The First Principles Of Radiopharmaceuticals

Webinar hosted on Dec 6th, 2021 - Download Slides
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Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Good morning, good afternoon, and good evening everyone, and thank you for attending POINT Biopharma’s “First Principles of Radiopharmaceuticals”. My name is Daniel Pearlstein, Associate Director Corporate Strategy here at POINT and I’m honored to be joined by my colleagues here to introduce to you how we think about radiopharmaceuticals. You’re joined by almost 400 registrants throughout the investment community, potential partners, as well as academia who are here to learn from us here from our downtown Toronto office, and you’re joining from North America, Europe, and Asia all over the world, so thank you so much for taking the time.Just a bit of a legal disclaimer as POINT is a publicly traded company, standard slide here up front. A bit of background, and this is really the only POINT-specific slide that you’ll see here, is POINT is creating a platform for next generation radiopharmaceuticals. The company is publicly traded on the NASDAQ: PNT, went public in July of 2021 earlier this year, and led by a deeply experienced mission- and vision-driven management team this company is looking to create a platform for next-generation radiopharmaceuticals. The company has a 100% owned manufacturing, deep expertise and relationships in supply chain, and as well as both late stage and early stage programs. Again, thanks for joining us. I’ll introduce my esteemed colleagues here as we pan over to them here shortly, we’re joined by Chief Executive Officer Dr. Joe McCann, co-founder, Chief Medical Officer Dr. Neil Fleshner, also a co-founder, and Vice President of Discovery and Translational Sciences Dr. Robin Hallett.So big picture for you is a bit of background. Joe was previously CEO and President of CPDC and helped set up their contract manufacturing radiopharmaceutical platform. Dr. Neil Fleshner, another co-founder, is a practicing uro-oncologist, trained clinician in urology and epidemiology, and his journey with radiopharmaceuticals really started with a mission to help his patients. And Robin being experienced in solid tumor drug development is a key person at the company to help our earlier stage platforms. So with that I’ll turn it over to Neil who will give you a little bit of a landscape of where radiopharmaceuticals fit into the treatment paradigm, Neil take it away.

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)Thank you very much Daniel, and it’s a pleasure, good day to everybody on the webinar. My name is Neil Fleshner and really as a practicing oncologist, I think it’s extremely important for the viewers today to really understand how clinicians treat cancer, and when a patient is diagnosed with cancer today, it really represents a panoply of treatment opportunities that really go back really into the late 1800s when the concept of using surgery to remove tumors was first applied. Then in the early 1900s with the discovery of x-rays, external beam radiotherapy came on board, the chemotherapy era then came in the 1950s really out of, it sounds horrible but, out of chemical warfare, and then we had our immuno-oncology revolution in the late 1990s and in the past decade. And these are sort of four pillars of oncology but what we believe certainly is there’s a new emerging pillar on oncology, and that really is the whole field of radiopharmaceuticals. When we think in the future in the next five to seven years we’re going to see radioligand therapy, which up till now has been used in a small volume of cancers, and a small number of indications, we are going to see this new form of cancer treatment become clinically relevant in common cancers; prostate cancer around the corner and other solid tumors and thus this will represent a new pillar in cancer therapy, a fifth one if you will.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Robin why don’t you take us away for the First Principle of Radiopharmaceuticals here.

