Biosimilars in the United States: Current Status and Future Implications

Biosimilars in the United States: Current Status and Future Implications

Disclosures: Hanauer reports associations with a number of device and pharmaceutical companies, including Abbvie, Amgen, Janssen, Novartis and Samsung Bioepis.
June 18, 2021
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Market gears up for biosimilar boom in 2023 as Humira exclusivity draws to a close

Disclosures: Hanauer reports associations with a number of device and pharmaceutical companies, including Abbvie, Amgen, Janssen, Novartis and Samsung Bioepis.
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On May 11, Icelandic-based drug developer Alvotech filed a lawsuit against AbbVie seeking to undo what it alleges is a “minefield” of “invalid” patents surrounding what is arguably the pharma giant’s most prized possession: Humira.

Just 2 weeks prior, AbbVie had filed a lawsuit of its own against Alvotech — currently seeking FDA approval for its Humira (adalimumab) biosimilar AVT02 — accusing Alvotech of patent infringement related to that biosimilar application.

“Because of patent settlements, patients will be able to access lower-cost biosimilar versions of Humira in 2023, approximately 14 years before some of the patents on Humira expire,” Karin Hessler told Healio Rheumatology. Source: Adobe Stock

This volley of dueling legal actions is merely the latest chapter in what has been a familiar story for AbbVie and its blockbuster TNF inhibitor, Humira. AbbVie has so far been successful in fending off the release of any adalimumab biosimilars since the FDA approved the first one, Amgen’s Amjevita (adalimumab-atto), in September 2016. Since then, the FDA has approved five other adalimumab biosimilars, none of which are currently available, as they have, until recently, been tied up in the tale of ongoing patent litigation.

But every story has an ending.

According to Stephen B. Hanauer, MD, Clifford Joseph Barborka professor of medicine at the Northwestern University Feinberg School of Medicine, the developers and patent holders of biosimilar reference products may have begun changing strategy. Rather than fight the release of biosimilars indefinitely through new patents for old drugs — a strategy that saw AbbVie apply for more than 250 U.S. patents for Humira, some of which will not expire until 2037 — Hanauer predicted that they may instead simply fend off competition until they can develop a new, more exclusive drug to market.

Stephen B. Hanauer

“As you know, biosimilars in inflammatory bowel disease are here for infliximab [Remicade; Janssen, Johnson & Johnson], and they have been around, but I think you have to understand the context of how this evolved,” Hanauer told Healio Rheumatology. “What Janssen did with Remicade was protect it until they had their next agent available, which was Stelara [ustekinumab], and now they are marketing Stelara.”

“AbbVie is doing the same thing with Humira, until they get their next JAK inhibitor and IL-23 drug marketed around the same time as these ancillary patents will run out,” he predicted. “At that time, they may shift gears, stop marketing Humira and start marketing their JAK inhibitor and IL-23 inhibitors.”

All Eyes on 2023

In May 2019, AbbVie and Boehringer Ingelheim announced a legal settlement that will allow the latter company to begin selling its own Humira biosimilar, Cyltezo (adalimumab-adbm) in the United States starting July 1, 2023, after paying royalties to AbbVie. At the time, it was the last major legal standoff over Humira, capping a string of lawsuits resulting in eight drug makers settling with AbbVie — all of them agreeing to delay the launch of their Humira biosimilars until at least 2023.

“Patent settlements remain a key tool to expedite patient access to generic and biosimilar medicines,” Karin Hessler, vice president and deputy general counsel for the Association for Accessible Medicines, told Healio Rheumatology. “Because of patent settlements, patients will be able to access lower-cost biosimilar versions of Humira in 2023, approximately 14 years before some of the patents on Humira expire.”

A total of six FDA-approved Humira biosimilars are now cleared for a 2023 release in the U.S. Besides Cyltezo, they include Amjevita, with a settlement-enforced launch date of no earlier than Jan. 31, 2023; Hyrimoz (adalimumab-adaz, Novartis Sandoz), no earlier than Sept. 30, 2023; Hadlima (adalimumab-bwwd, Samsung Bioepis), no earlier than June 30, 2023; Abrilada (adalimumab-afzb, Pfizer), no earlier than Nov. 23, 2023; and Hulio (adalimumab-fkjp, Mylan), no earlier than July 31, 2023.

The bottom line: All eyes are now focused on 2023. Barring any developments in the Alvotech case, that year will mark the official end of AbbVie’s exclusivity over the highest-grossing drug in the world, a product that netted the company $16 billion in U.S. revenue and $19.8 billion in global revenue in 2020 alone.

By then, however, AbbVie may have already moved on.

The very same year as the Boehringer settlement, AbbVie rolled out two new drugs that treat some of the same conditions as Humira. First, the IL-23A inhibitor Skyrizi (risankizumab), the product of a collaboration between AbbVie and Boehringer, saw an April 2019 debut in the U.S. and Europe for patients with plaque psoriasis. The second drug, upadacitinib, a JAK inhibitor sold under the brand name Rinvoq, gained FDA approval for rheumatoid arthritis in August 2019, and received European approval later that December.

In April, AbbVie submitted applications to the FDA and European Medicines Agency for Skyrizi in psoriatic arthritis.

“They call it lifecycle management,” Hanauer said. “They are staging their patent protection to protect them until they have new patented — and more expensive — agents. That is my take on this, anyway.”

According to Hanauer, as greater competition begins to erode Humira’s profits, a process that has already begun in Europe, AbbVie may cease marketing the drug altogether in favor of the newer, more exclusive products.

