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.

An FDA Filing for Momenta’s Adalimumab Biosimilar Coming Soon?

Momenta seems to be in final preparations for its first 351(k) filing to the Food and Drug Administration (FDA). In its recent investor conference, the company disclosed that it is ready to send M923, its adalimumab biosimilar, to the agency for approval.

Momenta's Adalimumab Biosimilar
Craig Wheeler, CEO of Momenta Pharmaceuticals

Despite this promising news, Momenta is facing strong headwinds. Even if it gains approval, Momenta expects that the US launch of the adalimumab biosimilar will not occur until 2023, owing to pending patent issues with Abbvie’s Humira®. The company does not yet have a marketing partner for this agent, though there appears to be plenty of time.

In addition, Momenta received a setback in November 2017 on another looming biosimilar candidate, when its biosimilar version of abatacept failed its phase 1 trial. Apparently, its M834 produced pharmacokinetic results that differed from the originator Orencia® in this early clinical study. Momenta is still studying the data and trying to come to grips with the surprising findings.

The company is also set to begin “pivotal” clinical trials on its other drug candidate M710, a biosimilar to aflibercept. The originator product is Eylea®, and it is indicated to treat wet age-related macular degeneration.

Momenta’s partnership with Mylan is moving forward with preclinical work on four other nonspecified biosimilars, according to the company. But all of this development costs money, and Momenta has acknowledged that it may need to raise cash for future development.

Momenta received approval in January for a generic form of the multiple sclerosis drug Copaxone® (glatiramer acetate). The approval of this agent, produced in partnership with Sandoz, had been delayed because of manufacturing issues. The company recognizes that the entry of Mylan (ironically) into this market may hinder its financial outlook.

As a result of these developments, Momenta stated it would entertain a sale of its adalimumab biosimilar “or other assets.”

 

The Patent Games: Another Sequel Underway

Roche/Genentech has filed suit in Delaware, citing the alleged violation of 37 patents by Amgen in its intent to market its biosimilar version of Herceptin®.  

The litigation was filed in response to Amgen’s stated intention of launching their product in October 2018, based on a May approval. Unfortunately, the Food and Drug Administration decided not to approve Amgen and Allergan’s initial 351(k) application in early June.

Roche has been engaged with Pfizer and the team of Celltrion and Teva on their trastuzumab biosimilars as well.

FDA Sets Advisory Board Review Date for Cancer Biosimilars

On July 13, the Food and Drug Administration’s Oncology Drug Advisory Committee will meet for 2 sessions to review biosimilars that were submitted via the 351(k) pathway in November 2016 to challenge reference agents manufactured by Roche/Genentech.

That morning, the committee will review Amgen and Allergan’s 351(k) submission for its biosimilar version of bevacizumab (Avastin®), which is used for the treatment of patients with metastatic carcinoma of the colon or rectum; nonsquamous, non–small cell lung cancer; gliobastoma in adults; metastatic renal cell carcinoma; and cervical cancer. Avastin is also used off-label to treat several ocular disorders, including wet age-related macular degeneration.

In the afternoon, the same committee will ruminate on the evidence for recommending Mylan/Biocon’s biosimilar version of trastuzumab (Herceptin®) for approval. This agent’s proposed indications include HER2 overexpressing breast cancer (early treatment and metastatic) and metastatic gastric adenocarcinoma.

Final decisions on the approval of these agents are expected in the early third quarter of this year. Recommendations for approval by the Advisory Committee of either or both products would likely result in the launch of the first biosimilars for the direct treatment of cancer.

In other news…This week’s Digestive Disease Week scientific sessions yielded additional positive results in switching studies on Pfizer/Celltrion’s infliximab-dyyb (Inflectra® in the US). In the first, a phase 3 double-blind, controlled trial of 220 patients with Crohn’s disease from 16 countries, found no significant difference in efficacy and safety results compared with the originator product. The second investigation reported extended (2-year) results of Norway’s well-publicized phase 4 NOR-SWITCH study, which comprised 481 patients with inflammatory bowel disease.

Mylan Clears the Way to Potential Trastuzumab Biosimilar Launch

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. Mylan, which holds a partnership agreement with Biocon, will market the new trastuzumab biosimilar once approved.

Under the agreement, Mylan will have a global license to commercialize the agent (except in Brazil, Japan, and Mexico). The agreement cancels all remaining patent litigation, including Mylan’s Inter Partes Review, which sought to invalidate 2 key patents on trastuzumab. It is assumed that Genentech and Hoffman-LaRoche will obtain royalty payments as part of the settlement, but terms of the deal were not released.

Filed in November, the current deadline for FDA action on Mylan’s 351(k) application is September 3, 2017. Theirs is the first (and only) trastuzumab biosimilar application filed in the US. In a press release, Mylan CEO Heather Bresch stated, “There is an unmet need for access to more affordable versions of biologic products such as trastuzumab. We look forward to enhancing access to this important treatment option, which complements our comprehensive cancer care offerings, in the US and around the world.”

Mylan and Biocon’s partnership breaks out commercial control as follows: Mylan will sell the product in North America, Australia and New Zealand, and in Europe; Biocon will hold rights to sell the product elsewhere.

Assuming the FDA approves the agent according to schedule, this would represent the first biosimilar agent to be marketed in the US for the direct treatment of cancer. However, Europe may see their first oncological biosimilar earlier: Mylan submitted its application for licensing with the European Medicines Agency (EMA) in November 2016, Celltrion’s CT-P6 was also submitted that month in Europe, but Samsung Bioepis applied for approval in August 2016 and may be the first reviewed by EMA.