History Repeating: Will US Stelara Settlements Follow Humira’s Lead?

Until recently, biosimilars industry analysts had predicted that Johnson & Johnson’s immunology blockbuster Stelara (ustekinumab) could face US competition before the end of 2023, with the September expiry of a key patent protecting the top-selling brand.

However, recent developments have now upset those expectations, with a pair of separate settlements over ustekinumab biosimilars suggesting that the industry could be in for a rerun of the Humira (adalimumab) saga that saw multiple competitors individually all settle with originator AbbVie, setting up a cascade of date-certain biosimilar launches beginning in January and running throughout this year.

The latest development on Stelara has seen biosimilar developer Alvotech and its US commercialization partner Teva together settle litigation with J&J in exchange for a launch date for their version of ustekinumab that will be “no later than 21 February 2025,” assuming US Food and Drug Administration approval (see sidebar).

This followed an earlier settlement between Amgen and the originator that provided a launch date of 1 January 2025 for Amgen’s own biosimilar. (Also see "Stelara Settlement Gives Amgen US Ustekinumab Entry Date" - Generics Bulletin, 24 May, 2023.)

Amgen had faced a lawsuit alleging infringement not only of longstanding ustekinumab compound patent 6,902,734, but also of US patent 10,961,307, shielding methods of treating ulcerative colitis, that issued in March 2021. (Also see "Amgen Sued On US Stelara Biosimilar After Providing May 2023 Intent" - Generics Bulletin, 1 Dec, 2022.)

“We will continue to defend the intellectual property associated with our medicines to protect our ability to innovate and develop life-changing therapies for patients,” J&J told Generics Bulletin, insisting that the Amgen settlement “supports our mission to ensure continuity of care for patients who are being treated with Stelara and those who can benefit from it in the future.”

Humira Settlements Were Criticized For Delaying Entry

The parallels between Stelara and Humira are clear. Both are hugely successful immunology biologic brands that have for years featured among the world’s top-selling pharmaceuticals. And both are protected by a host of US patents.

As such, settlement deals around these products are valuable to both the originator – potentially extending a lucrative monopoly – as well as to biosimilar developers that will benefit from a date-certain launch as well as relief from the cost and uncertainty attached to patent litigation.

For Humira – the largest single loss-of-exclusivity opportunity ever for the off-patent industry (see sidebar) – momentum started to build on settlements when originator AbbVie struck a deal with Amgen back in 2017 allowing it to launch adalimumab in the US at the beginning of 2023.

A host of subsequent settlements fell into place with other biosimilar developers, although none was able to match or improve upon the January launch date gained by Amgen, paving the way for the company to introduce its Amjevita (adalimumab-atto) version early this year with a six-month head start on other biosimilar rivals. (Also see "Amgen Delivers On Launch Of First US Humira Rival – At A 55% Discount" - Generics Bulletin, 31 Jan, 2023.)

While this situation may have been convenient for both AbbVie and Amgen – and equally, those developers that are among the second wave of biosimilars that are set to enter the US adalimumab market at the start of July may be happy with the terms of their settlements – the Humira settlements were not without their share of controversy.

According to a US House of Representatives’ committee in 2020, AbbVie ultimately delayed biosimilar competition to Humira “for far longer than warranted by its own internal evaluations of the strength of its patent portfolio, which anticipated biosimilar entry no later than 2017.”

“By delaying biosimilar entry,” the representatives insisted, “AbbVie extracted billions of dollars from the US healthcare system.” In particular, they said, “we question whether the 2023 biosimilar entry dates agreed to between AbbVie and its competitors were truly negotiated compromises reflecting the odds of the parties’ success in patent litigation.” (Also see "FTC Urged To Investigate AbbVie’s IP Strategy On Humira" - Generics Bulletin, 20 May, 2021.)

Legal attacks were also launched over the settlements, with some critics pointing to a stark divide between the continuing lack of biosimilar competition in the US market and earlier market entry for Humira biosimilars in Europe, which occurred in late 2018. (Also see "AbbVie's 'Unjustified' Humira Settlements Divide Market, Claims Class Action" - Generics Bulletin, 26 Mar, 2019.)

