At an earnings call this week, Pfizer’s CEO highlighted the
impending launches of Ruxience®
not long after the previously announced launch of Zirabev®
(bevacizumab) at the end of this year.
The New York–based pharmaceutical manufacturer plans to
begin marketing Ruxience in January 2020, and Trazimera February 15, 2020. This
would make Pfizer first to market with a Rituxan® competitor. Pfizer
follows Amgen to market with Trazimera, as Kanjinti®
launched in July this year.
On the call, Albert Bourla, PhD, indicated that the
company’s infliximab biosimilar (Inflectra®) had grown 8% for the
third quarter of 2019 over the same quarter in 2018 (to $77 million). Inflectra’s
marketshare in the US still remains below 10%, according to IQVIA.
The partnership of Amgen and Allergan made a huge splash in the biosimilar market by announcing the simultaneous US launches of the first two biosimilars of anticancer monoclonal antibodies. The agents Kanjinta® (trastuzumab-anns) and Mvasi® (bevacizumab-awwb) were officially made available July 18.
The move occurred almost simultaneously with a court denial
of Genentech’s request for a restraining
order against Amgen. For Amgen, this marks the first two biosimilars to
The launch discounts associated with these two agents is only 15% off of average wholesale price (AWP), but the manufacturers point out that is still significantly below the average selling price (ASP) of the two reference drugs—13% lower than that for Herceptin® and 12% lower than that for Avastin®. This pricing does not include potential rebates or discounts that could further reduce the net costs of these biosimilars.
The launch timing raises the question of when the
FDA-approved biosimilar competition will be launched. Other biosimilars in the
trastuzumab space have signed
licensing agreements with Genentech, the maker of Herceptin. Their launch
dates have not been disclosed. Several biosimilar makers have also signed
licensing agreements with Genentech on their versions of Avastin, and their
launch dates may be upcoming as well.
Assuming the licensing agreements compel the other
manufacturers to pay some percentage of sales or profits to Genentech, this
could give Amgen/Allergan an automatic edge in profitability. It is unknown
whether the launch timing of Mvasi and Kanjinti, have any implications for the
existing licensing agreements. For example, it may be possible that an early
launch by an unlicensed competitor could negate specific clauses of these
The bevacizumab biosimilar class progress had stagnated
through court proceedings and licensing agreements. In a post from January
2019, we had noted that Amgen had notified the court that it was prepared to
launch as early as
On the trastuzumab side, Amgen/Allergan’s product was the most
recently approved biosimilar (in June 2019).
joint press release, they quoted Paula Schneider, CEO of the Susan G. Komen
Breast Cancer Foundation. “The introduction of biosimilars is an important
step in increasing options for treating HER2-positive breast cancers, which
account for about 25% of all breast cancers,” she said. “As patient
advocates, we are working to ensure that patients are educated about
biosimilars and understand that these FDA-approved treatments are just as
effective as the original biologic drugs.”
And then there was one. Samsung Bioepis and Genentech filed
in District Court to drop all pending patent litigation regarding Ontruzant®,
an approved Herceptin® biosimilar. A Joint Stipulation of Dismissal
is usually the confirmation that a licensing agreement has been reached.
This leaves one
remaining approved trastuzumab biosimilar maker that has not settled with
Genentech (a subsidiary of Roche). Amgen’s product Kanjinti®, which
was the last trastuzumab biosimilar approved (in June), is the last of 5 approved agents
that is not yet subject to a Genentech agreement. The other manufacturers,
Mylan/Biocon, Teva/Celltrion, Pfizer, and now Samsung Bioepis, will likely pay
a royalty to Genentech whenever their products are launched.
Launch dates have not been announced (nor have the terms of
these agreements) for any Herceptin biosimilar. However, the principal patent
for Herceptin® has expired, so biosimilar competition should be available
before the end of the year.
In other biosimilar
Biosciences announced that it has manufactured its 400,000th dose of its
pegfilgrastim biosimilar Udenyca®. Additionally, its unaudited second
quarter earnings seem to indicate positive movement, as much as $84 million (more
than doubling first-quarter earnings of $37 million).
Five trastuzumab biosimilars have been approved for
marketing in the US, and the composition-of-matter patent for the reference
product, Herceptin®, expires June 30, 2019. That doesn’t mean we’ll
see a jail break of competition, like that seen in the EU last October with
adalimumab’s patent expiration. Yet there has been heavy interest in capturing
a slice of Herceptin’s $2.9
billion US sales (in 2018).
Three manufacturers have signed licensing agreements with
Genentech (subsidiary of Roche). In March 2017, Mylan signed the first
agreement for its product Ogivri®.
