Deana Ferreri, PhD

The cost of insulin is “a present, ongoing barrier for patients to achieve glycemic control,” according to researchers from Sandoz who reviewed current US policy regarding rising insulin costs, follow-on and biosimilar insulins, and factors affecting the successful adoption of biosimilar insulins. They cited a survey in which one-quarter of patients reported underuse of insulin due to the high cost. “As costs continue to rise, patients are forced to choose between obtaining their medications or paying for other necessities, leading to worse health outcomes,” they wrote.

Sandoz has candidate biosimilars for insulin aspart (Rapilin) and insulin glargine (Basilin) under development. 

According to the authors, increasing insulin costs are due in part to a “highly consolidated” insulin market controlled by 3 manufacturers: Eli Lilly, Novo Nordisk, and Sanofi. The authors suggested this keeps prices artificially high due to a “lack of robust competition.” Biosimilars could help to address the access and affordability concerns that have come with the recent rapid rise in insulin costs, they wrote, but they cautioned that insulin biosimilars “may also face adoption challenges from patients and health care providers alike.”

The reviewers discussed a recent change in the approval pathway for biosimilar insulins. Before 2020, follow-on insulins were approved via the new drug pathway under Food, Drug, and Cosmetic Act Section 505(b)(2). In March of 2020, the FDA “transitioned insulin to a streamlined regulatory framework for biologics as required by the Biologics Price Competition and Innovation Act (BPCIA),” which “creates an easier pathway for more affordable biosimilar and interchangeable insulins to enter the market.”

Basaglar, a follow-on referencing insulin glargine, and Admelog, a follow-on referencing insulin lispro, were approved via the new drug pathway, and are available but not considered biosimilars in the United States. They are considered biosimilars in other markets. Also available is Semglee, the first interchangeable insulin glargine biosimilar.

The authors noted concerns regarding potential differences in immunogenicity between originator products and biosimilars; however, “no such differences in immunogenicity have been observed to date with biosimilar use in various therapeutic areas approved in the United States or Europe.” Regarding the concern that switching may increase the risk of immunogenicity, they wrote, “no published data to date demonstrate this risk.” Furthermore, they cited the FDA’s draft guidance for biosimilar and interchangeable insulins, which states there should be “no residual uncertainty regarding immunogenicity” of a biosimilar if analytical assessment demonstrates it is highly similar to the reference product.

They also discussed the nocebo effect, stemming from a patient’s negative expectations of a biosimilar drug, which can “decrease adherence rates and lower the patient’s quality of life.” The authors recommended addressing these challenges through education, which they say will be “key to ensure patients and health care professionals alike are comfortable with biosimilar insulins.”

Available data on the cost of biosimilar insulins in the United States are “limited”; however, the authors cited a 

 suggesting that net insulin glargine prices decreased steadily after the approval of Basaglar. Prior to the introduction of Basaglar, the price of Lantus, the only insulin glargine on the market at the time, had increased steadily for several years. “The availability of Basaglar was associated with a significant downward trend in net price for Lantus and the average price across insulin glargine products,” they wrote.

Role of Government Policy Makers and Private Payers

The reviewers said that “Congress’ focus on the high cost of insulin is part of a larger legislative effort to lower prescription drug prices for Americans.” Proposals for reducing overall and out-of-pocket drug costs have been considered in Congress, and the former Trump administration issued several executive orders intended to lower prescription drug prices, which have been partly integrated into the drug policy planning under President Joe Biden’s administration, such as drug price negotiation and drug importation.

Nevertheless, they wrote, “the high cost of insulin continues to be a key issue in larger drug-pricing conversations and could potentially drive reintroduction of legislation or new proposals in the 117th Congress,” and Biden urged Congress in August 2021 “to implement reforms that would lower the cost of prescription drugs, specifically mentioning insulins.”

In response to the rising out-of-pocket and Medicare Part D spending on insulin in recent years, CMS began a new Part D Senior Savings Model in January 2021, which caps out-of-pocket insulin costs for beneficiaries. The authors said that CMS estimates an average savings of $446 per year in out-of-pocket costs for beneficiaries.

The authors noted that “the rising cost of insulin has also captured the attention of policymakers at the state level,” with legislation passed in at least 18 states that cap out-of-pocket costs for insulin. Private payers have taken action as well; they said several insurers, including Oscar Health, Cigna, CVS, and Medica, have offered caps on co-pays or programs that reduce or eliminate out-of-pocket costs.

Although at the federal policy level, “it remains to be seen if any new drug-pricing legislation or policies will move forward and how those would affect insulins,” the authors said, state and private payer initiatives are beginning to address insulin costs, and “biosimilar insulins can promote competition, potentially decreasing both drug and health care costs and increasing patient access.”

White J, Wagner A, Patel H. The impact of biosimilar insulins on the diabetes landscape. 

. Published online October 14, 2021. doi:10.18553/jmcp.2021.21253

Articles

In a review, Sandoz researchers discuss lingering barriers that prevent insulin prices from falling to more affordable levels.

Sandoz Reviews Insulin Access, Cost, and Biosimilar Potential

Machine learning shows promise as a complementary approach to chromatographic (mixture separation) techniques for assessing biosimilarity and stability, according to a recent study.

Investigators evaluated machine learning vs chromatographic analysis in the study of 3 trastuzumab biosimilars and their reference product (Herceptin) under control and stress conditions. They concluded the machine learning results correlated with the chromatographic data and revealed patterns elucidating the effects of pH and thermal stress conditions.

