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WHEN CHOICE ARRIVES: Competition & Consequences

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BIOSIMILAR APPROVALS

Skylar Jeremias is the Managing Editor for The Center for Biosimilars and The American Journal of Managed Care (AJMC).

Articles

Despite a dramatic shift toward biosimilar use following British Columbia’s policy, researchers found no rise in hospital visits or complications, underscoring the real-world reliability of etanercept biosimilars in managing inflammatory arthritis.

British Columbia’s Biosimilar Policy Shows No Impact on Hospital Visits

Starjemza gains FDA approval as the eighth ustekinumab biosimilar, enhancing treatment options for rheumatic and gastrointestinal conditions.

FDA Approves Starjemza as New Stelara Biosimilar

There's a need for early anti-tumor necrosis factor (TNF) therapy in inflammatory bowel disease (IBD), with new data showing that biosimilars can address cost barriers and enhance patient access and outcomes.

Biosimilars Can Help Expand Early Access Anti-TNF Therapy in IBD

Cameron Santoro is an associate editor for The Center for Biosimilars

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Elena Wolff-Holz, MD, discussed the rationale and safety surrounding the automatic substitution of biosimilars at the pharmacy level, as well as common misconceptions about these medications.

Automatic Biosimilar Substitution and Patient Education Advocated by Elena Wolff-Holz, MD

The Center for Biosimilars connects professionals with insights on biosimilars, health economics, regulatory outcomes, and emerging treatment paradigms.

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Projected savings from biosimilar natalizumab were $452,611 over 3 years, driven by decreased drug acquisition costs and a utilization shift from reference to biosimilar natalizumab.

Budget Impact Analysis of Biosimilar Natalizumab in the US

Patients with moderate-to-severe inflammatory bowel disease (IBD) “at high risk of disease progression and bowel damage, or those who do not respond to conventional therapies within a reasonable time," should receive anti-tumor necrosis factor (TNF)-α therapy as early as possible to prevent disease progression, but the high cost of anti-TNF therapy is a major barrier to timely treatment, according to a 

 by an expert panel of gastroenterologists.

The panel discussed strategies to increase biosimilar use in IBD with the goal of improving patient access to early initiation of anti-TNF therapy.

IBD, including Crohn disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases of the gastrointestinal system. TNF inhibitors, such as infliximab and adalimumab, are effective for treating moderate to severe IBD, but biologics are associated with high costs. The authors noted that the economic burden of IBD is driven mainly by the cost of anti-TNF biologics, which negatively affects patient access to treatment and, therefore, outcomes.

As of 2024, 17 biosimilars were approved for treating IBD in the US and European Union, and 15 in Canada, and biosimilars had been used in IBD for more than 10 years. However, the panel wrote, the use of biosimilars in clinical practice remains “suboptimal.”

Early Treatment With Anti-TNF Biologics Could Delay Disease Progression

Research suggests that initiation of anti-TNF therapy earlier in the disease course could improve outcomes and delay disease progression, especially in CD. With evidence for a “top-down” approach to IBD treatment accumulating, the authors said, treatment guidelines are shifting, but standard treatment for IBD in many regions still follows a “step-up” approach, in which non-biologic therapies, such as aminosalicylates, corticosteroids, or immunomodulators, must be failed before biologics can be initiated.

According to the panel, the major barrier to anti-TNF use overall is cost, and biosimilars could address the cost barrier. Research has confirmed the effectiveness and safety of biosimilars, and the authors noted that many professional societies, including the American Gastroenterological Association (AGA) and the European Crohn’s and Colitis Organisation (ECCO), support the use of biosimilars in IBD, including switching patients from an originator to a biosimilar. Furthermore, surveys suggest that physician confidence in biosimilars is growing.

However, they said a disconnect exists between guidance and clinical practice. They continued by discussing barriers that may be limiting the use of anti-TNF biosimilars in IBD, and potential solutions.

Barrier 1: Complex Reimbursement/Insurance Policies

According to the expert panel, this barrier is “particularly true” in the US, with many insurance companies requiring prior authorization which may delay treatment and charging high co-pays for biologics as “specialty drugs” which increases out-of-pocket spending. They cited a study that reported over 90% of US-based insurance companies required failure of at least 1 conventional therapy before permitting biologic treatment. Additionally, several countries with single-payer systems require failure of one or even 2 non-biologic treatments before biologic treatment becomes reimbursable.

