Video Transcription
Eric Van der Putten 00:02
Thank you. Good morning. There's bad news. This is not hardcore med tech. This is therapeutics. And there's even more bad news because it's going to be hardcore chemistry. Well, it's not. But I'm showing you here the molecular structure of very effective anti-cancer agents, the taxane drug class of agents. They've been around for a while, very effective drugs being used in several indications, breast cancer, prostate cancer, and many, many more. However, these very effective drugs face some serious problems. These current generation taxane chemotherapies are definitely widely used but have significant disadvantages. First, they're inconvenient for patients, painful, and expensive because it takes a half-day hospital admission to administer those agents, and on top of that, they come with very serious and definitely unpleasant side effects. So an obvious solution could be to replace those intravenously administered drugs with oral formulations. But there are a couple of challenges too, to be precise. First, a chemical problem, because I think you all remember from the first slide looking at those molecular structures that those are poorly water-soluble agents, and they are. So we've come up with a solution that produces a water-soluble tablet formulation of these taxane agents. And actually, we've developed formulations for all of the three major taxanes in the market: docetaxel, paclitaxel, and cabazitaxel. But once you get the water-soluble drug into the gut, there are actually two more problems. One is the drug efflux by P-glycoprotein (PGP) transporters; they pump the drug out of the gut wall, which is actually a natural defense mechanism. So that's not so bad. However, it prevents the necessary amount of drug from getting into the systemic blood flow. So that's one problem. Another problem is, once you get through the liver, those drugs are metabolized by CYP3A4 enzymes, again reducing the effectiveness of the drugs. So what we've done is come up with a combination product, where the oral taxane tablets are combined with a booster drug, and ritonavir is actually capable of blocking both PGP drug efflux as well as CYP3A4 metabolism. So our solution is actually a combination product, or combination products, where we combine oral taxanes with ritonavir, so those tablets can be taken by patients at home; they don't have to come to the hospital, and as I will show you, also have significantly less serious side effects. So for those of you who are not familiar with this, this is a typical representation of the difference between a pharmacokinetics curve, concentration of drug over time exposure of a typical IV compound, intravenous compound administered, and an oral drug, and you'll see a major difference. With the intravenously administered drug, and I'm assuming you can imagine how that happens, is that you get a peak concentration immediately because you directly inject it into the bloodstream, and then it drops off. With the oral formulation, you get a slightly different shape of the drug distribution curve, or the concentration over time curve, which is more gradual. And what you will see is that despite the fact that you see this peak concentration with IV first, actually the amount of drug exposure can be the same. The total drug administered over time can actually be the same between the oral and the IV product. And that's what we've seen in our early phase 1 dose-finding and pharmacokinetic studies with the oral product that we have. The first product, the lead product, is a horrible acronym, MOTO-DOC O6R. MOTO-DOC O6R is the oral tablet dose-doxorubicin tablet, the lead product combined with ritonavir. And what we've consistently seen is, as displayed here, that we see similar exposure area under the curve, but a significantly lower peak plasma level, and the importance of that I will highlight at the end of my talk. So this is what we've done in finding the right target indication for this lead product. We've done a phase 2b study in metastatic castration-resistant prostate cancer for patients that are suitable for treatment with a taxane. We compared the oral product, the oral combination product, oral docetaxel, with intravenous docetaxel, standard of care, 75 milligrams per meter square. And actually, we had two dosing cohorts in the experimental arm, in the MOTO-DOC arm, and I'll explain in the next few slides what happened there. So we started out with a relatively high dose of the oral combination product. You can forget about the dosing schedules that are displayed on the left-hand side of the screen. Basically, what we are doing is, in this example, giving patients 50 milligrams, a flat dose, 50 milligrams of docetaxel on a weekly basis. So we have 50 milligrams, and we repeat that every week and compare that to the standard of care, IV docetaxel. So what we saw with this first relatively high dose cohort is that we got an improvement in some of the key toxicities of the IV product. However, we also saw an uptick in some of the other toxicities, in particular GI toxicities, gastrointestinal toxicities, and that's something we didn't want; that didn't fit the target product profile that we had in mind, not only replacing IV but also having less toxicity. So that's why we dropped down the dose. We took a dose that was also safe and efficacious from our phase 1b study, so 40 milligrams, a flat dose on a weekly basis, and there we saw a comparable amount of GI toxicities, but more importantly, a dramatic drop in some of the key toxicities of the IV product. So basically, we saw no neutropenia, which is the main dose-limiting toxicity of IV docetaxel, and certainly didn't see any severe toxicities. So the obvious question next is, if you look at the low dose, that's all fine, that you reduce the toxicities, but do you have equal efficacy? And the answer is yes. We saw in this, these are small patient numbers, although we did a 100 patient study. So we divided it up into subgroups per dose cohort. And here you see, if you look at objective response rate, biochemical response, actually the oral product is even slightly better. So the takeaway message from that trial is definitely equal efficacy of the oral product versus the IV product, but significantly less toxicities in some of the key toxicity areas. So in summary, we are focusing on developing oral formulations of important taxane drugs, which have some significant drawbacks: the inconvenience of going to the hospital, painful infusions, and lots of unpleasant side effects. And actually, and I promise to get back on that, so our explanation, actually, we've done some work on that, is the difference between the pharmacokinetic profiles is actually causing the difference in the clinical profile because we believe, and we've demonstrated, that the activity of the drug is driven by the exposure, by the area under the curve, while some of the toxicities are driven by the peak plasma level, the C max that you don't have with the oral product. So what we currently are developing, or have been developing, is a phase two-three seamless Phase Two-Three registration trial that we want to take forward, and we need 6 million euros in funding to get the phase two portion of that pivotal trial started, and I've got about eight seconds left. Thank you. Applause.
