Okay, so we're going to get started. Thanks, everyone, for coming here. We're going to start the prostate cancer panel, and from Fusion Pharmaceuticals we have Mohit Rawat, the President and CEO, then Paul Blanchfield, the President of Lantheus, and Scott Koenig, the CEO and President of MacroGenics. So I guess to kick it off, we can start with some more general thematic questions. And so I guess to start there, can you tell us a little bit from your market research and understanding of the general prostate cancer market, how many patients are there, how many will relapse, and give us a better understanding of the standard of care and how that's evolving with Pluvicto treatment emerging? Let's start.
Go.
Mohit?
Sure. So you're going to feed that into your models, I guess?
Sure.
Yeah, I mean, so our focus is mCRPC space, and then it depends. It's the two real epicenters that a lot of people use. So we estimate around 70,000-75,000 drug-treated patients, probably splits like 35,000-25,000 to 15,000 or so. And then obviously there's the metastatic hormone-sensitive space and the BCR space, which are pretty substantial. And I mean, the one area which people call non-metastatic CRPC is really going away because with the PSMA PET imaging tools, like Paul can talk about, really, you're able to detect the tumors much better, especially PSMA-positive tumors. And I would say Pluvicto is really the starting third line, mCRPC, but we'll see after PSMAfore approval likely move second line and above.
Paul and Scott.
Yeah. I mean, I don't have a lot to add. I mean, obviously it's a large market. There's 3 million men living with prostate cancer in the U.S. That continues to grow from an incidence, more men being diagnosed through great tools like PSA and PSMA. But then fortunately, those men are also living longer. And so we do see that continued growth in incidence and prevalence. Very much agree that RLT has largely been used in the post-chemo setting, but obviously being studied in the pre-chemo and even in the hormone-sensitive. And so still a significant opportunity for growth. I think it's an attractive market given how men present. Guidelines generally support PSA testing at 45 on an annual basis, which helps understand the extent and be able to monitor that.
Now with additional tools beyond just biopsy like PSMA-PET imaging, the ability to understand the extent and amount of disease and to be able to track that over time is a terrific opportunity. 75%-85% of men present with PSMA, which means it's a very targetable disease, recognizing that that is presented in the majority of prostate cancer cases. There still are other non-PSMA-expressed tumors, so there is still a heterogeneity in the population. But there's products in development for some of those non-PSMA targets as well. And so a terrific opportunity, and I think that's why we've seen RLT and PSMA imaging really take off here, just given the size of the population and the targetability of PSMA is a great opportunity. Unfortunately, more men continue to come down with prostate cancer, but they're living longer, so a big opportunity overall.
Yeah, well, I just have a limited add-on to what has already been said, which is obviously the aging of the population, which I'm part of that population, are living longer, and therefore we will continue to see increased incidence of the disease. With regard to the PSMA story, just to add on what Paul said is that as the disease progresses into a later-line mCRPC setting, PSMA expression drops down. That obviously helps a target like we're pursuing for B7-H3, which seems to be expressed both very early at a new diagnosis all the way through late-stage disease. So it lends a great opportunity to address a non-PSMA-expressing story. The only other addition I would argue is that we haven't seen the full story on Pluvicto work played out.
While we are anticipating, even with the hazard ratio setting right now in PSMAfore as is, that the drug is likely to get improved in the chemo-inexperienced population, I think the practice and use of that drug, given the toxicity profile, particularly on bone marrow, may lend the ultimate use for a very late-line population. So even though it may get the label, it may not be just naturally moving up to early line because once you have the toxicity on marrow that is persistent with regard to those patients, then you can't treat them on anything else at that point.
Okay, thanks. So all right, there've been a few recent trials lately that have been significant on rPFS, but mature OS has not been. It's more trending in a negative direction. So maybe let's start with Paul on this. Why do you think that is? And is it perhaps that maybe they don't necessarily correlate, or what are your thoughts on that?
So I think it's a very astute observation. rPFS is fundamentally a surrogate endpoint, but it is the most easily tracked and available kind of earlier, if you will, than overall survival. Obviously, overall survival, the FDA has viewed as effectively the gold standard in improving oncologic treatments. And so that will continue to likely be the case. But I wouldn't say they're not necessarily correlated. I think in many cases, and I'll refer to specifically to PNT-2002 SPLASH trial, which was led by Point Biopharma, now a part of Lilly that's been our partner, as well as Novartis's PSMAfore, although naturally you should go to Novartis for specific questions about theirs, is that in both cases, for PSMAfore and SPLASH, the rPFS data met its primary endpoint.
We saw a statistically significant difference in radiographic progression-free survival for the treatment arm using RLT and the control arm using an ARPI, whether it's abiraterone or enzalutamide. However, due to both of those trials, and I'll point to really trial design, in the pre-chemo setting, the FDA has effectively requested for the crossover to be a potential. So following a control arm of an ARRPI and failure on that, you have the ability to cross over to the treatment arm. And in both the SPLASH trial as well as in the PSMAfore trial, north of 80% of patients crossed over. And so obviously, this is a rather large confounding variable to isolate the impact of the control arm versus the treatment arm. And hence, you see overall survival hazard ratios north of 1, 1.11 for SPLASH and approximately 1.16 based on what Novartis has released.
