Deana Ferreri, PhD

A sub-study of a clinical trial comparing the adalimumab biosimilar PF-06410293 (Pfizer; Abrilada US, Amsparity EU) to the EU reference product (Humira) in rheumatoid arthritis (RA) evaluated the usability of prefilled pens (PFP) by patients and their caregivers.

and demonstrated that patients with RA and their caregivers can safety and effectively administer the biosimilar using a PFP.

The authors noted previous studies had shown that Humira autoinjector pens are “suitable” and “generally preferred by patients due to their ease of use and convenience.”

Adalimumab is a monoclonal antibody to tumor necrosis factor (TNF) alpha. The reference product has been marketed in the United States and European Union since 2002 and 2003 to treat RA and is approved for multiple other indications.

The investigators evaluated injection success by patients and their caregivers in administering the 

 via PFP, based on assessments by the patients and staff at the study site. The sub-study took place during an open-label treatment period in a phase 3 trial comparing the biosimilar adalimumab to its EU reference product and included 49 adult patients with active RA not adequately controlled with methotrexate.

Prior to the sub-study, the patients had been randomized 1:1 to receive the biosimilar or reference product, which was administered via prefilled syringe (PFS). At week 26, the patients on the reference product were re-randomized to continue or switch to the biosimilar. At week 52, the start of the sub-study, the remaining patients in the reference product group were switched to the biosimilar.

The patients received 2 doses of the biosimilar via PFS at weeks 52 and 54, and then received 6 additional biweekly doses via the PFP device. The study site personnel trained patients or their caregivers to administer the biosimilar using the device; none of the patients had received an injection via an autoinjector or injection pen prior to the sub-study. All injections were given by patients or their caregivers, with doses alternating between the study site and home.

The primary endpoint of the study was the delivery system success rate (DSSR): the percentage of participants who successfully delivered each of the 6 attempted injections with the PFP device.

The success of home-administered injections were assessed by the patient or caregiver, and the devices were later inspected by study staff to confirm full injection volume was delivered. The success of study site-administered injections was assessed by study personnel who observed the injections. After administering over 294 total injections, the DSSR was 100% (95% confidence interval 92.0-100%), and “complete injection was confirmed following inspection of 292 used and returned PFPs.”

The authors noted that safety indicators will be reported along with the main study results, and there were no additional safety assessments conducted for the PFP sub-study. However, the adverse events reported in the sub-study population “were consistent with those reported for the first year of the overall study population.”

They added that there were no medical device complaints, and “47/49 (95.9%) participants who completed the sub-study elected to continue study treatment using PFP injections, rather than switching back to the PFS.”

The investigators concluded “all actual PFP users could safely and effectively administer ADL-PF by PFP at each visit, and nearly all participants who completed the sub-study elected to continue study treatment using PFP injections.”

Fleischmann RM, Bock AE, Zhang W, et al. Usability study of PF-06410293, an adalimumab biosimilar, by prefilled pen: Open-label, single-arm, sub-study of a phase 3 trial in patients with rheumatoid arthritis. 

. Published online, March 18, 2022. doi:10.1007/s40744-022-00439-8.

Articles

A sub-study assessing the affects of using a prefilled pen vs a prefilled syringe found that the pen was easy for patients to use and was favored by over 90% of patients.

Over 90% of Patients Preferred Biosimilar Delivery With Prefilled Pen vs Syringe

A retrospective, real world study found similar effectiveness and safety of biosimilar ranibizumab (Razumab; Intas) and its reference product (Accentrix; Novartis) in patients with diabetic macular edema (DME) in a network of eye care centers and teaching hospitals in eastern India.

The authors noted DME “is one of the leading causes of visual impairment globally and the increasing prevalence of diabetes means that there will be an exponential rise in the number of patients with DME.” They also said that the treatment of DME “has seen paradigm shifts in the

last decade” because of the use of anti-vascular endothelial growth factor (VEGF) therapies, such as ranibizumab.

