Skylar Jeremias

As the United Kingdom adds another oncology biosimilar to its collection, the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion for another ranibizumab candidate.

The United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA), the nation’s pharmaceutical regulatory agency post-Brexit, approved Celltrion Healthcare’s bevacizumab biosimilar (Vegzelma) for the treatment of various cancers.

 from Korea Biomedical Review, Celltrion received approval for all indications of the reference product (Avastin), including metastatic colorectal cancer, non-small cell lung cancer, metastatic renal cell cancer, cervical cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and metastatic breast cancer.

The approval comes after the European Commission gave its decision to 

 to Vegzelma for the markets within the European Union in August 2022.

Vegzelma marks the third oncology biosimilar developed by Celltrion to be approved in the United Kingdom, following the approvals for Truxima (rituximab) and Herzuma (trastuzumab). Celltrion plans to launch the biosimilar on the UK market “as soon as possible,” and gain approval for Vegzelma in the Republic of Korea and the United States later in 2022.

 for STADA Arzneimittel and Xbrane Biopharma’s ranibizumab biosimilar candidate (Ximluci) referencing Lucentis.

Ranibizumab products are used in patients with several retinal conditions including neovascular age-related macular degeneration (wet AMD), diabetic macular edema, diabetic retinopathy, retinal vein occlusion, and visual impairment due to choroidal neovascularization.

The CHMP’s positive opinion will be reviewed by the European Commission, which will decide whether or not to grant marketing authorization for the biosimilar. If approved, Ximluci will become the third ranibizumab biosimilar in the region.

“The positive opinion of the CHMP is a great milestone for Xbrane as it paves the way for approval of our first biosimilar candidate in Europe. We are pleased to be able to make available a more affordable treatment option for patients suffering from these severe eye diseases,” said Martin Åmark, CEO of Xbrane, in a company statement.

The CHMP’s opinion was based on data from a phase 3 clinical study that confirmed comparable safety and efficacy of Ximluci with Lucentis in 580 patients with wet AMD. The primary endpoint of the study was change from baseline to week 8 for best corrected visual acuity, which fell within the predefined equivalence margin.

STADA and Xbrane entered into a commercialization agreement in July 2018. Under the agreement, the 2 companies are both responsible for the development, manufacturing, and obtaining regulatory approval of the product in multiple global markets, including the European Union, the United States, countries in the Middle East and North Africa region, and several markets in the Asia-Pacific region.

Articles

Oncology, Ophthalmology Biosimilars Progress in Europe

 in Japan found similar pharmacokinetic (PK) and glucose pharmacodynamic (PD) parameters between the biosimilar SAR342434 (SAR-Lis, Sanofi) and the Japan-reference insulin lispro (Humalog) in healthy male participants.

Insulin lispro is a rapid-acting insulin analog used to treat adults and children with type 1 and type 2 diabetes. 

 was the first insulin lispro biosimilar authorized in the European Union in 2017 and in Japan in 2020. Although similar PK and PD parameters, efficacy, safety, and immunogenicity have been demonstrated between SAR-Lis and the US and EU reference products, Japan’s regulatory guidelines require that PK and PD similarity be shown between the biosimilar and the Japanese reference product.

The randomized, double-blind, crossover study included 36 healthy male participants. Following a single subcutaneous dose of SAR-Lis or the reference product, a euglycemic clamp held blood glucose stable for 10 hours, and the glucose infusion rate (GIR) required to maintain the stable glucose concentration was recorded. The primary PK endpoints measured were maximum plasma insulin lispro concentration (Cmax) and area under the insulin lispro concentration-time curve (AUC) from time 0 to the time of the last quantifiable data point (AUClast), and primary PD endpoints were area under the GIR-time curve from time 0 to 10 hours (GIR-AUC0-10h) and maximum GIR.

Pharmacokinetic and Pharmacodynamic Parameters “Similar Between Treatments”

For the primary PK and PD parameters, the investigators reported that all geometric mean ratios were close to 1, and the corresponding 90% confidence intervals (CI) for PK endpoints and 95% CIs for PD endpoints were within the equivalence range of 0.80 to 1.25. The geometric mean ratios were 0.99 (90% CI, 0.93-1.05) for Cmax, 1.00 (90% CI, 0.97-1.02) for AUClast, 1.07 (95% CI, 0.99-1.15) for GIR-AUC0-10h, and 1.07 (95% CI, 1.00-1.15) for GIRmax. Confidence intervals for secondary PK endpoints (AUC from time 0 to infinity, time to Cmax, and terminal half-life) also fell within bioequivalence margins of 0.80 to 1.25.

