Deana Ferreri, PhD

Pooled data from 3 randomized controlled trials on biosimilar pegfilgrastim-cbqv (

) suggested “similar immunogenicity” to the reference product (Neulasta), according to a new 

Pegfilgrastim is a pegylated, long-acting form of granulocyte colony-stimulating factor (G-CSF), used to prevent febrile neutropenia in patients who receiving myelosuppressive chemotherapy by stimulating neutrophil production.

The authors noted that “all biologic therapeutics can be immunogenic or elicit an immune response,” and that an assessment of immunogenicity is part of the totality of evidence required for regulatory approval of biosimilars. Anti-drug antibodies (ADAs) “may have no clinical impact or they may affect the bioavailability, efficacy, and safety of the therapeutic to various degrees,” they wrote, adding that immunogenicity of the reference product has been reported as “low with no reported clinical impact.”

The study pooled data from 3 clinical studies in healthy participants: 1 designed to evaluate immunogenicity of the biosimilar compared to the reference product, and 2  studies designed to assess pharmacokinetic (PK) and pharmacodynamic (PD) similarity.

The immunogenicity study included 303 subjects (242 evaluated for ADAs) in two treatment groups receiving either the reference product or biosimilar. The 2 PK and PD studies were crossover studies (enrolling 122 and 116 subjects) in which a single dose of the originator and biosimilar was administered to each participant on different days, spaced apart by several weeks.

Anti-drug antibodies in the immunogenicity study

The presence of ADAs, along with ADA binding specificity, titer, and neutralizing activity were evaluated. No treatment-emergent neutralizing antibodies were detected in the immunogenicity study.

In both groups, the authors reported, most ADAs reacted either with the polyethylene glycol (PEG) portion of the molecule, or both PEG and G-CSF. Three subjects (2 in biosimilar group, 1 in reference product group) had measurable anti-G-CSF titers, which the authors said were transient. They found no cases of ADAs that reacted only with G-CSF.

Overall, the incidence of treatment-emergent ADAs was 32.2% (39 subjects) in those administered the biosimilar and 23.9% (28 subjects) in those administered the reference product. Incidence of treatment-emergent, persistent ADAs with measurable titer (titer 2 or greater) was 9.8% in subjects receiving the biosimilar and 5.0% in subjects receiving the reference product. The differences between groups in ADAs was “driven by non-neutralizing, low-titer, polyethylene glycol (PEG)-reactive ADAs, which are commonly present in healthy subjects,” according to the authors.

To assess the clinical impact of ADAs, the authors compared pharmacokinetics, pharmacodynamics, and safety profiles of ADA-positive and ADA-negative participants in the immunogenicity study. They found “no apparent impact of ADAs on pharmacokinetics, pharmacodynamics or safety.”

The safety profiles of the biosimilar and reference product in this study “were consistent with the known pegfilgrastim safety profile and appeared to be unaffected by the presence of ADA,” the authors wrote. Overall, adverse events occurred in 89.7% of subjects receiving the biosimilar and 92.9% of those receiving the reference product. The most common were musculoskeletal pain and headache.

Anti-drug antibodies in the pooled analysis

The authors reported that the incidence of treatment-emergent ADAs in the pooled analysis was comparable, with ADAs detected in 31.6% (72) of subjects receiving the biosimilar and 29.3% (76) receiving the originator. In the individual PK/PD studies, treatment-emergent ADAs were detected in 28.6% compared to 33.3% and 30.0% compared to 34.6% of participants receiving the biosimilar and reference product..

Similar to the results of the immunogenicity study alone, the authors reported that in the pooled analysis, most treatment-emergent ADAs were reactive to PEG, no treatment-emergent ADAs reactive only with G-CSF were detected, and no treatment-emergent neutralizing antibodies were detected.

The authors concluded their pooled analysis “demonstrates the low immunogenic risk of pegfilgrastim-cbqv and supports the overall demonstration of similarity between pegfilgrastim-cbqv and pegfilgrastim.”

