Tag: Teva

Partners Teva/Celltrion Seek the Jump on Pfizer, Launch Their Rituximab Biosimilar Next Week

When Pfizer announced its intention just more than a week ago to begin marketing its rituximab biosimilar Ruxience® in January 2020, industry watchers wondered when we might hear a response from its sole approved competitor. The wait was over quickly: Teva and Celltrion will begin shipping their own rituximab biosimilar Truxima® on November 11.

Truxima was approved in October 2018 for the cancer indications of Genentech’s reference product Rituxan®. In a joint press release issued by both companies, Brendan O’Grady, Teva’s Executive Vice President and Head of North America Commercial Operations, stated, “We are excited about the first FDA-approved biosimilar to rituximab in the US. Teva’s commitment to biosimilars is focused on the potential to create lower healthcare costs and increased price competition. This focus is consistent with Teva’s mission of making accessible medications to help improve the lives of patients.”

The press release also mentioned a key detail of the partners’ patent settlement with Genentech. Specifically, Celltrion and Teva will be able to market the autoimmune indications (rheumatoid arthritis, granulomatosis, with polyangiitis, and microscopic polyangiitis) in the second quarter of 2020, assuming they receive approval from the Food and Drug Administration for the broader indications. Ruxience is not currently indicated for these same autoimmune disorders.

The partners announced that the wholesale acquisition cost (WAC) for Truxima will be just 10% below that for Rituxan, which will be subject to further discounts and rebates negotiated with individual payers. That works out to a WAC of $845.55 for 100 mg vial (or $4227.75 for 500 mg vial). Teva will be responsible for marketing Truxima in the US.

Pfizer has not yet announced their intended WAC for Ruxience’s launch in January.

Don’t Expect All-Out Biosimilar Competition for Herceptin—Just Yet

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 Herzuma® biosimilar.

Herceptin patent litigation

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 manufacturer? Since 2006, US drug sales of Herceptin have been greater than $1 billion annually. 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.

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.

Fresenius Kabi and Celltrion Get Good News

A German manufacturer is considering its options after the successful completion of two clinical studies involving a pegfilgrastim biosimilar (MSB11455).

Fresenius Kabi, which completed its purchase of the biosimilar business from Merck KGaA in September 2017, announced its investigational biosimilar agent had proved sufficiently similar to the reference product Neulasta® in these phase 1 investigations (conducted in healthy participants). These may serve as pivotal investigations for the manufacturer, which said in its release, “Both studies are designed to enable the application for marketing authorization in the EU and US.” This may be the first indication that Fresenius Kabi seeks to be a player in the US.

Fresenius Kabi does not yet have an approved biosimilar on the European market. It hopes that MSB11455 may propel its fortunes on both sides of the Atlantic.

Food and Drug AdministrationIn its first study, the company reported that its biosimilar “met all primary pharmacokinetic endpoints, [maximum plasma concentration], and area under the curve, as well as the primary pharmacodynamic endpoints of absolute neutrophil count (ANC).” Fresenius Kabi added that there were no meaningful differences in the frequency of adverse events in these healthy volunteers. The second study focused on the biosimilar’s potential for immunogenicity, and this was also determined to be no different between the reference drug and the biosimilar. In addition, neutralizng antibodies were not found.

If Fresenius Kabi proceeds with an application for approval in either market, it will find a good deal of competition for pegfilgrastim biosimilars. In Europe, up to 5 biosimilars may be approved (2 already are). In the US, Mylan’s product is the only one to be approved, but another (Coherus Biosciences) is expecting a decision from the Food and Drug Administration (FDA) in early November. Two others (Sandoz and Apotex) are seeking US drug approval.

In other biosimilar news…The Food and Drug Administration’s Oncology Drug Advisory Committee voted unanimously (16-0) today to recommend Celltrion’s CT-P10 rituximab biosimilar for approval. If the biosimilar is approved by the FDA, it will be marketed by Teva….Mundipharma purchased European biosimilar maker Cinfa, which has a pegfilgrastim that has received a CHMP recommendation for approval in the EU.

