Cameron Santoro is an associate editor for The Center for Biosimilars

Cameron Santoro

Dermatologist examining skin | Image Credit: fusssergei - stock.adobe.com

 found comparable efficacy, safety, pharmacokinetics (PKs), and immunogenicity between Stelara, the ustekinumab originator, and the biosimilar candidate, CT-P43 for patients with moderate to severe plaque psoriasis.

Patients varied among 34 different centers across Estonia, Poland, Ukraine, and the Republic of Korea to participate in 2 treatment periods ranging from January 2021 to November 2021. Treatment period I randomized patients to receive either the originator ustekinumab or CT-P43 from baseline to week 16. Treatment period II rerandomized patients to either continue receiving the originator, continue CT-P43, or switch from the originator to CT-P43 from week 16 to week 40. Eligible patients were 18 to 80 years old with more male patients than female in both the originator (male, n = 173, F: 80) and CT-P43 (M: 161, F: 95).

A total of 509 patients participated in treatment period I with 253 receiving the originator and 256 receiving CT-P43. Drug administration took place at week 0 and week 4 where patients less than or about 100 kg received 45 mg doses while patients more than 100 kg received 90 mg doses.

Treatment period II randomized patients to continue the originator, switch to CT-P43, or continue CT-P43 from week 16 to week 40 (n = 125, 124, 253, respectively). Drug administration took place at weeks 16, 28, and 40 with doses adjusted at week 16 pre-dose to reflect any weight changes. Near the end of the study, 3 patients discontinued CT-P43 in the continued group (n = 250) and 2 patients discontinued treatment in the originator group (n = 123) while the switched group did not have discontinuations.

Efficacy results were comparable among treatment periods in improved Psoriasis Area and Severity Index (PASI) scores. At baseline, the average PASI score was 21.51 in the CT-P43 group and 20.88 in the ustekinumab group. At week 12, the proportions of patients who achieved PASI scores of 50/75/90/100% were 86.05 for CT-P43 and 83.99 for ustekinumab. By week 28, the proportions of patients who experienced improvements in their PASI scores were 92.55% in the continued ustekinumab group, 95.07% in the continued CT-P43 group, and 92.86% in the switched groups.

Efficacy endpoints included patients’ Dermatology Life Quality Index (DLQI) score with patients in the CT-P43 group (DLQI, 13.2) and the originator group (DLQI, 11.9) at baseline. By week 12, the mean changes from baseline in DLQI score were –9.7 and –8.5 for CT-P43 and the originator groups, respectively. At week 28, the continued CT-P43 group, continued originator group, and the switched to CT-P43 group had mean DLQI score changes of –10.9, –8.8, and –9.4, respectively.

Safety was evaluated based on treatment-emergent adverse events (TEAEs) where 18 patients in CT-P43 and 15 in the originator groups experienced at least 1, none leading to discontinuation. Treatment-emergent serious adverse events (TESAE) were present in 4 patients in each group. The continued CT-P43 group, continued originator, and switched to CT-P43 group had 4, 5, and 6 patients, respectively, with a drug experience related to TEAE but no TESAEs. The majority of TEAEs were grade 1-2 in intensity. Baseline injection-site reactions (ISRs) 3 patients in the biosimilar group and 2 in the originator group, but 0 patients in the continued groups experienced them. Those who switched to CT-P43 had an ISR in 2 patients.

Three patients discontinued the study drug in the biosimilar group and 4 discontinued in the originator ustekinumab group.

PKs were consistent with serum ustekinumab concentrations at all timepoints measured. Treatment groups and dose were generally similar, including after transitioning from originator to biosimilar candidate or vice versa.

Regarding immunogenicity, patients in the CT-P43 group had lower results of positive antidrug antibodies (ADAs) compared with the originator in treatment period I. No major change in ADA frequency occurred in period II. By week 28, ADA positive patients included 26 in the CT-P43 group, 21 in the continued reference product group, and 22 who switched to CT-P43. Treatment period I had slightly lower ADA-positive serum concentrations vs ADA-negative subgroups among both treatment II groups. There were no correlations in treatment period I between ADA positivity and TEAEs, TESAEs, ISRs, or hypersensitivity reactions.

Limitations included singular focus on the switch rather than the absence of multiple switch combinations throughout the study design. Patients and other investigators remained blinded but staff administering drugs could not be blinded. The study also took place during the COVID-19 pandemic and excluded patients with protocol deviations.

