Inflectra

Product Profile:

Infliximab-dyyb (Inflectra)

Drug Category: Anti-TNF/Autoimmune

Target Indications: Crohn’s disease (adult and pediatric), ulcerative colitis, rheumatoid arthritis, plaque psoriasis, ankylosing spondylitis, psoriatic arthritis

Manufactured by Celltrion Health; Marketed by Pfizer

Summary: Inflectra was the first FDA-approved biosimilar version of infliximab (reference product, Remicade®) manufactured by Janssen Pharmaceuticals.

Originally designated CT-P13, Celltrion submitted a biologic license application for approval via the 351(k) biosimilar pathway in August 2014. The Food and Drug Administration (FDA) approved the biosimilar in April 2016, and it was marketed by the end of the year. The European Medicines Agency approved the product in 2015 and it has been marketed in the EU as Remsima. Of note, Celltrion and Pfizer decided to launch Inflectra “at risk,” meaning that before its patent litigation had been completed.

Celltrion is also testing an investigational subcutaneous formulation of Inflectra.

About the Manufacturer

Celltrion was founded in 2002 in Incheon, South Korea. Its first biosimilar product was approved in 2013 by the European Medicines Agency. Inflectra was first approved in the US in 2016. Another biosimilar product (Truxima) was approved in November 2018, and Celltrion has several other biosimilar products in development. Inflectra is the only product resulting from the partnership between Celltrion and Pfizer; two other biosimilars were also involved, but the rights to CT-P6 and CT-P10 were returned to Celltrion after Pfizer’s acquisition of Hospira. Celltrion also partnered with Teva for marketing activities in 2016. This partnership involves Truxima and Herzuma (which is also approved in the US).

In addition, Celltrion’s pipeline includes several products at various stages of development, including adalimumab, bevacizumab, cetuximab, etanercept, palivizumab, and a subcutaneous formulation of Inflectra.

News, Commentary, and Intelligence

Competitor Products and Manufacturer Analysis

BIOSIMILARS APPROVED BY THE FDA: FDA FILING DATES AND ACTIONS

Biosimilar

Manufacturer

Brand Name & Designation

Innovator Product

FDA Filing Date

Status

Infliximab

Celltrion/Pfizer

Inflectra (infliximab-dyyb)

Remicade

August 8, 2014

Approved April 5, 2016; marketed

Infliximab

Samsung Bioepis/Merck

Renflexis (infliximab-abda)

Remicade

May 23, 2016

Approved April 21, 2017; marketed

Infliximab

Pfizer

Ixifi (infliximab-qbtx)

Remicade

April 2017

Approved December 14, 2017, all indications; will not be marketed in US

Updated January 3, 2019.

Infliximab Biosimilar(s) in Development

Company name, Country

Product name

Stage of development

Amgen

ABP 710

FDA BLA Application filed December 17, 2018

Nichi-Iko Pharmaceutical,  Japan

NI-071

Phase III trial in rheumatoid arthritis expected to be completed in March 2015. Approved in Japan in September 2017. US phase III trial in rheumatoid arthritis expected to be completed February 2019

Implications of UnitedHealthcare’s Preference of Remicade and Neulasta to Their Biosimilars

(May 30, 2019) Effective July 1, 2019, approximately 22.5 million commercial and 6 million Medicaid UHC members will not be able to access these biosimilars without trying the reference agents first (virtually eliminating biosimilar use).

Amgen Submits Application for Biosimilar Inflximab

(December 17, 2018) ABP 710 was the subject of a phase 3 trial in patients with moderate-to-severe rheumatoid arthritis.

Infliximab Biosimilars Savings Could Exceed $400 Million Dollars Annually

(June 21, 2018) Everyone with an opinion believes that biosimilar drug use will save the health system considerable money. Calculations for biosimilar savings have been hampered by several factors. For example, previous high estimates have not been based on real-life scenarios.

How Will Biosimilars Be Affected by Trump’s Drug Price Reform Measures?