SAR-Lis and the Reference Product Were Well Tolerated

The authors reported no serious adverse events (AEs), AEs of special interest, or treatment-emergent AEs (TEAEs) leading to treatment discontinuation. Three mild or moderate TEAEs occurred, 2 after administration of the biosimilar and 1 after the reference product. None of these were considered related to the study medication. The authors also reported “few potentially clinically significant abnormalities in laboratory tests and ECG parameters, with no notable difference between SAR-Lis and [the reference product].”

The investigators concluded that the biosimilar and reference product “showed similar PK exposure profiles and PD potency” in healthy Japanese males, consistent with previous evidence in US and EU populations and providing evidence in support of the use of SAR-Lis as an insulin lispro biosimilar.

Shiramoto M, Yoshihara T, Schmider W, Takahashi Y, Nowotny I, Kajiwara M, Muto H. Similar pharmacokinetics and pharmacodynamics of biosimilar SAR342434 insulin lispro and Japan-approved Humalog insulin lispro in healthy Japanese subjects. 

. 2022;11(6):754-760. doi:10.1002/cpdd.1068

A phase 1 study in Japan found similar pharmacokinetic (PK) and glucose pharmacodynamic (PD) parameters between the biosimilar SAR342434 (SAR-Lis, Sanofi) and the Japan-reference insulin lispro (Humalog) in healthy male participants.

Biosimilar Insulin Lispro Shows Similar PK and PD Parameters to Humalog

Hi, I’m Skylar Jeremias for The Center for Biosimilars®, your resource for clinical, regulatory, business, and policy news in the rapidly changing world of biosimilars.

Here are the top 5 biosimilar articles for the week of September 12, 2022.

Number 5: As Alvotech’s biosimilars are included in a commercialization deal in the Philippines, the company 

 in its quest for FDA approval of its adalimumab biosimilar; the FDA gives EpiVax a $2 million grant to run immunogenicity testing for biosimilars.

 of this 4-part series took a look at what patients and employers can expect when adalimumab biosimilars hit the market in 2023.

Number 3: As part of a larger series preparing for the US market entrance of adalimumab biosimilars in 2023, Steven Lucio, PharmD, BCPS, senior principal of pharmacy solutions at Vizient, makes predictions for how the rollout of these biosimilars may play out and offers advice to stakeholders for how to 

 for an ustekinumab biosimilar, and Samsung Bioepis announced long-term safety and efficacy results for its adalimumab biosimilar.

Number 1: In a recent paper, Sarfaraz K. Niazi, PhD, argued that getting rid of clinical efficacy testing for biosimilars could 

 with current guidelines, save companies money on development, and improve data sensitivity.

To read all of these articles and more, visit 

Videos

The Top 5 Biosimilar Articles for the Week of September 12

Starting in 2023, patients receiving therapy with Humira (adalimumab) will have several lower-cost options available. As the year unfolds, between 7 and 12 adalimumab biosimilars will launch on the US market, and all are slated to be priced at a significant discount to the originator.

However, there are many aspects of this competition that are still flying under the radar. Will these lower prices be offered to patients? Will patients be forced to switch therapies? Is switching from a reference product to a biosimilar safe? How will interchangeability influence prescribing habits? What role can employers play in ensuring patient satisfaction and substantial savings?

 is looking at all aspects of what the launch of adalimumab biosimilars in the US market will mean for stakeholders, from lessons learned in other markets to the need to hear from providers who must decide whether to prescribe new products. This second installment in a 4-part series examines how the introduction of adalimumab biosimilars will impact patients and employers and the steps each group can take now to prepare.

Will Patients See Savings, and How Much Is Expected?

Projections show that adalimumab biosimilars could generate 

 in savings by 2025, a 50% share of the total amount of saving expected from biosimilars between 2021 and 2025. However, whether those savings will impact patients directly depends on a few things:

Price discounts of biosimilars and reference products

As biosimilars enter the market, companies developing these competitors will have to set launch prices, which will likely be considerably lower than Humira. Additionally, AbbVie, the maker of Humira, will also have to determine whether to lower its price for Humira to compete against the biosimilars.