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍Great thank you Daniel for hosting and just wanted to thank the audience for tuning in, and the way radiopharmaceuticals work is by delivering radiation to the tumor and the more radiation you’re able to deliver to the tumor the more likely likely you are to kill tumor cells. And this is fundamentally a different mechanism of action than traditional targeted therapeutics as it relies, it’s much less dependent on understanding the signaling pathways as well as biological processes required for tumor growth. Ionizing radiation delivered by radiopharmaceuticals can damage DNA, this can be a direct DNA damage through strand breaks, this can be single-stranded DNA breaks as well as double-stranded DNA breaks, which is dependent on both the amount and type of radiation delivered. Ionizing radiation can also induce radiolysis of H2O molecules which can lead to peroxides as well as hydroxyl radicals which can go on and indirectly damage DNA as well.What we know about radiopharmaceuticals today is they can have monotherapy activity in advanced cancer patients, but there’s also a very strong scientific rationale that underpins potential for combination effects based on synergistic mechanism of action particularly with immunotherapy as well as agents that target DNA repair pathways and so really what we see today is that radiopharmaceuticals are prime candidates for combination with checkpoint inhibitors by virtue of the immune amplifying effects of radiation and potentially based on what we know about the ability of radiopharmaceuticals to induce DNA damage, PARP inhibitors would also be a rational combination partner.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍So Joe why don’t you kick us off on the Second Principle here.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Sure definitely, so an unstable isotope will emit radiation until it stabilizes. So we’re going to start at the beginning here, very basic with most basic form of matter which is an atom. Atoms are made up of protons electrons and neutrons and that combination creates what is an element. So as you look at the elements in a periodic table they’ll have different combinations of protons neutrons and electrons, and that makes them what they are. And when you look at something like hydrogen where it has one proton in the nucleus as you add more neutrons to that you actually create unstable versions of that called called isotopes of that element. And shown here on the screen right now when an element when that nucleus is unstable it actually drives towards stability, and when it does that it releases various particles. So shown kind of on the top left hand corner of that diagram there that’s when it’s emitting things that actually can be detected and used from an imaging standpoint, and in the bottom left-hand corner of that those are particles that it emit that actually cause damage in or can physically interact with DNA.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Neil why don’t you take us over a little bit of how the multi purpose of radioligands in clinical practice here?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Right so you know again as Joe McCann just mentioned, certain isotopes are ideal for imaging, other isotopes are ideal for therapeutic value, and really what’s very interesting about this emerging field of theranostics is we can take the same molecule, and the best way to just to think of what a ligand is it’s sort of like a key that will fit into a lock so all the cancer cells on their cell surface would have a keyhole if you will, and what happens here which is kind of interesting is you could attach to the key like a key chain, if you will, a molecule that would emit for example a PET, a positron or emit a gamma particle, and you can then do what’s called a PET scan for example. And this is an example of what we call PSMA PET scan, so a gentleman with advanced cancer we inject this PSMA imaging-based isotope into him and we can get these nice pictures. You could then change the keychain you could then take out the actual imaging piece and then put a therapeutic isotope, and then actually get tumor kill and a reversion of his cancer in this case, and you can see how the spots disappear. So what’s really attractive about this is by using the imaging it’s essentially a biomarker, so we could not only identify where cancer is but more importantly it can be used as a theranostic, it’ll tell us which man is likely to do well in this particular case, or in other cancer which women is likely to do well, by pairing the imaging and the therapeutic.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍And that’s a really good segue into our third topic where Joe maybe you can kick us off here as well.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Sure so this is medical isotopes must have goldilocks properties. So looking at all the medical isotopes out there, you know what you need to pick from here are ones that are commercially available, have a have a half-life that is of a time frame that can be medically useful, have an emission type that is suitable for what you’re looking to do is either imaging or treatment, and then as well has an energy transfer, and this more speaks to the treatment side where the delivery and the energy associated with that particle being released from the nucleus will actually do damage to the DNA.And when we take this and apply it to alpha particles, so we know there are over 100 alpha particles that are known and then as we look at this through that funnel, we actually go from 100 down to 10 that would actually have the properties that would be suitable in use in medicine. When you actually look at that there’s even smaller numbers that are actually commercially available.Then if we take a step back and just look at all the different types of radioisotopes that you have; you have alpha decay which is used in therapy these are some common isotopes or radioisotopes that you’ll see in clinical use; you have beta particles such as lutetium which is often talked about a lot in in this space; you have positron emitters and these are used for PET imaging, fluorine or F-18 is a very common isotope in this space as well as gallium; and then finally you have a gamma emission and that occurs and you can use that for SPECT imaging so another form of imaging and it’s interesting here is you actually have lutetium show up which is an example of a radioisotope that can both be used for therapy as well as imaging applications. And looking across the whole clinical landscape and on clinicaltrials.gov getting an understanding of how these are being used right now lutetium-177 still carries a lion’s share of the work.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Neil can you maybe also add to that as well from your day-to-day? You probably get to see that in your practice.

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah no question I mean there’s a lot of excitement obviously in my field urologic oncology around lutetium-based PSMA molecules. There’s a lot of pivotal phase three trials and really a host of other studies, but really also interest in other isotopes particularly actinium, of course we’ve also known that radium-223 has been also in the landscape for prostate cancer, albeit not a true theranostic because it doesn’t have that specificity that the PSMA-based therapies do. So again, I think lutetium right now is the hot molecule but certainly a lot of interest particularly in alpha emitters like actinium.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍And then how does this kind of translate to actually being used in day to day?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah I think what’s also really exciting about the field is I think if you look at the first generation of radiopharmaceuticals, they have these connotations of lead-lined rooms that patients are placed in and can’t have visitors, and then these are injected and patients stay there for days, and perhaps even when they go home they can’t be close to loved ones. And some of these novel isotopes really don’t have those properties, these can now be administered almost like an intravenous infusion like you would have for a chemotherapy or for a rheumatologic drug, so these can be delivered, and as you can see on the on the slide, there’s over 1400 outpatient clinics right now that can deliver this in the U.S. alone, so we will see an increasing supply chain of ways to deliver these therapies. But suffice it to say the modern radiopharmaceutical agents, the next-generation ones, are really going to be easy to deliver.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Robin how does that exactly fit into how you think about our next-generation programs and where the field is going, with respect to how easily that they can be administered in an outpatient capacity?