Papp KA, Lebwohl MG, Thaçi D, et al. Efficacy and safety of candidate biosimilar CT-P43 versus originator ustekinumab in moderate to severe plaque psoriasis: 28-week results of a randomised, active-controlled, double-blind, phase III study. 

. 2024;38(1):121-131. doi:10.1007/s40259-023-00630-5

Articles

Similar efficacy, safety, pharmacokinetics, and immunogenicity were found when comparing Stelara, originator ustekinumab, and CT-P43, an ustekinumab biosimilar candidate, in patients with moderate to severe plaque psoriasis.

Biosimilar Candidate CT-P43 Shows Biosimilarity With Ustekinumab Originator in Plaque Psoriasis

Ha Kung Wong, JD 1

, Ha Kung Wong, JD, is a lawyer practicing general intellectual property law, emphasizing patent and trade secret litigations. Wong negotiates for mergers, acquisitions, vendor agreements, and collaborations in pharmaceuticals, biologics, chemistry, medical devices, digital health, and artificial intelligence. He has represented Alkermes, Allergan, Alnylam, Materia, Shionogi, Stemline, UCB, and Bill & Melinda Gates Foundation and Gates MRI as clients.

This interview for the Center for Biosimilars

 focuses on Wong's perspective of the patent legal system, the importance of this process, and how it affects biosimilar development.

Can you explain the patent legal system biosimilars are required to undergo and why this process is important to their development?

Sure, so for biosimilars, there's the BPCIA or the Biologics Price Competition and Innovation Act of 2009, which is actually an optional framework of information exchanges between biosimilars and the reference product sponsor, or what we call the RPS, prior to filing an infringement lawsuit.

The BPCIA allows for 2 phases of litigation. One, following the biosimilars aBLA [abbreviated biologics license application] submission and the second phase triggered by the biosimilars notice of commercial marketing. Now, the idea is that the most important patents can be dealt with while the biosimilar application is under FDA review. That gives the possibility of resolving the lawsuit after only litigating a small subset of patents, instead of the RPS' entire portfolio. That can be quite large and sometimes in the hundreds.

So, to start this first phase exchange of materials, which is often referred to as the patent dance, the biosimilar notifies the RPS that the FDA has accepted its biosimilar application within 20 days of that acceptance and provides the RPS with its aBLA and "other manufacturing information".

That starts off this kind of exchange of information regarding the patents that might be infringed by the biosimilar and which they think might be likely to be licensed whether the biosimilar feels like there is an infringement, validity, or enforceability problem or not. Ultimately, what happens in the first round of litigation is that you narrow the number of patents that you actually litigate right away. If the parties can't agree, the BPCIA gives a provision for determining the list of patents that can be litigated in the first phase and the remainder gets litigated in the second phase.

For most BPCIA litigations that most parties have participated in at least some part of the dance and as I mentioned before, it was after the statute came out it was decided by the courts that this was optional.

A lot of people said, "Well, why would anybody go through this?" It turns out, it helps both sides, right? The biosimilar gets that chance to narrow it down to the patents that are most important so they're not expending an enormous amount of resources litigating hundreds of patents, and the RPS gets a chance to really zone in on the patents that are most important to them and try to protect them first, then try to seek licenses on those that can be some sort of settlement. So 24 of the litigations that have occurred, have completed this entire patent dance, 19 participated in some portion of it and didn't finish, but only 9 didn't participate.

You can see that even though it's optional, a lot of parties find some benefit to going through this process. Now, the interesting thing about it is that when it came out, I thought this is the most half-baked process ever.

That's still true, but it's better than nothing is what I think is happening. Most of the BPCIA litigations are actually ending in settlements. Thirty-one of 46, or 67%, of terminated BPCIA litigations ended in settlement or stipulated voluntary dismissals.

Very few cases have gotten the verdict, which is actually part of what we want. I think this statistic that I'm raising is demonstrating that the primary benefit of the BPCIA process is being met. That was to resolve any patent related disputes early, prior to impact on the market, thus allowing both parties to direct resources appropriately to their respective products and avoid the need to address potential damages.

In many ways, this is similar to what the Hatch-Waxman process was meant to address for small molecules. So far, it appears to be working for biologics and biosimilars, and really helping in development on both sides.

Videos

In an interview with Ha Kung Wong, JD, he addresses the patent legal system biosimilars are required to undergo and how this helps resolve patent disputes early in the development process. 