I wouldn't necessarily say they're not correlated, but they're different measures, and they are driven by the timing of that measure, with rPFS effectively being an interim measure and a surrogate endpoint, whereas OS is obviously the ultimate standard. When you have this crossover dynamic, it's very difficult to isolate the true impact of the products and the treatments that are being studied. Ultimately, we're going to have to wait for that OS data to mature. Now, that hasn't been the case in the post-chemo settings because of the trial design and what the FDA has allowed. Ultimately, we're going to have to wait. Lantheus will be waiting, and I would expect Novartis will be waiting for some of that OS data to mature to further understand what that looks like.
I think it's clear that the products are efficacious when you just look at the surrogate endpoints and that there is a role. Obviously, there's some differences in safety and tolerability, but there is a role in seeing a meaningful difference in radiographic progression-free survival. How that carries over due to trial design, I would say more than ultimately the efficacy of the products remains to be seen. And that's obviously a regulatory question and a data timing question, where at least Lantheus has said that we will be waiting until the second half of this year for more mature, roughly around 75% data maturity of our OS data to understand what that ultimate OS data looks like, with the goal ultimately of it being kind of one or less, and then subsequently having the appropriate conversations with the FDA.
But I think this is more of a trial design question than it is ultimately efficacy of the products. So on that note, right, with the trial design and the crossover, most of these trials are pretty much all of these trials that are pivotal right now are using an ARAT as the second ARAT is the control arm. Is there a better control arm? Is chemotherapy better? Is there something else out there that could help with these trial designs that could help with this question to allow for a decreased crossover potentially for anyone?
Maybe I'll start. So I think the issue that Paul was raising, it's a little bit of a catch-22. So if you don't have crossover, you're not giving patients the chance to get on the experimental treatment, right? So you can have different control arms. You can have chemo in there. But also, so two factors. One, the ethical or the recruitment question comes in. So if you don't have that, how is it going to impact your recruitment? What does it look from an ethical perspective? I think the second piece is look at the real-world clinical usage of these agents. And Lantheus and Novartis and Curium is doing the same design. Their defense is ARPI switch is still used significantly more than chemo, and chemo usage has been decreasing year over year, getting relegated, again, because of the toxicity, which patients and physicians don't prefer.
There's no perfect design. I would say you just have to look at what the trade-offs are.
I agree. Ultimately, it's the patient's decision there. Ultimately, a physician can guide to what the data is in terms of improvement there and maybe the appropriate academic view is you should be on chemotherapy, but if the patient doesn't want it, you have to give them what they want.
I guess I want to ask a general question about radiotherapy. What led to the decision to select Actinium or Lutetium for your two relative radioisotopes?
I can speak to Actinium, but we tried Lutetium as well. So look, when Fusion was founded 7 years ago, we made a conscious decision to focus on alphas, specifically Actinium. And why we like Actinium? 1,500 times more linear energy transfer than Lutetium. It's basically the most potent cancer-killing bomb out there, like bar none. Gives off 4 alphas in quick succession. And especially if you're internalized within the cell, that is damage that you can't compare to anything else. Can work in hypoxic tumors, can work in radioresistant tumors, and it's half-life of 10 days, which is ideal for centralized manufacturing and distribution, which is obviously a key part in the radioligand space. And when we started, we compared Actinium with literally every isotope out there. And every single time in models, Actinium won out, unsurprisingly, right?
So that's kind of, again, what we prefer because of the potency, the efficacy, the ability to ship and manufacture, and data supports it. And again, there was kind of the theories and dogma in this field because the alphas travel shorter distance, they cannot work in big tumors. However, clinical data is clearly debunking that theory. I mean, in our own study, we've seen tumors as big as three or four centimeters shrink. Obviously, Xofigo itself has a label of can work into tumors up to three centimeters, another alpha. So this is something that we're excited. We see the field moving towards as well. Having said that, I think different isotopes have a place. And obviously, companies are looking at their own strategy. This is something that we decided and the rationale for going that way.
Yeah, so I think there's been a lot of questions, and there's a lot of investor commentary on what is the right isotope and what's the isotope that's going to win in the long run. I think I would say that Lantheus focuses a little bit more broadly and to say that the isotope is one key component, but not the only component in a broader treatment paradigm. The first is naturally the targeting moiety. What are you targeting? And how attached are you going to be to that specific target and not unattached to other things to potentially either have a false positive rate from a diagnostic perspective or potentially off-target toxicity from a therapeutic perspective? I think when we think about the linker and the ability to sustain that attachment to the target that you're looking at is also equally important.
Then increasingly, the chelator for an ionized isotope is incredibly important to keep that isotope attached so that when you are attaching to a specific target, that you stay there, not only through the initial radiation, but through the progeny or the daughters that come through radioisotope decay. I think that's a key piece, that it's not just the single isotope, but it's how all four of those pieces work collectively to be able to best deliver and maintain radiation at a specific target. I'd use an example. We recently announced a partnership at the beginning of this year with Perspective for their two lead assets for Lead-212. We like Lead-212 as an alpha because we think there's a role for both alphas and betas.