Exacerbating the issue in the US, there are financial incentives for pharmacy benefit managers to place higher-cost reference biologics on formularies, which favors those reference products over biosimilars and leaves many healthcare professionals unable to choose a biosimilar for their patients.

The panel recommended the removal of payer requirements for the patient to fail on conventional therapies before initiating biologics to allow for earlier initiation of anti-TNF therapy and bring the ‘top-down’ treatment guidance into clinical practice. They added that the improved outcomes from earlier initiation of biologics could “potentially support a reduction in the cumulative costs of sustained disease.”

Barrier 2: Concerns of Health Care Professionals

Although attitudes of health care professionals are trending toward acceptance of biosimilars, “some resistance” persists,” the authors wrote, citing a US study from 2020 that found 73% of physicians surveyed refrained from prescribing biosimilars. The panel explained that physician skepticism and lack of confidence in biosimilars may stem from the differences in the development and approval pathways between originators and biosimilars, and a lack of understanding of extrapolation to additional indications or biosimilar switching data. Importantly, patients are likely to lack confidence in biosimilars if their physician does.

As a solution to address this barrier, the expert panel proposed continued education on the robustness of the biosimilar development process and safety of switching between originator and biosimilar products, as well as encouraging peer-to-peer education for physicians to share their experiences with biosimilars. They also recommended conducting more randomized controlled trials and real-world studies to address physician concerns, development of tailored educational materials on biosimilars that address specific needs and concerns of subpopulations of health care professionals, and integrating biosimilar education into medical and pharmacy school curricula.

A patient’s concerns around biosimilars could lead to reluctance to begin treatment, as well as poorer outcomes due to the nocebo effect. The panel cited research showing that people with IBD frequently share negative experiences around biologics on social media, including concerns about safety and side effects. A lack of understanding of biosimilars can lead to a lack of confidence. The panel cited surveys finding large proportions of patients had not heard of biosimilars, and many of those who had were not confident in their effectiveness and safety, or viewed them as of lesser quality than reference biologics.

That anti-TNF biologics are delivered via intravenous or subcutaneous injection is another source of hesitation for some patients, due to fear of needles or previous injection site reactions or pain.

The panel recommended leveraging the educational materials of nonprofits and IBD patient support groups, such as the European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA), and discussed essential aspects of communication with patients, such as providing understandable, consistent, and up-to-date information, communicating transparently and positively to reduce the likelihood of a nocebo effect, and tailoring the materials to individual patient needs. They recommended physicians, nurses, and pharmacists adopt these strategies to ensure that information is accurate and explain how biosimilars can support the patient’s treatment goals.

Although there are structural barriers to the use of anti-TNF biosimilars, the expert panel emphasized that healthcare professionals can take action now to increase confidence in anti-TNF biosimilars in IBD, supporting the “top-down” approach to IBD treatment, “ultimately improving long-term disease management and patient outcomes, as well as paving the way for the future biosimilar landscape in IBD.”

Fiorino G, Ananthakrishnan A, Cohen RD, Cross RK, Deepak P, Farraye FA, Halfvarson J, Steinhart AH. Accelerating earlier access to anti-TNF-α agents with biosimilar medicines in the management of inflammatory bowel disease. 

. 2025;14(5):1561. doi:10.3390/jcm14051561

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The monthly savings from a 100% conversion of Medicare patients with metastatic colorectal cancer (mCRC) and non-squamous metastatic non-small cell lung cancer (mNSCLC) from the reference bevacizumab (Avastin) to bevacizumab-bvzr (Zirabev; Pfizer) could fund 13,887 additional patient-months of treatment in mCRC and 8,959 in mNSCLC, concluded the authors of a cost-effectiveness 

Originator bevacizumab, a vascular endothelial growth factor inhibitor, is approved by the FDA for multiple solid tumor indications, including first-line treatment of mCRC in combination with fluorouracil-based chemotherapy, and first-line treatment of unresectable, locally advanced, recurrent, or mNSCLC in combination with carboplatin and paclitaxel. According to the authors, although bevacizumab has improved outcomes in mCRC and mNSCLC, treatment costs may exceed $11,000 per patient per month.

After the reference product lost exclusivity in the US in 2019, Zirabev was the first biosimilar to be approved by the FDA and enter the US market. Additional biosimilars have since been approved, including bevacizumab-adcd, bevacizumab-awwb, and bevacizumab-maly.

Medicare is one of the largest payers for bevacizumab therapy in the US, the authors said, spending approximately $700 million in 2022. Thus, the authors aimed to estimate cost savings and potential for expanded access to therapy associated with substituting a biosimilar for the originator.