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍Well I think it just increases our ability to bring more agents forward and have opportunities to test new and better agents, and that’s really something I’m focusing on right now.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Great. Now for the Fourth Principle. A lot of people don’t really have a great appreciation for this, but Joe this is a good section for you to start us off here.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Sure so, medical isotopes are not commodities. We can talk a little bit about this, and I think what’s really important to know in this space is that medical isotopes are driven out of ultra rare input materials, have to gain access to reactors and cyclotrons which are not readily available worldwide, and then finally require purification processes, and as well these purification processes are not always the same, and it’s not a like for like, as you go through production of lutetium, it can be carrier added lutetium versus no-carrier-added lutetium – so there are differences among this amongst this, so that makes them not interchangeable. I touched upon the raw material piece, which you’re looking for very ultra ultra rare input material that has to go into these reactors, we have a very limited supply of neutrons in these reactors to actually irradiate them, and then as well you have this purification process tied to this. So all of these actually lead to the last piece which is they cannot be stockpiled. So once you’ve made an isotope it starts decaying and you can’t put it up on the shelf, so it has to be immediately put into a drug product. And here’s some examples of recent news articles, that have been put out there just highlighting the consistent concern that is related to medical isotope supply. This started with moly really the world being exposed to this in 2009, and that’s really been advanced as there’s greater and more interest in this use medically, there’s more news coming forward that this still remains a really rare source of materials.And then although there are very exciting emerging isotopes that are coming, terbium being one of them, astatine being another, the one aspect to that is you still have to deal with these challenges, you have to find those rare rare input materials, you have to purify them, you have to come up with new purification processes, and again you have to get access to those cyclotrons and reactors, but I think there’s good news – and if you advance to the next slide – there’s a lot of effort being put in, now that we’ve seen that these work, Neil touched on this a little bit earlier that the clinical data is very positive, there’s a lot of effort being put around cyclotron technology, reactor technology, and purification technology that is actually bringing forward these isotopes for use, which is exciting for POINT, as we and Robin put these into our preclinical programs, for Neil as we can get these into our clinical programs, but I think there’s a large number of tools that puts in our toolbox and we’re excited to take these forward into the clinic.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Neil just going back a slide, about the chicken in the egg idea of you need to have trials to get the isotope you can’t get the isotope in order to get the trials, can you talk a little bit about that kind of dynamic from what you see in the clinic?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah it’s an iterative relationship it’s going to be one step, two steps forward, perhaps a half a step backwards, however as Joe mentioned there is an effort now to try and ramp up commercial scale. You know a good example is actinium where there’s a lot of interest in actinium right now, but you could only source it through the Department of Energy in the U.S. and there is essentially not even enough to meet the clinical trial demand out there today. So this will change, new companies coming on board, new processes coming on board, but the key piece is I still think because of the comments made that it still won’t become a commodity even five or ten years from now, because of the specialization involved in sourcing and manufacturing and separating these isotopes.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍And now a little bit into the logistics Joe, having run a facility like this before, how does that come into play on top of the supply or manufacturing, now it’s actually getting it out the door?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Yes once that isotope has arrived then you have a really quick turnaround that has to go into getting that into the drug product, and then getting that around the world. And typically in some of these cases you only have about four days to go from isotope arrives on site, incorporation, and then shipment to clinic. So that means that your locations that you choose for your manufacturing facilities are very important, and it also means a real education and working very closely with regulators on this.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Now leading to our Fifth Principle, Robin why don’t you kick us off again here?