Navigating the Biosimilar Patent Landscape With Ha Kung Wong

The top 5 biosimilar articles for the week of February 5, 2024. 

 found that the introduction of biosimilar drugs significantly increased access to biologic therapies and Janus kinase (JAK) inhibitors for patients with rheumatic musculoskeletal diseases (RMDs), while also reducing treatment costs.

 greater biosimilar adoption than the English average after it implemented a new policy that prioritizes best-value biologics, including biosimilars, for new-start patients and those already treated with originators.

 (Cimerli) to Sandoz; Celltrion has completed its biologics license application filing for its tocilizumab biosimilar (CT-P47); Alvotech shares positive pharmacokinetic results for its denosumab biosimilar candidate.

 tend to be the most common type of patent referenced in litigation regarding biosimilar development, other patents actually have a greater impact on delays for biosimilar market launches.

Since January 31, 2023, the United States has seen a 

. With 9 adalimumab biosimilars launching throughout the year, the US rheumatology, immunology, dermatology, and gastroenterology treatment spaces have a wealth of newer and cheaper alternatives to Humira (reference adalimumab).

To read all of these articles and more, visit 

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

The Top 5 Biosimilar Articles for the Week of February 5

Etanercept medical injection | Image Credit: luchschenF - stock.adobe.com

 found the persistence of treatment was similar between the etanercept originator (ETN; Enbrel) and the biosimilar SB4 (Brenzys) treatment groups for patients with rheumatoid arthritis (RA), while considering the potential cost-savings implications. 

 in Australia as the first ever biologic disease-modifying antirheumatic drug (bDMARDs) with tumor necrosis factor inhibitors (TNFis). This was a major achievement because RA drugs are often inaccessible for patient populations due to their expensive price, whereas a biosimilar option often offers a cheaper alternative. The Australian Therapeutic Goods Administration approved the first etanercept biosimilar in 

Due to costly medications, the Australian government implemented a reference pricing policy guaranteeing price reductions of new treatments with biosimilars. A base price is set using the Pharmaceutical Benefits Scheme, fixing the cost as the lowest-priced option listed. The government ensures their benefits from biosimilars by setting statutory price reductions and disclosures, allowing both the originator and biosimilar drugs to cheapen market costs. Overall, the Australian reimbursement system has encouraged clinicians to prescribe biosimilar treatments, but ultimately, they have their own discretion when choosing the brand.

The OPAL study included real-world data that was entered into a customized electronic medical record (Audit 4). Patient data were included if the patient had an RA diagnosis, were between 18 and 95 years old, and initiated treatment with originator or biosimilar etanercept as the first recorded bDMARD or targeted synthetic (ts)DMARD treatment with at least 3 months of follow-up. RA severity for the cohort ranged from moderate to severe.

A total of 1153 patients with RA were considered eligible, of whom 386 had at least 3 months of follow-up recorded. Propensity score (PS) matching was utilized to increase the similarity of the baseline demographic and clinical features of the patients in the originator and biosimilar treatment groups. In total, 350 were matched for analysis (ETN, n = 209; SB4, n = 141).

Most patients were older than 50 and women (ETN: ≥ 50 years, n = 100; female, n = 144; SB4: ≥ 50 years, n = 69; female, n = 98). Based on disease activity measures, slightly higher scores were presented in the originator group for the Physical Global Assessment, Patient Global Assessment, Disease Activity Score 28, Crohn Disease Activity Index, and Simplified Disease Index.

Efficacy was measured through treatment persistence among participants. The average duration of treatment from baseline to 50% of participants discontinuing therapy was 19.4 months for the originator and 22.4 for the biosimilar. Both groups had participants who experienced adverse reactions, leading 25 patients on the originator and 17 patients on the biosimilar to discontinue treatment. The most common adverse reactions were rashes and injection site reactions (ETN, 3; Biosimilar, 4; SB4, 6; Biosimilar, 2). There were no switches from the biosimilar to the originator recorded among the population.

Before releasing the biosimilar in 2017, etanercept was priced at approximately AU $1600 (USD $1068) for 50 mg/L 4 × 1 mL pen device. Once the biosimilar was listed, both the originator and biosimilar were about AU $960 (USD $641), experiencing a 40% decrease in price due to reference pricing policies. The country experienced an average of 6 million dollars in cost-savings following the introduction of the biosimilar.

Study limitations were the focus on patients who began etanercept as a first-line agent during the study period. Patients switching from the originator to the biosimilar were not examined within the study.