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), is approved as a treatment for metastatic breast cancer, early breast cancer, and metastatic gastric cancer. The investigators found that the biosimilars showed high similarity under control conditions, but “differences in degradation patterns were detected under…forced degradation conditions” in the study.

First, physicochemical characteristics of the reference product and biosimilar trastuzumab products (approved for use in Egypt; and referred to as B1, B2, and B3 in the study) were determined by size exclusion chromatography, cation exchange chromatography, and peptide mapping. The biologics were evaluated under control conditions and under pH and thermal stress. The investigators then used unsupervised machine learning techniques to find patterns in the chromatographic data.

The authors said primary structure and size and charge variants are quality attributes expected to affect the quality, safety, and efficacy of biologic drugs including trastuzumab. These attributes were similar in the biosimilars and reference product under control conditions, the authors found.

Thermal and pH stress, the authors noted, “are among the most studied stress conditions in forced degradation studies due to their direct effect on the size and charge variant profiles of [monoclonal antibodies] mAbs through deamidation and oxidation.” Under thermal and pH stress, the investigators did find differences in the degradation of the different products.

Based on size exclusion chromatography, B2 and B3 showed a tendency to form high- and low-molecular weight variants under acidic and basic stress, and B2 showed 83% degradation by the 2-week time point under acidic stress. Under thermal stress, B3 showed the greatest degradation, 39% after 2 weeks.

Under acidic stress, the products varied from 19.9% degradation of the main variant of the reference product at 2 weeks to 93% for B2. Under basic stress, all samples showed a comparable increase in abundance of acidic variants. Under thermal stress, the charge variant distribution of B2 and B3 were similar to charge variant distribution for the reference product, while B1 showed a greater abundance of acidic variants.

The investigators used unsupervised machine learning techniques, which find patterns in data with no prior training or predefined subcategories. Principal component analysis (PCA) is a method for reducing complexity in high-dimensional data to a small number of components that explain the greatest percentage of the variance in the data set.

The authors plotted size exclusion chromatography and cation exchange chromatography data on 2-dimensional coordinates representing the 2 components (PC1 and PC2) that explained the most variance to identify patterns in the data. Primary component analysis of chromatographic and peptide mapping data of the control samples showed no outliers, which the authors said supports biosimilarity of the products.

The plot of control and acidic stressed samples showed that the control samples were separated along the primary component 1 (PC1) axis, while the stressed samples were distributed along the PC2 axis. Samples of the same product were clustered “relevantly close to each other,” the authors said, and their PCA results on control and acidic-stressed samples suggested 41% of the variance in the data was due to the applied stress, and 25% was due to inherent differences in the chromatographic profiles of the products.

The investigators also used 2 clustering techniques, k-means and density-based spatial clustering of applications with noise (DBSCAN), on the data from the top 2 PCs from their primary component analysis. According to the authors, cluster analysis is “an unsupervised exploratory technique aiming to find natural grouping in data so that items in the same cluster are more similar to each other than to those from different clusters.”

Due to the “inherent variability” and “large number of possible structural variants” of monoclonal antibodies, the authors said, machine learning–aided approaches have “great value” for assessing their critical quality attributes. They cited previous research using PCA to reveal patterns in the data on biosimilarity and stability of other biologics, recombinant human growth hormone and infliximab.

K-means clustering of the unstressed samples segregated the products into 3 clusters, with the reference product and B2 each forming their own cluster, and B1 and B3 allocated to the same cluster. DBSCAN segregated each product to its own cluster.

K-means clustering was able to separate control and pH-stressed samples into different clusters, although B2 control samples were clustered with the stressed reference product and B3 samples. Cluster analysis suggested B3 was most similar to the reference product under acidic stress, while B2 was most similar under thermal stress, and all products had a similar response to basic pH stress. The greatest variability between control samples was between the reference product and B2.

Finally, application of principal component and clustering analyses to the collective data set from all the applied chromatographic techniques supported biosimilarity of the products, the authors said. This principal component analysis identified no samples that were significantly different from the others; k-means identified 3 clusters (reference product, B1 + B3, and B2), and DBSCAN identified 4 clusters, one containing each product.

The authors concluded their results supported the biosimilarity of the products analyzed, and “highlighted that regarding the charge and size profiles of the studied products, B2 showed higher variability (than B1 and B3) compared to HC under both control and stress conditions.” They said that the chromatographic fingerprints and machine learning results “were correlated and were able to reveal patterns related to the effect of different stress conditions on the different investigated products.” They recommended future studies explore other machine learning tools to interpret physicochemical data on biologic products.

The European Medicines Authority reports on a 

 in tailoring development of biosimilars, or eliminating unnecessary testing, and the World Health Organization 

Shatat SM, Al-Ghobashy MA, Fathalla FA, Abbas SS, Eltanany BM. Coupling of trastuzumab chromatographic profiling with machine learning tools: a complementary approach for biosimilarity and stability assessment. 

J Chromatogr B Analyt Technol Biomed Life Sci

. 2021;1184:122976. doi:10.1016/j.jchromb.2021.122976

A study of trastuzumab biosimilars and the reference product (Herceptin) under control and stress conditions elucidated the value of machine learning. 

Machine Learning Clarifies Stress-Based Degradation of Biosimilars

Authors of a review of 100 years of insulin therapy for diabetes contend that manufacturers have systematically exploited the patent system and market to generate profits at the expense of patients, but they note progress in the development and availability of biosimilar insulin.