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍Great, so radiation toxicity is the limiting factor of a radiopharmaceutical. And really an ideal radiopharmaceutical targets tumors very quickly and it does not target normal tissues, and this minimizes the side effects with the radiopharmaceutical.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍And Neil for some context can you tell our audience what we’re kind of looking at here?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah so basically what we’re seeing is the accumulation of a radiopharmaceutical in a patient, but I think you also see some, the blue there, are some normal organs, the kidneys. So one of the tricks like any drug that’s ingested it tends to be eliminated from the body either through the kidneys or through the liver and that’s generally how drugs are excreted. So what we need here is to have drugs that attack the tumor when injected and ideally stick to the tumor as long as possible, and are either minimally excreted, or if they are, they’re excreted quickly, with sort of a quick transit time through those organs so that there’s minimal exposure. But of course the other piece is there are when we talk about these ligands they’re not necessarily as specific as we wish they were, particularly the first generation. You can see here this is a PSMA-based PET scan in a patient and for those of you who are watching those two black balls in the middle of the abdomen are the kidneys, and the kidneys light up because PSMA is not only on the prostate cancer cells but there is some PSA in parts of the kidney anatomy as well, and there’s actually also the salivary glands what looks like eyes, eye sockets, are actually salivary glands on those pictures. So the salivary glands also share properties of PSMA, so what right now what limits some of the toxicity of the first generation agents is the fact that renal function could perhaps be impaired or salivary gland, you know dry mouth is the manifestation of that, function can be impaired. So as novel agents new generation radiopharmaceutical agents are developed we want to see them have maximal binding to the tumor but minimal what we call off-target, meaning minimal salivary glands in this example and minimal kidney effects, so that really we could reach a point where these drugs are truly specific even on a molecular level.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Robin I know that you spend a lot of time thinking about the kidneys, so can you maybe explain a little bit more about kind of what’s going on here in the diagram and how that also relates to some of what Neil was just saying?

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍Yeah no problem and really the way I think about this is I would call this on-target off-tissue toxicity, and we know that kidneys and salivary glands express PSMA, we know that prostate tumors express high levels of PSMA, and so PSMA radioligands are effective at treating prostate tumors but they also can travel to the kidney and salivary glands as Neil mentioned. And so we want to think of ways to prevent this and with first generation PSMA ligands really the focus is on radio-protection of tissues like the salivary gland or uptake prevention, but really what we’re most excited about I would say is how do you get agents that don’t even go to these normal tissues or have drug properties that really bias the uptake into the tumors themselves, rather than seeing this on-target off-tissue toxicity. And there’s been a number of projects and a number of scientific efforts behind understanding what should a next generation ligand look like, and what are the properties of next generation ligands, focusing on really specific tumor uptake and specific tumor retention. And some of the focus has been on new targets, so really specific target expression within the tumor relative to normal tissues, tuning drug properties such as pharmacokinetics to really try and bias the distribution of a radiopharmaceutical to favor uptake and retention within the tumor, and then really new techniques that I would consider transformational in terms of their potential to eliminate normal tissue uptake by exploiting microenvironment chemistry within tumors that you don’t find in normal tissues to get tumor specific activation of radiopharmaceuticals, which I think could have a really transformational effect and really eliminate or almost eliminate uptake and retention within normal tissues.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Joe anything to add from your experience from the manufacturing and supply and how far ahead you actually have to make these decisions before you can actually start to hit the ground running?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍So we spent a lot of time in the early stages of the radioligand development focusing on ensuring that it’s stable, and that it’s going to actually work biologically, we need to ensure that it’s also able to be delivered to the patient. So as all the work’s being done in the chemistry and the biology side at the basic level, that’s being translated very quickly to understand how these will actually behave once you get them into a pharmaceutical solution. So all of that starts right at the beginning of the discovery of these molecules.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍In summary of our presentation portion of the session today why don’t you guys kind of just give your two thoughts, about a minute or two here, of how these all connect together?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah I can start, I think this is a really exciting time to be in the radiopharmaceutical business, it’s also an exciting time to be a clinician looking after patients because just around the corner, I’m quite confident that we will have effective new roads new therapeutic options for patients, even for tumors that perhaps have historically been fairly refractory to immuno-oncology and to chemotherapy, and using these principles. I’m also really excited about bringing combinations to the clinic because I think this will help realize sort of this this dream. My other sort of principle that I could see radiopharmaceuticals moving into is much earlier in the disease. I’m very interested, particularly as a surgeon, in taking patients who I know that I operate on for a tumor but I just know the cancer is going to come back, could be six months, one year, two years, five years, but I know it’s going to come back, can we at the microscopic level use these agents to sort of mop up the residual cancer in the body, and, this has been done in thyroid cancer using a radiopharmaceutical for decades and I think the modern radiochemistry, the modern isotopes, may actually make that for me as a surgeon a reality.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍So Robin why don’t you give your two cents and then we’ll finish it off with Joe?