The study authors stated, “Our analysis complements other published real-world studies, which described sustained low disease activity after switching from originator to biosimilar, and similar rates of persistence and disease activity relative to historical originator control groups.”

Deakin CT, Littlejohn GO, Griffiths H, et al. Comparative effectiveness of etanercept originator and biosimilar for treating rheumatoid arthritis: implications for cost-savings. 

. Published online November 27, 2023. doi:10.1111/imj.16296

Etanercept biosimilar SB4 is just as effective as the originator drug (Enbrel) in treating Australian patients with rheumatoid arthritis (RA), leading to significant cost savings.

Biosimilar Etanercept Similar to Enbrel in Persistence of Treatment, Cost Savings for Patients With RA

The Top 5 Biosimilar Articles for the Week of January 29, 2024.

 biosimilars concluded that these biosimilars “can be used as safely as their respective reference biologics.”

, published on the JAMA Health Forum, found biosimilar use and market share higher in 

 compared with traditional Medicare (TM) plans for most biosimilar products, except for bevacizumab.

 The FDA, Congress, biologic developers, and associations dedicated to 

evaluating the US biopharmaceutical space

 will need to work together to overcome challenges to biosimilar accessibility, says Sarfaraz K. Niazi, PhD, in his new column.

 A Korean health agency issued Samsung Bioepis an administrative penalty related to its biosimilar referencing Eylea (aflibercept); the FDA updates its labeling recommendations for 

; Alvotech receives another Form 483 after the FDA reinspected its Iceland-based manufacturing facility.

 in the first 3 years after initial launch; however, uptake speed continues to differ between treatment spaces, according to Samsung Bioepis’ 

Here are the top 5 biosimilar articles for the week of January 29, 2024.

The Top 5 Biosimilar Articles for the Week of January 29

Ophthalmologist with eye test | Image Credit: redgreystock - stock.adobe.com

 found comparable efficacy, safety, immunogenicity, and pharmacokinetics (PK) in SB15 vs reference aflibercept (AFL; Eylea), both as a first-line therapy and after switching from AFL to SB15 in neovascular age-related macular degeneration (nAMD).

A phase 3, prospective, double-masked, randomized trial had to include treatment-naïve subfoveal choroidal neovascularization (CNV) with AMD occupying at least 50% of the total lesion, a total lesion area of 9 or more disc areas (DA; including blood, scars, and neovascularization).

The main study period followed patients for up to 32 weeks. Patients were randomized to receive either 2 mg intravitreal injections of SB15 or AFL every 4 weeks for the first 3 injections followed by dosing once every 8 weeks up to week 48. At week 32, patients on the originator were re-randomized to switch to SB15 or maintain prior treatment (AFL/SB15 group; AFL/AFL group).

Efficacy was determined using optical coherence tomography combined with Early Treatment Diabetic Retinopathy Study charts based on retinal images found by a central reading center. Overall quality of life was measured using the National Eye Institute 25 Item Visual Function Questionnaire. Secondary efficacy endpoints were found in the changes in baseline best-corrected visual acuity (BCVA) score, up to week 56 along with proportions of participants losing less than 15 letters or gaining 15 or more letters.

Results included 56 study centers across Europe, US, Russia, the Republic of Korea, and Japan with a total of 425 participants completing 56 weeks of data from June 2020 to February 2021. Demographics from baseline to week 32 included similar ages across each group, majority of the cohort being female, White, and from European regions.

The BCVA total letter scores were similar values before and after switching (SB15, n = 10.6; AFL, n = 1.19, AFL/SB15, n = 11.37; AFL/AFL, n = 11.12). There were no significant differences in central subfield thickness (CST) from baseline to week 32 (SB15, 95.61 µm; AFL, 121.96 µm; AFL/SB15, 126.24 µm; AFL/AFL, 119.81 µm) nor did the total retinal thickness (TRT) in the SB15 and AFL groups before the switch (140.06 mm

, respectively) or afterwards (AFL/SB15; 166.17 mm

Patients with nAMD had almost no changes in choroidal neovascularization (CNV) area before or after switching (SB15, 4.34%; AFL, 4.76%; AFL/SB15, 4.59%; AFL/AFL, 4.86%). The subtle data changes acknowledge the comparable efficacy between SB15 and AFL.

At week 32, about 97.6% of participants from baseline continued treatment after switching but 94.7% completed the entire 56-week trial.

