FDA Approves Celltrion and Teva’s Herceptin® Biosimilar

On December 14, 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.

The decision marks the second trastuzumab biosimilar approval, and the 16th biosimilar agentthat has made it through the 351(k) regulatory pathway.

Herzuma was approved for a single indication: the treatment of HER2-overexpressing breast cancer. Unlike the other trastuzumab biosimilar, Ogivri®, and Herceptin, Herzuma does not carry the extrapolated indication for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

Originally submitted for approval by Celltrion in July 2017, the FDA issued a complete response letter because of plant manufacturing issues. A year later, after addressing these problems, Celltrion refiled its 351(k) application (June 2018).

Celltrion has launched Herzuma in Europe and elsewhere with marketing partners other than Teva. Neither Celltrion or Teva have announced at this time when the US launch may occur or how it will be priced. Partners Mylan and Biocon, makers of Ogivri, and Pfizer, the manufacturer of a potential competitor, have signed licensing agreements with Roche, makers of the reference product to delay launch.

Pfizer Signs Licensing Agreement With Roche on Trastuzumab Biosimilar

With Pfizer expecting to hear back on its 351(k) resubmission on a trastuzumab biosimilar in early 2019, Genentech and its parent, Roche, may have been getting nervous about their competitor’s intentions. After all, Pfizer was willing to launch at risk with its marketing of Inflectra®, the infliximab biosimilar manufactured by partner Celltrion. In fact, it is the only biosimilar manufacturer that has gambled on an at-risk biosimilar launch.

According to a report in the Pink Sheet, a district court filing on December 4 noted that the two parties signed a settlement that will put an end to their patent litigation, and presumably allow Pfizer to market its biosimilar trastuzumab in the US at a future date. As in previous agreements signed by Roche, the terms are confidential, and launch dates and licensing fees are unknown.

trastuzumab biosimilar

A similar confidential agreement was completed between Mylan and Roche, for Mylan and partner Biocon’s Ogivri®, the first trastuzumab biosimilar approved by the Food and Drug Administration (FDA) in April 2017.

Three other trastuzumab biosimilars are also trying to reach the market. Amgen and Allergan received a complete response letter in June 2018, and have not yet announced when it might resubmit its 351(k) application. Samsung Bioepis is awaiting its initial decision on its trastuzumab biosimilar, filed in January 2018. Teva and Celltrion seem to be on the cusp of an FDA decision, after receiving their initial rejection in July 2017.

Roche has it covered, though. It filed patient litigation against Samsung Bioepis in September 2018 and partners Celltrion and Teva as well.

This is the very situation that the federal government, payers, and patients want to try to avoid, however. Licensing fees paid to the reference manufacturers may work to significantly inflate the drug’s price to the health system. The lack of transparency characterizing these agreements and the associated delays in launch are being decried by those patients and entities who can benefit from access to biosimilar competition. Herceptin was first approved in 1998. No one envisioned Genentech having 20+ years of marketing exclusivity.

In other biosimilarnews… MomentaPharmaceuticals, which signed an Abbvie licensing agreement for its biosimilar adalimumab, said in a statement that it will delay FDA filing M923 beyond 2019, which will help reduce its corporate expenditures. This delay should not impact the expected commercial launch date of November 20, 2023, according to the company.

Celltrion announced that it has filed an application for European Medicines Agency approval for its subcutaneous form of its infliximab biosimilar Remsima (US brand name, Inflectra®). This would provide the first subcutaneous injection formulation of infliximab.

Rituximab Biosimilar Approved by FDA for Cancer Treatment

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. It is the first biosimilar agent approved for the treatment of relapsed or refractory, low grade, or follicular non-Hodgkin’s lymphoma—specifically in adult patients with the CD20+ B-cell variety. The drug makers did not seek approval for the Rituxan’s autoimmune indications, and the FDA did not grant extrapolated approval for them.

rituximab biosimilarAccording to the FDA’s announcement, the most common side effects of Truxima are infusion reactions, fever, abnormally low level of lymphocytes in the blood (lymphopenia), chills, infection and weakness (asthenia). Health care providers are advised to monitor patients for tumor lysis syndrome (a complication of treatment where tumor cells are killed off at the same time and released into the bloodstream), cardiac adverse reactions, damage to kidneys (renal toxicity), and bowel obstruction and perforation.

This leaves a wide open marketing window for Celltrion and Teva, as Sandoz announced in late October that it was halting its effort to bring its own rituximab biosimilar to the market. There is no word as of this writing regarding the launch and pricing of Truxima in the US. This also represents the second FDA approval for Celltrion; its infliximab biosimilar, Inflectra, was approved in 2016.

In Other Biosimilar News… As BR&R reported in our October discussion with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim had decided to forego marketing its adalimumab biosimilar Cyltezo® in the EU. This is likely owing to the highly competitive environment and the huge pricing discounts being signed by European countries. However, Boehringer has now announced its intention to discontinue all efforts to market and develop any biosimilars outside of the US market. This may come as little surprise, as the Boehringer biosimilar pipeline was not aggressively stocked. Instead, it has been focused on seeking interchangeability status for Cyltezo and to launch this product as soon as possible.

FDA Approval Eludes Amgen for Biosimilar Trastuzumab

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. biosimilar trastuzumab approvalIn a brief press release, Amgen announced receiving the complete response letter for ABP 980. In the announcement, it also said that the delay in its biosimilar trastuzumab approval should not “impact our US launch plan.” This may signal that even if it received approval, it would not market the biosimilar trastuzumab immediately.

The timing of the FDA announcement on the biosimilar trastuzumab approval contrasted with the near-simultaneous marketing authorization of this same trastuzumab biosimilar by the European Medicines Agency. The biologic will be marketed in Europe under the trade name Kanjinti™.

Mylan/Biocon’s Ogivri™ remains the only biosimilar trastuzumab approved by the FDA. It is not yet marketed, however. Separate trastuzumab biosimilars by Teva/Celltrion and Pfizer have been stalled by the FDA. Samsung Bioepis’s entry is due for an FDA approval decision in the fourth quarter of 2018.

In related biosimilar news… in September 2017, Mylan filed a 505(b)2 application for its insulin glargine agent. The manufacturing duo of Mylan and Biocon received a rejection from the FDA on June 1. The complete response letter specified issues raised by a change in manufacturing site (from one in India to a new facility in Malaysia). As reported by the Economic Times, the complete response letter was expected by Mylan and Biocon. They told the Economic Times, “Together, Mylan and Biocon are already executing on all required activities we had agreed upon with the FDA, and they are progressing according to plan,” the statement said.

Although insulins are not currently approved through the 351(k) biosimilar pathway, they are among the “transitional agents,” which by 2020 will be considered biosimilars by the FDA.