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍Great I’m excited like Neil but I’m also very compelled scientifically. In the past I focused on a lot of targeted agents where we’ve needed to understand tumor biology and the signaling pathways tumors used to survive and if I think with radiopharmaceuticals it offers you an opportunity to kill tumor cells without necessarily understanding how tumor cells work. And that is one of our the most complicated things to understand from a tumor biology standpoint, and so I find the delivery of ionizing radiation specifically to tumors but as well systemically to tumors to be very compelling and I’m just really excited to see what comes next.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Yeah thank you Robin, I agree with both Neil and Robin, this is an exciting time for these drugs. I think we’re just right at the tip of the iceberg though, I think there’s so much more to come with all of these advances in the supply of these products, with new isotopes emerging, with those supplies emerging, we’re going to be seeing a lot more coming out of the preclinical pipelines, and just given the excitement in prostate cancer alone right now, I think if you start to expand into larger indications like colorectal cancer, breast cancer, or some very underserved indications like pancreatic cancer, I think that’s just going to grow. And I think there’s a real bright future here and I’m very happy that POINT’s part of it.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Great, that sounds great, thank you guys, and that concludes our discussion part of our session, and we’ll now switch over to Q&A for the panelists. We’ll have some of our covering research analysts ask questions, and first up is Kemp Dolliver from Brookline Capital Markets, you’ve just been promoted to a panelist so your line is now open, thank you very much Kemp.

‍Kemp Dolliver – Director of Research and Senior Analyst (Brookline)
‍Thank you. Two questions related to supply and manufacturing. First relates to your location in Indianapolis, which is quite logical and also Novartis is planning to build a facility in Indianapolis, are there any other advantages to being there and also does the development of a critical mass of manufacturers there help create some advantages with regard to how the supply chain will ultimately function?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Yeah those are great questions Kemp. So I’d agree with you Indianapolis is an excellent location from a logistics standpoint, you’re able to reach 50% of the U.S. population and probably a majority of the Canadian population simply by driving, the remainder can be hit by air. So the advantages of being in Indianapolis is that’s one big reason, another one is it’s just down the road from the Missouri reactor, so it has ready access to neutrons which is about five hours just due west of the Indianapolis site. The other key part there is there are other pharma companies already there as well so a great source of talent including the universities that are there too and with the key aspect of others it’s really becoming a radiopharmaceutical hub, Telix is there other companies that are coming there, so I think you’re going to just get this real focused, Purdue university as well has a focus in radiopharmaceuticals, so all of that coming together is really going to make Indianapolis that mecca of radiopharmaceuticals going forward in the future.

‍Kemp Dolliver – Director of Research and Senior Analyst (Brookline)
‍That’s great thank you. If I can ask about another related topic so you mentioned terbium and astatine as emerging isotopes, but with supply constraints, can you tell us what’s being done with regard to increasing supply?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Sure yeah so speaking to astatine and terbium which are two very exciting isotopes that are coming forward, astatine is exciting because it has a single alpha that emits, so unlike actinium which has four different alphas so if you have any off target that can do some real damage, astatine could be very pure alpha that once it delivers that one alpha it’s done decaying. And some of the challenges there is it’s produced on cyclotrons and it has to be produced locally because it only has a seven hour half-life. So those are some challenges associated with it but these types of challenges have been overcome in the past and I think that clinical evidence comes forward for that as a modality I think that will drive the development of the manufacturing capability on the various cyclotrons that are located all around the U.S., Canada, and Europe. With respect to terbium, that brings forward probably a particle that not a lot of work has been done on, and these are Auger electrons so they actually create kind of like a cluster bomb when they emit very very localized, but it is showing some very interesting results preclinically that rival or could be better than lutetium, and its production is actually limited to again getting access to what you put in the reactor and bombard with neutrons which is called gadolinium, and so that is a constrained supply source, there is currently no suppliers out there, and we are looking for and working with some people to be able to bring that forward to irradiate in reactors and bring terbium into our pipeline, and look and see how that compares against other isotopes that we have in our toolbox.

‍Kemp Dolliver – Director of Research and Senior Analyst (Brookline)
‍Great let me turn over the microphone to another panelist.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Okay great next up we have Boris Peaker from Cowen, you’ve been promoted to a panelist and ask away when you’re ready.

