complex biologic therapies.

Currently, the patent dance is a required part of the biosimilar approval pathway and involves an exchange of information regarding patents, infringement, and validity positions 

. This early assessment, often initiated even before any litigation is filed, allows the involved parties to pinpoint and discuss specific patents that might be contested, facilitating earlier settlement discussions and minimizing the scope of costly litigation.

Patent litigation is often resource intensive on both sides. 

 with The Center for Biosimilars, Ha Kung Wong, JD, an intellectual property attorney and partner at Venable, noted that the patent dance has been instrumental in promoting settlements, reducing the need for many cases to proceed to trial.

“The patent dance allows for an early assessment of infringement and validity positions... If you don’t have a problem with the patents, then you can launch without any risk... It’s led to a great number of settlements, very few of them go to trial, which means we're not wasting resources on litigation,” he said.

Although this system has proven effective in fostering negotiation and settlement—ultimately helping to speed up biosimilar market entry—it is not without its criticisms. Some industry stakeholders argue that the BPCIA framework could be further streamlined to make the process less cumbersome and more predictable for biosimilar developers.

 As it stands, however, the patent dance remains a pivotal aspect of the biosimilar approval process, as it narrows down relevant patents and reduces potential legal roadblocks, benefiting both biosimilar manufacturers and original biologic developers.

In essence, the current state of the patent dance in the biosimilar landscape reflects an ongoing effort to balance innovation protection with the need to improve market access and affordability for biologic therapies. This system, while complex, is considered one of the primary drivers of efficient biosimilar development in the US, fostering a competitive landscape that promises greater access to these critical medicines for patients.

But, is the patent dance working? Is it helping biosimilars? What needs to be done to ensure innovation and competition aren’t hindered?

Patent Disputes Leading to Delayed Entries

The US patent system allows drug companies to obtain preliminary patents to obtain market exclusivity on a particular product, as well as patents on aspects like the manufacturing process, device design, development process, and others. This enables companies to create a wall of patents—in some cases, over 100 patents—that can be very difficult for biosimilar and generic manufacturers to comb through.

This creates an environment where originator companies are almost guaranteed to sue their future biosimilar competitors, resulting in launch delays.

Product launch delays leave the door open for companies to enact product hopping, when drug companies shift demand from an innovator drug facing or about to face generic or biosimilar competition to new, patented versions.

Although the first patents for the reference product Humira expired in 2018, biosimilar versions were not allowed to enter the market until 2023, with most not being able to launch until the second half of the year.

Humira’s maker, AbbVie was able to use patent legislation and pay-for-delay deals to get biosimilar companies to postpone launch dates.

 These lawsuits resulted in mass settlements with all adalimumab biosimilar manufacturers coupled with the promise not to launch until 2023, with Amgen’s Amjevita (adalimumab-atto) being the first to launch. Amjevita launched at the end of January 2023, followed by 7 products in July, 1 in October, and 1 in 2024.

The adalimumab biosimilar market has the highest number of products competing against a single originator, and most of the products launched in a 6-month span, the effects of which the US is still trying to observe. Already the delays have enabled AbbVie to convert a lot of its patients from Humira to Skyrizi (rizankizumab-rzaa), another one of its products.

 Although adoption of adalimumab biosimilars has grown significantly throughout 2024, the adalimumab market as a whole is shrinking due to patients switching to another AbbVie product instead of a biosimilar, leaving the sustainability of biosimilars in this space and others in limbo.

Similarly, this has happened with ustekinumab biosimilars, which, thanks to multiple settlements with reference manufacturer Johnson & Johnson, will not launch in the US until early 2025.

 This was pushed back from the initial launch prediction of late 2023 or early 2024.

Aflibercept biosimilars also have been postponed due to litigation. However, in September 2023, a federal judge in West Virginia ruled that originator manufacturer Regeneron cannot immediately restrict Amgen’s US sales of a biosimilar to Eylea (reference aflibercept).

 Aflibercept biosimilars were supposed launch in 2024 but are now expected to start launching in 2025.

The postponement of ustekinumab, aflibercept, and other molecules creates an opportunity for companies to stifle competition and savings for patients by preventing access to lower-cost medications.

Additionally, patent litigation is very expensive for biosimilar manufacturers. Negotiation for settlements coupled with delayed profits from postponing a market launch can make pursuing biosimilar development very unattractive. In fact, 47% of the originator molecules with the potential to have biosimilars in the future do not have biosimilars in development, raising the question of whether companies will continue to see revenue potential from the biosimilar space.

Without policy reform and action, how can biosimilar companies keep up? And how can industry leaders prevent companies from feeling so discouraged by patent hurdles and delayed returns that they consider leaving the biosimilar market for good?

Several policy initiatives aim to promote fair competition in the pharmaceutical market, which is a start. In 2022, Congress directed the Federal Trade Commission (FTC) to address product hopping, leading to an FTC report that highlighted antitrust concerns with brand name companies’ efforts to obstruct competition between original and reformulated drugs.