Overall, list price discounts for biosimilars average about 30% to 40% lower than the reference products. However, biosimilars in the US immunology space, such as those referencing Remicade (infliximab) tend to launch at a 

In Europe, where 10 adalimumab biosimilars compete against Humira, there’s more hope for biosimilar discounts. One analysis published by 

 showed that after the first quarter of 2020, when compared with the Humira’s list price 1 year before biosimilar market entry, adalimumab biosimilars averaged net price reductions from the reference product ranging from 15% to 29% in France to 

 in Denmark, Germany, Hungary, Italy, Poland, and Sweden.

Even more impressive, the threat of biosimilar competition has been enough to get AbbVie to lower its price for Humira 

However, for the first 6 months of biosimilar competition, Humira will only face 1 competitor, making it difficult to tell exactly how much of a price reduction biosimilars will cause in the long run. In July 2023, between 5 and 9 biosimilars are expected to launch. Many biosimilar companies will have less time to gauge the market to determine a launch price.

 the US price of Humira over the past few years, increasing its wholesale acquisition cost by 7.3% and its net price by 9.6% between 2019 and 2020.

 can be a tricky field to navigate because they are determined by health insurers, also known as payers. Co-payments, or co-pays, are fixed dollar amounts that patients pay for many prescription drugs and health services such as office visits, and often do not count toward a deductible. Coinsurance costs, which act as a cost sharing measure between patients and payers, are calculated as a percentage of the cost of some medicines and health services that patients must pay after they meet their deductible.

For Medicare beneficiaries, cost sharing gets even more 

. For most, adalimumab would be covered under Part D, but some beneficiaries may be covered under Part C if they are enrolled in Medicare Advantage or even Part B if they receive treatment in a doctor’s office. Historically, cost sharing varies over the year as out-of-pocket spending hits certain benchmarks.

Assuming prices of adalimumab biosimilars and Humira are lower than the current prices of Humira, patients with plans using coinsurance will likely see lower out-of-pocket costs. Additionally, a report from the 

 (ERIC), found that US patients who took a covered biosimilar over the reference product paid an average of 12% to 45% ($300 to $600) less out-of-pocket annually than those who took the reference product.

 for insulin, so far, they only apply to patients enrolled in Medicare Part D plans. The Inflation Reduction Act, signed August 16, 2022, creates a 

 on out-of-pocket spending in Part D starting in 2025, although this provision awaits a rulemaking process. Again, this cap does not extend to commercial plans.

Some pharmaceutical companies may offer co-pay assistance programs that can help patients afford medicines and encourage them to maintain loyalty to their drug. However, patients should check with their insurance providers, as some may exclude co-pays paid through patient assistance programs or drug company-issued coupons from 

Additionally, some insurance companies, such as Cigna, have implemented 

. Cigna, for example, offered patients a $500 debit card to switch to biosimilars. The program was designed to encourage patients to ask for biosimilar versions of expensive originators, saving both the patients and the plans money.

How Will Coverage Work? And Will There Be Changes?

Patients should be aware that their pharmaceutical coverage may change, meaning that patients currently on a therapeutic regimen with Humira may suddenly be given a biosimilar.

Coverage options are dictated by a pharmacy benefit manager (PBMs), a third-party entity that makes decisions on which drugs will be included on formulary lists and which preference tiers they fall on, which correspond with their level of coverage. As a result, every insurance plan may have a different list of adalimumab products that may be covered.

Vizient’s Pharmacy Market Outlook Report

, plans will cover adalimumab products in 1 of 3 ways: preference for biosimilars, preference for the reference product, or coverage for the reference product and biosimilars at parity (no preference). Patients will not have much of a say in which strategies their plans will implement. Additionally, different plans may have different policies on 

 patients or their providers on coverage changes.

However, if patients see that their Humira prescription has changed to another adalimumab product, they should try not to worry. The FDA has some of the strictest guidelines in the world for approving a biosimilar, and every FDA-approved biosimilar has met the agency’s standards.

 have demonstrated the safety of switching from a reference product to a biosimilar. Early studies have also shown that switching from a 

 does not impact clinical outcomes. In many cases, if a patient does experience negative clinical outcomes from the result of a switch, they can talk to their doctor about switching back to the original product.

Employers and patients can also look at international experiences to see how switching from reference products to biosimilars has not disrupted clinical outcomes. Many 

 have experience with biosimilar switching, and clinical outcomes have not been compromised as a result.

If a patient wants to save money by using a biosimilar, they should talk with their physician to understand their options.