Alphas, certainly, as Mohit mentioned, do give a tremendous amount of punch to be able to dramatically impact tumor growth. But we've also seen betas have quite a significant uptake. If we look at what Pluvicto and Lutathera have been able to do with lutetium-177, it is a commercially available, well-adopted, well-understood isotope that clinics upwards of 300 are now using to be able to treat patients. And so we think that's also an attractive opportunity. But there's a role for alphas. And as I mentioned, what we looked at with Perspective was not only the benefits of Lead-212 as an alpha. It's readily available as we think about the parent thorium being readily available and having a year half-life, which allows for effectively the storage of inventory, at least at the parent isotope, which has not normally existed in radioisotopes.
But importantly, and I think an underappreciated component of that is the proprietary chelator that allows, as lead decays or as any isotope decays, for those future energies and isotopes to stay attached. Because simplistically, you don't want to just have an attachment when that initial dose of radiation goes on. As those products decay and continue to emit radiation, you want to ensure that they stay attached to the cancer cell and not necessarily have off-target impacts. And so I think, and I believe Lantheus believes, there's a broad role for multiple isotopes. We've seen a remarkable growth back from the early days of just iodine to then growing into alphas with some of those earlier therapies, betas coming, having a significant growth with lutetium-177. And there will be a role for alphas and both betas going forward.
But it's that combination of targeting moiety, linker, chelator as applicable, and the isotope that truly make for a great RLT, both diagnostically or therapeutically. Moving into just a question on the diagnostics for this. So obviously, there is that role with the different radioisotopes, as you were alluding to, in the therapy space. How does this work for diagnostics? Is it as broad of a role? Is it fewer radioisotopes that you can actually look at for a diagnostic? Or how do you make that decision, and how did you choose for PYLARIFY?
So there's certainly a number of different imaging agents that could be used. Certainly, more of the talk has been on the therapeutic side, and that suits us just fine from a competitive perspective. We ultimately looked at the marketplace and decided that given the scale of PSMA diagnostic potential, that you really needed to be able to have an infrastructure that you could plug into and to be able to manufacture at scale. I would put that in contrast. Gallium-68 is a fantastic diagnostic agent. It is used in approved products, but it has more traditionally been used in a rare disease model where you need product on demand, but not necessarily at the scale. If we look at the largest radiopharmaceutical diagnostic in the marketplace by volume, that's FDG, which has been around for 30+ years.
There are over 100 PET manufacturing facilities in the U.S. alone making that product on a daily basis to the tune of 2 million doses. If we think about serving a market like prostate cancer with 3 million patients and an addressable market that we would estimate to be on the imaging side alone about $3 billion by the end of the decade, you need to be able to manufacture at scale. This is not just treating a small patient population. PET / machines are running multiple patients on a daily basis. And so the ability to manufacture at scale, to do so with a half-life that's reasonable for, I would call it regionalized distribution. It may not be at every radio pharmacy, but being able to do that at scale, that's incredibly important.
For us, in identifying when we first were looking at Progenics, who had developed the piflufolastat and now PYLARIFY asset, it was not only the targeting moiety and its attachment rate to PSMA of how it's going to be cleared through the body and potentially limit false positive, but there really was that scale manufacturing piece to be able to do that. Now, there's other assets out there. If we look at earlier stages in some of our other indications, we're studying FAP with a copper asset that has a longer half-life and would allow for potentially more centralized production. But overall, I think when we looked at the combination of the targeting moiety, the linker, the chelator, and the F-18 isotope, PYLARIFY, and specifically that combination was the best to be able to serve the prostate cancer community.
But as we look at a different market, if we were to look at neuroendocrine tumors or if we were looking at renal cell carcinoma, that may require a very different dynamic from a scale and manufacturing piece. And therefore, you have to make those decisions looking at the totality of information, not just saying F18 or Lutetium or Actinium is the right isotope for everything. I think that's an overly simplistic assumption.
All right. So Scott, I want to ask you the next question. How do you think radioisotopes will combine with chemo or with ADCs? And is that something that you're interested in doing in the future?
Well, certainly, the opportunity, as you know, we've taken a very broad view mechanistically and looking at orthogonal mechanisms to enhance not only for treatment of prostate cancer, but other diseases. We don't have currently experience in looking either in combining it with a radioisotope or even in the experience to date is very limited in the post-radiotherapy setting. But as you know, we are pursuing two distinct lines of therapy in the prostate setting with an ADC molecule that is a DNA alkylator and with a checkpoint combination bispecific targeting PD-1 CTLA-4. Both are showing very good activity. Ultimately, it will be determined based on the side effect profile that one observes. Given that for many of the radiotherapeutics, you may have increased bone toxicity, you then have to pick whether you're using these in combination or sequentially, and what do you use before?
Ultimately, if we want to see a tail in terms of therapy, because given the reality of prostate cancer, we're not curing mCRPC patients, if we can keep these patients alive longer and symptom-free longer, most of the data to date suggests that if you have a good immunologically defined immune system agent, you should be able to achieve that. So ultimately, as we see the data emerge from the radiopharmaceutical studies, we will jump in with our molecules to say which setting is it best used in, combined prior to or thereafter.
