Highlights from the FDA Guidance on Dosage Optimization for Therapeutic Radiopharmaceuticals

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Hello and welcome to another episode of Certara Talks.

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I’m here with my colleague, Senior Director of Clinical Pharmacology, Dr Amandine Manon.

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Welcome to Certara Talks.

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I was thinking, Amandine, that we could talk about an emerging class of therapeutics that’s gaining a lot of attention, particularly in the oncology landscape, and those are therapeutic radiopharmaceuticals.

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So could you define what those are for our audience that might not be familiar with this class?

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Sure.

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So these drugs are quite complex drugs.

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So it’s composed of a vector, which is generally a lot of it can be a small molecule, A peptide, A monoclonal antibody or even sometimes a single domain antibody.

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Then there is a linker and a chelator and the chelator covalently binds the radionuclide.

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So the radionuclide is the the active moiety and the vector is targeting A receptor that is overexpressed on tumour cells because as you said, the application right now within oncology, but there are also other therapeutic areas being being explored.

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So it will probably, yeah, we will have a broader range of therapeutic area maybe in the future.

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Yeah.

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It sounds like a benefit of this class of drugs is that it’s a way of using radioactivity but targeting it to cancer, cancer cells so that patients get a more targeted treatment with more efficacy and less toxicity.

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Yeah, exactly.

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The the goal is really to have a receptor, targeting receptor that are overexpressed on the tumour but not in the normal organs to try to spare the normal organs and avoid delivering too much radioactivity in the kidney and the bone marrow, for example, that are sensitive tissues and really just target the the tumour.

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So that’s the theory.

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In reality, you have obviously some radioactivity also that by that distributing the in the body.

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But you know, it’s, it’s definitely an exciting science.

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And I saw that recently the FDA issued a draft guidance for oncology for therapeutic radiopharmaceuticals.

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And I know that you read it.

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And could you tell our audience what you thought some of the main takeaways were?

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So yeah, the main takeaways, I think it focus on 4 main topics to me.

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So first, the FDA acknowledged the difference between external beam radiation therapy and RPTS.

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So it’s a it’s a great achievement for the field because they have been fighting for that for for a long time.

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So that’s good.

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The second topic is the risk of long term radiation toxicities.

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It’s not a surprise with this type of drug.

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Then the FDA reiterate that the good principles of those optimization, so a car project Optimus apply to RPTS.

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So now it’s clear and finally they, they really highlight the critical role of dosimetry in, in the development of RPTS.

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So I think I, I would like to maybe discuss a bit more on the first topic, if you if you’re OK.

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Yeah, good.

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So I think it’s important that the FDA recognise the difference between EBRT and RPT in terms of dose rate, radiation distribution.

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So they confirm that the starting dose in the first in human study must have projected organ absorb dose below EBRT result.

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So using really the data we have under external radiation therapy that is used for ages, but now they open the possibility to the to the companies to escalate to doses to cumulative activity that exceed this EBRT result.

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So that’s a big change for us because now the EBRT threshold are more considered as a starting point than a stopping criteria for the dose escalation because before it was really a stopping criteria.

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So it will give the the opportunity to the companies to evaluate higher cumulative activities that may or may not translate we don’t know yet into better efficacy.

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So that’s that’s was a that’s a very important consideration in in that, in that guidance.

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And related to that, obviously those optimization project Optimus the good principles apply especially it’s not good news the randomised dose finding.

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So you have to test to evaluate at least to those level in a randomised manner as for any other drugs.

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So that’s, that’s it.

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Now it’s clear and it’s written in the guidance.

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They already told that in a workshop last year in May 2024 FDS and MMI workshop.

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So now it’s confirmed in the guidance.

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That’s great to know.

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And for our readers who may not be familiar with Project Optimus, that’s the FDA’s initiative that for oncology the maximum tolerated dose is no longer an acceptable dosing paradigm.

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And yeah, and you really have to optimise dosing for oncology therapeutics just like you would for any other therapeutic class.

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So Amandine, is there anything as you were reading the guidance, was there anything that stuck out to you as something that you didn’t see in see in the guidance that you would have liked to have seen?

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Yeah, when we read the guidance from Certara’s point of view, we thought that really the big missing piece was modelling and simulation.

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There is almost nothing about modelling and simulation in this guidance.

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So in the introduction they refer to the famous Optimus guidance that discuss a lot modelling and simulation.

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But it would have been better to clearly outline the need for modelling and simulation modelling informed drug development in that guideline as well.

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So for example, we can build pharmacokinetic bio distribution model that allow to derive the organ absorb dose or the biological effective dose and then correlate this organ absorb dose or BDS to efficacy and toxicity.

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Because that’s really a key question.

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Also that is highlighted in the guideline is what is the correlation between the radiation dose delivered and the toxicities and the long term toxicity.

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So clearly modelling and simulation can play a great role to do that.

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And that’s especially surprising because it’s written in all pre IND feedback within that they are requesting for pick and exposure response.

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So why not specifying that in in the guidance.

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That’s that’s surprising to us.

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Yeah, yeah.

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So for me that the main missing piece, but there are maybe two small other commands for those imagery, the states critical, but they don’t give really any insights on when and how to to perform those imagery.

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We know from or based on our experience that there are requesting those imagery at all cycles in a large number of patient.

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So it could also have been specified in the guidance.

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It’s not it’s not written and the last maybe small pieces that is missing that they are not really describing the selection of starting those except that they say that it should remain below IBRT’s result.

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But no, no, no details probably because it’s also discussed in the non clinical guidance, the translational one, but it’s very high level description in the non clinical.

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So I think the guideline may benefit also to give a bit more details and again, maybe refer to modelling and simulation, for example, quantitative systems pharmacology or translational PKPD model that can be really helpful for a first in human dose selection and and those range selection in general.

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So that’s are my key takeaways from from the guidance.

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Well, that is that’s great to know and for our readers to know if you need help with dose optimization of your targeted radiopharmaceutical.

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Dr Mano has a team of works with a team of clinical pharmacologists and modellers at Sirtara and they can certainly help you out.

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So thank you so much Amandine, always a pleasure talking to you.

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Thank you, Susan.

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And you’ve been for our audience.

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You’ve been watching Sirtara talks.

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If you have more questions on this topic, reach out to us on our website.

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And as always, I’m Suzanne Minton, and we’ll see you next time.