As discussed in the first article in this series, 

 is a US regulatory designation that allows for reference products to be substituted at the pharmacy level without requiring permission from a physician prior to dispensing. The FDA awards this designation when companies submit data from switching studies, in which patients are switched back and forth between the biosimilar and the reference product several times to establish that switching is safe and doesn’t impact clinical outcomes.

Interchangeable biosimilars allow patients to have easier and accelerated access to lower-cost biologic drugs by alleviating prior authorization requirements; the designation prevents patients from waiting long periods for their biosimilar prescription to be approved.

An interchangeable biosimilar is not better or safer than a biosimilar without the designation.

 The clinical safety and effectiveness are the same. Interchangeability only impacts the requirements for pharmacists before dispensing a biosimilar to a patient.

 have an interchangeability designation. Two have not entered the market yet, 

 more companies are seeking an interchangeable designation for their respective adalimumab biosimilars, signaling that more are expected to reach the market.

Although the United States doesn’t have much experience with interchangeable biosimilars, every state and the District of Columbia has implemented laws on interchangeability. Most states have passed legislation that requires pharmacists to notify providers and/or patients that an interchangeable biosimilar is substituting for the reference product listed on the prescription (

). Every state gives physicians the power to deny substitutions. Many allow for providers to write “dispense as written” or “brand medically necessary” on the prescription.

However, 4 states (South Carolina, Indiana, Alabama, and Washington) have laws that restrict interchangeability, meaning that every prescription must be approved by a physician prior to dispensing regardless of whether the FDA has deemed the product to be interchangeable. Providers may indicate on prescriptions that substitutions are permitted.

Additionally, the laws in Mississippi and Idaho for alerting patients and providers are expected to expire July 1, 2026, and July 1, 2025, respectively. So far, there is no sign that a law will be passed as a replacement.

Those who wish to know more about the specific language in the laws from their state can visit Cardinal Health’s 

How Much Can Employers Save and What Can They Do?

 in 2018 had they completely ceased use of Remicade (reference infliximab) and Neupogen (reference filgrastim) in favor of biosimilars.

 has already saved $5 million by switching patients to 5 biosimilars.

Despite how much power PBMs and other health care entities have over coverage options, employers have more power than they realize.

“If we look at the way the health insurance markets are today, they're driven by the employers…. As large employers switch, you have that double effect of one; they're moving a large population toward more-affordable drugs—that is a beneficial impact—but [you also have] the secondary impacts of news stories that come from it and the awareness that those drive other large, as well as smaller, payers towards embracing biosimilars,” said Wayne Winegarden, PhD, senior fellow in business and economics at the Pacific Research Institute (PRI), director of PRI’s Center for Medical Economics and Innovation, and a member of The Center for Biosimilars®’s Advisory Board, in 

Already, large employers and benefit funds, such as 

, have analyzed how much they were paying for biologic drugs, negotiated with their payers, and have worked hard to drive more patient use of biosimilars and generate savings.

Employers can advocate for policy changes that promote biosimilar use by contacting federal and state legislators to encourage them to support biosimilars legislation, such as the 

National Alliance of Healthcare Purchaser Coalitions

 outlined several steps that employers can take to get biosimilars on formulary and improve employee satisfaction. They include:

Creating an additional tier or preferred reimbursement for biosimilars and reference products or adding biosimilars to the branded tier without having to change cost-sharing or co-pay models

Ending relationships with PBMs and payers that have spread misconceptions about biosimilars being more expensive and less safe than reference products and search for those that are more transparent

Include all biosimilars on formulary and offer incentives for their use over reference products

Explore a precision-medicine model to help patients receive the right treatment on the first try

Employers may need to be persistent during negotiations, as many biosimilars may be on the medical benefit; this 

 more preparatory work to ensure that cost share is lower or nonexistent.

Overall, employers spend around 40% to 50% of their health care costs on specialty medications, including adalimumab. Employers can also work with employer support organizations, such as 

, which helps employers oversee pharmacy plan performance and secure health benefits that can help patients and save them money.

Coghlan J, He H, Schwendeman AS. Overview of Humira® biosimilars: current European landscape and future implications. 

. 2021;110(4):1572-1582. doi:10.1016/j.xphs.2021.02.003

Parekh KD, Wong WB, Zullig LL. Impact of Co-pay Assistance on Patient, Clinical, and Economic Outcomes. 