Ranibizumab is an anti-VEGF antibody fragment, delivered via intravitreal injection to treat 

 such as neovascular (wet) age-related macular degeneration, DME, and myopic choroidal neovascularization. In the United States, Accentrix is marketed under the name Lucentis and is commercialized by Genentech.

The authors commented that although reference ranibizumab “is available at a substantially reduced cost in India,” multiple injections “can be cost-prohibitive.” The biosimilar Razumab, the world’s first ranibizumab biosimilar, was approved by the drug controller general of India (DGCI) in 2015. According to the authors, the institutions involved in the study have been “increasingly” adopting the biosimilar in recent years “as confidence in this molecule grows; currently, more than half of all our patients receive [biosimilar ranibizumab].”

In the US, Samsung Bioepis and Biogen’s Byooviz was the first ranibizumab biosimilar to gain 

in 2021. Byooviz was approved by Canadian regulatory authorities in 

The researchers analyzed electronic health records of patients with DME at their network of eye care centers and hospitals who received at least 3 injections of the originator or biosimilar plus 6 months of follow-up in their pro re nata (PRN) treatment protocol. They found 333 eyes that met their inclusion criteria and were able to be matched for similar follow-up duration, of which 264 were treated with the originator and 69 were treated with the biosimilar. Baseline characteristics, duration of follow-up, and mean number of injections were similar in the reference product and biosimilar groups.

The primary outcome of the study was a comparison of improvement in the best corrected visual acuity (BCVA) at 6 months between the reference product and biosimilar. Overall, the mean BCVA improved from baseline to 3 months, then remained stable at 6 months and 1 year, with a mean improvement of 0.24 (+/- 0.39) logarithm of minimum angle of resolution (logMAR) units at 1 year among all patients. The researchers found no differences in BCVA between groups at any time point.

Another effectiveness outcome the researchers analyzed was central macular thickness (CMT). The overall mean CMT improved from baseline to 1 month and 1 month to 3 months, then remained stable at 6 months and 1 year. Similar to BCVA, no differences were detected between groups at any time point. The mean reduction in CMT was 120 (+/- 196) μm in the patients treated with the reference product and 105 (+/- 187) μm in the patients treated with the biosimilar. The authors noted, “macular edema also decreased over time and equally well in both groups.”

The researchers reported no adverse events, saying “none of the eyes included in this

study experienced any adverse reactions such as intraocular inflammation or endophthalmitis,

and none of the patients suffered any drug-related systemic adverse events such as thromboembolism, myocardial infarction, or stroke during the follow-up period.”

In the study, no differences in visual and anatomical outcomes were found between treatment-naive patients with DME who received the originator vs the biosimilar ranibizumab. Although “lack of comparative studies with a significant period of follow-up with the innovator molecule has led to skepticism amongst physicians and has prevented widespread adoption,” the authors wrote, “our results are encouraging and should alleviate concerns about efficacy of the biosimilar for management of DME.”

Chakraborty D, Sengupta S, Mondal S, et al. Comparison of innovator vs. biosimilar ranibizumab in treating diabetic macular edema: A multicenter retrospective study. 

. 2022;11(2):629-638. doi:10.1007/s40123-022-00463-5

A real-world analysis found similar safety and efficacy profiles between a biosimilar ranibizumab (Razumab) and the reference product (Lucentis, Accentrix) in Indian patients with diabetic macular edema.

 Real-world Study of Reference vs Biosimilar Ranibizumab for Treatment of Diabetic Macular Edema in India

reviewed the totality of evidence leading to the approval of Amgen’s infliximab biosimilar ABP 710 (Avsola), which is currently 

 in the US and Canada for all the indications of the originator.

The reference product (Remicade), a monoclonal antibody targeting tumor necrosis factor alpha (TNF- 𝝰), was the first biologic to demonstrate efficacy in rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis, and the first biologic approved to treat inflammatory bowel disease (IBD), the reviewers noted. ABP 710 is 1 of several infliximab biosimilars currently available, including CT-P13 (Remsima, Inflectra) and SB2 (Renflexis).

