All you need to know about PANTS
The anti-TNFα drugs infliximab and adalimumab are known to be effective treatments for patients with Crohn’s disease that do not respond to conventional therapies. Unfortunately, even using these alternative biotherapeutics, treatment failure is still quite common. The personalised anti-TNF therapy in Crohn’s disease study (PANTS)[1] was set up to establish a biorepository to investigate genetic and other factors associated with anti-TNF treatment failure in patients with active luminal Crohn’s disease naïve to biological therapies, and is the largest known investigation of its type.
What are anti-TNF drugs?
Anti-tumour necrosis factor alpha (anti-TNF) drugs are large, complex molecules that work by blocking TNF, a systemic pro-inflammatory cytokine associated with gut inflammation. For some patients, the end result of repeatedly taking one of these drugs is that the immune system starts to see it as a potential threat, rather than something beneficial. This results in the body generating anti-drug antibodies that block the action of anti-TNF drugs, as well as increasing the rate at which they are removed from the body, reducing treatment effectiveness.
What is PANTS about?
Multiple patient-, disease- and drug-related factors have been linked to anti-TNF treatment failure but, prior to PANTS, no adequately powered prospective studies had explored their relative effects, interactions and impact on drug and anti-drug antibody concentrations. The aim of PANTS was to follow the disease course of patients with active luminal Crohn’s disease to identify those at risk of treatment failure – primary non-response to treatment at week 14, non-remission by week 54 and withdrawal of treatment due to adverse side effects – sooner. This information could lead to direct monitoring and early dose optimisation, along with strategies to mitigate the development of anti-drug antibodies, which, in turn, will allow safer and more cost-effective use of anti-TNF drugs.
PANTS followed 1,610 Crohn’s patients at 120 hospitals across the UK who were starting anti-TNF treatment with infliximab, the biosimilar CT-P13, or adalimumab. These drugs are used as an alternative treatment when other therapies have failed. However, while they have proved a gamechanger for many sufferers, they are not effective for every patient. PANTS looked at why this might be the case.
What did the study involve?
Patients enrolled on PANTS had study visits scheduled at first dose (week 0), post-induction (week 14), and at weeks 30 and 54 after first dose. Further visits were scheduled for infliximab-treated patients at each infusion, and for both groups at the time of treatment failure or discontinuation. A range of baseline data was recorded at the start of the trial, including demographic data, smoking status, age at diagnosis, disease duration, Montreal classification of disease location and behaviour, previous medical and drug history, and past Crohn’s disease-related surgeries. Disease activity score, weight, therapy and adverse events were also recorded at every visit.
Patients were monitored by analysing blood and stool samples, using IDKmonitor ELISAs to measure drug and total anti-drug antibody concentrations. Choosing a drug-tolerant anti-drug antibody assay allowed all patients with immunogenicity to be identified, irrespective of circulating drug concentration.
What were the findings?
The study showed that about a quarter of the patients did not respond to anti-TNF therapy, and around a third responded well initially, but then lost response. Only a third of patients were in remission at week 54. Researchers found that treatment failure was related to week 14 drug concentrations and immunogenicity. Low drug concentrations at week 14 were the main factor associated with immunogenicity by week 54, while immunogenicity was the main factor associated with low drug concentrations by week 54. They also noted that immunogenicity was twice as common in patients treated with infliximab as with adalimumab at week 54. The optimal drug concentrations associated with remission at both week 14 and week 54 were 7 mg/l for infliximab and 12 mg/l for adalimumab – a key to providing therapeutic drug monitoring services for Crohn’s disease patients.
Where to next?
Armed with the knowledge that anti-TNF treatment failure is associated with suboptimal drug concentrations, researchers suggested that boosting effective drug concentrations may help to improve outcomes for Crohn’s patients.
Personalised, intensified dosing during induction in at-risk patients – the obese, smokers, and patients with more active disease – might enhance the longer-term effectiveness of anti-TNF treatment, as well as iterative dose adjustment aiming for higher target drug concentrations than those currently recommended. Encouragingly, treatment failure, safety and the proportion of patients who developed anti-drug antibodies were similar between those prescribed infliximab and the biosimilar. Prescribing the biosimilar rather than the branded drug could help to offset the costs associated with dose intensification. The increased immunogenicity seen at week 54 in patients treated with infliximab could also be mitigated by combination therapy with a thiopurine or methotrexate.
To read the PANTS publication, go to https://www.thelancet.com/journals/langas/article/PIIS2468-1253(19)30012-3/fulltext
To learn more about IDKmonitor assays, visit https://www.biohithealthcare.co.uk/products/therapeutic-drug-monitoring/
References
- Nicholas A Kennedy et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019 May;4(5):341-353. doi: 10.1016/S2468-1253(19)30012-3. Epub 2019 Feb 27.
