Welcome everyone to our next fireside chat. Again, my name is James Molloy, biotech and specialty pharmaceutical analyst here at A.G.P. In this chat, we're talking with another of my coverage companies, BioCardia, which we have as buy rated with a $6 price target. BioCardia is a late-stage developmental company with an autologous stem cell therapy for ischemic heart failure, HF, and chronic myocardial infarction, ischemia, CMI, excuse me, or angina pectoris. That's in two separate phase III trials. BioCardia has recently shared that they're in discussions with Japan's Pharmaceuticals and Medical Devices Agency, that this agency has supported the submission of an approval based on the recently completed CardiAMP HF trial. With us today from BioCardia is CEO Peter Altman. Thank you for joining us here today, Peter.
Appreciate for having us, Jim. Am I on the screen here? I'm not seeing myself.
Perhaps the screen share is on.
Yes.
Yes. I see the screen share's on, and the two of us are on. Yes.
Okay, great, a ppreciate that. Excellent job this morning, by the way. I've been watching the talks. It's amazing you keep track of all this, you and your colleague. BioCardia is focused on cardiovascular and pulmonary cell and cell-derived therapies. Today, as you shared, we have great news from Japan PMDA that they're inclined to accept our current data in heart failure and we're pretty jazzed about taking that program forward.
Well, before we go on talking about the trial and the data, let's talk about that, the Japan PMDA, and their ability to recognize the data you have to date and how that guides their decision to support BioCardia's submission.
Sounds good. Let me step back a little bit and just detail for folks who may be new to BioCardia, that our focus is really targeting ischemic etiology heart failure, and fundamentally it's characterized by a large dilated heart. It is literally an enormous problem worldwide. To date, all of the therapies that are out there are primarily neurohormonal, and so what we're pursuing is a new mechanism of action that's been discussed in the literature for quite some time of really trying to treat microvascular dysfunction. What that means is, if I take you to this slide here, it's sort of a cartoon, that on the structural tissue basis, we're really trying to promote enhanced capillary density and reduce fibrosis locally in the tissue. What this does is in an ischemic situation, this is a disease that's initiated by poor perfusion to the tissue.
First and foremost, increasing the microvascular capillary density helps address that. We all know about angioplasty, where you open up a large vessel, but the disease is also on a microvascular level. In advancing this therapy, we're trying to target the process where these cells release cytokines such as VEGF and cause the promotion of new capillary growth and reduce fibrosis, which has been seen in a lot of early studies. As we've taken this forward in our conversations with regulators around the world, we've cleared a whole number of hurdles here. As everybody knows, therapeutic development takes an enormous amount of time. We have FDA breakthrough designation, we have Medicare reimbursement, which is important for Japan, and I'll touch on that. We've completed three clinical trials.
At the end of these trials, we've come to PMDA, and we've said, "This data is excellent in that it can help patients who have no other options other than really death or maybe receiving a left ventricular assist device," because they don't do transplantation in Japan, to have an additional therapeutic option. The data on which that is based is these three trials, but the most recent data is shown here. What you're seeing here is this is a number of endpoints that are hierarchical in our trial. In a hierarchical trial endpoint, which is really important, you're trying to have every patient's outcome contribute to the decision of is this therapy better for this patient or not.
Many of the drug companies, the larger drug companies, will focus on a single mortality endpoint, which requires 8,000 patients to be enrolled in a trial. Here what we've done is we've introduced, we're not the ones who've innovated this in heart failure, these are new endpoints where you say, "Look, the most important decision is the patient's heart still viable?" That's what we call a tier 1 endpoint, death, heart transplant, or LVAD are what that criteria is. In this situation, in this subgroup where we're talking about approval in Japan, we have a 13% reduction in death, heart transplant, and LVAD in these patients. The next tier that we assess these patients on are, have they had a nonfatal MACE event? Have they had a heart attack? Have they had a stroke?
Have they had hospitalization for heart failure? All enormously expensive to society. Here we see we've got a 10% reduction on the patients who didn't have a tier 1 event. Combined in tier 1 and tier 2. We already have a 23% reduction in these events, which you're seeing here in this Kaplan-Meier survival curve over here on the right. For investors who are not familiar with heart failure care, the separation of these curves in terms of these two very significant leading endpoints is enormously important, and it's very large relative to other therapies. Again, this is on top of all the existing therapies these patients have. This is not instead of, it's in addition to. It's really a new mechanism of action, new therapeutic option.
In tier 3, which is the other component of this composite endpoint, we have two arms to this, either a six-minute walk distance, how far a patient can walk in 6 minutes, or a quality of life measure, which is well-established, called the Minnesota Living with Heart Failure Questionnaire. In both of these scenarios, this therapy shows benefit in these patients.
Japan PMDA, looking at this data, knowing this is an autologous therapy, looking at our safety data from 200 odd patients, and knowing that these patients, their really only option is mortality, and also being keenly interested on investing in treating patients with these new interventional cell-based therapies, has said, "Yeah, we're willing to take the next step with you guys and take this potentially to approval." We still have some work to do here, but the key takeaway is this is why they're supporting this, and so here's essentially a high-level timeline. Forgive me for running over. That background, I think, is really important.