Semglee (insulin glargine), for example, was originally launched in 2020 as a standalone drug, but its status was 

 to “interchangeable biosimilar” in 2021, potentially giving it access to a larger share of the market for reference product Lantus. The official relaunch of the product as a biosimilar was November 16, 2021, and this made Semglee the first official insulin biosimilar available in the United States.

In tandem with the redesignation of Semglee, which has an identical amino acid sequence to Lantus, the pharmacy benefit managers (PBMs) 

 have announced intentions to give this product preferred formulary status, boosting access to patients and, potentially, savings.

Semglee was the first biosimilar to receive interchangeable status. An interchangeable can be dispensed at the pharmacy counter instead of higher-priced reference products without physician authorization. According to AmerisourceBergen, there are multiple rapid-acting and long-acting insulin biosimilars in development that could potentially complement the price-reducing effect of Semglee.

Insulin was discovered in 1921 in Toronto, Canada, and first used to treat diabetes in a human in January 1922. Recognizing insulin’s value for human health, its discoverers famously sold their patent rights for $1 each to keep insulin “accessible and affordable for everyone with diabetes”; yet after nearly 100 years of insulin, fewer than half of patients with diabetes worldwide can’t access or afford the drug, and up to 30% of individuals in the United States with diabetes report rationing or skipping insulin doses because of cost, according to authors of the review, which explores why insulin remains expensive and how its cost could be controlled.

“Insulin prices and expenditures have increased dramatically over the past decade in the United States, and high prices and out-of-pocket costs are barriers to insulin treatment for people with diabetes,” the authors wrote.

They cited several factors that are driving up the cost of insulin, including clinicians’ prescribing practices, price increases across all insulin products, regulatory and policy barriers, and a lack of transparency throughout the supply chain. They outlined strategies at clinical, policy, and regulatory levels to improve access to and affordability of insulin.

A Shift in Clinician Prescribing Practices

First, they noted increasing use of more expensive insulin analogs in place of human and animal insulins, which has “negatively affected the affordability of insulin for health systems and individuals around the world.” 

Insulin prices and expenditures have increased dramatically over the past decade in the United States, and high prices and out-of-pocket costs are barriers to insulin treatment for people with diabetes.

Clinicians should weigh the benefits and costs of insulin analogs (laboratory grown and genetically modified to accelerate or control the drug’s effect), because less-expensive human insulins “may be appropriate alternatives” for some patients, the authors said. They cited research suggesting that insulin analogs did not reduce the risk of hypoglycemia or improve glycemic control compared with human neutral protamine Hagedorn (NPH; isophane) insulin in patients with type 2 diabetes.

The authors recommended regulatory changes, saying that “although patents and exclusivities serve to promote innovation, they can negatively impact competition.” For example, they recommended regulatory action to discourage manufacturers from applying for multiple patents on the same drug or making slight modifications in product to extend patent protection.

Additionally, they advised that manufacturer agreements that block the launch of generics or biosimilars (pay for delay) “should be curtailed,” and they said the 180-day exclusivity period for the first manufacturer to apply for a generic drug application “should be revised to close loopholes that limit competition beyond 180 days.” Plus, they said regulators should contemplate shortening the allowable period of market exclusivity for original biological products and removing market barriers to biosimilar entry.

Flexibility of Payers to Negotiate Drug Prices

The federal government’s limited flexibility to negotiate drug prices is another contributor to rising insulin costs, the authors said. Medicaid is permitted to negotiate drug prices “and by doing so is able to provide beneficiaries with an extensive choice of medications at low out-of-pocket costs,” but Medicare Part D is prohibited from negotiating drug prices. The authors recommended that “all federal drug benefit programs be given greater flexibility to negotiate medication prices with manufacturers and PBMs to capitalize on their market shares and volumes.”

Under the Build Back Better Act, currently under negotiation in Congress, Medicare Part D would be allowed to negotiate the prices of the highest cost drugs once they have been on the market for a certain length of time. The market exposure time for small molecule (generic) drugs would be 9 years, and the time limit for large molecule (biologics) would be 12 years. Medicare could negotiate up to 10 drugs per year in 2023, and in succeeding years the total could climb to 22 drugs negotiated.

For every $100 spent on retail drugs, $41 goes to parties in the distribution chain: wholesalers, pharmacies, pharmacy benefit managers, and insurers.

The authors also discussed the Part D Senior Savings model, “a promising new model for pharmacy payment,” launched by the Center for Medicare and Medicaid Innovation in January 2021. This savings model offers beneficiaries “broad access to multiple types of insulin at a maximum copay of $35 per insulin per month.”

With value-based pricing, “the price paid for medication is based on the benefits to the patient as indicated by clinical or financial measures.” The authors encouraged the use of value-based pricing for insulin or alternatively, value-based insurance design (VBID), which is intended to promote cost-efficient health care and consumer choices, with the goal of lowering costs and improving health care quality. The authors noted that VBID principles are already in place in the Affordable Care Act, which requires health plans to cover certain preventive services with no patient co-pay. 

The authors noted the growing difference between the list price and the net price of insulin due to rebates and discounts, saying “for every $100 spent on retail drugs, $41 goes to parties in the distribution chain: wholesalers, pharmacies, pharmacy benefit managers, and insurers.” They urged “greater transparency and simplicity” in insulin pricing “to eliminate distortions that are currently beyond individual payers’ ability to address.”

Herman WH, Kuo S. 100 years of insulin: why is insulin so expensive and what can be done to control its cost? 