Civoli F, Finck B, Tang H, et al. Biosimilar pegfilgrastim-cbqv demonstrated similar immunogenicity to pegfilgrastim in healthy subjects across three randomized clinical studies. 

. 2022; Published online January 16, 2022. doi: 10.1007/s12325-021-02024-x.

Articles

The authors noted that “all biologic therapeutics can be immunogenic or elicit an immune response,” and that an assessment of immunogenicity is part of the totality of evidence required for regulatory approval of biosimilars. 

Pooled Analysis of 3 Trials Finds Biosimilar Pegfilgrastim-cbqv Has Similar Immunogenicity to Reference Product 

Two new studies have investigated the adalimumab biosimilar SB5 (Imraldi; Samsung Bioepis) in inflammatory bowel disease (IBD; Crohn disease and ulcerative colitis)

 and non-anterior uveitis associated with Behcet's syndrome (BS).

According to the authors of the real-world study in IBD, their effectiveness data “shows comparability with the [adalimumab] originator.” Adalimumab drug persistence was 62.5% in patients starting on SB5 and 83.1% in patients switching from the reference product to biosimilar SB5. Those figures, the authors wrote, are “in line with drug persistence data from previous studies with the originator.”

In the retrospective study on BS-associated uveitis, all 8 patients who were treated with SB5 over an average of 16 months experienced complete resolution of inflammation. Retinal vasculitis resolved in all four eyes that were affected at baseline.

Adalimumab is a monoclonal antibody targeting tumor necrosis factor (TNF) alpha. The reference product (Humira) was first approved by the FDA in 2002 and the European Medicines Agency in 2003. Adalimumab biosimilars are currently available in the European Union, but market entry for has been delayed 

 due to additional patents and legal settlements.

The investigators noted that several studies have demonstrated the effectiveness and safety of biosimilars to infliximab, another anti-TNF biologic. 

However, they wrote, “data on [adalimumab] biosimilars are scarce.” At the time their study was published, they wrote, "no randomized controlled trials comparing a biosimilar to the originator in IBD have yet been published." (Since then, recent data from VOLTAIRE-CD have shown that safety and efficacy were similar in patients with Crohn's disease treated with BI 695501 or the adalimumab reference product, Humira.) 

Their retrospective observational cohort study, conducted in Scotland, examined long-term outcomes of 481 patients with IBD taking SB5. Of those, 256 switched from the originator to SB5 (switch cohort), while 225 who were not being treated with adalimumab at baseline started treatment with the biosimilar (start cohort). Notably, their study included 35 patients who underwent a double switch from the reference product to SB5 to another adalimumab biosimilar, ABP 501.

The primary outcome of the study was drug persistence. In the switch cohort, 213 patients (84.6%) remained on the biosimilar after 26 weeks, and at 52 weeks 163 (70.8%) were still being treated with SB5. Over a median 13.7-month follow-up, 90 (35.2%) patients discontinued biosimilar treatment, 46 due to adverse events and 37 due to secondary loss of response. The investigators found no differences in the proportion of patients in clinical remission, or median C-reactive protein, fecal calprotectin, or adalimumab trough levels between baseline, week 26, and week 52 following the switch.

In the start cohort, at week 26, 137 patients (77.8%) remained on SB5 treatment, and 65 (60.3%) remained at 52 weeks. Over a median follow-up of 18.3 months, 81 patients (36%) discontinued SB5 therapy, 22 due to primary non-response, 26 due to secondary non-response, and 24 due to adverse events.

Pain at the injection site was the most frequent adverse event in the switch cohort. Three patients developed a skin rash and 5 patients developed an infection requiring temporary discontinuation of therapy. Of the 256 patients in the switch cohort, 51 patients experienced adverse events that required suspending or discontinuing SB5 therapy. In the start cohort, 39 of the 225 patients experienced any adverse event, the most frequent of which were infections. Of 17 infections, 7 required temporary suspension of treatment, and 10 required permanent discontinuation.

The majority of patients in the switch cohort (76.1%), and a minority of patients in the start cohort (3.1%) who discontinued SB5 due to side effects switched to another adalimumab product. Taking these numbers into account, the authors said drug persistence on adalimumab overall was 90.9% and 83.1% at week 26 and 52 in the switch cohort and 80.1% and 62.8% in the start cohort.

