Deana Ferreri, PhD

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

Articles

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. 

Deana Ferreri, PhD

Investigators Review Marketed Adalimumab Biosimilars for Switching Differences

Study: Zarxio More Costly Than Neupogen in Outpatient Hospital Setting

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

Study: Biosimilar rhGH Well Tolerated and Effective in Turner Syndrome