. 2021;50(3 suppl):e21-e34. doi:10.1016/j.ecl.2021.09.001

Authors of a review discuss barriers to insulin access and potential solutions as the 100-year anniversary of the drug's first use for diabetes gets closer. 

High Cost, Low Access Still Plague Insulin Market at 100-Year Anniversary

Switching between reference adalimumab (Humira) and its approved biosimilars results in no differences in efficacy, safety, and immunogenicity, investigators in Spain have concluded following a 

 of available studies that was published in 

The authors conducted a systematic review of the 21 studies that met their inclusion criteria. These included 2802 adult patients treated with 8 adalimumab biosimilars for chronic immune-mediated inflammatory diseases. Investigators reviewed 8 studies on rheumatoid arthritis, 6 on psoriasis, 6 on inflammatory bowel diseases, and 1 on multiple diseases.

Adalimumab, a monoclonal antibody to tumor necrosis factor alpha, was first approved by the FDA in 2002 and European Commission in 2003. By 2017, the authors said, “it was the best-selling drug worldwide, with global sales of $18 billion.” 

In the European Union, Humira’s key patent expired in 2018, and adalimumab biosimilars have long been available there for patient treatment. In the United States, Humira’s compound patent expired in 2016; however, due to other patents and settlements between AbbVie and biosimilar manufacturers, biosimilars will not enter the US market 

The systematic review encompassed studies on adalimumab biosimilars approved in the United States and European Union:

SB5 (Hadlima; Samsung Bioepis; 5 studies)

FKB327 (Hulio; Mylan with Fujifilm Kyowa Kirin Biologics; 2 studies)

BI695501 (Cyltezo; Boehringer Ingelheim; 1 study)

MSB11022 (Idacio; Fresenius Kabi; 1 study)

PF-061410293 (Amsparity/Abrilada; Pfizer; 1 study)

Of the 21 studies, 19 assessed clinical efficacy and 10 of these were double-blind, randomized, placebo-controlled trials. According to the authors, no significant differences in efficacy (or effectiveness) were demonstrated between switch and no-switch groups in these trials.

Safety was investigated in 18 studies. The authors found that infection was the most frequently reported treatment-emergent adverse event, and rates of adverse events were similar between switch and no-switch groups in these studies. Notably, the authors wrote, their finding “contradicts the information from some systematic reviews where there appears to be a greater number of treatment cessations following the switching due to the possible nocebo effect.”

Greater pain at the injection site was reported in switch groups than no-switch groups in 2 studies reviewed by the authors, which they noted were nonrandomized studies, indicating a possible nocebo effect. They suggested “careful communication among all the implicated health professionals—doctors, nurses and pharmacists—and a clear explanation of the treatment schedule to the patient could help to minimize this nocebo effect.”

Fifteen studies evaluated immunogenicity, which was indicated by the percentage of patients who developed neutralizing antidrug antibodies (ADAs). Rates of development of ADAs were comparable, with no significant differences between reference adalimumab, biosimilar, and switching groups in these studies, according to the authors.

The authors concluded their systematic review suggests switching between adalimumab and its biosimilars has “no impact on efficacy, safety, and immunogenicity in patients with chronic immune-mediated inflammatory diseases.” They said this finding was consistent across the different adalimumab biosimilars they studied.

The authors contended their review is significant because “both health care professionals and patients, as well as health administrations, need this information to conduct safe switching of these medicines and gain confidence in their management.”

They wrote their review was limited by the relatively small number of studies, which did not allow them to conduct a meta-analysis, and the quality of the studies, some of which were not blinded and randomized. Also, just 1 study investigated multiple switches, and none investigated switching between different biosimilars.

Pego Reigosa JM, García Beloso N, Altabás González I, et al. Switching between reference adalimumab and biosimilars in chronic immune-mediated inflammatory diseases: a systematic literature review. 

. Published online October 8, 2021. doi:10.1111/bcp.15101

Investigators in Spain said they found no significant differences in outcomes for patients who switched from adalimumab originator to 1 of multiple adalimumab biosimilars. 

Investigators Review Marketed Adalimumab Biosimilars for Switching Differences

Costs of administering reference (Neupogen) or biosimilar filgrastim (Zarxio) are predictably higher in the outpatient hospital setting than in the office setting, although savings were nonexistent when administering the biosimilar vs reference product in the outpatient hospital setting, 

Filgrastim is a granulocyte colony-stimulating factor drug used to prevent or treat chemotherapy induced neutropenia (lower-than-normal levels of white blood cells).

Investigators conducted a retrospective study of 65,372 episodes of filgrastim use from 2014 to 2019 among commercially covered women and men in health care settings across the United States. They sought to evaluate potential savings for use of Zarxio, tbo-filgrastim (Granix), and the reference product. Granix is approved in the European Union as a biosimilar, but in the United States it is considered a version of filgrastim because its approval did not come through the biosimilar pathway.

Median costs were higher in the outpatient hospital setting compared with the office setting for all 3 filgrastim products, the authors wrote in T

). Additionally, after results were adjusted for patient characteristics and geography, the investigators found cost savings associated with the biosimilar filgrastim “were limited to the office setting, with no savings in the outpatient hospital setting.”

The authors defined an episode as 1 or more filgrastim administrations and fewer than 7 days between administrations. Median costs were adjusted for patient characteristics and geographic differences. The cost of administration was defined as the “sum of out-of-pocket and health plan paid amounts for the drug per date of service.”

