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Michael Hofman: Thank you very much. I'm going to change tracks and talk about Terbium-161. And our experience at Peter Mac. Isotopia has provided our Terbium-161 for our clinical trial

So I think the audience is very familiar with alphas and betas and maybe some not as familiar with Auger electrons. So these sit halfway between. They've got a linear energy transfer that's an order of magnitude higher than the betas, but less than the alphas and an ultrashort path length, so much so that it travels less than the diameter of a single cell.

When we look at the periodic table, there is one element that can do everything, PET, SPECT, beta, alpha and Auger in different isotopes, and that's Terbium-161. And at Peter Mac, we've been running the VIOLET study with a 30‑patient phase I/II trial.

The rationale for this trial was that with lutetium, and maybe sometimes we do see complete responses. But resistance and progression are inevitable. And this may originate from micrometastases that are too small to receive a lethal dose of beta radiation.

When we compare terbium to lutetium in cell models or Monte‑Carlo modeling. In theory, terbium performs much better than lutetium for these small single‑cell clusters or single‑cells. If we envisage lutetium traveling one millimeter, when you get down to that last cell, the radiation is deposited outside the cell failing to eradicate the last cell.

We also have some cellular models and mouse experiments comparing lutetium to terbium suggesting superiority of terbium. It's important to note that 7.4 gigabecquerels of terbium is not the equivalent of 7.4 gigabecquerels of lutetium.

Terbium, actually, emits both a beta and an Auger. And the beta has a higher energy. So actually 5.4 gigabecquerels is equivalent to 7.4. That's just from the beta and not accounting for the Auger.

There is a case report from Samer Ezziddin's group, a response to terbium in a patient who progressed after eight cycles of lutetium. And he's also published a small five‑patient series in Theranostics

At Peter Mac, we've been running this 30‑patient trial. We've taken patients with disease progression after taxane and after androgen receptor pathway inhibitors with PSMA‑positive disease. This was a phase I trial up to six cycles every six weeks.

We started cautiously with a starting dose of 4.4 and then went to 7.4 gigabecquerels. That was the end of the first phase of the study. This year, we've opened a dose expansion cohort at 9.5 gigabecquerels.

Our trial completed six months ahead of schedule. This is important because it does demonstrate the feasibility of global Terbium-161 supply, a limitation with alpha emitters. And other boutique tracers beyond lutetium are often a failure for supply. Here, we're able to do this ahead of schedule. It's very pleasing.

The clinical trial protocol was published last year in the Journal of Nuclear Medicine. We have presented the radiation absorbed dose from some of this cohort at EANM.

There are a lot of challenges to the VIOLET study. In fact, Terbium-161, your dose calibrator may not know how to measure it. In fact, that's what we found.

And although we have quantitative SPECT/CT, the out‑of‑the‑box commercial solution could not do Terbium-161. So we really had to do a lot of things from scratch, including making sure our dose calibrators could actually measure how much we received and how much we were giving to our patients. And validating an in‑house method for quantitative SPECT/CT.

Here, you can see some phantom images. It emits three gamma peaks. So it's a little bit more challenging to image than Lutetium-177. But we do get very, very nice images.

Here's our absorbed dose to parotid, submandibular gland, kidney, liver, and spleen. And this is actually fairly similar to Lutetium-177.

However, our dosimetry models account for the beta. They don't actually account for the ultra‑short path length Augers. We extrapolated this to the six cycles. And to make sure that it would be safe within, let's say, external beam dose limits. And it did appear that this was the case

This is the very first patient we treated on the clinical trial. You can see the gallium PSMA on the left and then the 4‑, 24‑, and 96‑hour images. And this looks somewhat similar to lutetium. A very good retention. That's a subcentimeter para‑aortic node. And it's visualized very nicely on the SPECT/CT. And it's retained up to very delayed time points with washout from the salivary glands and kidneys. And this patient did very well with PSA declining to under one after five cycles of treatment.

From this early data, we concluded that the strengths are, it's a prospective study. It's actually the first terbium trial in any independent indication that's been reported. We did some good random validation. We still don't have good methods to quantify the Auger electrons. Partial voluming is a challenge. The normal organ safety looks very good, and similar to lutetium in terms of normal doses to organs. We are awaiting the efficacy results. This trial has now completed its first phase up to 7.4 gigabecquerels.

And if you come to ASCO, in a few weeks' time, you will see the results. They will be presented there. So there are three trials of Terbium-161 that I can find prospective in the registration to date. If there's one that I'm missing, please let me know.

There's the VIOLET study. There's a trial using SibuDAB PSMA, which is an albumin‑binding PSMA agent out of Basel. And a trial using DOTA‑LM3 for neuroendocrine tumors.

This was just published very, very recently from the Basel trial of the albumin PSMA, now also showing very good post‑therapy quantitative SPECT/CT images.

They've started with a one‑gigabecquerel dose. Level for cohort 1, which was three patients. So a very conservative dose. I think they've now escalated to the next dose level. But it's still much lower than the doses we're using at Peter Mac, albeit with their albumin‑binding agent. That probably needs a lower dose.

We've treated the first three patients in our 9.5 gigabecquerel cohort. And we're hoping to expand that to 12 patients. We published this commentary in JNM last year, "Is 161 Terbium really happening?" And the answer is, yes, it is. And so thank you to the Peter Mac team that makes this possible.