Its marketing partner is Biocon. In December 2018, Pfizer
followed suit for its recently approved agent Trazimera®.
None of the parties have indicated when a biosimilar agent will be launched. At
the end of December, Celltrion and Teva came to a similar agreement on its
According to Goodwin’s Big Molecule Watch, Roche’s infringement
claims against Samsung Bioepis (Ontrusant®) and Amgen/Allergan (Kanjinti®)
are still being litigated. For Genentech v. Samsung, the bench
trial is slated to begin December 9, 2019. In addition, Samsung Bioepis is appealing
the Patent Trial and Appeals Board ruling regarding the validity of Herceptin’s
method of use patents. Separately, Genentech is challenging the PTAB’s decision
that two other Herceptin patents were invalid. There’s a whole lot here that
needs to be resolved (or settled).
In the case of Amgen and Allergan, Genentech originally
brought suit claiming 38 patents were infringed (in June 2018). In July 2018,
Genentech reduced this figure to less than half (17). A month later, Amgen responded
to the suit. Little information is available on timing of next steps.
Based on this information, it is difficult to know just when
the first trastuzumab biosimilars will be launched. If Genentech followed
Abbvie’s example in its 2023 sequencing of adalimumab biosimilars, one might
expect Mylan’s product to be available first, perhaps as early as this summer,
with Pfizer’s and Celltrion to follow perhaps six months later.
Yet, unlike the Abbvie agreements, none of the Genentech licensing
settlements were made public (other than the actual dates of the agreement). Keep
in mind, Herceptin was first approved by the FDA in October
1998. In 2018, the drug’s sales in the US and EU combined was over $4.7
billion. Is 21 years of market exclusivity to anyone’s benefit, other than the
2006, US drug sales of Herceptin have been greater than $1 billion
If the biosimilar launches do not occur shortly, this may be a good test
case of the Federal Trade Commission’s commitment to clearing patents in the
name of competition.
A fourth trastuzumab biosimilar has been approved by the US Food and Drug Administration (FDA). Pfizer’s biosimilar version of trastuzumab-qyyp (Trazimera) gained approval on March 11.
The principal phase 3 study tested Trazimera against the EU-licensed version of Herceptin®. The REFLECTIONS B327-02 study found no relevant differences in the clinical and safety outcomes for patients with HER2–positive metastatic breast cancer, who also received paclitaxel. A second study tested Trazimera versus EU-licensed Herceptin in combination with docetaxel and carboplatin as neoadjuvant therapy, again demonstrating similar outcomes. The FDA’s approval covers both indications approved for Herceptin (treatment of HER2-overexpressing breast cancer and metastatic gastric/ gastroesophageal junction adenocarcinoma).
Pfizer first filed for
approval of its trastuzumab biosimilar in the third quarter of 2017, and received
a rejection from FDA in April 2018. Resubmission in June 2018, with additional information
requested by the FDA, resulted in the current approval. The product was
approved by the European Medicines Agency last year.
As with the other approved biosimilar versions of trastuzumab (Herzuma, Ogivri, and Ontruzant) in the United States, Trazimera is not yet available for prescription. Pfizer signed a licensing agreement with Herceptin’s maker Roche in December 2018, but a launch date is not yet available.
In other biosimilar
news…Biocon’s biosimilar manufacturing plant has received a second
citation from the FDA. The new Form 483 specified two issues, one involving
sanitizing a type of barrier
system and problems in tracking rejected vials.
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.
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.
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.
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.
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.
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.
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. In 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.
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).
In the April 2018 complete response letters sent by the Food and Drug Administration (FDA) on CT-P10 and the trastuzumab biosimilar CT-P6, FDA cited aseptic practices at the manufacturing plant that it announced in January. The resubmission should mean that a decision will come within six months of the application date, keeping it in the race for the first rituximab biosimilar.
Celltrion, in its announcement, also affirmed that it intends to resubmit its application for its trastuzumab biosimilar in June. In its press release, Celltrion stated, “Celltrion has made progress addressing the concerns raised by the FDA in the warning letter and is committed to working with the Agency to fully resolve all outstanding issues with the highest priority and urgency.”
This marks the quickest turnaround seen yet for reapplication following an FDA rejection of a biosimilar. Truxima® is the brand name of Celltrion’s rituxumab biosimilar that is approved in Europe.
In other biosimilar news…The European Commission announced a proposal that would enable biosimilar manufacturers to produce and export their products before EU full intellectual property rights terminate. This would obviate Special Protection Certificates, which were created in 1992. Under these certificates, intellectual property rights continue for 5 years after EU patent expiration. The announced change would be implemented by end of this year. It will mark the end of special compensation to pharmaceutical industry for the extended period required for research, development, and regulatory approval.