In the office setting, the median costs of the biosimilar filgrastim administration and tbo-filgrastim administration were $103.61 and $94.07 less than that of reference product administration, respectively, the investigators said.

There were no cost savings associated with use of the biosimilar in the outpatient hospital setting. The adjusted median cost of biosimilar administration was greater than reference product administration by $20.50 in this setting. In contrast, the cost of tbo-filgrastim administration in the outpatient hospital setting was $132.90 less than a reference product administration.

Although previous analyses have found lower costs for the biosimilar filgrastim than for reference filgrastim, the authors concluded their data suggest that “site of care can change this calculus, reducing savings.”

One possible contributing factor they suggested is the difference in payer payments for outpatient- vs office-based treatment.

"Although patients receive identical drug administrations in office or hospital outpatient settings, insurers generally reimburse higher payments to outpatient hospital settings to cover presumed greater overhead costs," they wrote.

The authors said that despite their findings being limited to commercially covered patients, the results suggest that “savings from biosimilar drugs are context specific,” although they said it is unknown whether the cost savings for other biosimilar drugs vary similarly by site of care.

“Biosimilars—drugs that are similar in quality, safety, and efficacy to reference biologic drugs—are intended to increase competition, reduce prices, and improve patient access to important treatments,” they said. They did not speculate on why in the outpatient hospital setting the cost of Zarxio administration was slightly higher, on average, than reference product administration.

They also did not speculate on why tbo-filgrastim was significantly less costly than reference filgrastim in both the outpatient and office settings, but not the biosimilar filgrastim. In addition to Neupogen, Zarxio, and Granix, another filgrastim product is available, the biosimilar Nivestym. This was approved and launched in late 2018, which was midway through the study period. Investigators did not review cost data for Nivestym.

Granix was approved in August 2012 and launched in November 2013, and Zarxio in March 2015 and September 2015, respectively.

Chang J, Karaca-Mandic P, Go RS, Schondelmeyer S, Weisdorf D, Jeffery MM. Site of care potentially limits cost savings from biosimilars. 

. 2021;27(8):e287-e289. doi:10.37765/ajmc.2021.88730

According to a multiyear, retrospective study, filgrastim biosimilar Zarxio cost $20.50 more on average per administration than reference Neupogen in the hospital outpatient setting. 

Study: Zarxio More Costly Than Neupogen in Outpatient Hospital Setting

The results of a meta-analysis of 3 phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) studies of the Sandoz 

 Ziextenzo support PK and PD similarity of the biosimilar to both US and EU reference versions of the originator (Neulasta).

Pegfilgrastim is a pegylated, long-acting form of filgrastim. Both are granulocyte colony-stimulating factor (

) drugs, which are used to stimulate neutrophil production in patients undergoing chemotherapy to reduce the risk of febrile neutropenia.

The investigators said that “since the designs of the 3 studies were different and the sensitivity of the bioanalytical assay varied slightly among the studies,” a meta-analysis could “provide a more precise estimate of biologics comparisons than the individual studies.” With this meta-analysis, they aimed to “address all aspects of residual uncertainty regarding the biosimilarity of Sandoz pegfilgrastim.”

The First PK/PD Study Failed to Demonstrate Biosimilarity

The first study, a 3-arm (biosimilar, US reference, EU reference) parallel-group study, in which participants receive separate drugs and regimens, failed to demonstrate biosimilarity, but “revealed an unexpected high intersubject variability” in PK parameters of pegfilgrastim, according to the authors. Plus, they said, a retrospective evaluation of study 1 found it was underpowered to demonstrate biosimilarity.

The authors noted that since the publication of this study, “the high degree of intersubject variability of the PK results has since been confirmed by others with the reference biologic.”

PD parameters, in contrast, were within the equivalence margins in this study, and there were “no meaningful differences” in safety, local tolerability, and immunogenicity between the biosimilar and reference groups.

The investigators said that study 1 demonstrated that a parallel design was not suitable, and “a crossover design is more appropriate for studies involving pegfilgrastim.” In a crossover study, each participant receives both the experimental drug (biosimilar, in this case) and the control (Neulasta).

Studies 2 and 3 Demonstrated Biosimilarity Using a Crossover Design

Study 2 was conducted to address the limitations of study 1. It compared the biosimilar with the EU reference product in 1 of 2 sequences. This study used a revised sample size estimation and tighter inclusion criteria for absolute neutrophil count and body mass index to address intra-individual variability and reduce the heterogeneity of the population, respectively. No meaningful differences in safety, local tolerability, or immunogenicity were detected in this study.

Study 3 used a 3-way, 6-sequence crossover design evaluating the biosimilar vs both US and EU reference products “to circumvent the interindividual variability and take into account intra-individual variability instead.” This study also demonstrated no meaningful differences in safety, local tolerability, and immunogenicity between the 3 pegfilgrastim products

The investigators considered biosimilarity to be demonstrated if all 90% confidence intervals (CIs) for the geometric mean ratios for treatment comparisons (comparison of biosimilar to US reference, etc) fell within the margins of 0.80 and 1.25.

They found that demographic and baseline characteristics were similar overall between the groups. They analyzed PK and PD parameters for 277 participants from study 1, 169 from study 2, and 496 from study 3. The 90% CIs of the geometric mean ratios for all 3 comparisons (biosimilar vs US reference, biosimilar vs EU reference, and biosimilar vs US reference and EU reference) were within the predefined equivalence margins, suggesting biosimilarity.

