Remsima® (infliximab) has been approved and listed on the PBS as the first subcutaneous (SC) biosimilar formulation of infliximab from the 1st of July 2021. This marks a significant development in the history of infliximab, which was first approved as an intravenous (IV) infusion over 20 years ago.^1-4

In that time, infliximab has become a well-established tumour-necrosis factor alpha (TNF-α) inhibitor, paving the way for other biologic and biosimilar therapies and arguably helping to bring inflammatory bowel disease (IBD) treatment into the modern era.⁵

The new listing was welcomed by A/Prof. Jake Begun, Director of Gastroenterology at the Mater Hospital Brisbane, who has extensive experience of using IV infliximab throughout his career and is currently treating patients with the SC formulation. “Infliximab really revolutionised the care of IBD patients in the modern era,⁵” said A/Prof. Begun. “It’s efficacious with early responses observed,^6,7” he added. The initial IV induction followed by SC maintenance may benefit infliximab-naïve patients, as C_max levels are achieved quickly following treatment initiation,^8,9 and can then be maintained with ongoing SC injections⁹.

A/Prof. Begun acknowledged that infliximab is an older agent but that in certain, more severe cases of Crohn’s disease and severe colitis rescue therapy, it’s still his biologic of choice.

A/Prof. Begun points out that efficacy is just one factor that affects decisions around choosing an appropriate treatment for patients. Everything from patient preference to the management of hospital resources plays a part, particularly when it comes to having the choice of a self-injected option.¹⁰

“The impact on patient lives and their resources is a very important consideration… Especially when sometimes people are coming in for infusions and they live hours away, from regional areas for example,” noted A/Prof. Begun. “Though it’s only an hour-long infusion, the whole process probably takes them two and a half to three hours…Even in our centre, where we do Saturday infusions, it’s still a big hassle…Also, infusion chairs can be a scarce resource at public hospitals – we often have to triage spaces for our patients,” he added

SC infliximab has comparable efficacy to the IV formulation⁹

The SC infliximab formulation, as a 120 mg/mL pre-filled syringe, was compared in a clinical trial with IV infliximab 5 mg/kg in terms of its pharmacokinetics, efficacy, safety and immunogenicity in patients with ulcerative colitis and Crohn’s disease (N=131).⁹

Patients went through an induction period with IV infliximab, given at Week 0 and 2, and at Week 6 were randomised (1:1) to receive SC infliximab every 2 weeks (Q2W) or IV infliximab every 8 weeks (Q8W).⁹ Then, at Week 30, all patients receiving IV infliximab were switched to the SC regimen.⁹

The pharmacokinetic non-inferiority primary endpoint was met with a 90% confidence interval, with SC infliximab C_trough levels consistently maintained above target therapeutic concentrations.⁹ Importantly, this result was consistent even in patients who switched to SC infliximab at Week 30.⁹ Immunogenicity and safety profiles did not differ between the two groups.⁹

In contrast, for patients in the IV arm, longer dosing intervals resulted in a gradual reduction in infliximab serum concentrations, with C_trough levels below target therapeutic concentrations, as observed between Week 22 and Week 30.⁹

A/Prof. Begun considered the more consistent serum concentrations were a potential clinical benefit of SC infliximab compared to the IV infusion. “With an 8-weekly infusion, you have high peak serum concentration, and then you have decay and the trough… But with 2-weekly dosing, it’s more of a steady-state that you achieve, and from the point of view of immunogenicity, this is an excellent property to have – you get fewer lows where you end up making anti-drug antibodies,”⁹ he explained.

The recommended and established dose for SC infliximab is 120 mg^2,9

A/Prof. Begun discussed the topic of the 120 mg/mL fixed-dose with the SC formulation.² Given that IV infusions of infliximab are titrated based on the patient’s weight (5 mg/kg), there is inherently less flexibility with the pre-filled syringe. A/Prof. Begun shared his thoughts on managing patients who would normally require higher doses with the IV formulation:

“The thing [some treating clinicians] worry about is what you do with obese patients,” explained A/Prof. Begun. “Because when you’re giving 5 mg/kg [of IV infliximab] it can be a pretty big dose. If you have a 100 kg person – that would be 500 mg of infliximab every 8 weeks,² whereas with SC dosing that would only be 480 mg over the same period,² and is that enough for heavier patients?” he explained.

Despite this concern, his own experience and the clinical trial data have reassured A/Prof. Begun that the current established SC dosing regimen of 120 mg is adequate for the majority of patients he sees. “The data would suggest that there’s no decrease in effect with obesity.⁹ With a morbidly obese patient it may be an issue, for example over 150 kg, but certainly, just in the heavy-set person, it doesn’t seem to be an issue,” he said.