. 2022;28(5):e189-e197. doi:10.37765/ajmc.2022.89151

Biosimilar interchangeability laws by state. Cardinal Health. Updated July 2021. Accessed August 5, 2021. 

https://www.cardinalhealth.com/content/dam/corp/web/documents/publication/Cardinal-Health-Biosimilar-Interchangeability-Laws-by-State.pdf

Part 1: Biosimilars to Bring a Bumper Crop of Adalimumab Options

Podcast 1: What Will Year 1 Look Like for Adalimumab Biosimilars?

The second part of this 4-part series looks at what patients and employers can expect when adalimumab biosimilars hit the market.

Part 2: For Patients and Employers, 2023 Means a Changed Landscape  

As Alvotech’s biosimilars are included in a commercialization deal in the Philippines, the company hits a setback in its quest for FDA approval of its adalimumab biosimilar; the FDA gives EpiVax a $2 million grant to run immunogenicity testing for biosimilars.

Reykjavik, Iceland–based Alvotech received a complete response letter (CRL) from the FDA for its biologics license application (BLA) for AVT02, the company’s adalimumab biosimilar referencing Humira.

The letter focused on a filed manufacturing facility inspection in March 2022. The CRL noted “deficiencies related to the Reykjavik facility and states that satisfactory resolution of the deficiencies is required before FDA may approve this BLA,” according to Alvotech’s 

Alvotech expressed that it will address the issues mentioned in the CRL and will continue to work with the FDA to complete the facility inspection. Mark Levick, Alvotech’s CEO, said that it still anticipates to get approval prior to its planned 

The company is looking to obtain regulatory approval and an 

 for AVT02, and the FDA is currently reviewing BLAs for both. AVT02 is available in 

Additionally, some of Alvotech’s biosimilars have an opportunity to reach a new market. As part of a commercialization agreement between Lupin Limited and DKSH, patients in the Philippines will have 

 developed by Alvotech. The agreement will apply for biosimilars referencing Prolia/Xgeva (

Multicare Pharmaceuticals, Lupin’s subsidiary in the Philippines, will be responsible for obtaining marketing approval in the country and will have the distribution and commercialization rights for the biosimilars upon approval. The biosimilars will be used to treat several bone conditions, cancer types, immune conditions, and retinal diseases.

DKSH is one of Alvotech’s commercial partners in several Asian markets, including Taiwan, Hong Kong, Cambodia, Malaysia, Singapore, Indonesia, India, Bangladesh, and Pakistan.

EpiVax Secures Funding for Immunogenicity Testing

EpiVax, a Providence, Rhode Island–based company, announced that it has received a 2-year, $2 million grant from the FDA’s Officer for Center for Drug Evaluation and Research (CDER) for immunogenicity testing of biosimilars.

The analyses will validate a method for immunogenicity risk assessment of host cell proteins (HCPs) for improving the development process of biosimilar candidates and assessing the interchangeability of biosimilars. EpiVax will begin its research in September 2022 and will finish in August 2024.

“[HCPs] have strong potential to enhance immunogenicity of biological therapeutics. Rapid and accurate methods for identifying of higher risk and lower risk HCP will permit drug developers to improve the safety profile of their biologic products,” said Amy Rosenberg, MD, senior director of immunogenicity of biological therapeutics at EpiVax, in a 

The grant will help EpiVax assess in silico tools for screening and triaging HCPs to see whether they “induce an unwanted immune response” in patients receiving a biosimilar. Preclinical validation of in silico tools and ensuring patient access to them could improve the safety of biologic drugs and accelerate the assessment process of immunogenicity risk for biosimilars.

Eye on Pharma: Good News, Bad News for Alvotech; EpiVax Secures FDA Grant for Biosimilar Testing

In 2023, between 7 and 10 adalimumab biosimilars referencing blockbuster drug Humira will finally enter the US market. This is most biosimilars the United States has ever had for the same reference product, and they’re all coming out in a short amount of time, meaning that everyone is wondering exactly how this is going to play out. 

This summer, Vizient, a member-owned health care consulting company, published its Pharmacy Market Outlook report for 2022. The report provided insight into the current status of the US biosimilar market place and broke down some of the key aspects stakeholders should keep an eye on as the United States enters a new phase of biosimilar competition.

 welcomes Steven Lucio, PharmD, BCPS, senior principal of pharmacy solutions at Vizient. Prior to his work with Vizient, Dr. Lucio practiced for almost 10 years within the Baylor Health Care System in various settings, including ICU clinical pharmacy and geriatric ambulatory care. Dr. Lucio has been working with Vizient on its Pharmacy Market Outlook report, which makes several predictions for how the biosimilar market is expected to develop in the near future, including how the first year of adalimumab biosimilars in the United States may play out.

