Truxima

Product Profile:

Rituximab-abbs (Truxima) 

Drug Category: Monoclonal anti-CD20 antibody

Target Indications:  Treatment of adult patients with low-grade follicular B-cell non-Hodgkin’s lymphoma who are CD20-positive and have failed prior treatments; patients who have CD20-positive B-cell non-Hodgkin’s lymphoma and who are stable after receiving a prior chemotherapy regimen containing cyclophosphamide, vincristine and prednisone; and patients with CD20-positive follicular lymphoma who are therapy naïve in combination with chemotherapy or who had responded to previous rituximab therapy

Developed by Celltrion and will be marketed by Teva in the US

Summary:  Truxima is the first FDA-approved biosimilar version of rituximab (reference product, Rituxan) manufactured by Genentech.

Originally designated CT-P10 by its manufacturer, Celltrion, which submitted a biologic license application for approval via the 351(k) biosimilar pathway in June 2017. The Food and Drug Administration (FDA) rejected the application in April 2018. Celltrion resubmitted to FDA the following month. It was recommended for approval in October 2018 by the FDA’s Oncology Drug Advisory Committee, and approved in November 2018.

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, and Inflectra was first approved in the US in 2016. Celltrion has six other biosimilar products in development.

In October 2016, Celltrion and Teva formed a partnership, in which Teva would commercialize two biosimilars, Truxima and Herzuma (both of which are approved but not yet marketed) in the US.

 

News, Commentary, and Intelligence

Competitor Products and Manufacturer Analysis

Truxima is the first rituximab biosimilar to be approved by the FDA. The product has not yet entered the marketplace.

Pfizer received approval for its agent Ruxience in July 2019; this agent has not yet been marketed. Boehringer Ingelheim and Sandoz both had biosimilars in Phase III development but made business decisions to not move forward with the products.

Rituximab Biosimilar(s) in Development

Company Name Product Name Brand Name Stage of Development

Amgen/Allergan

ABP798

TBD

Phase III trial expected to be completed in June 2019 for NHL

Phase III trial for rheumatoid arthritis was completed in October 2018

Mabion/Mylan

MabionCD20

TBD

Met with FDA in July 2018 to finalize “ the most optimal pathway towards registering” in the US; Filed for EMA approval in June 2018

The Biosimilar Mabs Have It: FDA Approves Biosimilars for Adalimumab and Rituxumab

(July 24, 2019) On July 22, 2019, the Food and Drug Administration (FDA) announced the approval of Pfizer’s Ruxience, a biosimilar of rituximab. Compared with reference agent MabThera, this biosimilar proved to produce equivalent efficacy and safety in a phase 3 trial.

Pfizer Signs Patent Settlement With Roche on Rituximab Biosimilar

(March 25, 2019) An agreement was announced between Pfizer and Roche (Genentech), which concludes litigation over a key patent for Rixutan. This may affect when Pfizer decides on marketing the product.

Rituximab Biosimilar Approved by FDA for Cancer Treatment

(November 28, 2018) On November 28, 2018, the Food and Drug Administration (FDA) announced the approval of rituximab-abbs (Truxima™), produced by Celltrion and marketed by Teva. Approval for this rituximab biosimilar was overwhelmingly recommended by the FDA’s Oncology Drug Advisory Committee by a vote of 16-0 in October.

Sandoz Decides Against Marketing Rituximab Biosimilar in US

(October 30, 2018) Sandoz announced that it would halt its efforts to obtain approval for its biosimilar version of rituximab from the US Food and Drug Administration (FDA).

Celltrion's Rituximab Biosimilar Earns Positive FDA Review

(October 8, 2018) The information package released by reviewers for the Food and Drug Administration (FDA) indicates that a positive recommendation for Celltrion’s rituximab biosimilar is likely at the Advisory Committee meeting on October 10.

Celltrion Bounces Back, Resubmits for FDA Approval of Rituximab Biosimilar

(May 30, 2018) Anticipating that its issues with the Incheon, South Korea, manufacturing plant will be resolved, Celltrion has resubmitted its biologic license application for a rituximab biosimilar (CT-P10).

FDA Hands Sandoz a Rejection on Its Rituximab Biosimilar

(May 2, 2018) Sandoz announced today that the Food and Drug Administration (FDA) has decided not to approve its biosimilar version of the oncology biosimilar rituximab.

Teva and Celltrion Receive Rejections on Trastuzumab and Rituximab Biosimilars

(April 5, 2018) Celltrion and its partner Teva were dealt a significant blow today, as the Korean manufacturer announced that the latest two biosimilar candidates were rejected by the Food and Drug Administration.