(May 14, 2018) When President Trump announced the broad strokes of his drug price reform initiative, some of these measures seemed on target to benefit the biosimilars industry. However long awaited, makers of originator biologics seemed not to be worried about its implications. The President may not be able to effect much change, without causing unintended adverse consequences

Plans Use Step Therapy to Encourage Utilization of Remicade Over Biosimilars

(May 9, 2018) Health plans and insurers are not yet turning to biosimilar infliximab as a preferred therapy, according to Gillian Woollett, DPhil, MA, of Avalere. Her new report surveyed publicly available policy about health plans across the nation. The principal finding was that step therapy was commonly used  to encourage use of the originator product.

Celltrion and Inflectra, Mylan and Botox, and a Biosimilar Blooper

(March 2, 2018) The second quarter is expected to be rife with news regarding Food and Drug Administration approval decisions on a biosimilar for rituximab and two pending applications for trastuzumab. Although biosimilars have not generated much news of importance lately, we wrap up the week with some items of interest.

Pfizer US Biosimilar Revenues Growing Slowly, Better News Internationally

(February 2, 2018) According to an article posted on the Market Realist website, Pfizer’s US and global biosimilars revenues are growing, but its sales of Inflectra remains stunted.

Pfizer’s At-Risk Launch of Inflectra Pays Off (at Least a Bit)

(January 25, 2018) The US Court of Appeals handed Pfizer a big victory in its gamble to bring its biosimilar version of Remicade® to the market before the completion of patent litigation.

A Health System Biosimilar Survey’s Implications

(December 18, 2017) On December 14, Pfizer got an early Christmas present, the approval by the Food and Drug Administration (FDA) of the second infliximab biosimilar in which it has a stake.

A Health System Biosimilar Survey’s Implications

(November 30, 2017) When asked about potential cost savings with the infliximab biosimilar, nearly one-quarter of health system respondents did not believe that it represented a cost savings opportunity for their organization, according to a newly published survey in the Journal of Managed Care and Specialty Pharmacy.

News in the Courts on Biosimilars

(November 14 2017) According to a Reuters report, Janssen Biotech withdrew its patent lawsuit against Samsung Bioepis on November 10. The suit alleged infringement in the manufacture of Samsung’s infliximab biosimilar. The action, which was filed in U.S. District Court of New Jersey, means that Merck and Samsung, which launched Renflexis™ in July, is no longer at risk…

Pfizer Sues J&J on Anticompetitive Practices on Infliximab in the US

(September 20, 2017) In late May, Merck was named in a UK lawsuit by Pfizer, which has been trying to expand its market for Inflectra®. Merck, which markets Remicade® (infliximab) in the EU, was accused of anticompetitive practices.

Inflectra Sales Lagging for Pfizer in Second Quarter

(August 4, 2017) Pfizer announced some disappointing results for the second quarter in its quest to advance a foothold in the biosimilar market. The second-quarter results hinted at more difficulties to come for the Inflectra® brand, with the most recent launch of Merck’s Renflexis®.

Living With Crohn's Disease

Understanding Biosimilars

Clinical Trials of Renflexis

Published Trial Results

Inflectra has been subject to an extensive clinical trial program. The US Food and Drug Administration evaluated 10 studies of the agent (both from US and ex-US populations). The results of three key phase 3 trials are featured here.

Rheumatoid Arthritis

A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study

In this randomized, double-blind, noninferiority trial of patients with rheumatoid arthritis (RA), 302 patients were assigned to receive CT-P13 and 304 patients were assigned to receive Remicade (median age, 50 yr). This was a global study (though ex-US), so the licensed versions of the biologic may have differed depending on study center location. All patients received 3 mg/kg intravenous infusions, in addition to methotrexate and folic acid. The primary endpoint was ACR20 response (i.e., a 20% improvement in the American College of Rheumatology symptom set) after 30 weeks of treatment. Also measured were additional ACR response endpoints, changes in Disease Activity Score 28 (DAS28), quality-of-life parameters, along with safety and immunogenicity outcomes. An extension study to 54 weeks was also completed (described in a separate publication). Noninferiority was determined if the results obtained with the biosimilar were within 15% of those attained with the reference product.