The simulation model estimated cost savings from using bevacizumab-bvzr or alternative biosimilars (bevacizumab-awwb, -maly, or -abcd) in place of the originator. They used Medicare enrollment data, SEER cancer incidence data, and the 2024 average sales price (ASP) to estimate numbers of patients expected to be treated and costs.

Assuming a 100% market shift from the originator to bevacizumab-bvzr, the per-patient per-month (PPPM) cost savings compared to the originator were $4,205 in mCRC. For the full mCRC cohort, the monthly savings were estimated at $27,664,432, a 68% reduction in cost. The number needed to convert (NNC) was 47 to treat an additional 100 patients with bevacizumab-bvzr + FOLFOX.

In mNSCLC, the mean PPPM savings were $8,410, and monthly savings in the full cohort were $32,319,323, a 70% reduction in cost compared to the reference product. The NNC to treat an additional 100 patients with bevacizumab-bvzr + paclitaxel + carboplatin was 43.

Bevacizumab-bvzr had the lowest ASP of the bevacizumab biosimilars. The cost savings associated with converting to bevacizumab-bvzr exceeded those for the alternative biosimilars in both indications. NNCs in mCRC for alternative biosimilars ranged from 60 to 4,564 and 55 to 4,422 in mNSCLC. “Medicare can potentially achieve the greatest degree of budget-neutral expanded access to bevacizumab through increased use of bevacizumab-bvzr,” the authors wrote.

Overall, bevacizumab biosimilars were more cost-effective than the reference product in all scenarios the authors modeled, and bevacizumab-bvzr was the most cost-effective for treating both mCRC and mNSCLC. The authors said the substantial cost savings to Medicare from converting from the reference product to bevacizumab-bvzr could be reinvested to treat more patients or fund other costs in Medicare on a budget-neutral basis, and that the cost savings could be passed on to patients to improve the affordability of treatment.

Roth JA, Kratochvil D, Dorman S, Bernauer M. Cost-efficiency and expanded access modeling of conversion to biosimilar bevacizumab in metastatic colorectal and non-squamous non-small cell lung cancer in Medicare. 

. 2025;28(1):378-386. doi:10.1080/13696998.2025.2474884

Monthly savings from fully converting Medicare patients with metastatic colorectal cancer (CRC) and non-squamous metastatic non-small cell lung cancer (NSCLC) from reference bevacizumab to bevacizumab-bvzr could fund 13,887 and 8,959 additional patient-months of treatment, respectively, according to a cost-effectiveness study.

Switching From Avastin to Bevacizumab-bvzr in CRC, NSCLC Can Reduce Medicare Costs

 of safety results from the VOLTAIRE clinical trials described the results of a recent 

 of safety data in patients with rheumatoid arthritis (RA), Crohn disease (CD), and chronic plaque psoriasis, which found no differences in safety outcomes between adalimumab-adbm (Cyltezo) and the reference product (Humira).

The purpose of the summary, according to authors from Boehringer Ingelheim, is to help patients understand the findings and help health care professionals make treatment decisions. The summary included concise explanations of the results and their meaning, the conditions included, study designs, and definitions of biologics, biosimilars, interchangeability, and adverse events. It also provided links to external resources, including the original pooled safety publication and plain language summaries of the individual VOLTAIRE trials.

Biosimilars referencing adalimumab, a monoclonal antibody targeting tumor necrosis factor-α, first entered the US market in 2023, and Cyltezo was the first adalimumab biosimilar to gain the 

The 5 VOLTAIRE clinical trials compared effectiveness and safety of continually receiving the adalimumab originator to switching one or more times between the originator and Cyltezo in patients with RA (VOLTAIRE-RA, VOLTAIRE-RAext), Crohn disease (VOLTAIRE-CD), and chronic plaque psoriasis (VOLTAIRE-X, VOLTAIRE-PsO). Pooled safety results of all five trials were 

 in November 2024. The authors of the summary explained that the data was pooled “to provide a better understanding of the overall safety” of adalimumab-adbm.

Across all VOLTAIRE clinical trials, there were 1368 participants, 645 in VOLTAIRE-RA, 147 in VOLTAIRE-CD, 317 in VOLTAIRE-PsO, and 259 in VOLTAIRE-X. The pooled analysis evaluated total and serious adverse events (AEs), discontinuation of treatment due to AEs, deaths, and AEs of special interest, which included serious infections, cancers, and major adverse cardiac-related events. The researchers also investigated whether there were any differences in safety based on sex or age group.

