Arkdeep, Lauren, John, Robert N., Joleeen, and Eric,
Once again, I'm replying on both discussion boards. I'm so thankful for your initial post and all of the responses so far.
The publication on ultra-low cut points, as Lauren suggested, is targeted toward the Bioanalytical Scientist to give them confidence that their cut point factor is solid (reliable and assay appropriate) as long as they assess the outlier removal and NC response vs the population. I couldn't agree more that the approach towards the assessment of unwanted immunogenicity could use a refresh. I love the idea of looking at S/N, which in most cases follows Titer, as a means of teasing out impact of ADA on pharmacokinetics, safety, and efficacy. Additionally, S/N has the advantage of a single sample measurement in the screening assay rather than going through the three-tiered approach cutting down on unnecessary sample analysis costs and timelines. If I may be so bold, S/N is a surrogate for ADA concentrations, just like titer is, and who knows, in the future immunogenicity assays may have a standard curve applied to them resulting in relative ADA 'concentrations'. To be clear, immunogenicity assays are not PK assays, they are biomarker assays, and many of the challenges with biomarker assays regarding reference standards would apply to quantitative immunogenicity assays. I'm also not advocating for such an approach, but it is one that could be taken.
Now to address Arkdeep's original point about clinical impact. I would say that in the case studies we explored, the rates of immunogenicity were not elevated, but I can't say for certain if those positive immunogenicity results were clinically impactful. My guess is they were not. I'd also say that immunogenicity assessments are almost always best understood with supplemental data in retrospect. It would be nearly impossible to say that a cut point is appropriate before conducting the clinical study (see Joleen's comment). In my situation, and probably similarly to what is being done with Lauren at Immunologix, you start stratifying the ADA responses with PK, efficacy, and safety data. For example, does an ADA S/N < 3 (or titers < 400) impact drug concentrations? If not, then you've got great supporting data to suggest that while 'low-level' ADA may be detected, below a certain threshold these ADA have no apparent clinical safety/efficacy impact. Then you can state things like 20% of subjects developed ADA, but only 5% developed ADA that led to decreased efficacy.
It is a shame that there is so much swirl when we are reporting high rates of immunogenicity where the bulk of the data shows that they are not impactful (summarizing Lauren's comment). I've been on programs where immunogenicity results led to product termination when there were no data showing impact on efficacy or safety, nevertheless "rate of immunogenicity" was a marketing concern. I'm so glad that Bioanalytical scientists (and AAPS) are having these discussions and publishing white papers and other examples demonstrating the use of alternative strategies to summarize the impact of ADA (e.g. S/N vs Titer, and utility of confirmatory assays). I hope that smart science continues to lead us towards better outcomes.
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Robert Kernstock
Principal Scientist
Astellas Research Institute of America LLC
Northbrook IL
[email protected]Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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Original Message:
Sent: 10-04-2025 18:11
From: Arkadeep Sinha
Subject: Strategies to mitigate ultra-low cut points
Thank you, Robert, for your detailed explanation on this topic. To be fair, my thoughts on this subject were prompted largely by recent discussions initiated by folks at Immunologix. To clarify my question further, my concern is not about the assay's performance or its ability to appropriately capture population variability, as monitoring the FPR can answer that. Rather, my concern lies with the low-titer true positives that are detected as a result of these ultra-low cut points. In many cases, these true low-titer ADA positives appear to lack clinical relevance. Given the recent emphasis on identifying clinically meaningful ADA responses and the broader discussions around shifting the testing paradigm, my post was intended to question whether it might be time to re-evaluate the relevance of maintaining such ultra-low cut points.
Your suggestion of using S/N is definitely one way of getting around this.
Thank you
Arkadeep
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Arkadeep Sinha, PhD
Director, Bioanalytical Sciences
Upstream Bio
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
Original Message:
Sent: 10-02-2025 15:47
From: Robert Neely
Subject: Strategies to mitigate ultra-low cut points
Hi Arkadeep,
Ultra-low ADA screening cut points are indeed a critical area in immunogenicity assessments. I believe there are several perspectives that can help address the challenges associated with overly sensitive thresholds.
First, to ensure ADA assays are both clinically relevant and scientifically robust, it's essential to start with the method development strategy. Assays should be designed to balance both sensitivity and specificity, being able to detect "real" ADA positive responses while minimizing false positives due to assay background or biological variability.
Second, alternative cut point strategies, such as the minimum 1.2, are a valid approach and can help avoid the ultra-low cut points. However, this may require adjusting the false positive rate threshold to something lower, such as 1%. Additionally, not removing biological outliers during the cut point determination could help raise the background levels while also better incorporating the potential heterogeneity of the patient population.
Lastly, there are alternative ADA interpretation approaches that go beyond the classical binary cut point determination. Evaluating ADA responses in the context of the entire patient profile allows for a more nuanced understanding of the potential clinical impacts. Using signal-to-noise (S/N) ratios as a continuous variable, similar to biomarker assays, avoids the need for a fixed cut point and enables integration of ADA data with other datasets to assess clinical impact more holistically.
Any approach to ADA assay design and interpretation should be grounded in the immunogenicity risk assessment of the molecule. This ensures that the monitoring strategy is tailored to identify clinically relevant ADA responses. At Immunologix, this is a frequent topic of discussion among our team and with our drug development partners. We've found that each program presents unique challenges, and that open, collaborative dialogue is key to developing a phase-appropriate and risk-based strategy for both immunogenicity monitoring and assay design. These conversations often lead us to the most effective and scientifically sound solutions.
Thanks
RJ
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Robert Neely Ph.D.
Scientific Director-Translational Sciences
Immunologix Laboratories
Mount Laurel NJ
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
Original Message:
Sent: 10-01-2025 22:13
From: Arkadeep Sinha
Subject: Strategies to mitigate ultra-low cut points
Hello everyone,
I would appreciate hearing your perspectives on strategies to avoid ultra-low ADA screening cut points. I have encountered discussions suggesting the use of a minimum cut point (for example, a cut point of 1.2 to incorporate the accepted CV allowance), even if that causes the FPR to fall below 5%, and leads to missing some low-titer, inconsequential ADA responses. Can anyone share their experiences/strategies on this topic?
Additionally, are there any publications/guidances on this topic that I may have missed?
Thank you
Arkadeep
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Arkadeep Sinha, PhD
Director, Bioanalytical Sciences
Upstream Bio
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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