A/Prof. Begun commented on dose escalation and his experience of switching dose-escalated IV infliximab patients over to the established 120 mg SC formulation. “I’m actually pretty comfortable, even with dose-escalated patients, switching them over to the SC dose, because I know that we’re going to get reasonably high serum levels of infliximab,” he said. “There is a little bit of research that’s been done out there on dose escalation with SC infliximab, but that’s an area of research that needs to be expanded, so we also understand better when to do this and how efficacious it is,” he added.

The SC formulation is a useful addition in particular settings and patients

A shift from in-hospital to home-based management arguably makes sense from the provider’s point of view, especially when considering the limited capacity for infusions, costs, and the backdrop of the current pandemic. However, A/Prof. Begun pointed out that it does remove an important touchpoint between doctor and patient, which, amongst other things, is a potential missed opportunity for future research. “When patients are coming in every couple of months for infusions, there’s an opportunity to follow them longitudinally for research purposes, and that is a lost opportunity for SC infliximab,” he noted.

A/Prof. Begun explained that there are also some patients who “simply do not do well with SC dosing” due to needle anxiety, as well as those who prefer the security of being in an infusion centre. “Some patients can be more anxious about giving themselves an injection than having a cannula put in,” noted A/Prof. Begun.

In all, A/Prof. Begun’s experience with SC infliximab has been positive. “It’s so great to have this on the PBS, it’s actually going to be really helpful in terms of resourcing at our IBD centre, where we have about 380 people on biologics. That’s a lot of logistical considerations, so this is going to make our lives a lot easier,” he said.

Abbreviations: Cmax, maximum drug concentration; Ctrough, trough drug concentration; IBD, Inflammatory Bowel Disease; IV, intravenous; kg, kilogram; mg, milligram; mL, millilitre; PBS, Pharmaceutical Benefit Scheme; Q2W, every two weeks; Q8W, every eight weeks; SC, subcutaneous, TNF-a, tumour necrosis factor alpha

For more information, please visit www.remsimate.com.au  or contact your Celltrion Healthcare representative on [email protected]

Footnotes:
Disclosures: A/Prof. Begun assisted with the PBS submission for Remsima® and has received an honorarium for his input with this article and other educational materials for Remsima® from Celltrion Healthcare Australia Pty Ltd.

*Remsima® is indicated for moderate to severe ulcerative colitis and Crohn’s disease, refractory fistulising Crohn’s disease, ankylosing spondylitis, psoriasis and psoriatic arthritis, and in rheumatoid arthritis in combination with methotrexate.2 Please note that not all TGA approved indications are listed on the PBS.

PBS Information: Authority required for the treatment of adults with severe Crohn’s Disease and moderate to severe ulcerative colitis. Refer to PBS Schedule for full authority required information. This product is not listed on the PBS for the treatment of refractory fistulising Crohn’s Disease.

BEFORE PRESCRIBING, PLEASE REVIEW FULL PRODUCT INFORMATION AVAILABLE HERE OR ON REQUEST FROM CELLTRION HEALTHCARE MEDICAL INFORMATION SERVICE (PHONE: 1800 325 228)

References:

1. PBS Submission Details for Remsima SC (infliximab). Available at: https://www.pbs.gov.au/medicinestatus/document/166.html. Accessed 2-Aug-2021.
2. Remsima® Product Information.
3. Remicade® Product Information.
4. European Agency for the Evaluation of Medicinal Products (EMEA). Application for Marketing Authorisation for Remicade. 5 March 1998. Available at: https://www.ema.europa.eu/en/documents/procedural-steps/remicade-epar-procedural-steps-taken-authorisation_en.pdf. Accessed 2-Aug-2021.
5. Melsheimer R, et al. Remicade (infliximab): 20 years of contributions to science and medicine. Biologics 2019;13:139–178.
6. Papamichael K et al. Infliximab in inflammatory bowel disease. Ther Adv Chronic Dis 2019;10:2040622319838443.
7. Vasudevan A, et al. Time to clinical response and remission for therapeutics in inflammatory bowel diseases: What should the clinician expect, what should patients be told? World J Gastroenterol 2017;23(35):6385–6402.
8. Bittner B, et al. Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities. BioDrugs 2018;32:425–440.
9. Schreiber S, et al. Randomized controlled trial: subcutaneous vs intravenous infliximab CT-P13 maintenance in inflammatory bowel disease. Gastroenterology 2021;160:2340–53, and supplementary appendix.
10. Stoner KL, et al. Intravenous versus subcutaneous drug administration. Which do patients prefer? Patient 2015;8:145–53.

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CELLREMTL_045 Material prepared: August 2021.