Humira Biosimilar Interchangeability: The Race Begins

Boehringer Ingelheim announcement is first public disclosure of interchangeability trial since US FDA draft guidance was released.

Is pink interchangeable with yellow?

Boehringer Ingelheim GMBH became the first company to publicly disclose the start of a biosimilar interchangeability trial since the US FDA issued draft guidance on the subject, displaying a fair bit of confidence in a product the agency hasn't even approved yet.

BI said July 27 that the first patient has been enrolled in its VOLTAIRE-X trial, which is designed to determine whether its proposed biosimilar, BI 695501, is interchangeable with the US-licensed version of AbbVie Inc.'s Humira (adalimumab). BI said in a statement that the study is the first in the US to investigate interchangeability with a Humira biosimilar candidate.

VOLTAIRE-X will compare the pharmacokinetics and clinical outcomes of moderate to severe plaque psoriasis patients receiving Humira continuously and those that switch repeatedly between Humira and BI 695501. It also will assess safety, immunogenicity and efficacy.

An interchangeability designation for Humira biosimilars may be especially attractive because the product is self-administered by patients and would be distributed at pharmacies, where substitution could be driven.

BI anticipates enrolling 240 patients for the 58-week trial. Completion is expected in July 2019.

The primary outcome measures are area under the adalimumab plasma concentration-time curve over the dosing interval of week 30-32 and maximum observed adalimumab plasma concentration during the dosing interval of week 30-32.

BI would not disclose the number of switches between the biosimilar and reference product that are planned. The company added that it was confident the trial will meet "the rigorous standards for an interchangeability designation, based on the latest FDA guidance for industry as well as our own expertise."

FDA draft guidance on interchangeability released in January recommends at least three transitions between the biosimilar and reference product. (Also see "Biosimilar Interchangeability: How To Design A Multiple-Switch Study" - Pink Sheet, 18 Jan, 2017.) The guidance also states that sponsors must use a US-licensed reference product in the switching study. (Also see "Make Interchangeability Great Again: Biosimilar Switching Studies Need US Comparators" - Pink Sheet, 18 Jan, 2017.)

BI told the Pink Sheet that it is "not in a position to disclose information about the timing" of its interchangeability filing.

To date no interchangeability application filings have been disclosed by sponsors.

Sandoz Inc., which obtained FDA's first biosimilar approval for Zarxio (filgrastim-sndz), a biosimilar of Amgen's Neupogen (filgrastim) and later obtained approval for Erelzi (etanercept-szzs), a biosimilar of Amgen's Enbrel (etanercept), conducted clinical studies with multiple switches between the reference and biosimilar as part of its BLA.

Sandoz would not comment on whether it planned to pursue interchangeability determinations for the products. But it was thought that the studies were structured to eventually support such an application, even though they were conducted before FDA issued its draft guidance. (Also see "Sandoz's Multi-Switch Biosimilar Trials: A View To Interchangeability?" - Pink Sheet, 21 Jul, 2016.)

Trial Starts With Product Approval Pending

Interestingly, BI's announcement of the trial came before its proposed biosimilar has been approved by FDA, although the move appears to indicate BI is expecting the agency eventually will rule favorably. If the agency thought the product needed formulation changes, for example, the interchangeability study could be rendered useless since would have be conducted with obsolete product.

FDA's goal for a decision on the BI 695501 biosimilar application is in September. (Also see "Pending Biosimilars" - Pink Sheet, 13 Feb, 2017.)

No advisory committee meeting for the product has been scheduled to date, but FDA practice suggests it may not be necessary because the agency already has approved a Humira biosimilar – Amgen Inc.'s Amjevita (adalimumab-atto) in September 2016.

FDA approved Samsung Bioepis Co. Ltd.'s Renflexis (infliximab-abda), which was the second approved biosimilar of Janssen Biotech Inc.'s Remicade (infliximab), without convening an advisory committee meeting. (Also see "Samsung’s Renflexis: Second US Biosimilar To Janssen’s Remicade, With A Few Firsts" - Pink Sheet, 21 Apr, 2017.)

Differing Viewpoints On Needing Interchangeability

With several Humira biosimilars under development, and one already approved by FDA, interchangeability may prove to be a important strategy to distinguish the products in the marketplace.

Humira, a TNF-inhibitor, is a biologic with significant commercial potential as a biosimilar: it is taken chronically and distributed through the pharmacy, making it a good candidate for substitution.

At least one other company appears interested in exploring interchangeability for a Humira biosimilar.

Oncobiologics Inc. Chairman, CEO and President Pankaj Mohan said in a recent interview with the Pink Sheet that the company asked FDA for guidance on seeking interchangeability for a Humira biosimilar in June 2016, which was several months before FDA released its guidance.

Pfizer Inc., which also has a Humira biosimilar currently in development, told the Pink Sheet that it does not comment on future development and commercialization strategies.

But at the same time, it also may have hinted at its thoughts on the necessity of interchangeability. The company said "approval of a biosimilar allows for physician-mediated switching. Such physician-directed switch does not require an interchangeability designation."

Several other companies with Humira biosimilars in the pipeline would not reveal plans, including Amgen, Momenta Pharmaceuticals Inc. and Coherus BioSciences Inc.

Momenta has previously argued that interchangeability ultimately may not be important, given the pricing pressure that biosimilars are expected to create. (Also see "Biosimilar Interchangeability May Be Losing Luster As Approval Goal" - Pink Sheet, 13 Sep, 2016.)

There are about 20 Humira biosimilars now in development around the world and may be affecting the market soon. Humira sales are expected to peak at $18.7bn in 2018 before beginning to decline, weighed down by competition from other branded products and biosimilars. (Also see "Humira's Inevitable Decline: What's Waiting In The Wings?" - Scrip, 8 Mar, 2017.)

Interchangeability As Sales Point

Interchangeability may be an integral part of the commercial strategy for Humira competitors.

While pharmacy substitution is possible with the determination, there is a question of whether some physicians could be swayed erroneously to believe that an interchangeable biologic is "better" than a biosimilar, said Gillian Woollett, senior VP at Avalere Health.

The designation also could serve as a hedge against a potential backlash over so-called non-medical switching, a worry of some patient groups and other stakeholders. (Also see "Biosimilar Non-Medical Switching: Advocacy Groups, FDA Advisors Push For Action" - Pink Sheet, 14 Jul, 2016.)

AbbVie also has argued to FDA that payers could decide to switch patients to Humira biosimilars without a medical reason even though the products are not ruled interchangeable. (Also see "Lobbying FDA: AbbVie Questions Humira Biosimilars In Private Meeting" - Pink Sheet, 5 Aug, 2016.)