“Competition is driven by marketing, and as I’ve already mentioned, Janssen is no longer marketing Remicade,” he said. “They are marketing Stelara and will continue to do so until whatever their next agent is comes along. Similarly, AbbVie is poised, with their two new drugs for RA and psoriasis that may be applied to inflammatory bowel disease, and they could shift their marketing strategies to the new marketed agents.”

What about the Alvotech Lawsuit?

Alvotech filed its lawsuit in the U.S. District Court for the Eastern District of Virginia, accusing AbbVie of trying to “overwhelm Alvotech with 60-plus patent claims of questionable validity in order to keep its closest competitor off the market, a tactic it has long used against other competitors.”

In addition, the lawsuit details a series of improper steps allegedly taken by AbbVie to “inflate its patent portfolio,” including patenting inventions that it does not use in Humira’s production, seeking multiple patents on the same invention to purposely cause confusion, acquiring patents through “inequitable conduct,” and seeking Humira patents already in the prior art.

Alvotech is seeking a declaratory judgement that its biosimilar does not infringe on AbbVie’s patients and that said patents are invalid.

According to Alvotech, its biosimilar is equal in strength to Humira’s latest formulation and could save U.S. taxpayers and “the overall health care system” approximately $8 to $10 billion annually.

“Alvotech is paving the way for a free and open adalimumab market, which could save consumers and the health care system up to $10 billion annually,” Alvotech CEO Mark Levick told Healio Rheumatology. “This legal challenge alone serves as a signal for biosimilar developers to utilize the tools at their disposal to bring access and affordability to the forefront.”

“We think that our product can bring savings to the system and to the patients quickly and we have tailored our strategy to ensure this,” he added. “Success for Alvotech would mean a direct and immediate benefit to patients. I think it would also be a shining example for biosimilars. One of our long-term goals at Alvotech is to advocate, not just for us, but for biosimilar development in general. However, if AbbVie continues its actions, unabated, patients will continue to pay the price.”

Asked to respond, a spokesperson for AbbVie released the following statement:

“AbbVie sued Alvotech on April 27, in the Northern District of Illinois on four Humira patents. Recently, Alvotech filed a declaratory judgement action against those same four patents in the Eastern District of Virginia. The Virginia lawsuit is duplicative to the first lawsuit AbbVie filed in Illinois 2 weeks ago. AbbVie’s Humira patents reflect the groundbreaking work of its scientists and clinical teams. Many of the Humira patents have been challenged unsuccessfully in [inter partes review] proceedings. Specifically, the Patent Office has rejected as baseless four separate validity attacks on one of the asserted patents.”

According to Hanauer, it remains unclear what impact the Alvotech lawsuit will have on Humira, its biosimilars and the drug market in general.

“The question is going to be timing,” he said. “They are already planning on the patent ending in 2023, and planning to launch their new drug in 2022 to 2023, so I think this may have only modest impact on Humira per se.”

That said, Hanauer predicted that AbbVie and companies will likely continue to try to profit from Humira, and other reference products, for as long as possible, particularly through discounts and rebates.

“The other thing that’s happened — and you can see this if you follow the process with Remicade — is that Humira may continue to offer substantial discounts and rebates as long as they can squeeze water out of that rock,” he said. “And when they can’t, they will likely continue to shift gears. The patent strategy has been just one strategy, and the other is discounts and rebates, which they may continue to offer.”

A Piece of the Pie

The same month Alvotech announced its lawsuit against AbbVie, the U.S. Supreme Court denied a petition from Novartis’ Sandoz to review an earlier U.S. appeals court ruling in favor of Amgen’s Enbrel (etanercept), and against Sandoz’s biosimilar Erelzi (etanercept-szzs).

This decision effectively blocks the biosimilar from entering the U.S. market, and was a stern reminder that biosimilars still have an uphill road to climb in the United States.

In the earlier ruling, the U.S. Court of Appeals for the Federal Circuit decided that Erelzi infringed on two Enbrel patents related to the active ingredient and the manufacturing process.

“We are pleased that the Supreme Court has declined to hear Sandoz’s appeal in the Enbrel patents case, finally bringing this dispute to an end,” Amgen said in a statement to Healio Rheumatology. “As the trial court and appeals court decisions make plain, upon both the facts and the law, these patents are valid and protect Enbrel until their expiration.”

Hessler, and the Association for Accessible Medicines, was less pleased.

“The Enbrel decision will provide a blueprint for gaming by brand-name drug companies and will make it more difficult for lower-cost biosimilars to come to market in a timely fashion,” Hessler said.

However, while it may be true that patent litigation can delay the introduction of certain biosimilars for years, it’s possible that most reference-product companies have come to the realization that they are, ultimately, inevitable, according to Hanauer.

“I think there will be more and more biosimilars available. You look at Humira, with all of the billions of dollars it makes each year — that pie is not going to disappear when AbbVie comes out with new products,” he said. “It’s going to gradually shrink over time, as patients migrate to ‘safer, more effective medicines.’ But that pie is going to be around for a while.”

For more information:

Stephen B. Hanauer, MD, can be reached at 676 N. St Clair Street – Suite 1400, Chicago IL, 60611; email: shanauer@northwestern.edu.
Karin Hessler can be reached via Rachel Schwartz: rachel.schwartz@accessiblemeds.org.
Mark Levick can be reached via Carolina Gamero: carolina.gamero@berlinrosen.com.
The AbbVie spokesperson can be reached via Frank Benenati: frank.benenati@abbvie.com.