‍Boris Peaker – Managing Director and Senior Research Analyst (Cowen)
‍My first question is how do you see the PSMA targeting radiopharmaceutical space evolving obviously? There’s some competition there, I mean if we see in terms of approvals and data updates over the next several years, maybe you could comment on that?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Sure I’d be happy to take that one. So yeah there’s a lot of excitement, I think we’ll see approval post chemotherapy of PSMA-617 in the next calendar year. I think we will see additional clinical trials many of which have started including our own in the pre-chemo space move forward, and then again really excitingly I think we’ll see moving at least for some IND enabling studies probably next calendar meaning 2023 coming in with some of these next-generation PSMA molecules, which I think will start looking at probably in earlier disease and perhaps even later disease, perhaps with actinium and again this concept of mopping up cancer but also looking at strategies in terms of is there a radiopharmaceutical solution or option for men who have already completed lutetium PSMA therapy. So I think that’s how we’re going to see change in the coming couple of years with PSMA.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍So maybe just to add on to that, the experience that we are seeing with men that are post lutetium PSMA and how they’re responding to actinium?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah right now there’s a host of literature that’s starting to come through that interestingly even though the PET scan could be avid for the PSMA, once lutetium stops working even though the PET scans can be avid, somehow a resistance is developed, and if you come in with actinium PSMA you can get additional responses. And so that’s again going to be an exciting, and may introduce frankly the third radioisotope for prostate cancer, you have radium now we have lutetium, and now we’ll see actinium being interrogated, so again this is really exciting for men’s health.

‍Boris Peaker – Managing Director and Senior Research Analyst (Cowen)
‍My second last question is, can you comment maybe on the physician economics of using radiopharmaceuticals, maybe now versus how it evolved over the last decade or so?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Joe do you want to handle that one? I think you’re talking about reimbursement?

‍Boris Peaker – Managing Director and Senior Research Analyst (Cowen)
‍Yes I’m talking about reimbursement and the financial incentives for using radiopharmaceuticals versus some other alternatives for oncologists?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Right so I can go ahead and start with this one Neil. So in the community based setting which is really right now driven by chemotherapy and based on the various reimbursement schemes that exist, this will actually position that quite nicely with respect to what physicians are currently experiencing with chemotherapies and other treatments that are done in the clinic. If you look institutionally especially when you have cost of goods advantages you can actually be able to offer these in at prices that are going to be very fair and reasonable that will allow this substitution into the current treatment paradigm that won’t see an impact on hospital budgets.

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍If I could just add in, I think the last I guess six weeks have almost been pivotal in the paradigm of managing advanced prostate cancer. So you had at ESMO released the results of the PEACE trial which for the first time demonstrated that adding chemotherapy up front with ARATs in the hormone sensitive space improved outcome. Literally two or three days ago, Bayer announced without actually announcing that their top line data from their ARASENS trial which does essentially the same thing, daralutamide plus chemo, so I think we’re going to see chemo and ARATs pushed way up to HSPC, and then when you’re going to be in the post ARAT space, certainly if you look at THERAP and if you look at other trials, I think that’s where we’re going to see the sweet spot for the non-chemotherapeutic agents like PSMA-based therapies perhaps like PARP inhibition for example. So I don’t think we’re going to be competing with chemo because it’s all going to be pushed upstream.

‍Boris Peaker – Managing Director and Senior Research Analyst (Cowen)
‍Great thanks for taking my questions.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Thanks Boris. Next up we have Neha Singh from Jefferies. We’ve just promoted you to a panelist, your line should be open here shortly.

‍Neha Singh – Senior Associate (Jefferies)
‍Thank you so much for giving this presentation, so my question is in line with the ligands, so one thing is like improving the radioisotope properties and another point you guys mentioned is how can you improve the ligand’s property itself. So can you just give some feedback on that side? On PSMA versus other ligands, how is the field improving on that aspect?

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍Great and thank you for the question, and I think this is something everyone’s thinking about, is how do you get better ligands. And I think one of the ways is to go after new targets, and targets with more specific expression on tumor cells relative to normal cells. The biggest issue for PSMA is what I call on-target but off-tissue effects, and this is likely going to be problematic for multiple ligands, and so really the thinking is how do you decouple on-target off-tissue from on-target on-tissue in the tumor, and one of the ways to exploit that is potentially by thinking about other properties in the tumor beyond ligand expression and try to use some of those properties such as a different enzyme profile for example, to potentially activate ligands specifically in the tumor microenvironment, and really target a protein that’s expressed in the tumor and normal tissue, but only get activation within the tumor to get selective retention and uptake within the tumor. And so I think that as an approach could be potentially transformative in terms of the next generation of radioligands.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Anything to add from the other guys?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Well I think Robin explained it extremely well, I think we will also see in addition to tumor microenvironment activation, just better ligands themselves, will sort of just improve the therapeutic index between, any drug any agent has a therapeutic index and I think the wider it is obviously the higher you can go with dose, or the lower you can go with less toxicity. So that’s that dual strategy right, it’ll be better ligands but as Robin mentioned, some sort of tumor microenvironment-activated ligand would be sort of a holy grail in the space.