This special episode is part of a larger series called “WHEN CHOICES ARRIVE: Competition & Consequences,” consisting of 4 articles and 2 podcasts. The series delves into everything that stakeholders need to know as everyone prepares for the 2023 introduction of adalimumab biosimilars.

 of the series are available now. Readers can expect podcast 2 on September 25 and part 4 on September 27.

To read part 1 of this series, “Biosimilars to Bring a Bumper Crop of Adalimumab Options,” click 

To read part 2 of this series, "Part 2: For Patients and Employers, 2023 Means a Changed Landscape," click 

To read more about Vizient’s Pharmacy Market Outlook report, click 

To read more about Vizient’s provider survey, click 

Podcasts

As part of a larger series preparing for the US market entrance of adalimumab biosimilars in 2023, Steven Lucio, PharmD, BCPS, senior principal of pharmacy solutions at Vizient, makes predictions for how the rollout of these biosimilars may play out and offers advice to stakeholders for how to maintain a robust market.

What Will Year 1 Look Like for Adalimumab Biosimilars?

 of enoxaparin sodium biosimilar Cloti-Xa found anti-factor Xa and anti-factor IIa activity within predefined bioequivalence margins in healthy participants, supporting biosimilarity.

 sodium, a low-molecular weight heparin (LMWH), is an antithrombotic medication used to treat or prevent arterial and venous thromboembolism, such as in deep vein thrombosis, pulmonary embolism, and acute coronary syndrome. Producing LMWH biosimilars “is a challenging task,” according to the authors: because of structural variability between molecules, different LMWHs tend to differ in their pharmacokinetic (PK) and pharmacodynamic (PD) properties.

The study compared a single dose of the biosimilar (Cloti-Xa; Venus Remedies Limited, India) to the originator (Clexane, Lovenox) in healthy volunteers in a randomized, double-blind, crossover study. Under fasting conditions, 24 male participants (mean age 35) were randomly administered subcutaneous injections of the biosimilar and reference product, separated by a 1-week washout period. Blood samples were taken multiple times over 24 hours after administration of the study drugs.

According to the investigators, pharmacokinetics of LMWHs cannot be assessed with conventional methods. As such, PK properties and bioavailability of LMWHs are typically determined using pharmacodynamic (PD) surrogates such as anti-Xa activity, anti-IIa activity, and activated partial thromboplastin time (aPTT). In line with European Medicines Agency (EMA) recommendations, the authors measured anti-Xa and anti-IIa as the primary PD endpoints to compare the biosimilar to the reference LMWH. Secondary parameters included the ratio of anti-Xa/anti-IIa activity, tissue factor pathway inhibitor (TFPI) activity, and aPTT.

Pharmacodynamic Parameters Met Criteria for Bioequivalence

The 90% confidence intervals (CIs) of the ratio of the primary PD parameters of the biosimilar to reference product were all within the predefined bioequivalence margins of 80% to 125%. For anti–Xa activity, the 90% CI for maximum activity (Amax) was 105.50% to 113.90%, and for area under the effect curve from 0 to the last measured activity (AUECt), the 90% CI was 103.97% to 112.08%. For anti-IIa activity, the 90% CI for Amax was 106.56% to 117.90% and the 90% CI for AUECt was 107.35% to 124.86%.

The authors noted that enoxaparin has a large ratio of anti-Xa to anti-IIa, and its anticoagulant effect correlates directly with its anti-Xa activity. They found that the CIs for the ratios of anti-Xa to anti-IIa activity were also within the bioequivalence margins, 95.05%-100.62% for Amax and 86.21%-100.75% for AUECt.

Secondary PD endpoints “compared well” between the 2 products, the authors said. Also, they submitted data on TFPI activity and aPTT as supportive evidence for biosimilarity, which they said were similar between the 2 products. All of the 90% CIs for TFPI and aPTT were within the bioequivalence margins except for AUECt for aPTT, which crossed the upper limit (95% CI, 98.80-129.14).

Cloti-Xa Was Well-tolerated By Healthy Subjects

Both the biosimilar and reference product were “well-tolerated” by the study subjects. Two adverse events (AEs) were reported, both of which were mild. One was a decrease in platelet count, possibly related to the study drug (Cloti-Xa). The other AE occurred in the originator group, but was considered unlikely to be related to the study drug. There were no serious AEs.

