The Implications of Celltrion’s Development of a Subcutaneous Infliximab

Celltrion received approval today in the European Union (EU) for its subcutaneous (SC or SubQ) form of infliximab (Remsima®, marketed as Inflectra® in the US) for treating rheumatoid arthritis. Currently, infliximab is available only as an office-based infusion.

Infliximab SC

The very interesting aspect to this is that the current 351(k) regulatory pathway does not provide guidance on the possibility of a new formulation of an existing biosimilar drug. In the EU, the subcutaneous formulation is not treated as a biosimilar, because such a form is not available as a reference product. A consequence of this is that regulatory extrapolation is not possible; Celltrion will likely need clinical studies for any indications it seeks, like a regular 351(a) submission. This would differ from a pegfilgrastim biosimilar seeking to gain approval for an on-body injector form similar to Neulasta OnPro® (the reference product).

An SC form of infliximab could be a very valuable niche in the US, as payers can place this in the pharmacy benefit as a self-administered injectable (to the chagrin of providers who were earning administration fees, at least). It thus could be managed through the additional pharmacy benefit tools at hand, and could serve as a preferred version of the medication. It should be noted that the dosage of the SC form is slightly different than the infusible form.

This scenario once again raises the weird and unwieldy specter of the nature of biosimilarity. What is biosimilar to what? As a 351(a) submission (if Celltrion takes that route in the US), a federal agency may (or may not) consider Inflectra SC to be clinically equivalent to Remicade®. It certainly couldn’t be interchangeable though, based on current regulatory guidelines and despite the NOR-SWITCH studies conducted with the infusible formulation. Will Celltrion go to lengths to prove that Inflectra SubQ is biosimilar or equivalent to Inflectra? It will almost certainly have to undergo this exercise if the manufacturer expects providers or payers to switch patients to it.

In clinical studies of the SC version in patients with RA, those taking the SC version experienced even greater increases in ACR 20, 50, and 70 improvements than on the IV form alone. I suppose that might qualify it for the “bio-better” label. (http://www.celltrion.com/ko-kr/business/newdrug)

From a pharmaceutical sales standpoint, this also raises a couple of additional questions: If Celltrion charges a premium for this agent over the IV form, will payers acquiesce to gain pharmacy benefit control over the product? Will patients prefer the SC formulation? Will plans and insurers keep both formulations available for patients who cannot self-inject? Or will they encourage initial use of the IV form before moving to an SC version (will this become ACR standard of care?)

Will Celltrion spend the money needed to fund phase 3 trials for each major indication (including Crohn’s disease [adult and pediatric], ulcerative colitis, RA, plaque psoriasis, ankylosing spondylitis, psoriatic arthritis)? Their study in Crohn’s disese is just underway.

From a payer’s perspective, will health plans and insurers allow these off-label indications, if the cost is demonstrably lower than the IV version? In other words, payers may extrapolate on their own if they find that the pricing and pharmacy benefit management of infliximab is worthwhile.

As can be seen, the effort to produce an SC version of infliximab raises far more questions than can be answered today. The difficulty in successfully introducing the SC must be high, or one might have thought Janssen wouldn’t have missed on the opportunity to gain another patent many years ago!

Large European Society Lends Its Support to Switching

In a recent statement published in the Journal of Crohn’s and Colitis, the European Crohn’s and Colitis Organization (ECCO) announced its support for switching from an originator product to a biosimilar in patients with inflammatory bowel disease  (IBD).

In its position statement, ECCO asserts that switching from the originator to a biosimilar in patients with IBD is acceptable if it is in line with national recommendations and has been discussed among the physician, nurse, pharmacist, and patient. This view, which represents a change from ECCO’s previous position, is based on the clinical experience gained from investigational studies and postmarketing trials using the biosimilar version of infliximab.

Lead author and President Elect of ECCO, Silvio Danese, MD, said, “Findings from the 2015 ECCO survey of IBD specialists found that around 80% of specialists are either totally confident, very confident or confident enough in using biosimilars, which is a huge change compared to 39% when a similar survey was conducted back in 2013.”

As for all biologics, traceability should be based on a robust pharmacovigilance system. The authors also noted that several postmarketing studies are ongoing or near publication, which lends further support to the improved confidence in the safety and efficacy of the biosimilar (Celltrion’s Remsima®, which is marketed in the US as Inflectra®).

This marks a significant shift in attitude from the previous ECCO position paper, which advised that switching from an established biologic to a biosimilar was inappropriate and called for more data on the safety and benefit of biosimilars in general.

Dr. Danese and his colleagues concluded, “there have been no reports so far that switching from the reference to the biosimilar infliximab [Remsima] has caused problems, in either adult or pediatric IBD patients. On the contrary, an increasing number of publications have shown that there are no safety or efficacy concerns about switching.”