‍Neha Singh – Senior Associate (Jefferies)
‍All right thank you, thank you so much.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Okay next up we have Ted Tentoff of Piper Sandler you’ve been promoted to a panelist, you can ask away when you get on.

‍Ted Tenthoff – Managing Director and Senior Research Analyst (Piper Sandler)
‍Great thank you so much for hosting this today, this is really informative. My question’s specifically on FAP as a target and you guys highlighted the opportunity to start to use radiopharmaceuticals more broadly, and I kind of wanted to use that agent specifically to discuss other cancers where you think radiopharmaceuticals, especially with the profound efficacy, could be applicable? So using that as an example where do you see other opportunities?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Sure I can start and I’m sure both Robin and Neil will have a lot to add to this. So FAP as a target, as many may know is expressed in 90% of epithelial tumors but not on healthy tissues, so you’ve got this, if you think of from an imaging standpoint if you image with FAP you’d have a very bright bright tumor or tumors in a metastatic patient, but none of the other organs would appear on that PET scan, so it’s a very very clean profile which is why we like it because you can enrich that isotope in the tumor, and as Robin mentioned earlier the more isotope in there, the longer it sits in there, the more damage it’s going to do. But what I’m going to do is, with that profile Neil, how do you look at this clinically and where this can go?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Right I mean it’s challenging actually, from a clinical development point of view when you have a drug that that potentially can work in dozens of cancers, where to start and I think we put a nice program together to do that but, again I think because we’re fortunate to have imaging as a biomarker, our plan is to bring this into both common cancers of which that it can be used as another line of therapy but also explore as we’ve talked about some cancers that historically have been resistant. Pancreas cancer is one of them in particular where there’s a huge societal need to move the needle in helping those individuals who usually get sick quite quickly. So we’re going to take that dual approach and also learn as we enter the clinic, which will be imminent, about this particular target.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍So to add to that Neil I think right now there’s a big discussion in the prostate cancer space with the PSMA targeted agents, neuroendocrine for a long time has been treated, thyroid cancer. How do you think about going in having that new dialogue, now we get to have dialogue with physicians that treat colorectal cancer, that treat lung cancer, breast cancer, so these very large indications that there still remains a lot of unmet need, a lot of patients die from those cancers, how do you see those discussions going and do you think riding this wave of what’s coming out of prostate cancer is going to continue to carry on to those larger indications?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah I think they will, the whole oncology community is excited, it’s not like we’re curing people with metastatic breast or colorectal cancer, so we do need additional lines of therapy, and certainly what it excites me, I mean when I look at Keytruda which started off in one particular tumor now has I believe 16 indications, so as time evolves and our studies evolve over the next year and year plus, we’ll really get a good idea of how this is going to shake out in the clinic.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍And speaking of preparing for that, I think Robin can probably comment on something that he probably thinks about all day?

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍So you know Neil I’m glad you raised pancreatic cancer for FAP because I think to me the stroma often gets ignored from a therapeutic standpoint, but also when people think about what are the important cells to target in tumors and I think in many pancreatic cancer patients there’s actually more stromal cells than there are epithelial tumor cells, and so by targeting radiation to the stroma especially with isotopes where the path length should allow penetration beyond the stroma, I think you have an opportunity to increase the amount of radiation you can deliver. And this is going to be true of desmoplastic tumors beyond pancreatic cancer but I think pancreatic cancer is a good example of potential benefits that come out of not just from specificity you see for FAP, but also really the amount of dose you can deliver by targeting such a common cell type within the tumor.

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍You know it’s funny because everyone says pancreatic cancer is radioresistant I mean that’s just a function, no cancer is radioresistant every cell as we talked about earlier could be killed with radiation, it’s a matter of toxicity adjacent organ damage with external beam, and that’s what’s really limited this strategy in pancreatic cancer. So using this radiotheranostic approach we overcome that, so hopefully we’re going to we’ll make a dent in that particular condition.

‍Ted Tenthoff – Managing Director and Senior Research Analyst (Piper Sandler)
‍And maybe as a quick follow-up, because hand in hand with that is the opportunity to expand logistically but beyond concentrated centers into more community centers with radiotherapy. So how does that occur over the next decade or several years as there is the opportunity to treat more cancers? How do you actually move outside of the centers and into more of a community setting?