The authors concluded that Cloti-Xa showed bioequivalence to the reference product after a single dose in healthy volunteers. They wrote that dose they used “has been found effective irrespective of the human body weight,” and was sufficient to demonstrate bioequivalence. However, they recommended higher doses be used in future bioequivalence studies, as previous clinical trials on other enoxaparin compounds have been conducted using multiple doses.

Saxena S, Chaudhary M, Chaudhary S, Aggarwal A. Bioequivalence of a biosimilar enoxaparin (Cloti-Xa™) and its innovator (Clexane® ): A single-dose, randomized, double-blind, two-period, two-treatment, two-sequence, crossover, balanced study in healthy human subjects. 

. 2022;10(4):e00979. doi:10.1002/prp2.979

A phase 1 study of an enoxaparin sodium biosimilar Cloti-Xa established similar pharmacodynamics and pharmacokinetic profiles with the reference product (Clexane, Lovenox) in healthy participants.

Phase 1 Study Demonstrates Bioequivalence Between Enoxaparin Biosimilar vs Reference Product

Number 5: In advance of the World Health Organization (WHO) updating its guidelines for biosimilar development, a review article concluded that comparative clinical efficacy and safety studies 

, The Center for Biosimilars® offers specifics for each of the adalimumab biosimilar products coming in 2023 and explains why the experience in Europe may differ from what’s coming in the United States.

 of its pegfilgrastim biosimilar referencing Neulasta, making it the sixth pegfilgrastim biosimilar to be approved in the United States.

Number 2: Thanks to the success of its adalimumab biosimilar in Canadian and European markets, Alvotech’s revenues reached 

 during the first 6 months of 2022, nearly 20 times more than its revenue from the same period in 2021.

Number 1: Ivo Abraham, PhD, chief scientist of Matrix45 and a professor at the University of Arizona, described the 

 and the savings potential for practices and payers if they prioritize greater biosimilar adoption.

Here are the top 5 biosimilar articles for the week of September 5, 2022.

The Top 5 Biosimilar Articles for the Week of September 5

In a recent paper, Sarfaraz K. Niazi, PhD, argues that getting rid of clinical efficacy testing for biosimilars could realign testing ethics with current guidelines and save companies money on development.

, could serve as a guide for policy makers to remove or replace requirements for clinical efficacy testing for biosimilars, describing the issues with this form of testing, suggestions for policy and guideline changes, and comparisons between the US regulatory system and the rest of the world.

The paper also comes as the World Health Organization prepares to update its guidance on clinical efficacy testing and a 

 that clinical efficacy testing may not be necessary to establish the safety and efficacy of bioismilars.

Niazi noted the slow acceptance that generic drugs faced when they first entered the market, during which companies were required to establish bioequivalence in healthy subjects. Later, the FDA accepted waivers of bioequivalence testing for generics once it realized that drug with high solubility and permeability don’t need to be tested. Niazi claimed that “when the biosimilars arrived, the history was repeated.”

“Since this is the first time we have faced this type of equivalence testing, it is taking longer to act,” he wrote. "These walls of resistance are falling slowly, but they need to come down quickly to enable biosimilars to find their place in assuring the affordability of lifesaving drugs."

The FDA has taken a number of steps to expedite the biosimilar approval process, including extending Q&A presentations, revising draft guidance, and updating the Frequently Asked Question section of the Purple Book. However, the FDA is subject to the provisions passed in the Biologics Price Competition and Innovation Act (BPCIA), including the requirement for clinical efficacy testing.

Some language in the BPCIA states that biosimilar approvals can be based on pharmacokinetic (PK) and pharmacodynamic (PD) data without a comparative clinical safety and efficacy analysis. Niazi mentioned how clinical efficacy analyses are often “redundant and unacceptable” for demonstrating biosmilarity and suggested for developers to challenge requirements. However, changes in the FDA guidelines can’t happen without rule changes, which can’t happen without a lot of political work.

According to Niazi, clinical efficacy studies 

 relevant information on biosimilarity or provide information that has already been established in other analyses. Clinical studies are also very expensive to developers, accounting for about 70% of the cost companies spend to develop biosimilars, costing about $150 million to $300 million.

Additionally, Niazi argued that clinical analyses violate the US provision that advises against unnecessary human testing, and since clinical efficacy studies are often least sensitive testing, their use creates ethical concerns.