Regarding BCVA, the treatment groups had similar least mean square (LSmean) results (SB15/SB15, 7.4 letters; AFL/AFL, 7 letters; AFL/SB15, 7.9 letters). No notable changes in CST during the study period were observed (SB15, 119.2 µm; AFL/AFL, 126.6 µm; AFL/SB15, 136.4 µm). There were no significant changes in TRT from baseline to week 56 (SB15/SB15, 132.4 µm; AFL/AFL,136.3µm; AFL/SB15, 151.1 µm). The changes in CNV size before and after the treatment switches were not significantly different (SB15/SB15, 1.26 mm

Most treatment-emergent adverse events (TEAEs) were mild or moderate, usually unrelated to the study drug or injection procedure, ensuring treatment safety. Each group had the presence of TEAEs in comparable amounts (SB15/SB15, 36.50%; AFL/SB15, 35.10%; AFL/AFL, 29.80%). The rates of non-ocular TEAEs were comparable between the groups (SB15/SB15, 25.10%; AFL/SB15, 22.50%; AFL/AFL, 23.10%). Ocular TEAEs by preferred term in the study eye had more patients experiencing cataracts and visual acuity reduction in the SB15 and AFL continuation groups while the AFL/SB15 group had higher percentages of posterior capsule opacification and xerophthalmia. 

The study showed comparable treatment-induced and treatment-boosted antidrug antibodies (ADAs) between all groups. Following week 32, 1% of the AFL/AFL group developed treatment-induced ADAs but the SB15/SB15 and AFL/SB15 did not.

Prior to week 32, serum concentrations were similar in PK between SB15 and AFL groups. After switching, all treatment groups were below the limit of quantification, measuring C

 predose at weeks 40 and 56 (BLQ; 5 ng/mL).

Limitations of the study are the small sample sizes of the AFL/SB15 and AFL/AFL treatment groups in comparison with the SB15/SB15 groups. The study should be reviewed cautiously at week 56 because it was not meant to assess equivalence between treatment groups.

The biosimilarity of SB15 maintained comparable efficacy, safety, immunogenicity, and PK to AFL throughout 56 weeks in patients with nAMD. Overall, the study supports switching patients from AFL to SB15 treatment.

Woo SJ, Sadda SR, Bradvica M, et al. Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial. 

. Published online December 29, 2023. doi:10.1136/bmjophth-2023-001561

A study found SB15, an aflibercept biosimilar, is just as effective as its reference drug Eylea, the current standard treatment for neovascular age-related macular degeneration (nAMD), a condition that causes vision loss.

SB15 Effective, Safe in Treating nAMD Before, After Switching

Adalimumab IV treatment | Image Credit: LASZLO - stock.adobe.com

 found significant increases in access to biologic disease-modifying antirheumatic drugs (bDMARDs) and janus kinase inhibitors (JAKis) in higher-priced innovative drugs instead of cheaper tumor necrosis factor inhibitors (TNFis) among patients with rheumatic musculoskeletal diseases (RMDs) over a 10-year time period.

A public payer database collected research on biological treatments and synthetic drugs during the biosimilar market competition period in RMDs from 2013 up until 2022. In total, 22,104 patients with RMDs were treated with either adalimumab (ADA), etanercept (ETN), infliximab (INF), certolizumab (CZP), golimumab (GOL), rituximab (RTX), tocilizumab (TCZ), secukinumab (SEC), ixekizumab (IXE), tofacitinib (TOF), baricitinib (BAR), and upadacitinib (UPA). The TCZ patient data includes intravenous (IV) and subcutaneous (SC) options.

Each drug was categorized based on the mechanism of action it had on either rheumatoid arthritis (RA), psoriatic arthritis (PsA), or axial spondylarthritis (axSpA) patients. Medications were deciphered as TNFi, interleukin (IL)-6 inhibitors, anti-CD20, IL-17 inhibitors, and JAKis. Subgroups were divided into less costly TNFi and other TNFi.

The results of patients with RMDs and treatment access in Poland increased notably from introduction, following the 10-year study period. Between 2013 and 2022, 16,979 more patients received treatment with bDMARDs or JAKis (RA, n = 8,239; PsA; 3,696; axSpA, n = 5,044). The overall percentage of patients with access to bDMARDS and JAKis increased from 0.8% to 3.2% for RA, 1.4% to 8.7% for PsA, and 0.8% to 3.5% for axSpA.

