The Biosimilar Mabs Have It: FDA Approves Biosimilars for Adalimumab and Rituxumab

In a busy beginning of the week, the US Food and Drug Administration approved new biosimilars for Humira®and Rituxan®. Samsung Bioepis gained approval for Hadlima™ (adalimumab-bwwd), and Pfizer scored with Ruxience™ (rituximab-pvvr).

HADLIMA

The approval for Hadlima covers the following indications:

  • Rheumatoid arthritis
  • Juvenile idiopathic arthritis
  • Psoriatic arthritis
  • Ankylosing spondylitis
  • Crohn’s disease in adults
  • Ulcerative colitis
  • Plaque psoriasis

Formerly known as SB5, Samsung Bioepis secured Hadlima’s approval on the basis of phase 1 and phase 3 studies in rheumatoid arthritis. The phase 3 investigation included over 500 patients, finding ACR20 responses to be equivalent to that of Humira (at 72%). Immunogenicity profiles for the two agents were also similar through 52 weeks of a switching study.

According to its licensing agreement with Abbvie, manufacturer of Humira, Samsung will not be able to market this agent until end of June 2023. This agent joins Samsung’s two other approved anti-TNF biosimilars, Renflexis (infliximab) and Eticovo (etanercept). Only Renflexis is currently marketed in the US.

RUXIENCE

Pfizer’s newest biosimilar entry, Ruxience, has been approved for a subset of indications of reference product Rituxan, including:

  • Treatment of adult patients with relapsed or refractory, low-grade or  follicular B-cell non-Hodgkin’s lymphoma who are CD20-positive and have failed prior treatments
  • Patients who have nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin’s lymphoma and who are stable after receiving a prior chemotherapy regimen containing cyclophosphamide, vincristine and prednisone
  • Patients with CD20-positive follicular lymphoma who are therapy naïve in combination with chemotherapy or who had responded to previous rituximab therapy
  • Patients with CD20-positive chronic lymphocytic leukemia in combination with fludarabine and cyclophosphamide
  • Granulomatosis with polyangiitis in adult patients in combination with glucocorticoids

The biosimilar does not include Rituxan’s labeled indication for rheumatoid arthritis, similar to the other approved rituximab biosimilar.

The application for Ruxience included the results of the phase 3 clinical trial (REFLECTIONS), which included 394 patients with follicular lymphoma. Compared with the EU-licensed version of rituximab (MabThera®), Ruxience was found to provide equivalent clinical and safety outcomes.

Originally designated PF-05280586, Pfizer has not disclosed when Ruxience will be available. Pfizer signed a settlement with Roche (Genentech) over litigation for a key Rituxan patent, but terms of this agreement were not disclosed. The other FDA-approved biosimilar competitor in this space, Celltrion’s Truxima®, is similarly awaiting launch.

Samsung Bioepis Signals a Settlement With Genentech on Herceptin Biosimilar

And then there was one. Samsung Bioepis and Genentech filed a motion 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 news…Coherus 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).

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.

Second Etanercept Biosimilar Receives FDA Approval

Samsung Bioepis scored another biosimilar approval in the US, as the Food and Drug Administration gave its nod to etanercept-ykro on April 25, 2019. Formerly known as SB4, Samsung Bioepis dubbed this agent Eticovo™. It is the second
Enbrel® biosimilar to to receive US approval.
 
This approval covered all of the reference product’s autoimmune indications, including ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, and rheumatoid arthritis. Clinical studies were performed in patients with moderate-to-severe rheumatoid arthritis, finding that in combination with methotrexate, Eticovo achieved ACR20 scores that were equivalent to that of Enbrel by week 24 (78.1% vs. 80.3%, respectively). Safety and immunogenicity were also comparable with those of the reference agent.