The investigators noted that their results suggest that area under the curve and maximum serum concentration were approximately 5% to 7% higher with the biosimilar compared with the 2 reference products. However, they said this “slightly higher exposure did not translate into any differences in PD effects in the present study,” adding that no clinically meaningful differences in efficacy or safety were observed in the phase 3 clinical studies.

Safety and Tolerability Found to Be Similar

The authors did not perform a meta-analysis on the safety data, but pooled data from all subjects who received at least 1 dose of the study drug in any of the 3 studies, including 781 subjects who received the biosimilar, 604 who received the US reference product, and 772 who received the EU reference product. They reported safety and tolerability were similar between the biosimilar, US reference, and EU reference in these healthy subjects.

Treatment-emergent adverse events (TEAEs) considered related to the study drug occurred in 85.8% of subjects in the biosimilar groups, 84.3% in the US reference groups, and 86.3% in the EU reference groups. The most common TEAEs included headache, back pain, bone pain, and myalgia.

There were no serious drug-related AEs in any group in any study. Six participants treated with the biosimilar and 5 treated with the EU reference product had a study drug-related TEAE leading to discontinuation of the study.

Although study 1 did not demonstrate PK biosimilarity, when combined with studies 2 and 3 in this meta-analysis, the authors said, the data support PK and PD biosimilarity as demonstrated in studies 2 and 3, with no clinically meaningful differences in safety or tolerability, adding to the totality of evidence for the Sandoz pegfilgrastim. They added, “with data from 1040 healthy subjects, this is the largest-known evaluation of PK/PD parameters and safety of a biosimilar of pegfilgrastim.”

Gattu S, Wang J, Bellon A, Schelcher C, Nakov R, Arani R. Meta-analysis of pharmacokinetic/pharmacodynamic results of 3 phase 1 studies with biosimilar pegfilgrastim. 

. Published online August 4, 2021. doi:10.1002/cpdd.1005

A meta-analysis of pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of Sandoz pegfilgrastim biosimilar confirms biosimilarity. 

Meta-analysis of Sandoz Pegfilgrastim PK/PD Studies Supports Biosimilarity 

 of 348 children with Turner syndrome (TS) found that biosimilar recombinant human growth hormone (rhGH) therapy was safe and effective in real-life clinical practice.

The investigators reported on a subgroup of patients with TS from the PAtients TReated with Omnitrope (PATRO) Children study, a long-term, postmarketing surveillance study of children treated with biosimilar rhGH (Omnitrope; Sandoz).

TS is characterized by partial or complete loss of the second sex chromosome in females and is associated with comorbidities, including growth failure. TS has been treated with reference rhGH (Genotropin; Pfizer) since its approval in 1995. The biosimilar Omnitrope became available after approval by the European Medicines Agency and the FDA in 2006.

The investigators enrolled 348 patients being treated for TS at 130 centers across Europe. Their mean age was 9.0 (range, 0.7-18.5) years at baseline. Most (81.6%) were rhGH naïve, and 90.2% were prepubertal. The mean (SD) treatment duration in the study was 38.5 (26.8) months.

Safety was the primary end point of the study. The authors pointed out that rhGH is “generally well tolerated” in patients with TS; however, observational studies have reported greater risk for some adverse events (AEs) in patients with TS receiving rhGH. The AEs include intracranial hypertension, slipped capital femoral epiphyses, pancreatitis, and development or progression of scoliosis. The investigators wrote that their findings “do not support an increased risk of these events due to rhGH therapy.” However, noting the relatively short treatment duration in their study, they cautioned “longer-term follow-up would be required to verify these safety findings.”

Overall, approximately half of the patients (170; 48.9%) experienced AEs, most of which were mild or moderate. Twenty-five patients experienced treatment-related AEs, including headache, impaired glucose tolerance, increased insulin-like growth factor levels, and increased weight. One patient experienced scoliosis that was deemed treatment related.

Approximately half (172; 49.4%) of the patients discontinued the study. The most common reason (52 patients) for discontinuation was the attainment of adult height or bone age maturation. Six patients discontinued the study because of a lack of treatment response. Ten patients discontinued due to AEs, one of whom experienced a serious AE (intracranial hypertension) that was “possibly related to treatment.” The authors wrote that their safety findings “show no evidence of an increased risk of developing unexpected AEs or new malignancies during rhGH treatment.”

The investigators included 163 patients in their 3-year effectiveness cohort, 131 of whom were rhGH naïve prior to the study. Most patients (98.5% of the rhGH-naïve group and 90.6% of pretreated patients) were prepubertal.

Effectiveness was assessed by height velocity (HV), height standard deviation score (HSDS), and height velocity standard deviation score (HVSDS). The mean (SD) HV at 3 years was 5.2 (1.3) cm/year in prepubertal treatment-naïve patients and 4.7 (1.4) cm/year in prepubertal pretreated patients. From baseline to 3 years, gains in HSDS were 1.17 in prepubertal treatment-naïve patients and 0.04 in prepubertal pretreated patients. Mean increase in peak-centered HVSDS from baseline to 3 years was 3.94 in prepubertal rhGH-naïve patients and 0.47 in prepubertal pretreated patients.

Adult height was reached by 51 patients (31.1%), 35 of whom were rhGH naïve at baseline. In those 35 patients, the mean HSDS was –2.97 (1.03) at baseline, and at 3 years, the mean AHSDS was –2.02 (0.9). The AHSDS was similar in pretreated patients, at –2.10 (1.1).