The peak value of cost treatment was reached in 2018 but decreased for the following 3 years. In 2018, approximately €31 million in cost savings were accumulated; however, it took from 2019 to 2021 for the same amount to accumulate again. The largest decrease in the average cost of therapy occurred in 2019, the same year as the first ADA biosimilars reimbursements. These calculations remained consistent throughout 2020, but increased in 2021 and 2022, when the number of patients treated with bDMARDs or JAKis increased overall. 

The 3 largest increases in drug utilization and distribution occurred in the ADA, TCZ, and SEC. Cheaper TNFis like ADA, ETN, and INF and their biosimilars had larger increases while CZP, GOL, IL-6 inhibitors, IL-17 inhibitors, and JAKis followed.

The most common agent for patients with RA was TCZ (n = 3,278), ADA (n = 1,398), and ETN (n = 1,913). Patients with PsA were mostly treated with ADA (n= 1,398), then SEC (n = 1,205). Similarly, axSpA found ADA (n = 2,413) was most dominant, followed by ETN (n = 1,219), and SEC (n = 1,058).

The impact of the COVID-19 pandemic on access to treatment hindered the availability of IV treatment therapies. Other SC or oral therapies did not experience changes in use over the pandemic, including TCZ SC. It is likely there was a temporary suspension of the administration of IV INF, RTX, and TCV for some patients during the global societal restriction. The general RMDs population chose SC affordable therapies as their preferred method of treatment.

Patients with PsA and axSpA mostly utilized ADA and ETN, while patients with RA mainly utilized TCZ. A Among the overall RMD population, the use of cheaper TNFis (ADA, ETN, INF) dropped from 87% in 2013 to 69% in 2016 to 46% in 2022 compared to other drugs. While physicians in Poland are responsible for providing therapy options for patients, the market share of the less costly agents remains high.

From 2019 to 2021, the biosimilar market had the greatest net benefit out of 10 years. On average, annual treatment therapy costs for patients with RMD declined by 60% over the 10 year span.

Limitations include the public payer data neglecting all cases using the described treatment methods and does not account for epidemiologic variation in the RMD population over time.

Innovative treatment developments should consider patients’ socioeconomic status, country regulations, cost reimbursements, and patient preferences for oral or SC formulas. Policy implementation is necessary for bDMARD users to incentivize them to reinvest in reimbursement options of less costly agents to take advantage of their access.

Stajszczyk M, Kwiatkowska B, Żuber ZM, Batko B. Access to biologics and JAK inhibitors for the treatment of rheumatic diseases in the biosimilars era in Poland: nation-level study. 

A 10-year analysis in Poland found that the introduction of biosimilar drugs significantly increased access to biologic therapies and Janus kinase (JAK) inhibitors for patients with rheumatic musculoskeletal diseases (RMDs), while also reducing treatment costs. 

Biosimilars Improve Access to Biologic Therapies, JAK Inhibitors for Patients With RMDs

The Top 5 Biosimilar Articles for the Week of January 22, 2024.

 uptake patterns within different health insurance plans found that low-flexibility plans, such as health maintenance organizations and exclusive provider organizations, were more likely to initiate biosimilar therapies than more flexible plans.

 (Rixathon and Truxima) and the reference drug (Rituxan) exhibited similar safety and efficacy outcomes in patients with immune thrombocytopenia (ITP), an autoimmune disease followed by a low platelet count, according to a recent analysis.

 Coherus Biosciences’ on-body injector version of Udenyca (pegfilgrastim-cbqv), making it the first biosimilar to reference Neulasta Onpro, the pegfilgrastim product that holds the majority of the pegfilgrastim market share.

, the IQVIA Institute for Human Data Science predicted that losses for originator products will rise from $111 billion to $192 billion by the end of 2028, thanks to market introductions of 

Here are the top 5 biosimilar articles for the week of January 22, 2024. 

The Top 5 Biosimilar Articles for the Week of January 22

Scientists reviewing research | Image Credit: N Felix/peopleimages.com - stock.adobe.com

 of 3 pharmacokinetic (PK) studies found comparable results in the bioequivalence margins, safety, and immunogenicity between MB02, a bevacizumab biosimilar, and the EU- and US-sourced reference product (Avastin).

Bevacizumab is a biologic medicinal product inhibiting angiogenesis by binding to vascular endothelial growth factor (VEGFs) and preventing its interaction with VEGF receptors on the surface of endothelial cells. The drug typically

 colorectal, nonsquamous non-small cell lung cancer, glioblastoma, kidney, cervical, and renal cell carcinoma.