Maybe I can comment from a radioligand perspective. So we love combinations. We believe in combinations. Combinations have been shown to be really future in most of the tumor types. And I think it'll happen here in prostate as well or radioligand as well. And the basic principle for a combination to be used is one plus one should equal three. So you're getting some synergistic efficacy benefit, and you're not doing more harm, which is the cumulative toxicity does not override the benefit and efficacy that you're achieving. And so again, from the beginning, we focused on a couple of combinations. One was with DDRi agents or some it's very simple. Alpha-caused double-stranded DNA breaks. DDRis prevent the DNA repair. It makes sense.
But when we tested it, what we found was you could dose-reduce the doses of the alpha and the DDRi agent, still get the synergistic effect in terms of efficacy. You have no overlapping cumulative tox. And there was a trial last year, LuPARP, which is Pluvicto plus olaparib, and showed exactly that thing where the efficacy was significantly better than Pluvicto alone with no worse safety. And the other combination we really like is a checkpoint, like Scott mentioned, because ultimately, to have longer responses, deeper responses, you had to bring in the immune system. So again, because of the mechanism of action of radioligand, especially alpha, the physical damage that created and the immune signals that sent out. So we've seen tumor-specific neoantigen production. And actually, we have a very strong IP position where we have a granted IP to combine Actinium with any checkpoint inhibitor.
We have filed.
We should talk.
Filed IP to combine Actinium with DDRIs. And I mean, chemo combination comes up as well. And you pointed out well, it's really you have to manage the overlapping toxicity. So you have to select the right chemo agent and the duration and the schedule. But ultimately, efficacy gain should not be compensated by safety loss.
Yeah, no, we totally agree. As you know quite well, we're also doing combination studies right now with our checkpoint as well as our DNA alkylating ADC molecule. Just as you point out, the reduction of those doses in those combinations, we too are looking for reductions in doses to mitigate any of the side effect profile to get a better ultimate efficacy. So I think we're all on the same page on what the ultimate goal is.
I agree.
I don't have a lot to add. 100% agree the world is going specifically in prostate is going to be going to combination therapy, which makes that safety and tolerability that much more important.
I would add on, in addition, it's not only the ones we've already talked about. Given that the whole spectrum of chemotherapeutics that one could use in this setting, the same thing can apply for ADCs. As you add on different mechanisms of action, which are hitting different parts of the cell cycle or the DNA replication cycle, you have opportunities to even combine those as well.
I think the combination, and then I would also say the sequencing, is going to be very important. Recognizing that oncologists are going to need the full armament of potential treatment options and understanding the sequencing may go beyond just what, if you will, FDA studies look like. Because of the hematological toxicities, the ability to tolerate something like chemo or other harsh agents in the future, making sure that you get that sequencing right such that you keep as many options open. Because unfortunately, while we've made significant progress in extending life, we aren't necessarily broadly curing prostate cancer. The number of occurrence, even if it's far out, still happens. And so ensuring that you sequence those appropriately. And that combination opportunity, I think, is a tremendous opportunity. Ultimately, products are usually approved monotherapy at first and then go into additional lines.
But I think we all agree that that's where the world would be going.
Yeah, that's great. So preceding news, just remember it happened at TD Cowen. Okay, I think we should probably move to companies with the questions. So actually, Mohit, can I start with you? I know you have the data from TATCIST coming up. And so I was wondering if you could review the general expectations for that and break down a little bit for us what the patient's baseline characteristics are going to be and if you're going to be showing the data broken down by those characteristics.
So just a quick background. TATCIST was an IST investigator-initiated trial that we took on with Actinium-PSMA I&T. We're going to disclose data from 25-30 patients in April. And it was really great timing that in Lancet a meta-analysis publication came out with 488 patients treated with Actinium-PSMA I&T, multiple investigators, multiple countries, which very nicely summarized the safety, the efficacy, and obviously the prognostic factors for response. So our objective from the beginning was to reproduce data that's going to be in line with literature. And now everyone has this fantastic publication. So guidance we've given is PSA 50. And our baseline, we will have both post-lutetium and pre-lutetium patients. However, our focus going forward in our registration trial will be post-lutetium as a first step. And definitely on the more heavily pretreated side because again, it started as an IST.
So guidance we've given is from efficacy perspective, PSA 50 of 30%-50%. It's driven by the baseline characteristics in terms of number of prior lines, prior chemo, prior lutetium, PSMA PET imaging uptake. All of those factors are nicely summarized in the publication. I think safety will be an important de-risking event as well because again, there were questions around, okay, alpha is super potent and Actinium is potent. So what about the safety side of things? And the guidance we've given is very consistent with the publication. So xerostomia, which is dry mouth, expected. It's on target. PSMA is expressed there. No grade threes, which is a challenge for patient quality of life and low single-digit rates of discontinuation, which means patients can stay on treatment and get the benefit that they expect from the drug.
No renal tox, which was again a big question. And that's what was shown in The Lancet publication. And low rates of high-grade heme tox. That's what I was referring to. So overall, again, we believe and that's why we went to the FDA already last year. We discussed our registration pathway because, as I said, so many patients have been treated with different investigators that this is probably one of the most de-risk clinical assets in radioligand treatment out there.