The investigators added that 35 patients underwent a double switch from the reference product to biosimilar SB5 and then to biosimilar ABP 501, all of whom underwent the second switch due to side effects on SB5 (33 for pain at injection site, 2 for skin rash). None of these patients discontinued adalimumab therapy over a median follow-up duration of 34 weeks.

Researchers conducted a retrospective study of eight patients with BS who had active non-anterior uveitis and/or systemic uncontrolled disease or were undergoing a nonmedical switch from the reference product to SB5.

 is one of the main clinical features of BS, which reduces visual acuity and negatively affects quality of life. However, “the use of monoclonal TNF-α antibodies has significantly improved visual prognosis in BS patients and widened therapeutic alternatives for the management of such a sight-threatening condition.”

The efficacy and safety of SB5 were originally demonstrated in rheumatoid arthritis, which the authors said “may not guarantee extrapolation to other indications, since it is not a very sensitive model for the detection of potential differences” between the biosimilar and reference product. They also mentioned data on SB5 in BS-related uveitis are scarce.

The 8 patients were treated with biosimilar SB5 for an average of 16.38 (standard deviation 3.93) months. In the 12 months prior to initiating adalimumab biosimilar therapy, there were 8 ocular relapses in the 8 patients. No ocular relapses were reported between baseline and the last follow-up visit.

At baseline, 4 of the 16 eyes had active retinal vasculitis, and all 4 had resolved by 3 months of SB5 therapy and remained resolved at the last follow-up. Furthermore, over the 16-month follow-up, “complete resolution of inflammation was observed in all affected eyes.” No adverse events were reported, and median visual acuity did not significantly change from baseline to the last follow-up visit. The investigators concluded SB5 is an effective treatment option for BS-related non-anterior uveitis.

The authors mentioned their findings “should be interpreted with caution” because of the small sample size and other study limitations. However, to their knowledge their study “represents the largest sample of BS patients affected by uveitis and successfully treated with SB5.

1. Derikx LAAP, Dolby HW, Plevris N, et al. Effectiveness and aafety of adalimumab biosimilar SB5 in inflammatory bowel disease: outcomes in originator to SB5 switch, double biosimilar switch and bio-naïve SB5 observational cohorts. 

. 2021;15(12):2011-2021. doi:10.1093/ecco-jcc/jjab100

2. Sota J, Gentileschi S, Perfetti MO, et al. Role of adalimumab biosimilar in the treatment of non-anterior uveitis associated with Behçet's syndrome. 

. 2021;10(4):1129-1135. doi:10.1007/s40123-021-00387-6

Two new studies have investigated the adalimumab biosimilar SB5 (Imraldi; Samsung Bioepis) in inflammatory bowel disease (IBD; Crohn’s disease and ulcerative colitis) and non-anterior uveitis associated with Behcet's syndrome (BS).

Adalimumab Biosimilar SB5 Effective in Behçet’s Syndrome-Related Uveitis and IBD, Studies Find

A retrospective study characterized the real-world use of the biosimilar bevacizumab-awwb (Mvasi) for metastatic colorectal cancer (mCRC) during the first year after it entered the market in the United States. The study authors said their analysis of patient records suggested US oncologists adopted the bevacizumab biosimilar in clinical practice for mCRC for both new patients and those already being treated with the reference product.

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor-A (VEGF), approved by the FDA for treating mCRC in 2004. Since then, the authors wrote, “bevacizumab has been an important biologic therapy in treating a range of solid tumor indications as the standard of care in oncology.” Mvasi was approved by the FDA in 2017 and entered the US market in July 2019 as the first bevacizumab biosimilar.

mCRC is an extrapolated indication for bevacizumab-awwb

Approval of Mvasi was based on a comparative clinical efficacy and safety study in patients with advanced non-small cell lung cancer. Metastatic colorectal cancer is one of multiple extrapolated indications for the biosimilar.

