11 September, 2017

Why are biomarkers for non-clinical infusion reactions so critical?

By Kirsten Mease

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It’s no secret that biomarkers for non-clinical infusion reactions (IRs) have become an important aspect of biotherapeutic development research. But why exactly is this topic so vital? And what are some of the main challenges it offers scientists?

Non-clinical infusion reactions manifest differently based on the compound, the target, and the species. There is high variability in inter-animal responses, even within a single study. Without biomarkers for non-clinical IRs, important novel lifesaving biotherapeutics may be killed prematurely in development.

Non-clinical infusion reactions: Background

IRs are an expected and known risk of administering foreign proteins to non-clinical species and humans. There are two categories of non-clinical IRs:

  • First dose IRs - generally as result of cytokine release
  • Delayed IRs - Anti-drug antibody (ADA)-mediated, occuring typically after the fifth weekly dose

Both types of reactions lead to adverse events. However, they need to be characterized to determine whether they might be immune-mediated and secondary to test article administration, or are a direct effect of the test article.

Revealing analysis

You’ll only find a few literature sources and peer-reviewed case studies about non-clinical IRs. However, you may be interested in a retrospective analysis that we conducted of the FDA Pharmacology Reviews for approved products. The analysis shows that IRs occurred in about a third of biotherapeutic products, approved from 2004 – through 2016. This includes first-dose reactions, and delayed ADA-mediated reactions - both of which are covered in our review paper.

Safety concern for humans

ADA-mediated IRs in non-clinical species don’t predict their occurrence or severity in humans because of the mechanistic difference. However, from our own experience, it appears that ADA-mediated IRs are becoming more frequent in both animals and humans. In the context of human clinical trials and therapeutics, this is a potential safety concern.

Profound impact

We’re at a new juncture with IRs. Yes, we know how to manage them. But how do we predict and prevent them? We can mitigate clinical observations, but that doesn’t prevent the decrease in exposure that leads to loss of efficacy.

Imagine if we could accurately predict which animals or humans are at risk. That would have a profound impact on animal welfare and human safety. 

Why biomarkers are critical

ADA assays can be difficult to develop. In fact, we’ve supported non-clinical programs without an ADA assay.  In these cases, biomarkers are even more critical. In part, we use biomarkers to develop a weight-of-evidence approach.  This can show which infusion reactions, adverse events, or lesions are a direct test-article effect versus those that are likely related to an ADA response, and thus are secondary to administration.

Weight-of-evidence approach

Many biomarkers are not validated. That’s why we champion a weight-of-evidence approach. We believe in using both validated and non-validated biomarkers to tell the full story. 

At the same time, collecting biomarker data just from animals with IRs is not enough. You must have samples from control and treated animals without an IR. You must also take them at an early time point post-dose, which is relevant to animals with IRs. Consistent timing and handling is vital as well as your sample management.

Worth the time and money

We use this approach to see if it’s worth the time and money to move forward with immunohistochemistry (IHC) analysis.  Based on our experience, IHC appears to be the most accurate in diagnosing ADA-mediated IRs in non-clinical species.

It’s important to use biomarkers to manage a study effectively when infusion reactions are occurring. Worthy of mention is that you can be put on clinical hold if you don’t investigate the cause of adverse reactions to biotherapeutics. Therefore, we highly recommend using biomarkers. A non-clinical package with dosing intervals and unscheduled euthanasias is a red flag for the FDA.

More research needed

In the end, we all want more patients to benefit from biotherapeutic products. Of course, IRs in animals don’t necessarily predict the incidence or severity of IRs in humans; that’s due to differing mechanisms. But IRs remain a potential safety concern in humans. We require more research to anticipate and prevent them from occurring in both animals and patients, and more sponsors to publish their experiences predicting and preventing these types of reactions.

Gain further insights on biomarkers for non-clinical IRs in marketed biotherapeutics and considerations for study design by reading ToxStrategies' review.


About the author

Kirsten Mease, Senior Scientist at ToxStrategies, recently presented her topic on biomarkers for non-clinical infusion reactions at the Annual Biologics Symposium (ABS) in New Jersey. This event was a fantastic forum to spend time with like-minded and passionate experts.



Category // Pharmaceutical development, Biomarker development