Soon after the initial introduction of infliximab in the late 1990s, physicians and researchers noticed that for patients with inflammatory bowel disease (IBD) who responded to therapy, a significant portion would experience loss of response over time. As a result, intensifying the dose of infliximab was found to be useful in maintaining remission. In fact, one of the supposed advantages of adalimumab when it was first introduced in 2003 was that it was a good alternative to infliximab, in that patients less frequently required dose escalation to maintain remission. Well, that sounded like a good option, even if it may not have been supported by the best evidence.
Today, there is general acknowledgement that dose escalation is needed in 30% to 40% of patients with IBD who receive any anti-TNF inhibitor, and this may in fact be a problem with the interleukin 12/23 inhibitor ustekinumab as well. Overall, loss of response to anti-TNF therapy may be a problem in one-third of patients each year they remain on treatment. According to a claims-based study, the newer anti-TNF inhibitors may be associated with fewer instances of dose escalation (14% to 23%). For ustekinumab, dose escalation was required in 22% of patients, but the mean dose escalation needed to maintain remission was a mean 131% of the original dose (compared with 70% for infliximab and 59% for adalimumab).
The dose-escalation issue is often set aside when considering the value of biosimilars and their cost effectiveness. A European literature review found that median time to dose escalation in patients who experienced loss of response was about 7 months for both infliximab and adalimumab. Interestingly, the American Gastroenterologists Association Crohn’s disease treatment guidelines do not address appropriate steps in terms of the need for dose escalation.
What is the bottom line here? First, the savings resulting from the lower cost of biosimilar IBD treatments relative to the originators may be magnified on a per-patient basis. If the biosimilar is less expensive based on standard doses, the money saved on additional doses may be that much greater. Since a significant proportion of patients need greater doses over time to combat loss of response, these savings could accrue quickly.
Second, will the greater doses necessary to attain remission be efficiently provided with existing dosing options? Humira® and some of the adalimumab biosimilars offer prefilled syringes and autoinjectors with a full range of dosing options: 10 mg, 20 mg, 40 mg, and 80 mg. For biosimilars that are available in limited dosing options, this could imply lesser cost savings and greater drug wastage. For example, Hadlima® and the interchangeable Simlandi® are available in 40-mg doses only, which could restrict provider choice when dose intensification is needed.
For patients receiving infusible infliximab, the potential for drug wastage may be minimized: A common approach is simply to administer infusions on a more frequent basis, rather than increasing the dosage in any one infusion. With the launch of subcutaneously injected infliximab, the dose-escalation approach may be a bit trickier. In the EU, Celltrion’s Remsima SC® was recently approved for use with a 240-mg option to address the need for dose escalation.
I would never claim that using a biosimilar infliximab or adalimumab will result in less dose escalation than if using the reference products. If the need for dose escalation is factored in the equation for calculating biosimilar savings, biosimilars may prove significantly more cost efficient for IBD.