The investigators said the purpose of their study was to evaluate the real-world use of the biosimilar in mCRC. They noted, “the American Society of Clinical Oncology has underlined the importance of postmarketing evidence to enhance patient and provider confidence in biosimilars.”

Patient characteristics and treatment patterns

Data on 304 patients who received the biosimilar during the first year of its availability were derived from the ConcertAI oncology dataset. About half of patients (47%) were bevacizumab-naïve. Investigators found demographic and clinical characteristics “appeared comparable” between bevacizumab-naïve and bevacizumab-experienced patients, and the characteristics of the patient population were “generally consistent with those of the US CRC population.”

Seventy-eight percent of patients overall were treated with the biosimilar as first-line therapy, and 91% among bevacizumab-naïve patients. The median time from mCRC diagnosis to initiation of biosimilar therapy was 63 days (interquartile range 36-138 days). Among patients previously treated with the reference product, 83% were switched to the biosimilar in the same line of therapy without disease progression. Most bevacizumab-experienced patients (74%) switched to the biosimilar within 28 days of their last reference product infusion. Among patients who switched without disease progression, 83% switched within 28 days of their last reference product infusion. The authors said these data suggest “early acceptance” of the biosimilar by US oncologists for both new and existing patients with mCRC.

The investigators wrote that their first-year post-marketing analysis of bevacizumab-awwb use “provides timely data in a tumor type where clinical trial data are not available.” They added that they are currently collecting data for a 12-month safety and effectiveness study in mCRC to be published in the future.

Rhodes W, DeClue RW, Accortt NA, Jin R, Sandschafer D, Wertz D, Patel K. Real-world use of bevacizumab-awwb, a bevacizumab biosimilar, in US patients with metastatic colorectal cancer. 

. 2021;17(36):5119-5127. doi: 10.2217/fon-2021-0588.

Records show the biosimilar for bevacizumab was used to treat both new patients and those already receiving care with the reference product. 

Real-world Study Sees Adoption of Mvasi by US Oncologists for Metastatic CRC

Insulin-R (Biocon), a proposed biosimilar referencing Eli Lilly’s Humulin-R, a short-acting recombinant human insulin, demonstrated equivalence in a pharmacokinetic (PK) and pharmacodynamic (PD) study published in 

 in recent years, and the authors of the study pointed out that high costs for many patients result in “nonadherence or rationing of insulin, leading to diabetic complications with early and increased morbidity and mortality.” The availability of biosimilars could help improve access to insulin, and the authors noted, “the Endocrine Society has made strong recommendations to expedite the approval of insulin biosimilars as one of the policies to increase access to life-saving insulins.”

According to the investigators, the proposed biosimilar has demonstrated similarity in structure and function in physicochemical analyses and nonclinical studies, and the current study evaluated PK/PD parameters in healthy subjects. They carried out a crossover study in which 42 healthy male participants aged 18 to 55 were randomized to a sequence of single doses of the reference product and the biosimilar. After a fast of at least 10 hours, the study drugs were administered, and plasma insulin and glucose infusion rates were assessed over 12 hours.

The authors noted that the FDA and European Medicines Agency (EMA) recommend the use of the euglycemic glucose clamp technique for evaluating PK/PD parameters of biosimilar insulin products. The clamp device automatically adjusted the glucose infusion rate (GIR) to maintain each subject’s blood glucose concentration at a target level of 81 mg/dl “with minimum deviations” over the 12 hours after injection of the study drugs.

The primary PK endpoints were area under the insulin concentration-time curve (AUC ins) and maximum insulin concentration (Cmax). The 90% confidence intervals (CIs) for both were within the predefined eqiuvalence margins of 80% to 125%. The confidence intervals were 97.02-101.81 for AUC ins and 87.34-97.61 for Cmax.