Yeah, agreed. And so then considering that most of the patients in TATCIST, since they were enrolled, you inherited this trial, since they're pre-lutetium, basically. So what is the read-through that we can try and think about ahead as we try and make sense of what we could possibly see in pivotal development? The results from this trial, should we expect slight worsening in the pivotal population, or how should we think of that?
I mean, again, difficult to say because we haven't started the pivotal trial. It starts in Q2 of this year. But I mean, directionally, what I would say is the IST had more looser criteria in terms of patient characteristics. So we tightened it in line with the registration trial that we want to see. For example, baseline PSMA PET imaging, it was more loose. So we really changed it to be VISION-like criteria because that's what every phase 3 trial has used. That's what we'll be using. So that makes it obviously a tighter population. Things like patients with super scans. So this is where the disease is highly diffuse in the bone. They were excluded from all phase 3 trials. Same again. So we'll do the same thing. So we're not trying to reinvent the wheel.
Our goal is really to be the first Actinium PSMA agent to the market. Very importantly, so we have a two-step strategy. The first step in the first-to-market approach is in the post-lutetium setting. So as Novartis and Lantheus, they get their lutetium agents approved, especially in early lines, could be a potential $5 billion-plus market. That makes the post-lutetium market because patients will progress and will either not respond immediately or relapse. That makes it a blockbuster opportunity just in the post-lutetium setting. And then step two for us is going in the early line setting, which we are initiating that trial in the first half of this year where we are going in combination with olaparib. So overall, again, look at it as a multi-billion opportunity. As I said, clinically de-risked. It's safe. It's efficacious. It works.
Now, obviously, we need to generate the data in the registration trial in our own hands. But again, clear alignment and line of sight from the FDA.
Okay, great. Just to be clear, are you going to be breaking it out in the data so that we can clearly see the pre and post?
We will. But again, 25-30 patients, you slice and dice it. Too much, it becomes meaningless. But yes, we'll obviously show the data in the post-lutetium versus pre-lutetium because the first indication will be the post-lutetium setting. And we'll contextualize it in line with literature, with all the criteria like I was describing in terms of the baseline. So again, people can see what's the output you're seeing in context of the baseline. That's what is very critical.
All right. Slice and dice is what we do best in this industry. Nick, do you want to ask Lantheus a question?
Yeah. So obviously, people are definitely caring about PYLARIFY right now because that's the driving force right now of their revenue. So it's currently the market leader in the radiodiagnostic space. There has, of course, been a few competitors that have come in with Illuccix and also with the newest F-18 that has come in with Posluma. How have you seen that space evolve over time, the radiodiagnostic space in prostate cancer with these new entrants and specifically more so with Posluma coming in recently? So obviously, we've been really pleased with the overall growth of the PSMA diagnostic market. But two years ago, we had set the total addressable market at about $1.2 billion or $1.3 billion. We got a lot of cross-eyed looks saying that couldn't anywhere be possible. There's no way a diagnostic market could be that large.
And about a year later, people were saying, "Is it only $1.3 billion? What's happening? Is growth going to fall out?" And so I think overall, in the competitive dynamics, first and foremost, it's terrific that we have more folks out there talking about PSMA PET imaging. We think we have just scratched the surface of the market potential. We've highlighted that this year, we think it has an addressable market of $2 billion, and that could grow to $3 billion by the end of the decade. And so far and away, the largest PET diagnostic market that we've seen. And we still think there's obviously significant room to grow from that. New competitors, if nothing else, have certainly raised the surround sound about that awareness. While we get up every day and talk about PSMA PET imaging with PYLARIFY, there are still physicians out there who have not prescribed.
There are still physicians out there that do not fully understand the extent to which PSMA PET imaging can be used. I was with a customer last Monday, and they think we're actually under-penetrated somewhat significantly in the high or very high-risk population because if you're a urologist with a scalpel, everything may look like a prostatectomy. And so PSMA PET imaging could actually determine that you have systemic disease and therefore may not be appropriate for a prostatectomy. And yet, that's what the standard of care has been for so long. And that still takes a tremendous amount of work to educate. And so naturally, we've been very pleased with the overall market growth. There is a role for multiple players and multiple isotopes and multiple agents out there.
There's an old adage in nuclear medicine that the best agent out there is the one that you can get, that you can get reliably. Now, fortunately, PYLARIFY has a 98%+ on-time and full rate. So we're able to get it to 47 states, D.C., and Puerto Rico to be able to have access to in a repeatable on-time perspective. But there's a role for other agents. And indeed, we have a significant amount of respect for Novartis' Locametz, for Telix with their Illuccix, and now Blue Earth with Posluma. Clearly, our expectation is to continue to remain the number one PSMA-ordered agent and the clear market leader. We believe we can continue to do that. There's been a lot of focus specifically on the launch of a new F-18. I mentioned before some of the differences between Gallium and F-18.
Blue Earth Diagnostics, a company that's owned by Bracco, which we have a lot of respect for and been competing against for over a dozen years in our ultrasound-enhancing agent business, they came out with a new F-18 agent in May of last year called Posluma. Naturally, there's been a lot of attention there. We've noted as recently as a week and a half ago that we've seen minimal impact of their product in the marketplace. I would note that Telix noted the same thing on their fourth-quarter call. We have a tremendous amount of respect for that organization. Ultimately, we do believe that PYLARIFY is both clinically and commercially differentiated. Clinically, from a positive predictive value perspective of what you see, we do believe can be determined to be prostate cancer at an attractive rate. Therefore, it gives physicians confidence.