The totality of evidence required to support approval of a proposed biosimilar by the US FDA and European Medicines Agency includes evaluation of physicochemical attributes, non-clinical assessments of the mechanism(s) of action, a pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers, and a comparative clinical study in a representative indication of the reference product (RP).

Analytical studies compared ABP 710 to reference infliximab sourced from both the US and EU. These studies demonstrated similarity in primary structure, including amino acid sequence and post-translational modifications, higher-order structure, particles and aggregates, and purity.

Minor differences in physicochemical attributes and post-translational modifications were observed in these studies. The authors explained that these differences were consistent with the different cell lines used to produce the RP and ABP 710, and “comprehensive biological characterization was used to verify that these mostly minor differences did not translate into functional differences.”

 studies found ABP 710 had functional similarity to the infliximab originator in binding to soluble and membrane-bound TNF-𝝰, subsequent neutralization of TNF-𝝰’s proinflammatory biological activity, and effector functions.

The authors noted that these functions are relevant to multiple immune-mediated inflammatory disorders, and the results of the mechanisms of action studies “supported extrapolation to additional indications including IBD.”

PK/PD studies in healthy volunteers are carried out, according to the authors, not only to demonstrate PK and PD similarity, “but also to understand the comparative safety and immunogenicity of the proposed biosimilar and its RP.”

A randomized, single-blind, single-dose study in healthy participants demonstrated similarity of ABP 710 to the originator sourced from the US and EU. Furthermore, safety and immunogenicity were comparable: according to the authors, similar incidences of treatment-related adverse events (AEs), binding anti-drug antibodies (ADAs), and neutralizing ADAs were reported in the three groups.

A comparative clinical trial in a representative indication of the RP is the final step in generating the totality of evidence to support the approval of a proposed biosimilar. For ABP 710, a comparative clinical trial demonstrated similarity in efficacy, safety, and immunogenicity to the RP in patients with rheumatoid arthritis (RA).

Patients with moderate-to-severe active RA and an inadequate response to methotrexate were enrolled in the 50-week study and were randomized to receive infusions of the biosimilar or the RP. At week 22, patients in the biosimilar group continued to receive ABP 710, and patients in the RP group were re-randomized to either continue the RP or switch to the biosimilar for the remainder of the study.

The primary endpoint of the study was the response difference in 20% improvement from baseline in the American College of Rheumatology core set of measurements at week 22 between the biosimilar and originator. The lower bound of the 90% confidence interval was within the predefined equivalence margin, whereas the upper bound exceeded the margin by 0.96%, meaning superiority could not be ruled out. However, the authors said, “post hoc analyses were consistent with both non-inferiority and non-superiority.”

Taking into account the primary endpoint and additional efficacy endpoints, the reviewers wrote, “overall results demonstrated that there were no clinically meaningful differences between ABP 710 and infliximab RP.”

Safety and immunogenicity outcomes were also similar between groups “and were not impacted by the single transition from infliximab RP to ABP 710.” Infections were the most common AEs, and AE incidence rates were similar in the 2 groups. Also, the results “were consistent with the known safety profile of infliximab with no new or unexpected safety signals.”

The authors concluded the totality of evidence “supported the conclusion that ABP 710 is highly similar to infliximab RP and supported scientific justification for extrapolation to all approved indications of infliximab RP, including IBD.” They added that use of infliximab biosimilars has grown since the approval of CT-P13 in 2016, and “ABP 710 offers another treatment alternative among infliximab biosimilars.”

Reinisch W, Cohen S, Ramchandani M, et al. A review of the totality of evidence for the development and approval of ABP 710 (Avsola), an infliximab biosimilar. 

. 2022;39(1):44-57. doi:10.1007/s12325-021-01944-y

An article reviewed the totality of evidence leading to the approval of Amgen’s infliximab biosimilar ABP 710 (Avsola), which is currently approved in the US and Canada for all the indications of the originator (Remicade).