In the pooled analysis, rates of AEs, serious AEs, and discontinuations were similar in patients with RA and chronic plaque psoriasis, regardless of whether they were treated with Cyltezo or the originator. Patients with CD had “slightly higher” rates of AEs, serious AEs, and discontinuations than the other two conditions in both biosimilar and reference product groups. There were no significant differences in deaths between conditions or between biosimilar and reference product groups. There were also no significant differences in safety outcomes between treatments in patients who were 65 or older, or those who were under 65.

Cancers and major adverse cardiac-related events were only reported in patients with RA and were not significantly different between treatment groups. Serious infections were reported in patients with RA and chronic plaque psoriasis, and there were no significant differences between groups. There were no AEs of special interest observed in patients with CD.

Limitations of the VOLTAIRE trials discussed by the authors included that the participants were predominantly white, thus the results may not be representative of all patients, and that the findings may not be applicable to patients with autoimmune conditions other than those included in the trials. When explaining the meaning of the results, the authors said since there were no differences in safety outcomes between biosimilar and reference product groups across the VOLTAIRE trials, patients with RA, CD, and chronic plaque psoriasis who take Cyltezo can expect similar side effects to those of the reference product.

Cohen S, Bender S, Shaberman A, Vinisko R, McCabe D. A plain language summary of the pooled safety results of adalimumab-adbm from the VOLTAIRE clinical trials in people with rheumatoid arthritis, Crohn's disease, and chronic plaque psoriasis. 

. 2025;25(4):323-329. doi:10.1080/14712598.2025.2476033

A plain language summary for patients explains there were no differences in safety outcomes between adalimumab-adbm and the originator in a pooled analysis of the VOLTAIRE clinical trials.

Clinical Evidence Shows No Safety Gaps Between Biosimilar, Reference Adalimumab

 Wyost/Jubbonti (denosumab-bddz; GP2411), the first biosimilar to reference Xgeva/Prolia (denosumab) in the US.

 The drugs will be used to treat osteoporosis and hypercalcemia as well as prevent skeletal-related events associated with bone metastases from solid tumors.

The FDA accepted Sandoz’ biologics license application for Wyost/Jubbonti in 

. This approval is also notable in that there are currently no denosumab biosimilars approved in the European Union. The news comes after the same products were approved in Canada 

Similar to the reference products, the biosimilars have the same drug compound (denosumab-bddz) but were approved with 2 brand names that will be used for different indications:

Wyost vs Jubbonti

Jubbonti is interchangeable with Prolia, and Wyost is interchangeable with Xgeva.

Wyost and Jubbonti were also approved with interchangeability designations, allowing them to be substituted for their respective reference product at the pharmacy level without needing to wait for a provider to give permission. It is the ninth biosimilar to receive this label.

"Sandoz has achieved the first FDA approval for biosimilars to denosumab, a medicine that can address primary and secondary bone loss, such as osteoporosis, as well as cancer-related skeletal events, which are disease states that can profoundly reduce quality of life for patients. I am proud that Sandoz continues to pioneer access to these life-changing medicines for the patients who need them most," commented Keren Haruvi, President Sandoz North America, in a statement.

According to Sandoz, over 10 million adults over age 50 in the US have osteoporosis, of whom most (> 80%) are women. It is predicted that 1 in 2 women and 1 in 4 men will experience an osteoporosis-related fracture in their lifetime, which could result in decreased quality of life, disability, and death.

The approval of Wyost/Jubbonti was based on a comprehensive data package containing 

 results that were presented at the American Society of Clinical Oncology annual meeting 2023 and the American Society for Bone and Mineral Research annual meeting 2023, respectively.

Denosumab products are human monoclonal antibodies that bind to the RANKL protein, preventing activation of the RANK receptor on the surface of osteoclasts and preventing osteoclastic bone resorption.

The phase 1 study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab-bddz compared with the reference product (EU authorized and US licensed) in 499 healthy participants (mean [SD] age, 64.6 [6.1] years; White, 90.9%).

 The double-blind, 3-arm, parallel-group analysis was conducted at 2 German centers. Participants were randomized 1:1:1 to receive the biosimilar or the EU- or US-sourced reference agents.