Eticovo has been approved in the EU and Canada, in addition to other parts of the world, under the brand names Benepali and Brenzys. Samsung Bioepis has not announced a launch date in the US for its biosimilar, and this can be delayed for quite some time. Sandoz’s Erelzi® was approved in 2016, but has not yet reached the market because of patent litigation. Amgen, which manufacturers Enbrel, believes its patents extend effectively into 2028, which would provide for nearly 30 years of product exclusivity.


Both Coherus and Lupin have investigational etanercept biosimilars that are in phase 3 trials. Neither has publicly filed for FDA approval to date.

Does Mass Signing of Adalimumab Licensing Deals Add Up to Biosimilar Access Collusion?

As reported by the Center for Biosimilars, a union has filed a class-action lawsuit against AbbVie and the eight prospective biosimilar adalimumab makers who agreed to delay bringing their agents to market through a royalty arrangement.

Only Boehringer Ingelheim remains as a biosimilar maker who has an approved version of adalimumab but who has not signed on with AbbVie. United Food and Commercial Workers Local 1500 has filed the suit with the other manufacturers and AbbVie, claiming that by their actions, they are trying to “divide the market for adalimumab between Europe and the United States,” according to the Center for Biosimilars report.

This is an interesting question. The individual motivations of the first companies to come to agreement with AbbVie (Amgen, then Samsung Bioepis) included an end to interminable patent legislation in the US. They wanted the ability to immediately plan launches in Europe (starting in October 2018). The motivations of most other subsequent signees almost certainly was to not forfeit marketshare in Europe, which was needed to help sustain biosimilar development efforts for the US market. In fact, many of these prospective US manufacturers already had received approval in the EU.

AbbVie’s principal patents on Humira® expired in Europe in October 2018. The last of the principal patents are supposed to expire around 2023 in the US anyway. Was it necessary to arrange serial US launches as demonstrated in this link? Would patent litigation have continued well past the supposed patent expiration date? Knowing AbbVie, this is likely. Their several patents involving adalimumab use to treat individual diseases would provide AbbVie a basis for forging ahead with lawsuits that would have gained them additional billions of dollars in sales while the suits meandered toward conclusion.

Does this mean that access to Humira is accelerated through the signing of the royalty agreements, rather than delayed through acts of collusion? That is difficult to say. Although should the lone holdout—Boehringer Ingelheim—decide that it makes business sense to launch at risk, it could topple the carefully orchestrated structure of the agreements. Amgen believes that it will launch the first adalimumab biosimilar, and experience a few months of exclusivity in the US. At that point, Amgen (and every subsequent adalimumab biosimilar maker) would have to decide whether (1) to do the same or risk losing its advantage, (2) start working towards marketing plan B, or (3) cede the initial marketshare and its billions in revenue and wait it out. If Boehringer obtains its sought after interchangeability designation, that may well speed up the process.

Personally, I find it hard to believe that these individual acts represent premeditated collusion; although the resulting lack of access to the many biosimilar versions may look to others as an orchestrated maneuver.

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

The US Food and Drug Administration (FDA) announced on January 18, 2019 the approval of a new biosimilar version of trastuzumab. Produced by Samsung Bioepis, this agent was dubbed Ontruzant (trastuzumab-dttb).

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®). As with biosimilars other than Herzuma and the reference biologic Herceptin®, this agent is approved for use in the treatment of HER2-overexpressing breast cancer and the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Herzuma is not approved for the latter indication.

As with Renflexis®, Samsung Bioepis’ first FDA-approved biosimilar, Merck will market the product in the US when launched. No launch date has yet been revealed.

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 has an investigational trastuzumab biosimilar, and they too have signed a licensing agreement with Roche.

Will the Government Shutdown Slow Biosimilar Approvals?

The partial federal government shutdown is having specific effects in various important areas of government, but it may not be particularly troubling for FDA user-fee funded activities.

Scott Gottlieb, MD, Commissioner of the FDA, has been especially busy on Twitter, trying to inform the public how the government shut down is affecting FDA operations. He made it clear that the agency is prioritizing its efforts on ensuring consumer safety.

