麻豆传媒

PHILADELPHIA -- Pfizer has made the case for gaining the coveted "interchangeability" status for its adalimumab biosimilar (Abrilada), a study presented here suggested.

A pivotal trial involving nearly 445 rheumatoid arthritis patients ticked all the boxes required by the FDA for equivalence to the original adalimumab (Humira) in pharmacokinetics, immunogenicity, and safety, according to Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas.

At the American College of Rheumatology's annual meeting here, he presented a series of tables and graphs documenting that Pfizer's biosimilar, technically known as adalimumab-afzb, was essentially identical to AbbVie's original version for every pharmacokinetic parameter analyzed: maximum and trough concentrations, average concentration, time to reach maximum concentration, total drug exposure over time, and others.

Immunogenicity markers were also highly similar, Fleischmann reported, as were adverse event profiles in the study that compared patients staying on original adalimumab with another set who switched back and forth between the two versions.

He said he believes this to be the first interchangeability study of an adalimumab biosimilar to be conducted in rheumatoid arthritis patients. Another adalimumab biosimilar developed by Boehringer Ingelheim, trade-named Cyltezo, gained interchangeability status last October, but its trial was . It nevertheless is approved for the same wide range of indications as the , ranging from rheumatoid arthritis to inflammatory bowel disease (nine in all), and the same is likely to be true of the Pfizer product if approved.

calls on sponsors to demonstrate "that the proposed interchangeable can be expected to produce the same clinical result as the reference product in any given patient; and that the risk in terms of safety or diminished efficacy of alternating or switching between the proposed interchangeable and the reference product is not greater than the risk of using the reference product without such alternation or switch."

However, this does not require that sponsors conduct a new clinical efficacy study. In Pfizer's case and every other thus far, the proposed interchangeable product has already been approved as a biosimilar under a process that included such a study. With that already in hand, only data on pharmacokinetics, immunogenicity, and safety involved with switching between versions is needed to secure interchangeability.

The FDA is for interchangeability status, with a decision expected by year end. Success would likely make it the third interchangeable biosimilar to win approval in the U.S.; besides Boehringer's adalimumab, a biosimilar for the anti-angiogenesis drug ranibizumab got the okay for interchangeability in August.

In the trial reported by Fleischmann, 445 patients were randomized to two arms: one in which patients received the original adalimumab for 36 weeks, the other involving a switching regimen. Patients took their assigned agents every two weeks at 40 mg per injection. All patients received original adalimumab for 10 weeks, then the two arms diverged. In the switching arm, patients were moved to the Pfizer product for 6 weeks, back to the original version for 6 weeks, and then the biosimilar again for the final 10 weeks. Pharmacokinetic studies were conducted during the treatment period's final 2 weeks, after the penultimate dosing. Safety data were collected for 4 additional weeks after the last dose.

Only very slight differences were seen in the study's many pharmacokinetic parameters, which Fleischmann reported as group averages. (The FDA does not interpret its call to demonstrate equivalence in "any given patient" to require such demonstration in every study participant.) For example, maximal concentrations averaged 8.21 μg/mL in the switching arm versus 8.00 for those taking original adalimumab throughout. A graph of maximal concentrations over seven samplings during the 2-week pharmacokinetic study showed the two lines almost superimposed.

Both versions were also associated with nearly the same levels of anti-drug antibodies, which were seen in just under half of participants at week 32.

The only finding that looked like a substantial difference was in overall adverse events. These were seen in 38.5% of the switching group versus 29.0% of the non-switching participants. Fleischmann dismissed it as unimportant, however, noting that serious treatment-emergent events were less common in the switching group (three cases versus eight in the non-switch group) and discontinuations due to adverse events were nearly identical (eight and nine, respectively).

Following his presentation, an audience member asked whether the patient population really matters in these studies, given that, under the FDA's approval standards, biosimilars so far do seem to be pretty much identical to the original versions. Proof of efficacy in rheumatoid arthritis should be transferable to the other indications for which adalimumab is approved, the questioner suggested.

Fleischmann readily agreed, despite having earlier stressed that the current study is the first for interchangeability to be conducted in rheumatoid arthritis patients. "If you have a biosimilar that acts exactly the same as the bio-original [in rheumatoid arthritis], why would you not expect it to be as effective in Crohn's disease? Why would you not expect it in ankylosing spondylitis? ... If you do a study in one disease, you should expect the same results in another disease," he said.

If approved for interchangeability, Pfizer expects its product to hit the market in July 2023, as will the Boehringer version -- both companies negotiated the launch date with AbbVie to resolve potential patent infringement.

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