Participants were between 28 and 65 years old and weighed between 50 and 90 kg. PK end points were measured by area under the serum concentration-time curve measured from the time of dosing and extrapolated to infinity (AUC

), or to the last measurable concentration (AUC

), and maximum observed serum concentration (C

). PD end points were measured by the area under the effect-time curve of the percentage change from baseline (AUEC %CfB) in serum carboxy-terminal crosslinked telopeptide of type I collagen (CTX) and CTX and procollagen I N-terminal propeptide (PINP) serum concentration per visit.

Results showed that the treatment arms (biosimilar vs EU-sourced reference product; biosimilar vs US-sourced reference product) showed statistically similar values for AUC

 (1.02; 1.00), and AUEC %CfB in CTX (1.01; 1.01). Changes from baseline to Week 39 in serum concentrations of CTX and PINP were also similar between groups.

The international, double-blind, parallel group phase 3 trial (ROSALIA study; 

) looked at the clinical efficacy, safety, and tolerability of denosumab-bddz compared with the reference product through 52 and 78 weeks.

 Postmenopausal women with osteoporosis aged 55 to 80 years who had bone mineral density (BMD) T-scores between 2.5 and 4.0 at the lumbar spine were eligible for participation.

In total, 527 patients were randomized 1:1 to receive a 60-mg dose of Wyost or the EU-authorized reference product on day 1 and at week 26. Prior to the third dose at week 52, patients who were receiving the reference product were rerandomized to remain on the reference product or switch to the biosimilar.

Overall, 502 patients received a third dose (biosimilar to biosimilar, n = 253; reference to reference, n = 125; reference to biosimilar, n = 124). The mean age of the participants was 64.6 (6.15) years, and most (91.3%) were White.

No clinically meaningful differences between the groups regarding new vertebral fractures were observed. Switching from the reference product to the biosimilar did not affect the incidence or severity of treatment-emergent adverse events (TEAEs). Immunogenicity profiles were similar between groups.

Most TEAEs were grade 1 or 2, most of which were not considered treatment related, and no treatment discontinuations occurred as a result. The most common TEAEs reported were hypocalcemia, COVID-19 infection, and nasopharyngitis.

The majority of antidrug antibodies had very low, nonreportable titers (< 20 mg/mL), were nonneutralizing, and transient.

In its company statement, Sandoz declined to comment on a launch timeline due to ongoing litigation issues with the reference product manufacturer (Amgen).

I think they are excited for these biosimilars to come to market and are ready to prescribe them to patients.

I think they will wait for more real-world data with these products before prescribing them.

I think they will need more education on the safety and efficacy on these products before feeling comfortable prescribing them.

Sandoz receives FDA approval for first and only denosumab biosimilars. News release. Sandoz; March 5, 2024. Accessed March 5, 2024. 

https://www.marketscreener.com/quote/stock/SANDOZ-GROUP-AG-160016887/news/Sandoz-receives-FDA-approval-for-first-and-only-denosumab-biosimilars-46097288/

2. Vogg B, Poetzl J, El Galta R, Fuhr R, Schwebig A, Sekhar S. Pharmacokinetics and pharmacodynamics of proposed denosumab biosimilar and reference denosumab in healthy male subjects. Presented at: 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Poster SAT-436.

3. Jeka S, Dokoupilová E, Kivitz A, et al. Pharmacokinetics and pharmacodynamics of proposed denosumab biosimilar and reference denosumab in postmenopausal osteoporosis: the ROSALIA study. Presented at: ASBMR 2023 Annual Meeting; October 13-16, 2023; Vancouver, Canada. Poster P303.

Sandoz’ Wyost/Jubbonti (denosumab-bddz) references Prolia and Xgeva and can be used to treat osteoporosis and hypercalcemia as well as prevent skeletal-related events associated with bone metastases from solid tumors.

Approvals Launches

FDA Approves First Denosumab Biosimilars

The House of Representatives has approved the bipartisan 21st Century Cures legislation, which includes funding for innovative research and provisions to speed up the drug approval process.

By a vote of 392-26, the House approved the 21st Century Cures Act. The House had passed an earlier version of the bill in July 2015 but continued to revise and update it, releasing the most recent draft of the bill last week. These updates included provisions for mental health, substance abuse, and child and family services.

Members of both political parties have been vocal in their support of the legislation, often citing its passage as a top priority during the lame-duck Congressional session. Prior to the election, Senate Majority Leader Mitch McConnell, R-Kentucky, had said it “could end up being the most significant piece of legislation we pass in the whole Congress." 

Adrian Goh, MEc

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