This study was conducted in 2010–2011. Of the 606 patients randomized to the treatment groups (the intent-to-treat population), 515 finished the study (the per protocol population). The most common decision to withdraw from the trial was adverse events (9%).

Table 1 provides the principal clinical results in the Per Protocol Group after 30 weeks.

 

Variable

CT-P13 Group

Remicade Group

ACR20

72.6%

65.3%

ACR50

42.3%

40.6%

ACR70

20.2%

17.9%

DAS28 (low disease/remission)

40.9%

39.0%

ACR/EULAR defined-remission

6.9%

6.9%

Antidrug antibodies

48.4%

48.2%

Infusion-related reactions

6.6%

8.3%

Treatment-emergent adverse events

60.1%

60.8%

Similar trends were seen at week 14; biosimilar infliximab was associated with a slight, nonsignificant improvement compared with the reference product. The researchers noted that the conclusion of noninferiority was also demonstrated in an analysis of the ITT population, and in studies of quality of life, immunogenicity, and safety.

In the extension study, 455 of the patients completed 54 weeks of treatment and follow-up. The researchers found very similar trends in longer-term outcomes, and deemed the CT-P13 to be noninferior to Remicade.

 

Ankylosing Spondylitis

Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study.

Researchers from a multinational team conducted a phase 3 study of 250 patients with ankylosing spondylitis (AS) that compared clinical, pharmacokinetic, and safety outcomes of CT-P13 with those of the reference product Remicade. The patients were randomized to one of two groups (CT-P13) or Remicade 5 mg/kg. Their progress was followed for 54 weeks.

 An analysis of clinical response (ASAS20, ASAS40, and ASAS-defined partial remission) revealed no significant differences between the biosimilar or reference groups. After 54 weeks, 19% of those taking the biosimilar and 23% of those receiving the reference drug demonstrated antidrug antibodies.

Patient-reported outcomes, using the Short Form-36 health survey and the Bath AS Functional Index, did not demonstrate significant differences between groups. They also found pharmacokinetic parameters to be comparable between the CT-P13 and the Remicade groups of patients.

 

Switching Study

Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): A 52-week, randomised, double-blind, non-inferiority trial.

The NOR-SWITCH study has been the subject of much attention in the scientific community. This study, from Norway, involved 482 adult patients across the autoimmune disease spectrum (Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis). Designed as a postmarketing (phase 4) trial, it was randomized, double-blinded and included 52 weeks of follow-up.

Patients entering the study received Remicade for no less than 6 months and had stable disease. At baseline, they were randomly assigned to continue on their present EU-licensed Remicade regimen (241 patients) or given the same dose of CT-P13 (241 patients). The primary study endpoint was disease worsening. Sufficient data were gathered on 408 patients, comprising the per-protocol group.

The researchers found that 30% of those switched to infliximab experienced disease worsening compared with 26% of those continuing with Remicade. The frequency of adverse events remained similar throughout the study period, with serious adverse events occurring in 9% of those switched to infliximab versus 10% in those receiving Remicade (adverse events of any kind, 68% for CT-P13 and 70% for the originator). The investigators determined that overall, switching did not result in inferior treatment results. However, they did note that the study was not powered to determine whether any significant differences may have existed among patients with a specific autoimmune disease. Other investigations evaluated switches in individual diseases (e.g., inflammatory bowel disease). In Crohn’s disease, specifically, the NOR-SWITCH researchers found no relevant differences in immunogenicity, safety, or efficacy.

An open-label extension trial added further to the knowledge gained with the NOR-SWITCH patients. In this study, additional Remicade patients were switched to the biosimilar at week 5

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