The phase 1 studies were single-dose, double-blind, three-arm, parallel group designs. MB02-A-02-17 and MB02-A-05-18 analyzed the use of the EU-approved and US-approved reference product compared with the biosimilar in healthy Caucasian males. The third study (MB02-A-04-18) examined Japanese male participants treated with MB02 or the EU-sourced originator, where the duration covered more than 3.5 times the terminal half-life of bevacizumab.

MB02-A-02-17 collected data from 2 sites in the United Kingdom (UK) from November 2018 to May 2019, MB02-A-05-18 pooled data from a single center in Germany from September 2019 to March 2020, and MB02-A-04-18 contained data from a single Japanese center from August to December 2019.

All patients were randomized to receive a 3 mg/kg single 90-minute intravenous dose of either MB02, the reference EU-bevacizumab, or US-bevacizumab. The study population only included men, revealing few differences between demographics. The age range of the UK and German participants was 18 to 55 years, and the range for the Japanese participants was 20 to 55 years.

Study periods were 100 days for the UK and German studies, while the Japanese study lasted 70 days. Covance Laboratories performed the analyses with a validated enzyme-linked immunosorbent assay on their serum drug concentrations for MB02 and reference bevacizumab.

The PK parameters were measured by treatment group and as overall populations. The area under the serum concentration subtracted by the time curve measured from time zero and extrapolated to infinity did not express notable differences among MB02 or either of the EU- and US–reference bevacizumab groups (30258.8 vs 26091.65 vs 26436.53, respectively). The area under the serum concentration minus the time curve measured from time zero to the time of last quantifiable concentration did not include differences between the MB02 and EU- or US-bevacizumab groups (28811.74 vs 26091.65 vs 26436.53, respectively).

Maximum observed serum concentrations did not have any major differences among the 3 studies analyzed (MB02, 82.49; EU -bevacizumab, 77.57; US-bevacizumab, 71.92). The time of maximum observed serum concentration were almost identical between groups (MB02, 3; EU- and US-bevacizumab, 4). All pairwise comparisons within the studies had remained within the predefined bioequivalence margins, including the terminal half-life, total body clearance, and the volume of distribution during the terminal elimination phase.

Overall, 186 participants (67.4%) reported 483 treatment-emergent adverse events (TEAEs). Two reference bevacizumab groups had a higher report (166 TEAEs in EU-bevacizumab; 169 TEAEs in US-bevacizumab) of TEAEs compared with the MB02 group (148 TEAEs). The US-bevacizumab group had more TEAEs than the EU-bevacizumab and the MB02 group (80.3% vs 63% vs 62%, respectively). Most TEAEs were of mild severity and were similar between the studies (MB02, 52%; EU-bevacizumab, 43%; US-bevacizumab, 63.2%). The most frequent TEAEs were headaches and nasopharyngitis.

The MesoScale Discovery assay was utilized to determine the serum concentrations of antidrug antibodies. The studies had similar treatment induced antidrug antibodies developed in a total of 41 participants (MB02, 14%; EU-bevacizumab, 16%; US-bevacizumab; 14.47%). Five participants had neutralizing antibodies after treatment (MB02, .02%; EU-bevacizumab, .01%; US-bevacizumab, .03%).

The study populations limited the findings because the researchers did not correct the results from Asian participants to reflect the previous descriptions for bevacizumab PK characteristics. Additionally, the studies had short study periods and differing selected sampling schedules.

The authors noted that this is the largest known analysis in the field of biosimilar monoclonal antibodies, providing further evidence on PK similarities through larger populations.

Miguel-Lillo B, Sánchez-Vidaurre S, Pérez Díaz L, Paravisini A. Pooled analysis of three pharmacokinetic studies comparing biosimilar MB02 and reference bevacizumab. 

. 2023;11(6):e01139. doi:10.1002/prp2.1139

A combined analysis of 3 studies found that the drug MB02 is comparable to reference bevacizumab (Avastin) in terms of its pharmacokinetics, safety, and immunogenicity.

Bevacizumab Biosimilar MB02 Demonstrates Bioequivalence in Key Safety Parameters With Avastin

Medicare enrollment form | Image Credit: zimmytws - stock.adobe.com

, found biosimilar use and market share higher in Medicare Advantage (MA) plans compared with traditional Medicare (TM) plans for most biosimilar products, except for bevacizumab.