Biosimilar Rituximab Under FDA Review

(July 5, 2017) Celltrion announced June 30, 2017 that it has submitted its 351(k) application to the Food and Drug Administration for approval of its biosimilar version of rituximab. This represents the first biosimilar application for rituximab, a monoclonal antibody to CD20..

Celltrion’s Rituximab Recommended for Approval in Europe

(January 3, 2017) Just weeks after Celltrion presented data at the American College of Rheumatology meeting demonstrating that its product CT-P10 is as safe and effective as Rituxan®for the treatment of rheumatoid arthritis (RA), the European Medicines Agency (EMA) received the recommendation to approve the product for use in the EU.

CT-P10 Rituximab Biosimilar Phase 3 Clinical Trial Results Announced

(September 28, 2016) The results of a phase 3 trial presented at the American College of Rheumatology meeting proved that a biosimilar version of Rituxan provided equivalent results over a 24-week study period compared with the originator product.

Prognosis of Patients with B-Cell non-Hodgkins Lymphoma

Will Biosimilar Rituximab Replace the Originator Product?

Clinical Trials of Truxima

Clinical Trial Results

There were two clinical trials reviewed for the FDA approval of Truxima. Both of these trials compared Truxima to Rituxan in patients with follicular lymphoma. Clinical trial results for rheumatoid arthritis were also submitted to the FDA; however, an indication for this disease was not pursued by Celltrion.

Low Tumor Burden Follicular Lymphoma

To Compare Efficacy and Safety Between CT-P10 and Rituxan in Patients With Low Tumour Burden Follicular Lymphoma

Low Tumor Burden Follicular Lymphoma (LTBFL)

A total of 258 adult patients with low-tumor-burden follicular lymphoma (stages II–IV) were enrolled in a randomized, double-blind, parallel-group study. The patients received monotherapy with either the biosimilar CT-P10 or US-licensed rituximab. All patients received dosages of 375 mg/m2 weekly for 4 weeks. At the end of this period, those patients who had complete response (CR), unconfirmed compete response (uCR), partial response (PR), or stable disease were able to enter a maintenance study period, during which they received CT-P10 every 8 weeks up to a maximum of 12 cycles (≤ 2 years). The primary endpoint was the overall response rate (ORR) by 7 months.

Based on the prespecified benchmarks of equivalent efficacy set by the investigators, they determined that the biosimilar’s clinical outcomes were equivalent (see Table below) to those of the reference product.

 

Results (after 7 months’ treatment)

CT-P10

(N=130)

Rituxan

(N=128)

ORR

83.1%

81.3%

CR

27.7%

33.6%

uCR

4.6%

1.6%

PR

50.8%

46.1%

TEAEs

72.3%

70.3%

Severe AEs

5.4%

2.3%

The percentage of patients with treatment-emergent adverse events (TEAEs) were similar in both treatment groups, as well as those with severe AEs. The most common adverse events were infusion-related reactions and fatigue.

Advanced Follicular Lymphoma (AFL)

Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial.

One hundred forty patients with advanced follicular lymphoma participated in a phase 3 randomized, double-blind, parallel group investigation. They were randomized to receive either CT-P10 or US-licensed rituximab (375 mg/m2 via intravenous administration), in combination with cyclophosphamide, vincristine, and prednisone every 3 weeks for up to eight cycles. All patients received a premedication of an antipyretic, antihistamine and a glucocorticoid 30 minutes before the infusion of CT-P10 and reference biologic. After eight cycles, patients who had a response were invited to continue treatment in a maintenance study with the two medications being administered as monotherapy every 2 months, for a maximum of 12 cycles. The primary endpoints for the first eight 8 cycles was ORR, and the proportion of responders who achieved CR, uCR, or PR.

 

Results (after eight cycles of treatment)

CT-P10

(N=70)

Rituxan

(N=70)

 ORR

95.7%

90.0%

CR

30.0%

21.4%

uCR

8.6%

11.4%

PR

57.1%

57.1%

TEAEs

90.0%

85.7%

Serious AEs

30.0%

18.6%

 

Safety results were similar between the two groups. The most common adverse events were neutropenia and infusion related reactions.

Other Studies

Although a study of the effectiveness of CT-P10 was conducted in patients with rheumatoid arthritis, Celltrion did not seek approval for this indication. The assessment of immunogenenicity was limited to the rheumatoid arthritis trial, because drug concentrations achieved in this trial was higher than the threshold required immunogenicity assays in the lymphoma trials. At week 48 in the rheumatoid arthritis study, more patients were found to have anti-drug antibodies (ADA) in the US-licensed Rituxan group than in the biosimilar group (9.6% vs. 5.0%, respectively) whereas one patient in each group tested positive for neutralizing antibodies. The researchers deemed that the immunogenicity measures were noninferior for the biosimilar compared with the reference product.

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