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Background Analysis: US FDA Advisory Committee to Review CT-P10, a Proposed Biosimilar of Genentech’s Rituxan by Celltrion – OCT 10, 2018 (ODAC)

Announcement

The US FDA has scheduled an Oncologic Drugs Advisory Committee (ODAC) meeting for Wednesday, October 10, 2018 to discuss the resubmission of a biologics license application (BLA) for CT-P10, a proposed biosimilar to Rituxan (rituximab) by Celltrion, Inc. (Celltrion).

The meeting will be held from 8 am to 1 pm US EST. Teva Pharmaceutical Industries Ltd is responsible for all commercial activities in the US and Canada, pending regulatory approval.

Product Background

Description of Indication

CT-P10 is a proposed biosimilar to Rituxan (rituximab). Rituxan is a monoclonal antibody directed against the CD20 antigen. The FDA-approved indications for Rituxan are shown below. According to the FDA announcement, the indications that are presented below in underlined text will be discussed at the meeting.

1.1 Non-Hodgkin’s Lymphoma (NHL)

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.

Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to RITUXAN in combination with chemotherapy, as single-agent maintenance therapy.

Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.

Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

1.2 Chronic Lymphocytic Leukemia (CLL)

RITUXAN is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL.

1.3 Rheumatoid Arthritis (RA)

RITUXAN in combination with methotrexate is indicated for the treatment of adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

1.4 Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

RITUXAN, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

1.5 Pemphigus Vulgaris (PV)

RITUXAN is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris.

Comprehensive data from the BLA resubmission, including detailed analyses by the company and by the FDA, as well as specific FDA questions for the Committee, will be presented in briefing materials that will be posted ahead of the meeting. The briefing materials for the meeting will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

US-Approved Biosimilars

Twelve biosimilars have been US FDA-approved for eight reference biologics, as listed below.

1.     Neupogen biosimilars: Nivestym , (filgrastim-aafi) by Pfizer, approved July 2018 and Zarxio (Filgrastim-sndz), approved March 2015

2.     Neulasta biosmilar: Fulphila (pegfilgrastim-jmdb) by Mylan GmbH, approved June 2018

3.     Epogen/Procrit biosimilar: Retacrit (epoetin alfa-epbx) by Pfizer, approved May 2018

4.     Remicade biosimilars: Ixifi, (infliximab-qbtx) by Pfizer, approved December 2017; Renflexis (Infliximab-abda) by Merck Sharp & Dohme Corp, approved May 2017; and Inflectra (Infliximab-dyyb) by Celltrion, approved April 2016

5.     Herceptin biosimilar: Ogivri (trastuzumab-dkst) by Mylan GmbH, approved December 2017

6.     Avastin biosimilar: Mvasi (bevacizumab-awwb) by Amgen, approved September 2017

7.     Humira biosimilars: Cyltezo (adalimumab-adbm) by Boehringer Ingelheim Pharmaceuticals, approved August 2017 and Amjevita (adalimumab -atto) by Amgen, approved September 2016

8.     Enbrel biosimilar: Erelzi (etanercept-szzs) by Sandoz, approved August 2016

The US has lagged behind the EU in the number of biosimilar marketing approvals and launches. In July 2018, the FDA Commissioner, Dr. Scott Gottlieb, announced a Biosimilars Action plan aimed at promoting competition and affordability across the market for biologics and biosimilar products. The plan can be viewed at the following link: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM613761.pdf

Regulatory Background

US Regulatory Background

October 2018– BsUFA date (estimated based on a 6-month review of the BLA resubmission)

July 17, 2108 – Celltrion reported that the FDA completed its re-inspection of their Incheon, South Korea manufacturing site. This site received a Warning Letter from the FDA in January 2018 and contributed to the receipt of Complete Response Letters (CRLs) for the initial CT-P10 BLA, as well as for a BLA for a proposed Herceptin (trastuzumab) biosimilar, named CT-P6, in April 2018. The company stated, “After the re-inspection, FDA issued a Form 483 with 8 manageable and correctible inspection observations. Celltrion provided a comprehensive response ahead of schedule to the Agency to address the observations. Celltrion awaits the outcome of the recent re-inspection and expects outstanding observations will be lifted very soon. Celltrion is committed to working with the agency to gain approval of CT-P10 and CT-P6 by the end of this year.”

May 30, 2018 – Celltrion announced the BLA resubmission for CT-P10.

April 6, 2018 – Celltrion announced their receipt of the CRL in response to their initial NDA for CT-P10. The company stated, “The FDA Warning Letter issued to Celltrion in January 2018 was directly related to the receipt of the CRL.”

January 30, 2018 – Celltrion announced their receipt of a Warning Letter from the FDA related to an inspection the Agency carried out from May 22 to June 2, 2017 at the company’s drug manufacturing facility in Incheon, South Korea. The company stated, “The letter raises issues related to certain manufacturing process at the facility.”

June 30, 2016 – Celltrion announced that the initial BLA 761088 for CT-P10 was accepted for review.

EU Regulatory Background

February 2017 – The European Medicines Agency (EMA) approved CT-P10, using the trade name Truxima.

The currently approved indications for Truxima, as of September 11, 2018, are as follows:

Non-Hodgkin’s lymphoma (NHL)

Truxima is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.

Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.

Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. 

Chronic lymphocytic leukemia (CLL)

Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including Truxima or for patients refractory to previous Truxima plus chemotherapy. See section 5.1 for further information.

Rheumatoid arthritis

Truxima in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARD) including one or more tumor necrosis factor (TNF) inhibitor therapies.

Truxima has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.

Granulomatosis with polyangiitis and microscopic polyangiitis

Truxima, in combination with glucocorticoids, is indicated for the induction of remission in adult patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA).

Truxima was approved using the centralized procedure, and the company was granted rights to market Truxima without additional approval in 31 EU countries, including 28 EU countries such as the UK, Germany, Italy, France and Spain, and three European Economic Area (EEA) countries, Norway, Iceland and Liechtenstein.

What’s Next? (With Subscription)

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Celltrion Drug Name: CT-P10, rituximab Drug Class: CD20 monoclonal antibody Indication: Non-Hodgkin’s Lymphoma


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.