In January 2023, Senators John Cornyn (R, Texas) and Richard Blumenthal (D, Connecticut) introduced the Affordable Prescriptions for Patients Act of 2023 (S 150).

 The bill, which passed the Senate in July 2024, would ban product hopping and cap the number of patents a brand company can assert against a generic or biosimilar manufacturer at 20, with specific rules for adding new patents. However, Wong questioned whether this would have a practical effect, noting that most lawsuits are based on fewer than 10 patents.

Alas, like most biosimilar reforms in Congress, these pieces of legislation have been stalled, often trapped in committee hearings or on desk holds. Wong commented on the prospect of policy reforms making it out of congressional limbo to address ongoing challenges with the patent system and biosimilars: "Predicting whether there will be statutory shifts or reform in patent law is like trying to predict what will happen in the next Fast & Furious movie—you have no idea what specifically is going to happen but it's probably going to have some explosions that ultimately, will not be applicable to the real world."

Wong recommends that policymakers and other industry leaders keep in mind how patent reforms will impact the entire system and ensure that new policies aren’t implemented haphazardly.

"Reforms, like limiting the number of patents that can be asserted in a patent litigation, might have some effect, but we haven't seen significant changes yet. The challenge is that patents are often filed early in the development process, so it's unclear whether reform would make a big difference for biosimilars unless there are substantial follow-through actions."

1. Menchaca A. The inner workings of the BPCIA patent dance. The Center for Biosimilars. July 24, 2021. Accessed November 7, 2024. 

https://www.centerforbiosimilars.com/view/the-inner-workings-of-the-bpcia-patent-dance

2. Jeremias S, Santoro C. Patent dance insights: a Q&A on reducing legal battles in the biosimilar landscape. The Center for Biosimilars. August 18, 2024. Accessed November 6, 2024. 

https://www.centerforbiosimilars.com/view/patent-dance-insights-a-q-a-on-reducing-legal-battles-in-the-biosimilar-landscape

3. Jeremias S. Biosimilars Council Position paper calls for end to clinical efficacy trials for biosimilars. The Center for Biosimilars. June 4, 2024. Accessed November 7, 2024. 

https://www.centerforbiosimilars.com/view/biosimilars-council-position-paper-calls-for-end-to-clinical-efficacy-trials-for-biosimilars

4. Hagen T. Biopharmaceutical industry representatives discuss product hopping legislation. The Center for Biosimilars. September 24, 2020. Accessed November 5, 2024. 

https://www.centerforbiosimilars.com/view/biopharmaceutical-industry-representatives-discuss-product-hopping-legislation

5. Vaidya M. AbbVie’s successful hard-ball with Humira legal strategy unlikely to spawn similar efforts; potential appeals outcome unclear. Pharmaceutical Technology. February 19, 2021. Accessed November 6, 2024. 

https://www.pharmaceutical-technology.com/comment/abbvies-successful-hard-ball-with-humira/?cf-view

6. Jeremias S. The age of adalimumab is upon us: how stakeholders can prepare. The Center for Biosimilars. June 28, 2023. Accessed November 6, 2024. 

https://www.centerforbiosimilars.com/view/the-age-of-adalimumab-is-upon-us-how-stakeholders-can-prepare

7. Jeremias S. Happy birthday adalimumab biosimilars: reflecting on the first year of US competition. The Center for Biosimilars. January 31, 2024. Accessed November 6, 2024. 

https://www.centerforbiosimilars.com/view/happy-birthday-adalimumab-biosimilars-reflecting-on-the-first-year-of-us-competition

8. Jeremias S. Skyrizi Overtakes Humira: “Product hopping” leaves biosimilar market in limbo. The Center for Biosimilars. November 7, 2024. Accessed November 7, 2024. 

https://www.centerforbiosimilars.com/view/skyrizi-overtakes-humira-product-hopping-leaves-biosimilar-market-in-limbo

9. Jeremias S. Amgen’s Stelara biosimilar delayed until 2025 after settling with J&J. The Center for Biosimilars. May 29, 2024. Accessed November 6, 2024. 

https://www.centerforbiosimilars.com/view/amgen-s-stelara-biosimilar-delayed-until-2025-after-settling-with-j-j

10. Jeremias S. Eye on Pharma: aflibercept legal drama; PBM, Humira biosimilars; denosumab regulatory review. The Center for Biosimilars. October 15, 2024. Accessed November 7, 2024. 

https://www.centerforbiosimilars.com/view/eye-on-pharma-aflibercept-legal-drama-pbm-humira-biosimilars-denosumab-regulatory-review

11. Biosimilars in the United States 2023–2027. IQVIA. January 31, 2023. Accessed November 7, 2024. 

https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/biosimilars-in-the-united-states-2023-2027

Federal Trade Commission Report on Pharmaceutical Product Hopping

. Federal Trade Commission. October 2022. Accessed November 7, 2024. 

https://www.ftc.gov/system/files/ftc_gov/pdf/p223900reportpharmaceuticalproducthoppingoct2022.pdf

13. Affordable Prescriptions for Patients Act of 2023, S 150, 118th Cong (2023). Accessed November 7, 2024. 

https://www.congress.gov/bill/118th-congress/senate-bill/150

Part 1 of this 3-part series for Global Biosimilars Week focuses on legal barriers to biosimilar access in the US, including the patent system, and discusses ongoing legislative efforts to address these challenges.

