Ontruzant

Product Profile:

Trastuzumab-dttb (Ontruzant)

Drug Category: HER2/neu receptor antagonist

Target Indications: Treatment of HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma

Manufactured by Samsung Bioepsis; will be marketed by Merck

Summary: Ontruzant is an FDA-approved biosimilar version of traztuzumab (reference product, Herceptin, Roche).

Originally known as SB3, Samsung/Bioepsis submitted a biologic license application for approval via the 351(k) biosimilar pathway in December 2017. The Food and Drug Administration (FDA) approved the biosimilar on January 21, 2019. The drug has not yet been launched in the US; Merck will market the product in the US once launched. The European Medicines Agency approved Ontruzant for use in the EU in November 2017 and is available in several European countries.

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.

In addition to Ontruzant, Samsung Bioepsis also holds an FDA approval for Renflexis (an infliximab biosimilar) and Lusduna (a 505b2 approval for a follow-on biologic version of insulin glargine). The company is also seeking approval of biosimilars for adalimumab (FDA decision due in 2019), bevacizumab, etanercept, ranibizumab, and eculizumab.

News, Commentary, and Intelligence

Competitor Products and Manufacturer Analysis

Ontruzant was the third trastuzumab biosimilar to be approved by the FDA. It, like its competitors, is not yet available on the US market. Mylan and Biocon had signed a licensing agreement with Roche, the manufacturer of Herceptin, which ended their patent fight, but which delayed launch. Teva and Celltrion have not yet disclosed whether a similar deal has been reached with Roche. Pfizer also signed a licensing agreement with Roche.

APPROVED TRASTUZUMAB BIOSIMILARS

Company name

Brand name

When filed

Approval date/Marketing Status

Mylan/Biocon

Ogivri

November 2016

December 2017; not yet marketed

Celltrion/Teva

Herzuma

July 2017/June 2018

December 2018; not yet marketed

Samsung Bioepis/Merck

Ontruzant

December 2017

January 2019; not yet marketed

Pfizer

Trazimera

Q3 2017

March 2018; not yet marketed

TRASTUZUMAB BIOSIMILARS IN DEVELOPMENT

Company name

Product name

Stage of development

Amgen/Allergan

ABP 980

FDA issued complete response letter June 1, 2018

Pfizer Gains Approval for Trazimera, Its Trastuzumab Biosimilar

(March 11, 2019) The fourth biosimilar (Trazimera) was approved by the FDA. Dubbed trastuzumab-qyyp) it will compete for the Herceptin market at some point in the future.

Samsung Bioepis Scores FDA Approval of Ontruzant, the Third Biosimilar Trastuzuma

(January 18, 2019) This is the third trastuzumab biosimilar approved by the FDA, following those by Mylan and Biocon in December 2017 (Ogivri®) and Teva and Celltrion last month (Herzuma).

Second Trastuzumab Biosimilar Approved, Herzuma by Celltrion

(December 14, 2018) The US Food and Drug Administration gave its approval for a new trastuzumab biosimilar (Herzuma™). Manufactured by Celltrion and marketed in the US by Teva, this agent has been designated trastuzumab-pkrb.

Pfizer Signs Licensing Agreement with Roche on Trastuzumab Biosimilar

(December 10, 2018) Pfizer joined Mylan/Biocon in signing a confidential licensing agreement with Roche that cancels any patent litigation between the companies but delays launch.

Mylan Rethinking Its US Business Strategy?

(August 9, 2018) In reporting lower earnings on its second-quarter revenues, Mylan may have surprised industry observers by offering the possibility of some changes in strategic direction.

FDA Approval Eludes Amgen for Biosimilar Trastuzumab

(June 3, 2018) Amgen will have to wait a bit longer to market its biosimilar version of trastuzumab. On Friday, June 1, the Food and Drug Administration (FDA) rejected Amgen’s 351(k) application for its Herceptin® biosimilar.

Trastuzumab Dosing May Be Given in Half the Time: Will Costs/Revenues Be Cut as Well?

(May 18, 2018) A presentation at the annual American Society of Clinical Oncology (ASCO) meeting promised equal efficacy and much improved safety for patients with early-stage breast cancer receiving a 6-month instead of 12-month regimen of trastuzumab®.

Pfizer Receives FDA Rejection on Trastuzumab, Next up Is Amgen/Allergan

(April 24, 2018) When Pfizer announced that it received a complete response letter from the Food and Drug Administration (FDA), the wait for an available biosimilar to Herceptin®just got longer..

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.

Mylan/Biocon Receive First Approval for Trastuzumab Biosimilar, but First to Market?