Niazi wrote about some of the testing guidelines that other global entities have established. Although the European Union requires efficacy testing even with PD and PK data available, the region operates on a case-by-case basis, which it is able to do because the European Medicines Agency doesn’t require legislative action to make such changes.

The World Health Organizations revised its guidelines but refused to waive its recommendation for efficacy and safety study. When the United Kingdom finalized its guidelines in May 2022 after Brexit, it said that biosimilars would be evaluated on a case-by-case basis to evaluate whether clinical efficacy studies are needed. However, many countries treat biosimilars like generics and approve biosimilars without clinical testing.

Niazi gave some alternatives that would be better for confirming biosimilarity of biosimilars compared with their reference products, including:

He also called for sweeping regulatory changes around the world and predicted that developers will adopt newer testing methodologists that are more sensitive than clinical efficacy studies to establish similarity between 2 products.

Niazi concluded, “If a biosimilar product is well-characterized and demonstrates a highly similar clinical pharmacology profile, it should be safe and effective. Adding an efficacy study that is much less sensitive to identify is superfluous….But it will make biosimilars safer and more affordable. There is a dire need for the harmonization of biosimilars approval guidelines to remove many misconceptions, both at the regulatory agency and developer levels.”

Niazi SK. Scientific rationale for waiving clinical efficacy testing of biosimilars. 

. 2022;16:2803-2815. doi:10.2147/DDDT.S378813

In a recent paper, Sarfaraz K. Niazi, PhD, argues that getting rid of clinical efficacy testing for biosimilars could realign testing ethics with current guidelines, save companies money on development, and improve data sensitivity.

Getting Rid of Clinical Efficacy Testing for Biosimilars Is Needed, Ethical

Celltrion Healthcare released positive data for an ustekinumab biosimilar referencing Stelara and Samsung Bioepis announced long-term safety and efficacy results for its biosimilar referencing Humira (adalimumab). Both sets of data will be presented at the European Academy of Dermatology and Venereology Congress 2022 in Milan, Italy.

Samsung Bioepis shared data from a 3-year follow-up analysis of its adalimumab biosmilar (SB5; Hadlima) in patients with moderate to severe psoriasis.

The data was compiled from the British Association of Dermatologists Biologics and Immunomodulators Register, which is a registry for the United Kingdom and Ireland that assesses the long-term safety of biologics used to treat psoriasis. Samsung Bioepis has been participating in the registry since May 2016.

The study featured 1059 patients with psoriasis who were treated with SB5 between June 1, 2019 and August 31, 2021. After 3 years of therapy, the persistence rate for the cohort was 72.1%.

Therapy was discontinued for 275 out of 1096 treatments (25.1%). The mean (SD) duration of time that patients were on therapy was 19.3 (9.1) months. The cumulative persistence rate of SB5 at 1-year was 79.7%. At year 2, it was 73.5% and at year 3, it was 72.1%.

Jin Ah Jung, director of Medical Affairs Group at Samsung Bioepis commented on the results in a 

, saying, “Long-term real-world data on the effectiveness and safety of adalimumab biosimilars in psoriasis is limited, and study results from BADBIR demonstrate that SB5 is just as safe and effective as its reference adalimumab…. We hope that our continued efforts in providing real-world data help physicians and patients gain confidence in biosimilars.”

SB5 was granted marketing authorization in the European Union in August 2017, where it is marketed as Imraldi. Samsung Bioepis has a commercialization agreement with Biogen for the biosimilar, which gives Biogen the exclusive marketing rights to Imraldi along with Benepali (etanercept biosimilar; SB4) and Flixabi (infliximab biosimilar; SB2) throughout the European Union.

The low-concentration formulation of Hadlima was approved by the FDA in July 2019 and the 

 (Hadlima HCF) was approved in August 2022. Both formulations of the biosimilar will launch in July 2023 along with 5 or 6 others, depending on if the FDA also approves Alvotech’s candidate (AVT02) and Celltrion’s biosimilar (Yuflyma). Although the low-concentration Hadlima will have citrate, Hadlima HCF will be citrate-free.

Samsung Bioepis is currently testing Hadlima in switching studies so that it can apply for an interchangeability designation in the United States. However, the approval for interchangeability is expected after the products launches on the market.

Celltrion Results for Ustekinumab Biosimilar

Celltrion Healthcare released positive data for an ustekinumab biosimilar, and Samsung Bioepis announced long-term safety and efficacy results for its adalimumab biosimilar.