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.
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!