For PD, primary endpoints were area under the glucose infusion rate curve (AUC GIR) and maximum glucose infusion rate (GIRmax). The authors said GIR is “a surrogate PD marker” for insulins that “correlates with clinical efficacy.” Equivalence in PD parameters was also demonstrated, with 90% CIs within the predefined margins. The 90% CIs were 92.63-104.79 for AUC GIR and 89.46-101.74 for GIRmax. The investigators noted that, “although secondary end points were not expected to meet bioequivalence criteria,” some of the secondary PK end points (AUC ins 0-2 hours, AUC ins 0-6 hours, and AUC ins 0-infinity) and all the secondary PD end points also met the equivalence criteria.

No serious adverse events were reported in the study, and there were no significant differences in the safety profile between the originator and proposed biosimilar, according to the investigators. A total of 39 treatment-emergent adverse events (TEAE) were reported. Twelve participants treated with the biosimilar and 14 participants treated with the reference product reported adverse events. Most TEAEs were mild, and the most common were headache and injection-site reactions. Furthermore, the authors wrote, “there were no clinically significant findings in hematology, biochemistry or urinalysis laboratory tests that were assessed throughout the study.”

The investigators concluded their study demonstrated PK/PD equivalence between Insulin-R and the reference product Humulin R, and that both drugs were well-tolerated. Recombinant human insulin, they said, “is the standard of care in the management of diabetes,” and they proposed “introduction of Biocon’s Insulin-R can ensure reliable and affordable access, potentially bringing better management of diabetes and its complications and reducing the subsequent financial burden in the US and globally.”

Plum-Mörsch El L, Singh G, Murugesan SMN, et al. Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar Insulin-R with the US-licensed Humulin® R formulation in healthy subjects: results from the RHINE-1 (Recombinant Human INsulin Equivalence-1) study. 

. Published online January 3, 2022. doi: 10.1111/dom.14635.

Insulin costs have increased dramatically in recent years, and the study authors  note that high costs for many patients result in nonadherence or insulin rationing, leading to diabetic complications and even death. 

Pharmacokinetic and Pharmacodynamic Equivalence of Biocon’s Proposed Biosimilar Insulin-R to Humulin-R

A 40-week comparative study conducted in multiple sites across Malaysia and Korea demonstrated that efficacy and safety of the epoetin alfa biosimilar candidate PDA10 (PanGen Biotech) was comparable to the reference product (Eprex/Epogen) in patients with end-stage kidney disease (ESKD).

Anemia is a common complication of chronic kidney disease, and as renal function declines, the risk of anemia increases. In patients with ESKD, anemia can compromise the quality of life, require blood transfusions, and increase the risk of heart failure and mortality.

Erythropoietin-stimulating agents (ESAs), which promote survival, differentiation, proliferation, and maturation of red blood cells, are the standard of care for anemia associated with kidney disease. Up to 80% to 90% of patients on dialysis require ESAs, according to the authors of the study. However, access to ESAs is “limited” due to cost, which leads to suboptimal dosage. Biosimilars are a cost-effective alternative, they said.

PDA10 is a proposed epoetin alfa biosimilar. The only epoetin alfa biosimilar now available in the United States is Pfizer’s 

, approved by the FDA in 2018. Based on the results of phase 1 nonclinical studies and analytical similarity studies, the requirement for a phase 2 clinical study for PDA10 was waived by Korean regulatory authorities. This phase 3 study compared the safety and efficacy of PDA10 with the reference product in renal anemia in patients on hemodialysis. The study was conducted over 40 weeks at 29 sites in Malaysia and Korea. Patients ranged in age from 18 to 75 years, had ESKD, and were undergoing regular hemodialysis and erythropoietin therapy.

After a 12-week titration phase to assess disease stability and establish baseline characteristics, 296 patients were randomized to the reference product or biosimilar for a 28-week treatment phase, which was followed by a 24-week open-label extension phase. The investigators did not report on the open-label phase in the current publication.

The change in hemoglobin (Hb) levels, dose of epoetin alfa, and proportion of patients out of target Hb range were similar between groups

The investigators found baseline characteristics were similar between the originator and biosimilar groups. Differences in the primary efficacy end points were not significantly different between groups: the mean (SD) change in Hb was –0.176 (0.914) g/dL in the biosimilar group and –0.118 (1.114) g/dL in the originator group. The mean (SD) weekly dose change was 10.01 (44.64) IU/kg in the biosimilar group and –10.30 (56.09) IU/kg in the reference product group, a difference that was not statistically significant.