When we look at the scan consistency, regardless of who's reading that scan, our clinical trial showed that with the three different readers, that you can have confidence in the consistency of that scan. And then when we look at our change in intended management, where two-thirds of patients in one of our pivotal trials who had a PSMA with PYLARIFY scan had a change in intended management. I think that is one of the most important pieces of data from a diagnostic perspective because you are truly changing how you manage a patient's disease. And we think that speaks volumes in addition to some of the commercial differentiation, whether it's the multi-partner national PMF chains, whether it's the 90%+ covered lives, whether it's having TPT and then being able to be made at 54 sites and then promoted and educated by our market-leading and largest commercial sales forces.
We think there's a role for other competitors, but we wake up every day thinking about how we can ensure that PYLARIFY remains the market leader for many years to come. Got it. Then just one more on PYLARIFY with pass-through designation. Of course, you knew that question was coming. But this is obviously going to expire at the end of this year. What initiatives are taking place by either you or the government that could potentially extend this or lead to separate reimbursement completely? And then if this does not happen, what are the plans? How many patients would that affect? And would this be a quick effect? Would this be a slower over time?
A great question, one that I think we've received 5 times this morning in our one-on-ones, and I expect to receive in every one this afternoon. So transitional pass-through payment impacts about 20% of patients, recognizing that it's only the overlap of the hospital outpatient system, which is about 65% of the PSMA market overall. It only affects those in traditional Medicare fee-for-service. It does not affect commercial, does not affect Medicare Advantage. It's about 20% of the patient population. I think it's important to note that this really isn't a PYLARIFY issue as much as it is a PSMA PET issue. Well north of 90%, probably closer to 95% of the market will lose pass-through within the first 9 months of 2025. And so naturally, it's something that we take very seriously. We've been working for some time on mitigation strategies.
Indeed, the company shared about a week and a half ago at our fourth-quarter call that we've entered into a number of strategic partnerships, long-term in nature with our key customers to help mitigate that impact and to ensure that PYLARIFY remains accessible and the PSMA agent of choice in those markets. So that's something that we will certainly continue on this year. Perhaps more publicly, we have been working with the Centers for Medicare and Medicaid Services, CMS. They came out last July with proposed rules, a number of them, 4 to be specific, that would potentially mitigate any pass-through impact. There was overwhelming commentary submitted by September, albeit differences as to what that threshold should be to break out separate payment for radiopharmaceutical diagnostics. Then they ultimately chose to leave the status quo for December.
In conversations through parts of the broader coalition, they certainly understand that this is an access issue. We would expect to see CMS propose some additional rules this summer, take comments by September. Ultimately, it's up to them. We try not to put odds on government agencies taking action or not taking action. We'll see what those final rules look like. Naturally, we have the legislative pathway where the Facilitating Innovation in Nuclear Diagnostics Act or the FIND Act, which has broad support, has been introduced in the House and the Senate. I said I don't bet on regulatory agencies taking action. Given we're trying to pass a continuing resolution to keep the government open, I even less bet on Congress taking action. Those are two options.
Ultimately, in the long run, we certainly believe that pass-through would be solved, not just for PSMA PET diagnostics, but the market overall. We've got Alzheimer's agents, including our own, in development. And so this is clearly an access issue over time that is a bit of an arcane dynamic that considers PET diagnostic agents or radiotracers to be supplies rather than the drugs that they are and the FDA agrees they are. But needless to say, we're focused very acutely on this. We understand our customers. We focus on this quite closely. We understand their financial exposure from a reimbursement perspective and their financial sensitivity and continue to work with them to mitigate the impact and ensure that PSMA PET with PYLARIFY remains accessible and the clear market leader for many years to come.
All right, Scott. Can you tell us more about the ongoing dose work that you're doing? And ahead of the data that you plan on presenting mid-year, how can the changes in dose that you guys implemented result in similar efficacy but better safety, as you've stated?
Well, thank you very much for the question. As you know, we're very encouraged by the data that we've reported to date around vobra duo in the mCRPC setting. What we had observed in our phase 1b study of approximately 40 prostate patients is very good activity, about half the patients showing PSA 50 reductions compared to baseline values. Approximately a quarter of these patients, both confirmed and unconfirmed, having objective response rates. Our concern at the dose we were using there, which was 3 mg per kg on a q3 weekly basis, was too toxic. We were seeing the majority of the patients were either having dose interruptions, dose reductions, or complete stoppage in the setting where the patients were actually having clinical benefit, but because of the side effect profile, didn't like the tolerability.
As we have noted previously, there were particular side effects that were most notable that were most disturbing to patients. So palmar-plantar erythrodysesthesia or hand-foot syndrome, mostly grade 1-2, was most concerning, particularly when patients have grade 2 hand-foot syndrome, they develop pain in their extremities. And this is obviously a problem with older men who may have other confounding neurological problems that creates discomfort for them. We also saw evidence, obviously, of some fluid overload, which would manifest in patients, again, with pleural effusions, again, mostly grade 1-2 and in the majority of these cases, asymptomatic, typically picked up on scans. But there were patients with symptomatic, which required bringing them into the hospital as well. Other side effects as well.