However, ultimately the attempts to overturn the US settlements proved unsuccessful – and this year’s succession of adalimumab biosimilar launches are playing out according to their terms. (Also see "Biosimilar Humira Settlements Stand Firm In US" - Generics Bulletin, 10 Jun, 2020.)

What Next For Ustekinumab Developers?

While it may be too early to predict exactly how biosimilar competition to Stelara will play out in the US, the parallels with Humira are clear.

Ustekinumab first-filer Amgen was also the first to settle, reaching an agreement with J&J that offers a 1 January 2025 launch date; subsequent filer and settler Alvotech/Teva has gained a slightly later market entry date; and plenty of other developers are waiting in the wings, with a host of ustekinumab filings – and legal battles that could end in settlements – potentially set to follow.

However, analysts should perhaps be wary of attaching too much significance to the specific dates cited by the settling parties so far, as the history of Humira settlements demonstrates that these aspects can evolve.

Both Amgen’s statement and Teva and Alvotech’s announcement on their respective ustekinumab settlements used the language “no later than” to refer to their 2025 launch dates, leaving open the possibility of an earlier launch in both cases.

As the various Humira settlements were announced, they featured a range of dates throughout 2023 – but certain launch dates for early settlers eventually shifted to slightly earlier in the year as subsequent settlers reached agreements with AbbVie, ultimately leading to a glut of second-wave adalimumab launches that will come around the start of July.

Given the opaque nature of these settlements and the lack of visibility over their exact terms, it is possible that a similar shift could occur with Stelara.

In a 12 June note commenting on the Amgen and Teva-Alvotech settlements, Wells Fargo said “we see these settlements likely delaying US Stelara loss of exclusivity from September 2023 into 2024 and possibly later.”

A Major Target With Many Developers In The Race

One thing that seems certain is that ustekinumab will be another highly competitive market for US biosimilars. While its value may not quite match that of Humira, Stelara’s global turnover – which was ahead by 6.5% to $9.7bn in 2022, of which $6.4bn came from the US alone, representing US growth of 7.6% – makes it a major target for biosimilar developers.

Other firms looking to eventually launch ustekinumab biosimilars include Samsung Bioepis (Also see "Samsung Bioepis Reveals Ustekinumab Progress" - Generics Bulletin, 23 Mar, 2023.), as well as Formycon which has a global licensing partnership for its candidate with Fresenius Kabi. (Also see "Fresenius Kabi And Formycon Ally On Stelara Rival" - Generics Bulletin, 2 Feb, 2023.)

Celltrion has announced positive trial results for its CT-P43 proposed ustekinumab candidate, while Dong-A/Meiji Seika Pharma, BioFactura, and NeuClone are also developing Stelara biosimilars. (Also see "Celltrion Keeps Pace With Ustekinumab Rivals" - Generics Bulletin, 22 Dec, 2020.)

Biocon has also announced ustekinumab development plans. (Also see "Biocon Joins Fray For Denosumab, Ustekinumab Biosimilars" - Generics Bulletin, 6 May, 2022.) And Hikma has US rights to Bio-Thera’s version of ustekinumab. (Also see "Hikma’s US Biosimilars Ambitions Begin With $150m Ustekinumab Deal" - Generics Bulletin, 27 Aug, 2021.)

Reviewing the competition, Wells Fargo said it had concluded that “none will likely be ready to launch in 2023,” but that “Celltrion may be leading this remaining pack, with a launch possible in 2024,” based on previous comments by the Korean firm.

With so many other players in the race to compete with Stelara – and all of them yet to publicly disclose biosimilar filings in the US, let alone litigate and settle with J&J – it remains to be seen how US competition on ustekinumab will play out. However, from this early perspective it seems possible that Humira’s sequence of settlements could well provide a playbook for its fellow blockbuster immunology brand to follow.