Secondary end points examined by the authors included change in hematocrit (proportion of red blood cells in blood), the proportion of patients with Hb levels within or out of the target range (10-12 g/dL), and safety and immunogenicity indicators. These were also comparable between groups.

The mean (SD) change in hematocrit from baseline to treatment phase was –0.71% (2.944) in the PDA10 group and –0.007% (3.498) in the reference group. During the treatment phase, 111 (81.62%) patients in the biosimilar group and 108 (90.0%) patients in the reference group had an Hb level outside the target range of 10 to 12 g/dL.

In this 28-week randomized controlled study, PDA10 was shown to be therapeutically equivalent to the originator Eprex in terms of absolute change in hemoglobin levels and comparable safety profile in treating renal anemia for patients undergoing maintenance hemodialysis.

The investigators noted the “high proportion” of patients with Hb out of the target range, saying “these Hb fluctuations are not uncommon and have been well described in the use of ESA in renal anemia. However, with the appropriate epoetin dosage adjustment, these fluctuations did not increase occurrence of AEs secondary to high Hb level, such as worsening hypertension, stroke, and vascular access thrombosis,” they wrote.

No anti-epoetin antibodies were observed in either group at baseline or in the treatment phase.

There were no differences between groups in the number of patients who experienced treatment-emergent adverse events (TEAEs). The most common were respiratory tract infections, affecting 14.0% and 16.4% in the biosimilar and reference groups, respectively, and gastrointestinal infections, affecting 4.0% and 2.7%. Although there were more TEAEs leading to death in the originator group than the biosimilar group, the authors wrote “all TEAEs leading to death were considered unrelated to the products.”

The investigators concluded PDA10 and the reference product were “therapeutically equivalent,” with no significant differences in change in Hb, change in weekly dose, or safety parameters between groups. They also noted the dose required to maintain stable Hb levels was similar for the biosimilar and originator, saying “this biosimilar epoetin alfa may offer a more cost-effective erythropoietin therapy and improve the access of ESA therapy for patients undergoing hemodialysis treatment.”

Lim SK, Goh BL, Visvanathan R, et al. A multicentre, multi-national, double-blind, randomised, active-controlled, parallel-group clinical study to assess the safety and efficacy of PDA10 (epoetin-alpha) vs. Eprex in patients with anaemia of chronic renal failure. 

. 2021;22(1):391. doi:10.1186/s12882-021-02601-w

A comparative study of PanGen Biotech’s epoetin alfa biosimilar candidate PDA10 and the reference product, Retacrit, demonstrated comparable efficacy and safety.  

Study: Epoetin Alfa Biosimilar Candidate Equivalent to Epogen

The proposed biosimilar MYL-1402O (Abevmy; Viatris and Biocon Biologics) met predefined criteria for biosimilarity to reference bevacizumab in a 

in patients with stage IV nonsquamous non–small cell lung cancer (nsNSCLC).

The authors noted that lung cancer is the most common cause of cancer-related mortality in the United States and worldwide. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor A, retards blood vessel development that supports tumor growth. The reference product (Avastin) was approved to treat metastatic colorectal cancer by the FDA in 2004 and the European Medicines Agency (EMA) in 2005. Today, bevacizumab is authorized for multiple indications, including in combination with platinum-based chemotherapy as a first-line treatment for patients with advanced or recurrent nsNSCLC.

In many cancers, bevacizumab-based regimens have improved overall survival (OS) and progression-free survival (PFS); however, patient access can be limited due to high out-of-pocket costs, the authors said. Bevacizumab “has become an integral, standard-of-care component for many malignancies,” and biosimilars, which are often lower-cost alternatives to reference products, could improve access.

Previous studies have established the analytical and pharmacokinetic similarity of MYL-1402O to reference bevacizumab. The current study evaluated efficacy, safety, and immunogenicity of MYL-1402O compared with the reference product in combination with carboplatin and paclitaxel (CP) chemotherapy in patients with stage IV nsNSCLC.

