The Potential Effect of Amgen’s Launch on Biosimilar Licensing Deals

Imagine this interesting and perhaps very real-life scenario. It could have several implications for the present biosimilar marketing picture.

Biosimilar licensing deals

A reference manufacturer, we’ll call them Arby, signs multiple licensing deals with biosimilar manufacturers, to launch their products sequentially in 2025. The licensing deals all conclude outstanding patent litigation between the parties. But one biosimilar manufacturer doesn’t sign. We’ll call them Brooklyn Industries (BI for short).

Despite Arby’s contention that its patents on the reference product Yultira are valid until the year 2045, BI decides to launch at risk in July 2020. According to the phased launch schedule, another manufacturer, Thousand Oaks, was supposed to have the first biosimilar available on the market, with a three-month jump on the other seven competitors. Does that really give BI a five-year start over all of its competitors? And what if BI had an interchangeable biosimilar designation? Would that enable them to lock up the marketshare?

Biosimilar Licensing Deals: The Acceleration Effect

This scenario is actually playing out today with Amgen’s launch announcement of its trastuzumab and bevacizumab biosimilars (Kanjinti® and Mvasi®, respectively). Other manufacturers, including Pfizer, Samsung Bioepis, Mylan/Biocon, Teva/Celltrion have licensing agreements in place with Genentech (a subsidiary of Roche) for launch of their Herceptin® biosimilars. Only Amgen’s Mvasi and Pfizer’s Zirabev® are approved (so far) to compete for the bevacizumab business. The details of the licensing deals signed by Roche have not been released publicly, so we do not know when the first “authorized” biosimilars were supposed to launch. Conjecture abounded that it would be in 2019, nevertheless.

How does Amgen’s Kanjinti launch affect the licensing agreements that were signed with Roche? Does it mean that Amgen gets a substantial head start on the competition? Do the licensing contracts consider this possibility?

According to Kevin M. Nelson, JD, at the Chicago-based law firm Schiff Hardin, this scenario is considered in a typical pharmaceutical licensing arrangement. “Typically, settlement agreements in the pharma space include what are called acceleration clauses. Such clauses will allow an agreed-upon launch date to be accelerated to an earlier date in the event the patent or patents are invalidated or found not infringed in another litigation, or if a competing product or authorized competing product comes on the market before that agreed-upon date.”

Biosimilar licensing deals
Kevin M. Nelson, JD

He added that these acceleration provisions “can come in a variety of flavors from a change in royalty rate or structure, a requirement to leave the market if the ‘unauthorized entrant’ leaves the market, or perhaps agreed damages.” 

Accelerating Clauses Are One Thing. Accelerating Launch Is Another Matter

The fact that Amgen has announced its immediate launch may present more pragmatic problems for the other manufacturers, Mr. Nelson pointed out. Let’s say that you were a member of the Mylan/Biocon team. Your product was approved more than 18 months ago (the first one approved). Let’s also say that your licensing agreement with Genentech allowed you to launch after November 1 (a purely speculative, arbitrary date). Finally, assume that your licensing agreement was generous: it allowed you to launch as soon as possible after another competitor jumped the starter’s gun. Is it feasible to launch immediately, perhaps four months early?

“The biosimilar companies cannot just fire up the machines and have product ready tomorrow,” stated Mr. Nelson. There are all of the logistical issues surrounding a launch that must be considered: “Manufacturing, packaging, sales, and distribution all take time,” he said. “And you don’t want inventory to go bad—especially not this type as it is expensive. They may have some reserve lots or made small batches just in case, so we could see a trickle into the market.”

Remember, also, that payer and health system contracts are not arrived at overnight. Even if the Mylan/Biocon team did have lots available for shipment, they might not have places in the US to ship, other than to a group purchasing organization or distributor’s warehouse.

Typically, payers will not cover pharmaceutical agents outside of medical exceptions before the Pharmacy & Therapeutics Committee review, and this can happen anytime between 60 days and 9 months of the launch. And this is not a product that will revolutionize therapy or immediately fill an unmet clinical need. Only large discounts can move the needle here, and establish a contract quickly. Therefore, the anticipated short window of opportunity that Amgen may have in launching Kanjinti may get a little shorter but perhaps by not much.

When I mentioned the Arby, er Abbvie, scenario, Mr. Nelson agreed that it would be an entirely different ballgame. Had Boehringer Ingelheim decided to enter the market (as an interchangeable or not), their launch “would have caused absolute chaos.” Imagine trying to pull forward launch date plans of seven manufacturers by three years!

Amgen/Allergan Partners Announce Launches of Herceptin and Avastin Biosimilars

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 reach commercialization.

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 contracts.

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 April 2018.

On the trastuzumab side, Amgen/Allergan’s product was the most recently approved biosimilar (in June 2019).

In their 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.”

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.

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.