For the second day in a row, the FDA's Arthritis Advisory Committee (AAC) voted unanimously Wednesday to support approval of a biosimilar with extrapolated indications to treat several autoimmune diseases.

In what panelists described as an easier decision than the one they faced Tuesday, the committee voted 20-0 in support of Sandoz Inc.'s GP2015 as a biosimilar to Amgen Inc.'s Enbrel (etanercept). The follow-on was tested in plaque psoriasis against the EU-licensed version of Enbrel, with a bridging study to the U.S. version.

The FDA will likely follow the committee's recommendation, as it raised no concerns about the biosimilar and tried to assuage any lingering committee concerns about biosimilars and extrapolation in general.

Sandoz, part of Basel, Switzerland-based Novartis AG, is seeking a label that would reflect all the approved indications for Enbrel: rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis, as well as plaque psoriasis.

The vote puts Amgen, of Thousand Oaks, Calif., on both the defense and the offense. Looking to add biosimilars to its biologics lineup, Amgen received the AAC's support Tuesday for its first biosimilar candidate, a follow-on to Abbvie Inc.'s Humira (adalimumab). (See BioWorld Today, July 13, 2016.)

Like Enbrel, Humira is a blockbuster TNF inhibitor, a class of drugs that has revolutionized the rheumatology field. In February, the committee voted for approval of another TNF-blocking biosimilar, Celltrion Inc.'s follow-on to Remicade (infliximab, Janssen Biotech Inc.), which will be marketed as Inflectra in the U.S. by Pfizer Inc. (See BioWorld Today, Feb. 10, 2016.)

In addition to the arthritis and psoriasis indications, both Humira and Remicade are approved to treat inflammatory bowel diseases (IBDs) such as Crohn's. Extrapolating those indications when the biosimilar candidates were tested for psoriasis and RA gave some AAC panelists pause, given the differences in the indications.

The committee didn't have that struggle with GP2015, as Enbrel has no IBD indications. However, after voting in support of the Sandoz drug, panelist Erica Brittain, an NIH deputy branch chief and statistician, said she will always be uncomfortable with extrapolating any indications. She would like to see a robust, randomized, placebo-controlled trial for every indication, even though she knows that undermines the idea of biosimilars.

GROWING GRASP

Aside from Brittain's discomfort, the discussion and outcome of this week's meetings showed the AAC's growing grasp of the concepts driving biosimilar development. After listening to the committee grappling with those concepts Tuesday, Sandoz's Mark McCamish said he revised his presentation of GP2015 to help the panelists better understand the basics of biosimilar development.

Biosimilars "turn the world upside down" in terms of drug development, he explained in what amounted to a biosimilars 101 tutorial. Instead of rushing through analytics and nonclinical exercises to prove a concept in a massive clinical trial effort, biosimilar sponsors must build a strong structural and functional analytics foundation based on understanding the reference biologic and its variations over time.

McCamish also pointed out that extrapolation is from one molecule to another – not from one disease to another. If a follow-on is highly similar to the reference biologic, is essentially the same in clinical results and will function the same, it is essentially like having the original biologic being manufactured by a different company, he said.

While the schooling seemed to put panelists' minds at ease, as did the results of a trial that switched patients three times between Enbrel and GP2015, a few still had reservations. Noting the complexity of etanercept, William Hancock, a bioanalytical chemistry professor at Northeastern University, recommended a long-term quality program to ensure the biosimilar stays within specifications over time. FDA staff reminded him that even the innovator biologic can vary from batch to batch.

David Margolis, a professor of dermatology and epidemiology at the University of Pennsylvania School of Medicine, encouraged the use of postmarketing studies to confirm extrapolation and the long-term use of biosimilars.

While biosimilar sponsors are responsible for the same adverse event reporting as other drug manufacturers, the FDA does not require postmarketing studies for the follow-ons. Its stance is that if a molecule demonstrates biosimilarity, it will be as safe and effective as the reference product.

Postmarketing studies aren't needed in most countries with biosimilar regulatory paths, but a few countries have stringent pharmacovigilance requirements. For instance, when Japan created its path, it required sponsors to submit biweekly reports for every patient taking a biosimilar in the first six months following its approval.

Although the AAC was much more comfortable with biosimilars by the end of Wednesday's meeting, the panelists noted how much work needs to be done to educate the public. And like many of the patients and doctors speaking during the public hearing session, they worried about payers forcing nonmedical switching of biosimilars on patients who are stable on their current biologic. To combat that, biosimilars should clearly state on their labels that they are not interchangeables and the FDA must release guidance on interchangeability, panelists said.

The FDA's Leah Christl assured the committee that the FDA is determined to get the interchangeability guidance out. She wouldn't commit to a time frame, but she said it is a priority.

"We're all going to wait patiently" for that guidance, said David Solomon, the AAC acting chairman and a professor at Harvard Medical School.

WAITING FOR THE LAUNCH

The BsUFA date for GP2015 is early next month. If the FDA approves both it and Amgen's Humira biosimilar, the number of U.S.-licensed biosimilars would double, but the number actually marketed might not change for a few years.

So far, Sandoz's Zarxio, a biosimilar to Amgen's Neupogen (filgrastim), is the only biosimilar that's available in the U.S. Unless New York-based Pfizer chances an at-risk launch, Inflectra won't hit the market until a patent dispute is resolved. Last year, Janssen, a unit of Johnson & Johnson, of New Brunswick, N.J., sued Celltrion for patent infringement and has repeatedly vowed that it will robustly defend its remaining U.S. patent on Remicade. That patent won't expire until late 2018. The two companies are still hashing out the infringement litigation. (See BioWorld Today, April 6, 2016.)

Patents also could delay the launches of the Enbrel and Humira biosimilars, even though both Amgen and Sandoz have designed around the formulation patents of the reference products. Humira's U.S. composition-of-matter patent will expire at the end of the year, and a number of other patents will start expiring in 2022, including the main rheumatoid arthritis dosing patent, Jefferies equity analyst Eun Yang reported Tuesday.

Abbvie officials don't expect to see direct biosimilar competition until late 2018, when they said some of Humira's U.S. patents end. (See BioWorld Today, July 12, 2016.)

Although the FDA licensed Enbrel in 1998, a U.S. patent extension could protect the biologic for 12 more years. Meanwhile, the EMA approved the EU's first Enbrel biosimilar in January, giving the nod to Samsung Bioepis Co. Ltd.'s Benepali, which was launched last year in South Korea as Brenzys. (See BioWorld Today, Jan. 20, 2016.)