Renflexis

Product Profile:

Infliximab-abda (Renflexis)

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 Samsung Bioepis; Marketed by Merck

Summary: Renflexis (initially designated SB2) is a biosimilar version of infliximab (reference product, Remicade, Jannsen) manufactured by Samsung Bioepis/Merck. It is marketed in the US by Merck. A biologic license application for approval via the 351(k) biosimilar pathway was submitted to the Food and Drug Administration (FDA) in May 2016. The biologic was approved by the FDA in April 2017 and entered the market in July 2017 at a discount of 35% off the list price of Remicade.

About the Manufacturer

Samsung Bioepis Co., Ltd. develops and produces biopharmaceutical and biosimilar products. Samsung Bioepis is a joint venture between Samsung BioLogics and Biogen that operates as a subsidiary of Samsung Biologics Co., Ltd.  In Early 2013 Samsung Bioepsis and Merck entered into a business agreement to develop and commercialize biosimilars. Samsung Bioepis Co., Ltd. also entered into a strategic collaboration agreement with Takeda Pharmaceutical Company Limited in August 2017. The company was incorporated in 2012 and is based in Incheon, South Korea.

News, Commentary, and Intelligence

Competitor Products and Manufacturer Analysis

As of Q1 2019, Inflectra (Celltrion/Pfizer) and Renflexis were the two biosimilars approved by the FDA that have been available for prescription. Pfizer’s separate approval of Ixifi by the FDA was a result of its acquisition of Hospira. To avoid competition with Inflectra, for which it has marketing responsibilities in the US, Ixifi will not be launched in this country and sold exclusively overseas.

Renflexis was discounted 35% off the list price of Remicade at launch. This was greater than the 15% discount Inflectra was priced off the list price of Remicade at launch. Janssen Biotech has increased its rebates to gain the upper hand on net costs. Janssen is also the subject of a lawsuit by Pfizer that claims it is using exclusionary contracts practices to block coverage of the biosimilars. At present, Remicade revenues have been falling; this is more a result of lower net prices than of loss of marketshare.

Nichi-Iko Pharmaceuticals (and its US subsidiary Sargent Pharmaceuticals) is slated to complete a phase 3 trial in the US that may prove interchangeability with reference infliximab. At the last update (November 2018), preliminary results had not yet been announced.

INFLIXIMAB 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

Infliximab Biosimilar(s) in Development

Company name, Country

Product name

 

Stage of development

Amgen

ABP 710

 

FDA BLA Application filed December 17, 2018; FDA decision expected Q4 2019

Nichi-Iko Pharmaceutical,  Japan

NI-071

 

US phase III interchangeability trial in rheumatoid arthritis expected to be completed February 2019

Updated January 25, 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 Infliximab

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

Biosimilar Step Therapy for Medicare Part B: Does This Make Sense? An Inflximab Example

(October 18, 2018)  UnitedHealthcare has become the first to publicly implement step therapy policies for part B drugs. However, biosimilar step therapy is not the typical utilization management tool that industry executives are used to seeing.

Merck Gains VA Contract for Renflexis

(October 8, 2018) Merck has inked an exclusive contract to supply Renflexis with the US Department of Veterans Affairs.

Contracting “Schemes” to Prevent Biosimilar Infliximab Access: Let's Drop the Feigned Outrage

(July 18, 2018) Exclusive contracting for preferred drugs is an old tool from the pharmaceutical industry’s lifecycle management arsenal. Let’s not act like J&J’s actions on infliximab are a shocking new development.

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.

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…

Living With Crohn's Disease

Understanding Biosimilars

Clinical Trials of Renflexis

Published Trial Results

Renflexis was the subject of one phase 3, randomized double-blind trial comparing the biosimilar with the EU-licensed version of Remicade (a phase 1 pharmacokinetic bridging study proved equivalence between the EU- and US-licensed versions). Following this study, a six-month extension and switching investigation was completed.

Phase 3 Trials

A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy.

In this double-blinded phase 3 study, 584 patients (age range, 18–75 yr) with moderate-to-severe rheumatoid arthritis (RA) were randomized to receive either SB2 or the reference product Remicade, both dosed at 3 mg/kg for 54 weeks. The primary endpoint of this multinational study was a 20% improvement in symptoms based on the American College of Rheumatology criteria (ACR20) at week 30. In addition, ACR50 and ACR70 were also measured, as were DAS28 and EULAR scores.

Intravenous doses given over 2 hours were given at the initial administration of drug and at weeks 2, 6, 14, 22, 30, 38, and 46. Doses were permitted to be increased at week 30 (in increments of 1.5 mg/kg per visit, up to a total of 7.5 mg/kg). Study participants also received methotrexate either given orally or parenterally (10–25 mg/wk) along with folic acid (5–10 mg/wk). Participants could also receive non-steroidal anti-inflammatory agents and corticosteroids (≤10 mg prednisolone) if the doses were stabilized for 4 weeks before randomization into the study. Premedications to prevent infusion-related reactions were allowed if the investigator felt they were warranted.

Study results for full-set analysis at week 30 are shown in the Table below.

SB2 (N = 290) Remicade (N = 293)
ACR20 55.5% 59.0%
ACR50 30.7% 33.8%
ACR70 15.5% 17.1%

The results demonstrated that the biosimilar SB2 was equivalent to the reference product in terms of clinical outcomes.  The researchers also judged that DAS28, SDAI, CDAI and EULAR responses supported noninferiority of the biosimilar compared with Remicade.

In terms of safety, the investigators found that treatment-emergent adverse events (TEAEs) were similar between the two patient groups. Latent tuberculosis, increased alanine aminotransferase levels, and headache were the most commonly observed TEAEs. None of the study participants exhibiting latent tuberculosis progressed to TB. Infusion-related reactions were similar between the two groups even when considering the antidrug antibodies (ADAs) status of the study participants (which were also not determined to be statistically different between the biosimilar and reference study groups).

Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study.

The study was extended after 54 weeks another six months (at total of 78 weeks), whereby study participants receiving the reference product were randomized to either switch to SB2 treatment or continue with reference product therapy. Those receiving SB2 in the initial study continued using the biosimilar.

The investigators found that ACR20 responses were similar across all three study arms.

Patients Switched to SB2
(N = 94)
Patients Continuing on Remicade
(N = 101)
Patients Continuing on SB2
(N = 201)
ACR20
63.5%
68.8%
68.3%
ACR50
37.6%
47.3%
40.6%
ACR70
22.4%
31.2%
25.6%

The number of TEAEs was similar across the groups, 35.6%–40.3%). The most common TEAEs in the extended study were latent tuberculosis, nasopharyngitis and worsening RA. The percentages of patients who were ADA-negative during the first 52 weeks who became ADA-positive in the extension was 14.9% of those continuing with the reference product, 14.6% switching to SB2, and 14.1% staying on SB2.

Phase I Trial
Pharmacokinetic, safety, tolerability and immunogenicity study of SB2 in healthy subjects.

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