(December 3, 2017) On December 1, the team of Mylan and Biocon received their first biosimilar approval in the US, for an agent to compete with Roche’s Herceptin®. The approval decision on this product was delayed 3 months owing to potential issues involving Biocon’s manufacturing facility. However, this marks the first biosimilar approved for trastuzumab, beating entries from Amgen/Allergan and Celltrion to the 351(k) finish line.

Mylan Clears the Way to Potential Trastuzumab Biosimilar Launch

(March 3, 2017) A settlement reached with Genentech and F. Hoffmann-La Roche Ltd. should allow Mylan to launch its biosimilar version of Herceptin® soon after the completion of its Food and Drug Administration (FDA) review in September.

What Is HER2-Positive Breast Cancer?

The Basics of Biosimilars

Clinical Trials of Ontruzant

Phase 3 Trials

A Phase III Study Comparing SB3 (a Proposed Trastuzumab Biosimilar) and Trastuzumab Reference Product in HER2-Positive Early Breast Cancer Treated With Neoadjuvant-Adjuvant Treatment: Final Safety, Immunogenicity, and Survival Results.

Ontruzant was tested in women with HER2-positive breast cancer through a phase III, multicenter, randomized, double-blind, parallel-group trial. The study had both a neoadjuvant and adjuvant therapy period. The study participants received via intravenous infusion either the biosimilar (502 patients, per-protocol group) or Herceptin (398) every 3 weeks for 8 cycles with concurrent chemotherapy (4 cycles of taxane therapy followed by 4 weeks of combination chemotherapy [5-fluorouracil, epirubicin, and cyclophosphamide]) for the neoadjuvant phase of the trial. Adjuvant therapy for the second phase of the trial accompanied by radiation and/or hormone therapy for 10 cycles.

The primary endpoint was the breast pathologic response rate in the per-protocol analyses. To achieve equivalence, the 95% confidence interval of the ratio of response between the two study groups needed to be within ±13%. Other efficacy secondary endpoints were comparisons of total pathologic complete response rate, overall response rate, event-free survival, and overall survival. Safety and immunogenicity were also analyzed.

Efficacy results (full analysis set) in the neoadjuvant phase (after 24 weeks) is shown in the Table below:

Biosimilar SB3

N=402

EU-trastuzumab

N=398

Breast Pathologic Response Rate

49.0%

39.7%

Total Pathologic Complete Response Rate

41.2%

32.4%

Overall Response Rate

93.6%

87.0%

Event-Free Survival

92.2%

91.6%

Overall Survival

99.8%

98.9%

The adjusted ratio of breast pathologic response was 1.259 (95% C I: 1.085 – 1.460); the difference between the two groups was 10.70% (CI: 4.13% – 17.26%). Both results were within the predefined equivalence range.

The frequency of serious adverse events were similar between the two groups (56 in biosimilar group, 58 in the reference product group). Likewise, the number of study participants reporting > 5% of other adverse events was similar in the two study groups (97% in the Ontruzant group and 96% in the Herceptin group). Antidrug antibodies were observed in 3 patients in the biosimilar group and 0 patients in the reference product group.

The study investigators concluded that equivalence for efficacy was demonstrated while the safety and immunogenicity results were similar in the neo-adjuvant portion of the study.

 

A Phase III Study Comparing SB3 (a Proposed Trastuzumab Biosimilar) and Trastuzumab Reference Product in HER2-Positive Early Breast Cancer Treated With Neoadjuvant-Adjuvant Treatment: Final Safety, Immunogenicity, and Survival Results.

This publication provides the results for the entire neo-adjuvant and adjuvant therapy portions of trial of Ontruzant therapy.

The researchers reported that 764 patients compled both the neoadjuvant and adjuvant portions of the trial (380 in the biosimilar group and 384 in the reference product group). The median follow-up was 437 days.

Efficacy and safety results in the full analysis set for both portions of the trial were as follows:

Biosimilar SB3

N=437

EU-trastuzumab

N=438

Breast Cancer Pathologic Response Rate

49.0%

39.7%

Total Pathologic Complete Response Rate

41.2%

32.4%

Overall Response Rate

93.6%

87.0%

Event-free Survival

92.2%

91.6%

Overall Survival

99.8%

98.9%

Patients with ≥1 TEAE

56.3%

55.0%

Patients with Serious TEAEs

12.8%

13.2%

Safety results were similar over the total treatment period as were the immunogenicity results.

The investigators concluded that the long-term results further demonstrated the similarity of Ontruzant and EU-licensed Herceptin.

Ongoing Studies

A long-term 5-year study is being conducted in the initial study patients for cardiac safety and event-free and overall survival. This investigation is slated to conclude in 2021.

Phase 1 Study

A Randomized Phase I Pharmacokinetic Study Comparing Biosimilar Candidate SB3 and Trastuzumab in Healthy Male Subjects.

 

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