‍Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍I think we touched on this earlier I mean I think we as we showed you a map dotted with infusion centers I don’t think this has to be limited to centers of oncologic excellence and academic tertiary centers around the world, because of the nature of these agents the isotopes involved, the radiation safety protocols being safe first but not so rigid like in with the earlier generation, I see these drugs no different than any other anti-cancer treatments in the coming years.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍What about the radiation oncologists, nuc meds, etc.? Aren’t there different kinds of professionals that are starting to get familiar?

Dr. Neil Fleshner, M.D. – Chief Medical Officer (POINT Biopharma)
‍Yeah, think we will see the emergence of almost a new oncologic specialist, you know medical oncology only grew out of radiation oncology surgery, I mean these specialties come up as the technologies come, and I suspect we all see some mutated hybrid between a radiation oncologist, a medical oncologist, a nuc med doc.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Yeah I completely agree with that and I think there’s evidence of this already being very important in the treatment space with our first two clinical sites that were open for our SPLASH trial were in a community-based setting. If you look at the breakdown of infusion centers versus kind of institutional or large nuclear medicine type centers versus smaller more community-based centers, it’s about 50:50 already so there’s already this uptake there, there’s already the capacity and the ability to handle these much easier to handle isotopes in the past with iodine-131, so I think all of that is starting today and I think prostate cancer is really going to drive the growth of that tremendously just given the size of the prostate cancer indication that’s going to just continue to push that out, and I think as you look at those community-based chemotherapy infusion centers they’re going to see this opportunity to offer something new to their patients, that they can do in their setting because it’s so straightforward to handle.

‍Ted Tenthoff – Managing Director and Senior Research Analyst (Piper Sandler)
‍Great very helpful, thanks.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Okay looping back to Kemp Dolliver of Brookline who had a follow-up question, we are promoting you to a panelist right now, should hop on here again in a second.

‍Kemp Dolliver – Director of Research and Senior Analyst (Brookline)
‍Excellent could you talk about the timetables and details of executing some research in combination therapies?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍Sure definitely, so I’d say that’s underway but I’d turn to Robin here to touch on what we’re seeing out there but also what POINT’s looking at doing as well.

‍Dr. Robin Hallett, Ph.D. – Vice President, Discovery and Translational Sciences (POINT Biopharma)
‍Yeah from a preclinical standpoint I think it’s such an interesting field for drug development because you don’t necessarily have, you have a different kind of foundation I would say, than some of the inhibitors of specific mechanisms of biology, and I think one of the things we’re thinking about at POINT very much is how do we fully exploit the potential of a radiopharmaceutical with things like immunotherapy or inhibition of DNA repair pathways and how do we understand the fundamental biology that sort of integrates whether or not a cell dies based on the amount of radiation received, or is there a T cell close by that can kill it, or if we inhibit a DNA repair pathway, and so we’re really trying to do a lot of deep biology that will inform our clinical plans so that we move forward in the most logical and rational way. Yeah and I would also say, investigator initiated trials looking at these combinations, some have started others are in discussion with leading academically minded clinicians, so this I think you’ll see all this emerging in the next three to four quarters.

‍Kemp Dolliver – Director of Research and Senior Analyst (Brookline)
‍And what are you thinking with about with regard to your time frame? Would it that be in that three to four quarters time frame?

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍Isn’t there an investigator initiated trial that we can speak to a little bit?

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍So there’s definitely investigator interest, nothing that we can speak to specifically right now, but there’s definitely a large amount of investigator interest I would say from our preclinical programs. That work is initiating now so probably within the next 18 months to two years we could see some data that we that we can present, hopefully faster, as that moves forward in setting up the animal models. But I would say just to speak to that there’s activities already going on that we see in the academic centers definitely a lot of interest coming and directed at us to support some of these areas which we’re excited to do, and then Robin and along with our CMC teams and our radiochemistry teams are focusing on how to build that into the whole preclinical program that POINT has going, but I would say it’s there’s a lot of excitement coming and we look to give an update probably in the next year sometime.

‍Kemp Dolliver – Director of Research and Senior Analyst (Brookline)
‍Great thank you.

‍Dr. Joe McCann, Ph.D. – Chief Executive Officer (POINT Biopharma)
‍You’re welcome.

‍Daniel Pearlstein – Associate Director, Corporate Strategy (POINT Biopharma)
‍The team here is deeply passionate about creating a platform for next generation radiopharmaceuticals, and we look forward to continuing the discussion with many of you and collaborating for years to come From Neutron To Patient(TM).