Breaking Down Biosimilar Barriers: The Patent System

The prevalence of inflammatory bowel disease (IBD; Crohn disease and ulcerative colitis) is rising, approaching 1% in Europe and North America. According to a recent 

, alongside this increase in prevalence, health care costs associated with IBD are also rising. The authors said that increase in prevalence combined with shifts in IBD care and higher hospitalization costs is increasing the burden on health care systems. They discussed the challenges to making IBD costs sustainable and strategies toward achieving personalized, cost-effective care for IBD.

Direct and Indirect Costs Associated With IBD

Direct costs associated with IBD include ambulatory visits to gastroenterologists, emergency department visits, admissions for hospitalization or surgery, diagnostics, and medications. Although hospitalization rates have decreased, direct costs have not because of a trend toward more complex disease with greater severity, and rising costs of inpatient care. The authors cited The Lancet Gastroenterology & Hepatology Commission which estimated direct health care expenses associated with IBD are $9,000 to $12,000 per person per year in high income regions. However, they noted “these estimates do not fully account for factors such as disease severity, accessibility, and variability in health care infrastructure among regions.”

They also described the US as an “outlier” in direct health care costs. In the US, drug prices on average exceed international prices by several-fold due to a lack of nationwide price regulation, the fragmentation of the health care system, prolonged market exclusivity periods, and confidential rebates negotiated between private insurers and pharmaceutical manufacturers. “Patients seldom benefit” from these rebates, the authors added.

Indirect costs include lost wages from missing work, reduced capacity at work, early retirement, premature death, delayed workforce entry, and not achieving educational or professional potential. Despite studies attempting to quantify indirect costs, the authors wrote, “many aspects remain poorly understood, leading to an underestimation of their actual impact.”

Challenges to Achieving Cost Sustainability

Challenges the authors cited to reducing IBD costs and achieving sustainability include disparities in access, treatment affordability, underinsurance, and a lack of standardized cost-effective care guidelines. Unplanned health care utilization, for example emergency department visits, “drives much of the cost in IBD care,” they wrote, and cited research suggesting that low-income status leads to less access to timely and effective care, leading to unplanned health care utilization, which has detrimental effects on both long-term health and costs. Also, lower income patients may delay or skip treatments or diagnostics with high out-of-pocket costs.

Strategies the authors recommended to reduce costs included early implementation of biologics, a focus on cost-effectiveness in settings with limited resources, and promoting the use of 

. They also recommended several patient monitoring strategies, such as using telemedicine and noninvasive biomarkers of disease activity. In addition to treatment strategies, such as 

 when appropriate, they recommended support strategies, such as using multidisciplinary care models that provide holistic care, promoting healthy lifestyle behaviors, and recognizing barriers to care faced by vulnerable populations. Regarding settings with limited resources, they commented that there are no guidelines for de-escalating or withdrawing biologics, which could help to reduce costs if developed.

There is a “clear benefit” for achieving remission to a top-down approach of starting biologic therapy early, the authors said. However, less than 20% of private insurance companies in the US permit biologics as a first-line therapy for IBD. They added that based on data from Canada and the Netherlands, whether cost savings from avoided hospitalizations and surgeries outweigh the costs of biologic drugs is unclear.

Biosimilars Limited by Patent Thickets and Market Dynamics

Biosimilar uptake in the US has been “relatively modest,” the authors said. One reason is patent thickets created by originator manufacturers to extend market exclusivity, which have limited market entry of biosimilars. Additionally, after market entry, reimbursement dynamics have limited biosimilar uptake, as manufacturers of originators often offer confidential discounts to payers to outcompete biosimilars.

Addressing the increasing direct and indirect costs of IBD “demands a comprehensive strategy, tackling disparities, access barriers, and cost-effectiveness of therapeutics,” the authors wrote. They added that policy reforms to improve access to IBD care will also be required: for example, reforming prior authorization processes, enhancing drug price transparency, and introducing value-based reimbursement structures.

Burisch J, Claytor J, Hernandez I, Hou JK, Kaplan GG. The cost of inflammatory bowel disease care - how to make it sustainable. 

. 2024:S1542-3565(24)00729-8. doi:10.1016/j.cgh.2024.06.049

Surabhi Dangi-Garimella, PhD

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