Celltrion’s Rituximab Biosimilar Earns Positive Review

The information package released by reviewers for the Food and Drug Administration (FDA) indicates that a positive recommendation for Celltrion’s rituximab biosimilar is likely at the Advisory Committee meeting on October 10.

The members of the Oncologic Drugs Advisory Committee will review the data and hear public comments before voting to recommend that the FDA ultimately approve or reject CT-P10 for the treatment of non-Hodgkin lymphoma. Celltrion did not perform clinical trials for rituximab’s autoimmune indications. However, if the FDA approves CT-P10, it may extrapolate the approval to other indications as well.

The orirituximab biosimilarginal 351(k) application by Celltrion in April 2017 resulted in a complete response letter from the FDA. The rejection for this rituximab biosimilar cited multiple deficiencies, including “clinical, product quality, and facility” problems, as well as clinical study issues from the original submission.

According to the FDA reviewers, “In considering the totality of the evidence, the data submitted by [Celltrion] show that CT-P10 is highly similar to US-licensed Rituxan®, notwithstanding minor differences in clinically inactive compounds, and support a demonstration that there are no clinically meaningful differences between CT-P10 and US-licensed Rituxan in terms of safety, purity, and potency of the product.”

BR&R will cover the Oncology Drug Advisory Committee meeting and provide updates on its decision. If this rituximab biosimilar is eventually approved by the FDA, Teva would market the product in North America, based on a previous partnership agreement.

In other biosimilar news…Merck has inked an exclusive contract to supply its biosimilar infliximab (Renflexis®) with the US Department of Veterans Affairs. According to a report from Pharmaphorum, it will be the only infliximab biosimilar on the VA’s national formulary.

Pfizer Gets FDA’s Green Light on Its Filgrastim Biosimilar

Pfizer's Biosimilar Filgrastim
FILE PHOTO – The Pfizer logo is seen at their world headquarters in Manhattan, New York, U.S., August 1, 2016. REUTERS/Andrew Kelly/File Photo

On July 20, the US Food and Drug Administration (FDA) approved the second biosimilar version of filgrastim. Pfizer’s filgrastim biosimilar is named Nivestym™ (filgrastim-aafi).

The originator product, Amgen’s Neupogen®, has steep competition from two other products (Sandoz’s Zarxio® [filgrastim-sndz] and Teva’s Granix® (tbo-filgrastim]). Granix was approved as a follow-on biologic, before the biosimilar pathway was implemented.

The FDA granted Nivestym the following indications:

  • To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
  • For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
  • To reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).
  • For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
  • For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

Although a launch date was not announced for Pfizer’s filgrastim biosimilar, the company’s press release stated that “Nivestym is expected to be available in the US at a significant discount to the current wholesale acquisition cost (WAC) of Neupogen.”

Rather than competing aggressively for the filgrastim market, Amgen seems to be focusing its efforts on its pegfilgrastim brand, a longer-lasting version. Specifically, it is seeking to move its utilization to the Onpro formulation of Neulasta®. The first biosimilar to pegfilgrastim was approved in June (Mylan and Biocon’s Fulphila™).

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.

FDA Hands Sandoz a Rejection on Its Rituximab Biosimilar

Sandoz announced today that the Food and Drug Administration (FDA) has decided not to approve its biosimilar version of the oncology biosimilar rituximab. The content of the complete response letter was not revealed by Sandoz.

This marks the second rituximab biosimilar rejected by the FDA. Celltrion and Teva’s Truxima™ was also rejected in early April. Both Sandoz’s biosimilar (Rixathon™) and Truxima™ are marketed in Europe and in other parts of the globe. In Europe, Rixathon was approved in June 2017, and Truxima received marketing authorization in February of that year.

Although the European approval for Rixathon was for all of Rituxan/MabThera’s oncology and autoimmune indications, Sandoz was seeking oncology indications only in the US with its rituximab biosimilar.

Sandoz registered early success with filgrastim (Zarxio®) and etanercept (Erelzi®), but was handed a set back from FDA on its biosimilar pegfilgrastim. We’ll report any updates we receive on Sandoz’s progress in resolving the issues in question with rituximab.

Next up is the Allergan/Amgen biosimilar of trastuzumab, which has an FDA PDUFA date of May 28.