These effectiveness findings “are broadly in line with those from other observational studies in TS patients,” according to the authors.

The authors concluded that treatment with biosimilar rhGH was well tolerated in patients with TS, and no unexpected safety signals were identified.

“Several well-known AEs were observed, confirming the need for ongoing patient monitoring,” they wrote. Although safety was their primary end point, they wrote that their effectiveness data showed “substantial height gains were observed in prepubertal individuals over 3 years of treatment.”

Backeljauw P, Kanumakala S, Loche S, et al. Safety and effectiveness of recombinant human growth hormone in children with Turner syndrome: data from the PATRO children study. 

. 2021;94(3-4):133-143. doi:10.1159/000515875

A multicenter study of recombinant human growth hormone (rhGH) in children with Turner syndrome demonstrated safety and efficacy comparable to the reference product. 

Study: Biosimilar rhGH Well Tolerated and Effective in Turner Syndrome

Using data from a population-based cancer registry in the Netherlands, 

response and survival rates for patients with diffuse large B-cell lymphoma (DLBCL) who received either rituximab originator (Rituxan) or biosimilars. They found that 3-year overall survival (OS) was 73% in both the originator and biosimilar groups (

 = .855), and overall response rates (ORRs) were 85% in the originator group and 84% in the biosimilar group (

Rituximab, a monoclonal antibody to the B-cell surface antigen CD20, has been “the backbone of every treatment regimen in B-cell non-Hodgkin lymphomas” since its approval by the FDA in 1997 and European Medicines Agency (EMA) in 1998, the authors said. And in the Netherlands, rituximab biosimilars were rapidly incorporated into the treatment regiment for these cancers.

Two rituximab biosimilars, CT-P10 (Truxima; Celltrion) and GP2013 (Riximyo; Sandoz), were approved by the EMA in 2017. That year, the Dutch Association of Medical Specialists began to incorporate rituximab biosimilars into the standard of care. By 2018, the authors said, 91% of the rituximab purchased in the Netherlands was biosimilar product rather than originator, leading to a 43% reduction in annual expenditure on rituximab in 2019 compared with 2015.

The investigators noted that rituximab biosimilars were approved by the EMA based on studies in patients with rheumatoid arthritis and naïve follicular lymphoma. Until now, data on ORR and OS rates with rituximab biosimilars in DLBCL, they said, have been “limited to small postmarketing studies.”

Investigators identified 4429 patients from the Netherlands Cancer Registry with DLBCL who were 18 or older, received a diagnosis of DLBCL between 2014 and 2018, and received at least 1 cycle of R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which they noted is standard of care for patients with newly diagnosed DLBCL. There were 3553 patients treated with rituximab originator and 876 treated with a biosimilar. Of those treated with a biosimilar, 86% received CT-P10 and 14%, GP2013.

Complete response was achieved by 74% of patients in the reference cohort and 72% in the biosimilar group; 11% in each cohort achieved partial response (

Overall 3-year survival was 73% in each group. The risk of mortality was also similar between groups in a multivariate analysis that adjusted for age at diagnosis, sex, International Prognostic Index score, and number of cycles of R-CHOP in the biosimilar group (HR 0.89; 95% CI, 0.76-1.05; 

 = .182) compared with the originator group.

Because the study included patient data from several years prior to when rituximab biosimilars were routinely used in clinical practice, the median follow-up times were 62 months for the reference product and 32 months for the biosimilars. The authors used sensitivity analysis to account for this difference.

First, an analysis of 3-year overall survival was conducted excluding all patients treated with the reference product who were diagnosed prior to biosimilar approval. Analyzing just the 370 patients treated with the reference product and 876 patients treated with biosimilars who were diagnosed between April 2017 and December 2018, 3-year survival rates were similar, 74% and 73%, respectively (

In the second part of the sensitivity analysis, the researchers compared 3-year survival rates in patients receiving the originator before (n = 3183) and after (n = 370) biosimilar approval. They found 3-year survival rates of 73% for those diagnosed prior to April 2017 and 74% for those diagnosed afterward. “Overall, the results of the sensitivity analyses were similar to those of the primary analyses,” the authors wrote.

According to the authors, theirs is the first population-based study following EMA approval of the first rituximab biosimilar to investigate survival in patients with newly diagnosed DLBCL treated with the rituximab originator or biosimilar. They wrote that their data suggest that patients with DLBCL “benefit equally” from rituximab originator or biosimilars combined with CHOP treatment. They acknowledged “the lack of detailed information on dosage per cycle at the patient level and treatment-related toxicities, including infusion-related reactions,” as limitations of their study.

Brink M, Kahle XU, Vermaat JSP, et al. Impact of rituximab biosimilars on overall survival in diffuse large B-cell lymphoma: a Dutch population-based study. 

. 2021;5(15):2958-2964. doi:10.1182/bloodadvances.2021004295

A retrospective study of rituximab biosimilars Truxima and Riximyo demonstrated comparable response and survival for patients with diffuse large B-cell lymphoma (DLBCL).

Dutch Study Confirms Response, Survival for Rituximab Biosimilars in DLBCL

 examined pricing changes in the insulin glargine market following the FDA approval and entry of Basaglar (insulin glargine injection; Eli Lilly) into the market.