Review of Totality of Evidence for Infliximab Biosimilar ABP 710

Physicians from Loma Linda University Medical Center and the Veterans Affairs (VA) Loma Linda Healthcare System, writing in the 

 described a patient who developed auricular polychondritis while being treated with a biosimilar tumor necrosis factor (TNF) alpha inhibitor.

The 45-year-old man, who had HLA-B27-positive ankylosing spondylitis and ulcerative colitis (UC), had been receiving the biosimilar infliximab-dyyb (

) for 3 years at the time the symptoms appeared. Prior to the use of Inflectra and development of polychondritis, the patient had previously experienced lack of efficacy with “all the other anti-TNF medications,” according to the authors.

The authors said their patient presented with redness, warmth, and pain in the ears that had lasted for 3 days, plus intermittent fever, night sweats, sore throat, and photophobia. They admitted him, and first treated him with broad-spectrum antibiotics for possible cellulitis. His symptoms did not improve and infection was ruled out. He was subsequently diagnosed with polychondritis and treated with prednisone and methotrexate. Treatment continued for 4 weeks until the ear pain and redness resolved.

After the resolution of polychondritis symptoms the physicians decided to switch the patient from infliximab-dyyb to 

, “given the adverse reaction and for better control of his ulcerative colitis.”

 Ustekinumab (Janssen’s Stelara), a monoclonal antibody targeting interleukin-12 (IL-12) and interleukin-23 (IL-23), was approved by the FDA in 2019 for treating moderate-to-severe UC. In a 

, ustekinumab was superior to placebo at inducing and maintaining clinical remission in patients with UC who had previously had either an inadequate response or unacceptable side effects from other therapies, including anti-TNF biologics.

The authors commented, “ankylosing spondylitis and polychondritis have rarely been reported concomitantly in the literature, and it is unclear why it presents in patients with other autoimmune diseases.” Among patients who develop polychondritis, about one-third have another autoimmune disease.

The authors cited previous case reports of polychondritis in patients with spondyloarthritis being treated with anti-TNF agents, either etanercept or infliximab. Another reported polychondritis in a patient with ankylosing spondylitis being treated with the IL-17-inhibitor secukinumab. However, they said, “to our knowledge, this is the first reported case of a patient with ankylosing spondylitis developing polychondritis while getting treated with infliximab biosimilar, Inflectra.”

Duro T, Li S, Jose D, Khawar T. Polychondritis in a Patient With Ankylosing Spondylitis on an Anti-TNF-α Biosimilar Agent. 

. 2021;27(8S):S656. doi:10.1097/RHU.0000000000001650

Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. 

. 2019;381(13):1201-1214. doi:10.1056/NEJMoa1900750

Emmungil H, Aydın SZ. Relapsing polychondritis. 

. 2015;2(4):155-159. doi:10.5152/eurjrheum.2015.0036

A patient with ankylosing spondylitis (AS) and ulcerative colitis (UC) was diagnosed with polychondritis after taking an infliximab biosimilar, suggesting that patients with similar circumstances should be carefully monitored.

Case Study: Monitoring Needed for Patients With Both UC, AS Receiving Biosimilar Infliximab Treatment

Researchers using “a range of structural analytical techniques and a functional bioassay” found that biosimilar trastuzumab-qyyp is stable and maintains its biological activity under extended in-use conditions. They said that the findings, which were 

, are consistent with results from other studies on the reference product (Herceptin) and other trastuzumab biosimilars.

Pfizer Europe MA EEIG’s trastuzumab biosimilar (

) was granted marketing authorization for all indications of the originator by the European Medicines Agency (EMA) in 2018 and was 

 by the FDA in 2019. Trastuzumab is a recombinant monoclonal antibody to human epidermal growth factor receptor 2 (HER2). It is used to treat metastatic breast cancers and gastric cancers that overexpress HER2, either as monotherapy or together with other therapies.

