The Use of Biologics and Biosimilar in Asian patients with IBD: Are we ready?

Abstract

In the last three decades, Asia has witnessed a rapid upsurge of inflammatory bowel diseases. In contrast to initial thinking, Asian patients with IBD are not exempted from serious complications. IBD has become the major challenge for GI specialists in some Asian countries, particularly Japan, Korea, and China. It is therefore eminent to provide guideline on the use of immunomodulators and biologic agents in these conditions. In this issue of the Journal, Ooi and IBD experts in the Asia Pacific region put together 29 statements to guide the use these potent immunosuppressive agents in the control of ulcerative colitis and Crohn’s disease (Ooi et al. JGH 2019). Compare to the rather liberal strategy in using biologics in the West, there are a number of concerns for the use of these drugs in the East. First, latent infection is a major threat when using potent immunosuppressive agents. The high prevalence of subclinical or past infection of tuberculosis, viral hepatitis, and other latent infections poses potential danger of using biologics and biosimilar. The Asia Pacific Working Group emphasized on screening for TB (using chest X-ray, CT, interferon gamma release assay (IGRA), and tuberculin test), as well as hepatitis B virus (using HBsAg, HBcAb, and if tested positive, testing HBV DNA). Prophylaxis treatment of HBV with either tenofovir or entecavir should be offered 2 weeks before using biologics and biosimilars and continue for 6–12 months after the use of immunomodulators. Prophylaxis treatment of TB should be commenced 3–4 weeks prior to the use of biologics and biosimilar and be given according to local TB treatment guideline. Furthermore, IGRA should be tested every 6–12 months during immunomodulator therapy. While these recommendations look sensible and prudent, it should be noted that they are based on relatively weak evidence. There is no study designed to address this particular group of patients. Second, there are still a substantial number of patients not responding to biologics. In order to achieve optimal therapeutic effects, the Asia Pacific Working Group recommend to check anti-TNF drug concentrations as a routine. For infliximab, the steady-state trough level is recommended as 3–7 ug/mL and for adalimumab, 4–8 ug/mL. In patients who have fistula disease, a higher dose within these ranges are recommended. The authors admit that these recommended levels are based on studies which has much variations in study design as well as assay method and standardization. The levels choose are therefore somewhat arbitrary. Moreover, none of these studies are conducted among Asian population. The pharmacodynamics are therefore subjected to ethnic variability. There should be clinical trials to confirm that this target drug levels checking and titration of drug doses will translate to better clinical outcome, that is, earlier control of disease activity and less disease complication arising. Finally, the cost the biologics and biosimilar is imposing a heavy burden on the health-care system. The Asia Pacific Working Group reckons that early use of biologic therapy can improve clinical outcome. Yet a top-down approach, that is, using biologic as first line therapy and step down when stabilized, cannot be recommended in this region. Rather, an accelerated step-up usage of biologic therapy is proposed for the management of IBD patients with high risk factors and predictor of poor outcome. This is more an economical strategy than an evidence-based therapeutic consideration. The cost of biologic is substantial and may not be affordable by patients. Majority of population in Asia are not covered by health insurance, and health expenses are often paid out of pocket. The unit price of infliximab 100 mg and adalimumab 40 mg are USD $660 and USD $563 respectively while the unit price of azathioprine 50 mg is USD $0.09 each. The unit price of methotrexate 15 mg per week is USD.$21.27. The health-care cost of IBD has shifted from hospitalization and surgery to the use of anti-TNF in recent years. Anti-TNF was found to be the strongest indicator of high-cost outlier in IBD as shown in a recent study from Korea. With the emergence of newer generation of biologics, the cost of biological therapy will further increase. The unit price of newer generation of vedolizumab 300 mg is USD $1266 and ustekinumab 90 mg is USD $3248. As vedolizumab and ustekinumab are safer to use in patients with TB (and possibly other latent infections) and these newer drugs are more expensive, the cost of biologic therapy in Asia is likely to further escalate. There were hope that when biosimilar medication becomes available, treatment will become more affordable. So far, four biosimilar are approved by the FDA and are available in Asia: infliximab-dyyb (Infectra), infliximab-abda (Renflexis), adalimumab-atto (Amjevita), and adalimumab-adbm (Cyltezo), as they are proven to be safe and effective. Unfortunately, these drugs are not cheap. Their price has not been set significantly lower than the biologic mother molecules. This is a great disappointment to patients who require potent immunosuppressant to control their IBD. Beside, evidence of therapeutic efficacy of multiple switching or cross-switching between biosimilar and originator is lacking. Recent study in real-life cohort revealed similar efficacy, safety, and formation of antidrug antibodies in patients switching from infliximab biosimilar to the originator. However, the FDA has so far not yet designated any biosimilar as “interchangeable” with currently approved originator. There is more work need to be done to show that biosimilar can play an important role in the management of IBD. Cost-effectiveness model studies of IBD management is very much awaited. IBD has become a major health problem in Asia. While much progress is made in therapeutic advancement in the West, clinical doi:10.1111/jgh.14817