The study included 671 patients from 102 sites in 17 countries. After randomization, patients were treated with reference bevacizumab or the biosimilar plus CP for up to 18 weeks (6 cycles), followed by monotherapy with the reference drug or the biosimilar for up to 24 weeks.

Similar Overall and Progression-Free Survival Rates

The primary end point was overall response rate (ORR) at 18 weeks. The authors, noting “the FDA and the EMA use different approaches to determine equivalence based on the ORR,” reported ORR consistent with both FDA (ratio of ORR) and EMA (difference in ORR) requirements.

Overall, 41.5% and 43.1% of patients in the biosimilar and originator groups, respectively, had either a complete or partial response at 18 weeks. Efficacy based on ORR was comparable between groups. The ratio of ORR between groups was 0.96 (90% CI, 0.83-1.12) and the difference in ORR between groups was –1.6 (90% CI, –9.0 to 5.9). The 90% confidence intervals were within predefined margins for biosimilarity. The authors noted “the ORR data reported here are within the range of ORR reported in published data for the reference product.”

Subgroup analyses were carried out based on age, sex, race, smoking status, number of metastasis sites, prior radiation therapy, Eastern Cooperative Oncology Group status, negative or unknown sensitizing epidermal growth factor receptor mutation, negative or unknown sensitizing EML4-ALK rearrangement, and geographical region. Overall, the authors said, these results supported equivalence between the treatment groups; however, when the number of metastasis sites was limited to 1 and patients had had prior radiation therapy, there was evidence of a “slightly lower response” in the biosimilar group.

The investigators reported that secondary efficacy end points, including PFS, OS, disease control rate, and duration of response at 18 weeks and 42 weeks were comparable between groups. For example, the median PFS at 42 weeks was 7.6 months (95% CI, 7.0-9.5) in patients treated with MYL-1402O and 9.0 months (95% CI, 7.2-9.7) in patients treated with reference bevacizumab.

Adverse Events “Within the Expected Range”

On safety, the authors wrote, “the frequency, type, and severity of treatment-emergent adverse events (TEAEs) and AEs of interest were comparable between MYL-1402O and reference bevacizumab, falling within the expected range of the type and severity previously described in other bevacizumab biosimilar studies.”

Most patients (92.8% in the biosimilar group and 92.4% in the originator group) reported at least 1 TEAE during the study. The authors noted there were 8 (2.4% of patients) and 5 (1.5% of patients) TEAEs leading to death in the biosimilar and reference product groups, respectively, considered to be related to bevacizumab treatment. They also noted there was a higher incidence of serious TEAEs during the bevacizumab-plus-CP treatment period compared with the bevacizumab monotherapy period.

The investigators observed “no notable differences” between groups in treatment-emergent antidrug antibodies (ADAs), with 6.5% of patients treated with MYL-1402O and 4.8% of patients treated with the originator positive for ADAs. The incidence of neutralizing antibodies was lower in the biosimilar group (0.6%) compared with the originator group (2.5%).

The authors concluded MYL-1402O is therapeutically equivalent to bevacizumab in combination with CP, based on ORR by both FDA and EMA requirements. They added that their results support extrapolation to all applicable conditions for bevacizumab, because bevacizumab “has the same mechanism of action across all indications and the dose used for NSCLC is highest among all approved indications.”

In December, Tot Biopharm said it has been 

 for a bevacizumab biosimilar (Pusintin) by China’s National Medical Products Administration.

Socinski MA, Waller CF, Idris T, et al. Phase III double-blind study comparing the efficacy and safety of proposed biosimilar MYL-1402O and reference bevacizumab in stage IV non-small-cell lung cancer. 

. Published online November 18, 2021. doi:10.1177/17588359211045845

Patients with stage IV nonsquamous non–small cell lung cancer (NSCLC) demonstrated equivalent outcomes when treated with MYL-1402O or Avastin.

Bevacizumab Biosimilar Candidate Demonstrates High Similarity to Avastin in NSCLC

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

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.

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