Calculated cumulative data from May 2015 to September 2022 was used to evaluate biosimilar market shares for products with at least 1 biosimilar administration on or before September 30, 2019. A total of 20 biosimilar products were included, mainly used in Parts B and C, amongst 7 different product types.

Product types included infliximab, epoetin alfa, bevacizumab, pegfilgrastim, filgrastim, rituximab, and trastuzumab. Each product recorded a cumulative percentage market share from biosimilar introduction and throughout the 36 weeks following introduction. Market share was defined as the number of biosimilar administrations of the total administrations of biosimilars and their reference products.

 5 bevacizumab biosimilars, 4 infliximab biosmilars, 1 epoetin alfa biosimilar, 3 rituximab and filgrastim biosimilars each, 5 trastuzumab biosimilars, and 6 pegfilgrastim biosimilars. 

Vegzelma (bevacizumab-adcd), Mvasi (bevacizumab-awwb), Zirabev (bevacizumab-bvzr), Alymsys (bevacizumab-maly), and Avzivi (bevacizumab-tnjn) are the brand names for the bevavizumab biosimilars. Renflexis (infliximab-abda), Avsola (infliximab-axxq), Inflectra (infliximab-dyyb), and Ixifi (infliximab-qbtx) represent the approved infliximab biosimilars. Retacrit (epoetin alfa-epbx) is the only epoetin alfa biosimilar. Zarxio (filgrastim-sndz), Nivestym (filgrastim-aafi), and Releuko (filgrastim-ayow) are the filgrastim biosimilar products. Truxima (rituximab-abbs), Riabni (rituximab-arrx), and Ruxience (rituximab-pvvr) make up all the rituximab biosimilars. Kanjinti (trastuzumab-anns), Ogivri (trastuzumab-dkst), Ontruzant (trastuzumab-dttb), Herzuma (trastuzumab-pkrb), and Trazimera (trastuzumab-qyyp) all reference Herceptin (trastuzumab). Lastly, Nyvepria (pegfilgrastim-apgf), Ziextenzo (pegfilgrastim-bmez), Udenyca, (pegfilgrastim-cbqv), Stimufend (pegfilgrastim-fpgk), Fulphila - (pegfilgrastim-jmdb) and Fylnetra (pegfilgrastim-pbbk). In January, the on-body injector version of Udenyca was approved to compete against Neulasta Onpro (on-body injector reference pegfilgrastim).

Out of 6 of the 7 product types, results showed that MA plans had greater biosimilar uptake than TM plans. MA plans had 1.1 and 2.3 times greater uptake for trastuzumab and epoetin alfa biosimilars, respectively, compared with TM plans. All 7 products had a 1.3 (range, 0.7-2.3) median ratio for both MA and TM, with a median difference of 5.7% (range, –4.48% to 9.43%).

However, the products producing the least amount of biosimilar market share differed between MA and TM. For epoetin alfa biosimilars, MA had 5.7% times greater uptake than TM. Bevacizumab biosimilars had the lowest biosimilar market share for MA, with a –4.48% percentage point difference between plan types.

The indicator for bevacizumab was divided into ophthalmic vs oncologic usage. Although the reference product (Avastin) is only indicated for oncology use, it is often prescribed off-label for neovascular age-related macular degeneration. In the ophthalmic group, bevacizumab biosimilars had very low market share. However, market share was higher in TM plans than MA plans.

Data for epoetin alfa biosimilars, which originally had 2 times greater market share in MA plans than TM plans was stratified by end-stage kidney disease (ESKD) and non-ESKD utilization. Like other product types, epoetin alfa biosimilars had 1.5 to 1.7 times greater uptake in MA plans than TM plans. Combining uptake for ESKD and non-ESKD indications resulted in a higher relative weighting of MA biosimilar use.

Study limitations included the potential differences in population characteristics amongst MA and TM. The implementation of the Medicare inflationary rebate could also affect the biosimilar use and market share percentages of MA or TM.

The authors suggested that additional studies should incorporate all avenues of clinical indications. The authors concluded, “Thus, it is important to validate the increased biosimilar uptake observed in MA and investigate potential mechanisms through which managed care may encourage greater biosimilar use.”

Kozlowski S, Kwist A, McEvoy R, et al. Biosimilar uptake in medicare advantage vs traditional medicare. 

. 2023;4(12):e234335. doi:10.1001/jamahealthforum.2023.4335

Biosimilar uptake was greater in Medicare Advantage plans when compared with traditional Medicare plans. 