The authors said their data suggest the approval was followed by a “substantial change in the trajectory of net prices” for insulin glargine products. After a steady increase in prices for Lantus, the only insulin glargine on the market from 2010 to 2014—the FDA approved Biocon Biologics’ Semglee insulin glargine 

—the average net price of all insulin glargine products decreased from 2015 to 2020.1

Basaglar, although it has the identical amino acid sequence to Biocon Biologics and is referred to as a biosimilar in the publication, was approved as a new drug, not a biosimilar. Until 2020, new versions of insulin products were approved in the United States via the Food, Drug, and Cosmetic Act section 505(b)(2) new drug application pathway. 

, biosimilar insulin products could be approved instead via the Public Health Service Act section 351(k) biologics license application pathway.2

Insulin glargine, a long-acting form of insulin, has been sold under the name Lantus by Sanofi since 2000. However, the patent on insulin glargine expired in February 2015, opening an opportunity for new insulin glargine products. Basaglar was approved by the FDA in December 2015 after a tentative approval in 2014, and it entered the market in December 2016.

The researchers noted that patent litigation delayed Basaglar’s market entry following its approval. Prior to the launch of Basaglar, Sanofi launched Toujeo, a higher-concentration insulin glargine product “that would not directly compete with Basaglar,” which the researchers reasoned was “a possible strategic move to maintain market share.”

The researchers studied 10 years of net price estimates and sales data from the SSR Health Drug Database, from Q1 of 2010 to the Q2 of 2020, for all 3 insulin glargine products.

Prior to 2015, Lantus was the only insulin glargine product on the market. According to the authors, its list price rose from $9.23 per 100 IU in Q1 of 2010 to $22.21 in Q3 of 2014, a 4.9% increase per quarter. They noted net prices were lower than list prices ($6.94 and $12.79, respectively) and rose more slowly (3.8% quarterly).

From 2015 to 2020, list prices “remained steady”; however, net prices of Lantus and the weighted average of all insulin glargine products declined. The price of Lantus declined by 5.2% per 100 IU per quarter compared with the average net price decline of 3.4% per quarter.

The researchers found that Lantus maintained the highest net sales of the 3 products throughout the 10-year period. However, by Q2 of 2020, Basaglar accounted for up 42.2% of sales compared with 46.2% for Lantus. Sanofi’s Toujeo, sold after Lantus lost exclusivity, “never gained greater than 15% market share,” according to the authors.

The researchers also conducted a single-group interrupted time series analysis to evaluate the trends in the weighted average net price of insulin glargine before and after Q4 of 2014, the approximate time of tentative approval of Basaglar. Their model estimated that prior to Basaglar’s approval, the net price of 100 IU of insulin glargine increased an average $0.36 per quarter, followed by a downward trend after approval of approximately $0.67 per quarter.

The investigators identified their focus on net prices rather than list prices, evaluating total sales, and the 10-year span of the data as strengths of their research. They said these factors allowed them to avoid methodological challenges frequently encountered in studies on the entry of a biosimilar into a biologic market, such as “failing to account for manufacturer-provided rebates, examining only a segment of US payers, and focusing on short-term changes.”

Future research, they said, could examine the association of market entry of new insulin biosimilars on the prices of both direct and nondirect competitors, and “the outcomes of decreasing net prices on patient out-of-pocket costs should be further investigated.”

1. Levy J, Chowdhury ZM, Socal MP, Trujillo AJ. Changes associated with the entry of a biosimilar in the insulin glargine market. 

. Published online June 28, 2021. doi:10.1001/jamainternmed.2021.2769

2. Kim AP, Bindler RJ. The future of biosimilar insulins. 

. 2016;29(3):161-166. doi:10.2337/diaspect.29.3.161

The average net price of all insulin glargine products decreased between 2015 and 2020 following the steady price increase seen for Lantus from 2010 to 2014.

Average Net Price for Insulin Glargine Declined After Basaglar Won FDA Approval

in Italy demonstrated equivalent safety, efficacy, and tolerability for patients with inflammatory bowel disease (IBD) who switched from reference infliximab (Remicade) to the biosimilar Renflexis (SB2, Flixabi), investigators concluded.

They said this was the largest study (N = 85) to date investigating crossover from Remicade to SB2.

Our primary aim was to prospectively verify the ability of SB2 to maintain the clinical and biochemical response induced by IFX originator after switching.

“Our patients maintained clinical response to therapy after switching and did not develop serious adverse events (AEs). In addition, we did not find differences in immunogenicity between infliximab originator and SB2,” investigators said.

IBD includes ulcerative colitis (UC) and Crohn disease (CD), relapsing and remitting inflammatory diseases of the intestinal tract, for which anti–tumor necrosis factor (TNF) biologics including infliximab may be prescribed. TNF inhibitors have “greatly improved” outcomes for patients with refractory IBD and those who are intolerant to standard treatments, according to the researchers.

The authors explained that, in the context of IBD, there is “substantial and robust literature” on the biosimilar CT-P13 (Inflectra, Remsima) and only a “paucity of data” on 

. CT-P13 was approved by the European Medicines Agency in 2013 and FDA in 2016, and SB2 was approved in 2016 by the EMA and 2017 by the FDA.

This study was conducted between 2018 and 2020 at 3 IBD treatment centers in Italy. The patient population included 28 (32.9%) with UC and 57 (67.1%) with CD. This was the first switch between infliximab products for this patient cohort. Data were collected at the time of switch and then at the first 2 follow-up visits to the IBD clinic, on average 135 days and 329 days later.

The proportion of patients in clinical remission was 82% at baseline and 69% at the second visit

Real-world study in Italy finds most patients with inflammatory bowel disease (IBD) maintain clinical and biochemical response after switching from infliximab reference product to SB2.