During an extended tweet storm (the past 7 days), he has not directly addressed the effect of the shutdown on current drug approvals. However, since the pharmaceutical companies have paid into the drug approval activities of the Center for Drug Evaluation and Review, there may be sufficient funds and resources for ongoing approval activities. In a tweet last week, Dr. Gottlieb mentioned that FDA was bringing onto staff several new user-fee funded staffers. Yet, in a January 7 tweet, he promised additional information on how the shutdown would affect biosimilars; this has not yet been addressed.

In terms of biosimilars, two trastuzumab drug makers are expecting FDA decisions this quarter (Pfizer and Samsung Bioepis). However, Pfizer’s biosimilar launch is subject to a licensing agreement with Genentech (Roche), the maker of the reference product Herceptin®. Therefore, if there was a short delay in FDA approval, it will not likely have a material effect on availability for prescription. We anticipate that Pfizer will also be hearing from the FDA on its rituximab biosimilar in the second quarter.

This could raise a secondary problem with the shutdown: Will the current furlough cause a chain reaction of delays in the evaluation of existing biologic licensing applications? How long might it take the full FDA staff to catch up, if that is the case?

In a January 13 tweet, Dr. Gottlieb said, “The lapse in funding represents one of the most significant operational challenges in FDA’s recent history. But as an agency, we’re committed to fulfilling our consumer protection mandate, to the best of our abilities, under our current configuration.”

In other biosimilar news… A January 10 story in The Pink Sheet reported that Leah Christl, PhD, Associate Director of Therapeutic Biologics at FDA intends to depart the agency in the near future (a specific date was not given).

An Update on Potential Biosimilars for Bevacizumab

Embroiled in patent litigation, the partnership of Amgen and Allergan have waited for the opportunity to launch Mvasi® since September 2017. During this time, the competition has not been stagnant, with Pfizer moving towards an FDA decision. The next 6 months may prove critical, but when will providers, patients, and payers have access to Avastin® biosimilars? That may be based more on guesstimates than on fact.

Avastin patent litigation

WHAT DO WE KNOW?

(1) Amgen and Allergan received its FDA approval for Mvasi (bevacizumab-awwb) September 17, 2017. The approval covered all of the reference product’s indications. The drug was approved for use by the European Medicines Agency in January 2018.

(2) In court documents filed during its patent battle with Genentech, Amgen had originally stated that it planned to begin marketing Mvasi once the last 8 patents it considered valid expired on December 18, 2018.

(3) Amgen then revised this potential launch date, according to the court filing, saying that it could launch several months earlier, on April 5, 2018.

(4) In either case, the launch has not occurred. According to the Purple Book, Avastin was first approved by the FDA February 26, 2004. That is approximately 15 years, and counting.

(5) The US District Court handling the litigation is expressing impatience with the back and forth between the two parties (read the Judge’s concluding remarks). A trial court date was set for June 2020.

(6) Pfizer completed its phase 3 trial for PF-06439535 in nonsquamous non–small cell lung cancer and filed for FDA approval in August 2018. An FDA decision is expected in the second quarter of this year.

(7) In November 2018, Boehringer Ingelheim completed its phase 3 trial in lung cancer for BI 695502.

(8) Samsung Bioepis completed its phase 3 trial in lung cancer in October 2018 (compared with EU-licensed Avastin).

(9) In addition, Centus Biotherapeutics is scheduled to complete its phase 3 trial in June 2019 as well.

WHAT WE DON’T REALLY KNOW

So much for what we know. Here are some things we know less well.

At a drug pipeline update at the Academy of Managed Care Pharmacy in October 2018, Express Scripts’ Aimee Tharaldson, PharmD, Senior Clinical Consultant—Emerging Therapeutics, offered a projected launch date of July 2019. In an E-mail communication with Biosimilars Review & Report, Dr. Tharaldson clarified that this estimate was based on the anticipated expiration of a key patent on Avastin that month.

