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!

Biosimilar Step Therapy for Medicare Part B: Does This Make Sense?

The Centers for Medicare and Medicaid Services (CMS) has decided drugs covered under Medicare part B may be subject to step therapy, if so desired by Medicare Advantage plans. UnitedHealthcare has become the first to publicly implement step therapy policies for these drugs. However, biosimilar step therapy is not the typical utilization management tool that industry executives are used to seeing.

biosimilar step therapyTraditional step therapy or step edits for prior authorization policies are typically used to require the use of an effective, low-cost drug class before trying a more-expensive treatment. For example, a plan might have a step in place before a patient can receive Humira®, such as requiring documented failure on other disease-modifying anti-rheumatic drugs, like azathioprine or methotrexate. This makes very good sense when supported by practice guidelines or treatment pathways, based on solid supportive evidence.

For biosimilar manufacturers, the perspective on the revised CMS policy, seems to imply trying the biosimilar before receiving the branded originator product. This biosimilar step therapy would make very little sense. A doctor would not be practicing evidence-based medicine if he or she prescribed Remicade® to a patient after failure of Renflexis®. There is no evidence to show that the biosimilar will work in a patient who did not receive adequate clinical benefit from the reference product (and vice versa). Similarly, there is no information to show that a patient who has an adverse effect while taking Remicade will not have that adverse effect after injecting with Renflexis (or vice versa). In other words, after failing one, a new mechanism of action should be tried, not a product with a very similar structure. This may be a different argument, if a subcutaneous form of infliximab was introduced, and this might be reason to step the infusible form through this drug.

In United’s announcement, they are clearly seeking to increase biosimilar utilization, as designated preferred part B agents, at the expense of Remicade use, the nonpreferred agent. Therefore, it may make more sense that new patients will have to use a biosimilar before being prescribed the reference product. Step therapy in this case is almost an aside.

Ironically, the Department of Health and Human Services has also expressed its desire to move part B agents like self-administered injectables to part D. This may not apply to infliximab, as it is given as an in-office infusion. Should this be the case, plans will have many pharmacy tools at their disposal beyond biosimilar step therapy.

In other biosimilar news…Fresenius Kabi has signed an agreement with Abbvie to delay its adalimumab biosimilar market entry in the US until 2023. The manufacturer is currently trying to secure European approval for the product. A 351(k) application has not yet been filed by Fresenius in the US.

Is Celltrion Paving a New Road for Biosimilars? A New Route of Administration Being Tested for Infliximab

When payers, patients, or physicians discuss biosimilars, they assume that the biosimilar works just like the reference product. They also assume that the biosimilar is administered in the same way as the originator biologic. Celltrion is actively researching a new subcutaneous infliximab. This could result in a first for the biosimilar industry.

Sponsored by Celltrion and conducted in multiple sites, the research results were announced at the annual meeting of the European Congress of Rheumatology in June. The investigators presented outcomes data on the use of a subcutaneous (SC) form of infliximab-dyyb. Currently, infliximab is only available as an intravenous (IV) infusion at the physician’s office that takes at least 2 hours. Subcutaneous infliximab was given on a biweekly basis.

subcutaneous infliximabThe researchers studied 48 patients with rheumatoid arthritis, finding that outcomes were not clinically different through 30 weeks of follow-up. Three dosages were tested, and in this small study, no ACR20 differences were reported in any subgroup receiving infliximab infusions or SC injections.

Hypersensitivity reactions did occur in one patient each receiving the lowest dose (90 mg) SC and the middle dose (120 mg). None were seen in the group receiving the highest infliximab SC dose (180 mg). Injection site reactions occurred in two patients apiece in the 90 mg and 180 mg dose cohorts. receiving subcutaneous infliximab. The formation of antidrug antibodies was detected in nine patients receiving the standard infusion, but less than half that number in each of the subcutaneous groups.

Currently, infliximab treatment requires a lengthy office visit for each infusion (every 8 wk in the maintenance phase). It is one of the key limiting factors to its use. A self-injectable formulation should result in lower administration costs, and the potential for covering the agent through the pharmacy benefit.

A phase 1, open-label trial of subcutaneous infliximab has already been conducted by Celltrion in patients with Crohn’s disease. That trial found similar outcomes between the SC and IV formulations. Another phase 1 trial is wrapping up, this one evaluating safety and pharmacokinetics in healthy volunteers. Celltrion is also sponsoring a phase 3 trial of more than 300 patients with rheumatoid arthritis. Preliminary results will not be available until December 2018.

It is not yet clear, however, what type of data the Food and Drug Administration would require for approval of a new formulation of a biosimilar. The regulatory agency may decide to treat this as it would a new route of administration for any approved product, which would focus on pharmacokinetic and pharmacology factors. Celltrion seems to be covering all of its bases.