So our decision going forward was, could we find a lower dose that got as good or actually even better efficacy than what we observed in the original study? And so when we did that analysis, looking both at the side effect profile, the activity profile, the PK of the free drug, as well as the conjugated drug, we came to the conclusion that, A, we would be able to give the drug less frequently, going from a q3 to q4 weekly basis, and actually give lower doses of drug, given that's what ultimately, in terms of the course of what they were exposed to, they actually got a lot less drug. So we selected with consultation with the regulatory agencies, particularly the FDA, and came up with a dosing regimen of 2.7 mg on a q4 weekly basis versus 2 mg per kg on a q4 weekly basis.
As you know, we enrolled that study in TAMARACK. What we have indicated is that we anticipated originally 100 patients in that study. We ended up blowing through that number. As we announced at JPMorgan, over 150 patients. In fact, if you look at the majority of the patients that came in, they came in in the second part of the third quarter to the first half of the fourth quarter of 2023. But the majority of patients came in that very narrow window. That's giving us a great opportunity of actually seeing a readout contemporaneously for a large percentage of the patients. As we said, we'll provide first cuts of the data in the first six months of the year.
Important for that, though, is and the question that comes up is, one assumes that with reduction of dose, we'd see a reduction in the side effect profile. The question always comes up to us is, will the efficacy be as good or better? What I pointed out is that if you do an analysis of a 3 q3 versus, for instance, 2.7 q4, that's a 27% reduction of that dose. As compared to the 2 q4, that's a 47% reduction in that dose. But if you actually think about it, is that because we're and that's making the assumption that they get all their doses. If, in fact, as I've told you, the majority of these patients had discontinuation, reductions, and things, we actually believe that these patients, if the safety is better, are going to stay on drug longer. They're going to get more drug.
As long as they're on drug, they will have the clinical benefit going forward. We will see if that hypothesis turns out.
Yes, we will. Can you tell us more about these safety events that are concerning? Are they more cumulative or Cmax-based? Because I think it would help us to understand that. Because if you're giving a dose with similar Cmax, but over a longer period of time, what drives your confidence that we're not going to see more cumulative safety events, essentially?
So again, I can't conclude until I have the data what is driving that. If you look at the analysis where you're going from on a Cmax basis, 3 mix versus 2.7, it turns out not to be that difference on a Cmax basis. And then if we looked at actually on the PK, on looking at where the floor is on that, again, we're not dropping this long. So they're going to get pretty much a similar Cmax and exposure rate here. With regard to when the toxicities occurred, as we've noted before, if you look at either the mean or median time to any of the side effects I talked about, it typically occurred after a month and a half. So they've seen 2-3 doses. That means some before, some later.
So my sense is that there may be some contributions depending on the side effect of either Cmax or that. But we'll know very quickly where we stand. I think we hopefully achieved the Goldilocks situation where we're giving enough drug, they're tolerating long enough, and can stay on drug longer.
Great. Do you know if they're reversible, by the way?
Yes. So in general, stopping the drug reverses the ones we've talked about.
Great. That's generally a good sign for non-cumulative.
Yes, exactly.
Yeah. Okay. And then I guess a question for both Mohit and Scott. Considering the recent data sets from the last week from Janux, Amgen, do you think that this changes the bar at all for you as far as what PSA 50 the market would like to see in order to or even regulators for a successful PSA reduction?
I'll answer that, which is the regulators are not approving the drugs based on PSA 50. They're approving it on rPFS. One should discontinue the notion that any particular number is going to dictate ultimately how those patients are going to perform. You specified investors and regulators. You really should talk to the treating physician. The answer that we consistently get from treating physicians is duration of response in rPFS. Ultimately, as we discussed earlier, if it translates to OS, that is important. Those are the two parameters. If somebody has a 42 or 48 or 55, that's not going to be a differentiating factor here in terms of the activity of drug. With regard to the specific molecules that you described, which showed PSA 50 reductions initially, this is very early data. It's not showing any durability of the data.
With continued use of any drug, as you pointed out, in terms of cumulative toxicity, so can the mechanisms of action, whether, for instance, for T-cell activators, as you know, as you flog T-cells, many of them will go into an exhaustive or an apathetic pathway. If you're not going to continue to have the durability of the effect or function there, you will not have the durability of the clinical response. It's just too early to say how important those drugs will be at this point.
Yeah. I think you nicely summarized that the two aspects are durability and long-term cumulative tox. I understand it's a natural reaction, especially from the investor side. You look at the number and you have to jump on it and compare across trials. But look, I mean, the durability, especially for Janux, is 42 days. That's like one cycle of RLT treatment. So you need to see how long the response is going to last, whether you have PFS and OS. Yeah, I mean, T-cell engagers, CRS, even grade 2s require hospitalization. You're talking about two days of hospitalization at every dose of the loading cohort. So you can talk to any investigator or physician how they like that versus outpatient treatment. So again, long road ahead, intriguing data, early data, need to see long-term tox.