Bevacizumab Biosimilars
Aimee Tharaldson, PharmD

When we contacted a senior Amgen executive, he stated that the company declined to discuss potential launch dates.

Goodwin’s Big Molecule Watch, which keeps a close eye on biosimilar-related patent litigation, does not list any ongoing suits between Genentech and Pfizer or Boehringer Ingelheim regarding Avastin (which may be surprising in itself).

We would anticipate that Pfizer will launch as soon as feasible, if they receive an FDA approval by June. Pfizer has an established record of moving their biosimilars quickly to market (e.g., Inflectra® [with Celltrion], Retacrit®, and Nivestym®).

Samsung Bioepis has not yet revealed their plans around an FDA filing for their investigational biosimilar of bevacizumab.

Boehringer had not yet filed a 351(k) application for approval of BI 695502. Comments by Molly Burich, Director, Public Policy: Biosimilars and Pipeline, in our interview last Fall, made it clear that the company is laser focused on bringing its adalimumab biosimilar (Cytelzo®) to market. In fact, this bevacizumab biosimilar was no longer posted on their pipeline at that time.

WHAT WE FOUND OUT

Today, Susan Holz, Director, Communications, Specialty Care, confirmed that the company decided that this agent was not in its strategic plans and it simply allowed the study to be completed. She said, “Boehringer Ingelheim made the decision to terminate all activities related to the BI 695502 program, a biosimilar candidate to Avastin. It is important to note that this decision was not based on any safety or efficacy findings with the investigational medicinal product BI 695502. Boehringer Ingelheim continuously evaluates our business portfolio and assesses potential strategic partnerships to help enhance our pipeline and development capabilities.”

Perhaps several of these unknowns will be resolved by the end of July, and the clouds will lift a bit. I suspect at that time, we’ll be much closer to biosimilar access for this biologic, which racked up $7 billion worldwide in sales in 2017.

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.

Momenta Signs Licensing Deal With Abbvie. Did It Have a Choice?

We previously reported that Momenta Pharmaceuticals reevaluated its biopharmaceutical strategy going forward, deciding to move forward only with its investigational adalimumab and aflibercept biosimilars. Yesterday, Momenta announced that it has joined the long queue of pharmaceutical manufacturers signing a biosimilar licensing deal with Abbvie, which will allow commercialization of M923, its biosimilar to Humira, should it obtain regulatory approval. Momenta’s licensing deal is the fifth one signed by prospective biosimilar marketers in the US.

This agreement was pretty much a no-brainer for Momenta. The company did not have the stomach for attempting either an extended patent fight or an at-risk launch. However, the biosimilar licensing agreement only allows Momenta to market its adalimumab biosimilar in the US after December 2023, which will make it the fifth Humira biosimilar that will launch under the licensing agreements (Table). The main patents for Humira have expired in Europe, and these agreements have generally allowed the European launches to occur as of October 16 of this year.

Of the manufacturers signing biosimilar licensing deals with Abbvie , only Amgen and Sandoz have earned FDA approval for Amjevita® and Hyrimoz®, respectively. And Boehringer Ingelheim is still duking out patent litigation with Abbvie in the courts over its approved biosimilar agent Cytelzo®, for which it hopes to receive an interchangeability designation. The second through fifth agents entering the fight will be likely pounding away at subsequently smaller slices of revenue.

Perhaps the most frustrating part is that Abbvie is running a lucrative game; it will collect royalties from all of these manufacturers in 2023 and beyond, which will help offset declining marketshare from its biggest revenue contributor.

 

In Abbvie’s Web: Who Has Signed Licensing Agreements for Biosimilar Adalimumab?

Company/Partner

Drug Name

Launch Date

Amgen

Amjevita*

January 2023

Samsung Bioepis/Merck

SB5

June 2023

Mylan/Fujifilm Kyowa Kirin Biologics

Hulio

August 2023

Sandoz

Hyrimoz*

September 2023

Momenta

M923

December 2023

*Received FDA Approval.

Note: This post was revised and corrected, November 8, 2018.