Although trastuzumab provides “significant clinical benefit” in these conditions, the authors said, a “substantial portion” of patients with HER2-positive metastatic breast cancer in the United States and Europe don’t receive trastuzumab therapy. They cited surveys of physicians that identified barriers to trastuzumab prescription as primarily cost-related. The authors said the development of trastuzumab biosimilars could expand access to patients who could benefit from HER2-targeted therapy.

The investigators explained that trastuzumab requires dilution in 0.9% sodium chloride before it is administered to patients, and it is typically recommended to use the diluted trastuzumab within 24 hours “due to concerns with microbiological contamination.” However, they wrote, this is not necessarily the case in clinical practice, where “infusion solutions are often prepared well in advance of use,” and “robust data on product stability under extended in-use conditions would be beneficial to accommodate scheduling and logistics.”

The investigators followed guidelines established by The Specialist Pharmacy Service of the National Health Service (NHS) in the United Kingdom for assessing the stability of a biologic, which included measurement of the product’s physicochemical stability and biological activity. They tested trastuzumab-qyyp “over a range of concentrations and time periods that may be encountered prior to administration, using a wide range of analytical and cell-based techniques.”

To simulate possible storage conditions in a clinical setting, the biosimilar was diluted in 0.9% sodium chloride to concentrations ranging from 0.2 mg/ml to 4 mg/ml in 3 different types of infusion bags (polyolefin, ethylene vinyl acetate, and polyvinyl chloride), and stored for 24 hours at 25°C, followed by storage for 0, 1, 2, 4, or 6 weeks at between 2°C and 8°C.

Physicochemical characteristics and biological activity

No differences in visual characteristics were detected between samples, and there were “no substantial changes” in the pH of any of the samples over time, though the authors observed higher variability in pH in lower-concentration samples. They also reported no changes in protein concentration over the storage period, suggesting that there was “minimal” protein adsorption to the plastic infusion bags.

The investigators found no significant differences in molecular weight or charge variants for any of the concentrations, time points, and infusion bags they tested. The proportion of intact antibody was greater than 85% in all samples, and the authors found no evidence of an increase in antibody fragmentation over time.

Peptide mapping of the 4 mg/ml samples suggested no change in the primary structure of the protein during storage. The authors added that the “high degree of similarity between the chromatograms also indicates that no significant post-translational modification” occurred over the 6 weeks of storage. Further analysis of the 4 mg/ml samples found no indication of a change in the secondary structure or thermal stability of the protein throughout the study.

The authors wrote the degree of methionine oxidation of the antibody “remained consistently low throughout the study, with most samples showing <5% oxidation.” However, they added that low-concentration samples in ethylene vinyl acetate infusion bags showed higher levels of oxidation than those in polyolefin or polyvinyl chloride bags.

Cation-exchange chromatography demonstrated no significant change in relative abundance of the main charge species, or acidic or basic variants, over the course of the study.

Finally, biological activity of the antibody, as assessed using a cell-based growth inhibition assay, demonstrated that the relative potency of the biosimilar was maintained during the time in storage.

The authors concluded, “the physicochemical stability and biological activity of [trastuzumab-qyyp] was maintained following dilution and storage for 24 h at 25±5° C and then an extended period of up to 6 weeks at 2–8° C.” They added that their results were similar to those from previous studies on the reference product and other trastuzumab biosimilars.

Weiser S, Burns C, Zartler ER. Physicochemical stability of PF-05280014 (trastuzumab-qyyp; TrazimeraTM), a trastuzumab biosimilar, under extended in-use conditions. 

. 2022 Jan 24:10781552221074649. doi:10.1177/10781552221074649.

Pfizer’s trastuzumab biosimilar (trastuzumab-qyyp; Trazimera) was stable and efficacious under conditions of extended use in patients with breast cancer, investigators concluded.

Trastuzumab-qyyp Maintains Stability and Potency Under Extended In-Use Conditions

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.

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.  