That's where I would say kind of we were fortunate and comfortable to see all of this big pool of literature data across multiple investigators' side that gave us this confidence on, again, long-term effect.
So Paul, we've been talking about PSA 50, but you guys with PNT-2002, of course, have rPFS and initial OS data. So with rPFS, it was significant versus that second ARAT. With the OS, it was still immature. So when do you anticipate seeing that more mature OS data? And do you plan to file before having that OS data, or will we wait to file until after?
It's a great question. Thank you. So what we've said publicly is that we would expect more mature OS data, likely about 75% maturity sometime in the second half of this year. Ultimately, that timing is fluid. We can't give an exact date because, naturally, unfortunately, we're waiting for men in the both treatment and the control arm to pass away. And so we have a number of statistical models that would estimate when that would be. So at this point, we can say that would be in the second half of this year. We are very much taking a wait-and-see approach with a 1.11 hazard ratio. The goal is obviously to have that fall to 1 or better, at which point then we would continue to assess the regulatory options, including potential submission of an NDA to the FDA.
At this point, given the agreement that we have with Point, now part of Lilly, we have the ability to wait and to see what that data looks like in the second half of this year before making decisions both on the long-term opt-in approach as well as the potential timing and likelihood of a filing strategy. We'll know more in the second half of this year. Certainly, we'll be asked and we'll be providing updates at an appropriate time.
Okay. So we do have a hard stop at 11:30. So I want to make sure I ask for each of you. What are you most excited about coming up this year or over time from the pipeline or with revenue growth, starting with Mohit?
Okay. So very busy and very exciting year for us, first of all, with the data from the Actinium-PSMA TATCIST trial in April. We're starting our pivotal trial, the phase 2/3 in Q2 of this year. We are starting our early line trial where we, again, aim to become the treatment of choice in the early line setting in Q1 of this year in combinations. Then let's not forget our broad pipeline. So we have three other agents in the clinic. The second agent, it's an IGF-1R program. We disclosed really promising efficacy, I would say, for the first time with an antibody-based RLT, where it was grade 1 or less thrombocytopenia. We showed signs of anti-tumor activity. So we're going to provide a data update in the middle of the year.
We have the collaboration program with AZ on EGFR-cMET, very hot target, very exciting, going after multiple tumor types. So we're starting dosing that. And of course, we continue to work on expanding our Actinium supply and manufacturing capabilities. Our in-house manufacturing is up and running, producing clinical doses. At GMP, it has a capacity of 100,000 doses. And we are clear leaders in Actinium supply. So I would say just the breadth of the pipeline and the capabilities. So we will look forward to providing future updates this year and beyond for the investors and shareholders.
So this year, I'll think about a couple of different horizons. Naturally, this year, we're very focused on the continued growth and leadership for PYLARIFY. We believe that has the potential this year to be the first-ever billion-dollar PET radiotracer, which would be an incredibly exciting accomplishment. So we're hopeful that we accomplish that this year. I would also note we continue to focus on the rest of our business, including DEFINITY and ultrasound-enhancing agent approaching $300 million in revenue, grew 14% year-over-year. And so there's still significant growth opportunity there. Mid-stage, we're excited about being the first to file for PNT-2003 for neuroendocrine tumors and the potential to launch that commercially in the mid-2026. Naturally, we expect more data from PNT-2002.
But I'd also note some of our other internal assets, those of which we've licensed, whether it's top-line data or I should say data coming from Perspective later this year for their two lead assets that we license the options to, as well as sharing a regulatory path for MK-6240, our Alzheimer's agent, which we think has a significant opportunity being used in 90+ clinical trials. We generate significant cash. We've got over $700 million on the balance sheet as of the end of last year, generating over $100 million per quarter. We still think there's significant growth in the radiopharmaceutical space for smart partnerships and potentially acquisitions. So we remain active there and look forward to hopefully being able to share, bring in some things across the goal line this year.
Okay. Obviously, a lot of focus on TAMARACK. We've discussed that at length. We'll see the data in prostate in the first half of this year with further updates later this year as rPFS matures. Expansion of vobra duo into other indications, which we'll provide updates very shortly. Clearly, finishing out enrollment in the LORIKEET study of the PD-1 CTLA-4, the lorigerlimab, and the chemo-naïve population in combination with docetaxel, be an important study and having readout either beginning late this year or early next year. We're very excited about the breadth of our pipeline. So starting this first quarter, there will be a study called HEAT that will be starting in patients for neoadjuvant treatment of Gleason 8-10. This is a controlled study of 219 patients through an IST by notable experts in the field based on early data there.
We're very excited about the prospects of our new ADC molecules. So we have a 7-target deal with Synaffix. 2 of the new ADCs will go into the clinic this year, first quarter this year. IND filing in the second half of this year. We'll provide updates very shortly about the target there. And we're now working on targets 3, 4. And this is on top of also our redirected killing DART programs, our collaboration with Gilead on 2 molecules, one which is well known on the CD123 x CD3 and AML, a second molecule in research with them, and additional next-generation pipelines coming from the DART program.
Okay. Great. Thank you all for coming and joining us. Thank you all for watching The Prostate Show.