Imortality's a tough option, too t hat's for sure. It's always an option, isn't it? I guess, w alk us through the next, what are the timelines for the PMDA, and how quickly-- I believe it's the end of this year you're expecting to submit, and how quick a turnaround do you anticipate? Is that correct?
Yes, that is. I think what our guidance is, we're just getting into this now. We expect that it will take about six to seven months to complete this submission, and t hat will be this year. That submission process has a number of elements into it. We've already identified partners to help on these steps that are experienced in these requirements for submission, and we're moving towards agreements rapidly. We expect after that submission is in. While that submission's ongoing, we'll also be meeting with physicians, we'll be talking about the post-marketing study ahead. In fact, we've already been invited to some major cardiovascular conferences in Japan. After that submission is completed, the approval process takes about 12 months. PMDA is extremely thorough. They've gone through every iota of our data, and that's important for investors. PMDA is not just seeing an initial dossier.
They have dove through our data for over a year, asking questions on every aspect of it. They probably know our data better than I do at this point. As they've looked at this, yes, we need to go through appropriate Good Clinical Practice audits, manufacturing audits, but our sense is we're pretty confident that assuming that they stay the course, we would likely see an approval here in around 18 months for a heart failure market.
Walk our listeners through the opportunity. The size of that market, obviously, is smaller than the U.S., but a substantial opportunity and a good proof of concept for getting something approved.
Well, actually, yes, it is smaller than the United States, but the market in this indication in Japan is enormous. There's about 300,000 patients that would really qualify for this therapy in general. Similar to other therapies in heart failure in the United States, they enter the market in a place where the patients really have no other option. As they demonstrate value for the clinical community and they generate additional data, they expand into the larger indication. That 300,000 patients using our reimbursement today in the United States makes Japan a $6 billion market, which is enormous.
$6 billion would certainly do.
At the same time, we're focused initially on the roughly 20,000 patients which have no real option, which is about a $400 million market. Now, they have previously approved a cell therapy in Japan for a cardiac indication similar to ours at $124,000. That's not the number we're using in our analysis. We're actually using the U.S. reimbursement that we have today from Medicare. That part of the logic behind that is it's an established data point for PMDA. With the current administration in the United States, with the Most Favored Nation mindset, it'll be hard to go below that $20,000 in the U.S. for PMDA.
Over to the in the U.S., the CardiAMP BCDA-01, CardiAMP HF trial, can you walk our listeners through how that's set up, when you expect to have data from that trial?
Right. In the United States, we've actually just had conversations with the agency recently on earlier approval pathways for CardiAMP in light of the data I just shared and in light of in the United States, these patients also don't have great alternatives that are non-invasive. In those conversations, we have this ongoing trial, which we call CardiAMP HF II. It's a confirmatory trial. In this trial, it's designed as a double-blind, randomized placebo-controlled trial, and patients are essentially treated with therapy or they receive a procedure placebo. At the end of the follow-up, which is a minimum of one to two years, we will assess them on a substantially the same endpoint.
These patients, this is precision medicine we're rolling out because in CardiAMP HF II, we are focused in on the patients who have quality cells that we can assess with our proprietary cell population analysis, and we're focusing on the patients who have elevated markers of heart stress, showing that they have significant need. We've had the strongest signals in that population. Currently, this trial is active at four world-class centers. We have quite a few other centers that are interested in being involved. We have patients in the queue at all of these centers today. The enrollment process is a little bit slow for each patient as it moves through because we have also a one-month screening delay at baseline to look at the Hawthorne effect. That's the concept that once you start observing a patient, their behavior changes.
They become more compliant with medications and what have you. This is just to further enhance the rigor of this study to maximize its probability of technical success. Right now we only need 160 patients to have 80% power in this trial using this composite endpoint approach. Although the trial is approved up to 250 patients at 40 centers.
Well, let's go over to the CMI, BCDA-02 CardiAMP CMI trial, chronic myocardial ischemia. Walk our listeners through this disease state and you're guided to reporting interim six-month data at the upcoming EuroPCR Conference in Paris, today, right? Did that already go?
That is true, my friend. It's actually exciting. We did share top-line data at 6 months for this, and actually, I'm going to punt to a degree. This indication is chronic refractory myocardial ischemia. It's characterized by chest pain in these patients. Until you've actually observed some of these patients' charts, you don't realize how horrible an indication this can be for patients. We have been literally delighted with the six-month data we shared top-line data on previously. In this clinical indication, which is about 800,000 patients in the United States and has been treated with a drug called ranolazine that was doing, I think, $800 million in revenue, which most of the physician community, they're glad they have a drug, but it's not great, has said we need something more.
The only thing out there that has moved the needle on the two key endpoints of exercise tolerance and reduction in the pain episodes has been cell therapy. So we were delighted to share previously at six months that we moved the needle on both of those. This data is being presented today in Paris on a little bit longer-term follow-up. I expect we will have a press release tomorrow morning on this data. It's being presented by Dr. Amish Raval, who's the first name on this list out of the University of Wisconsin. We'll also have the slides from this presentation available on our website tomorrow morning. The key takeaway is at 6 months follow-up for an autologous cell therapy with no real significant treatment emergent safety issues of concern, it's fabulous.
For us as a small company, even though we have Medicare reimbursement, we're not able to drive this forward on our own right now, but success in Japan will give us plenty of capital to take this forward. This also presents to partners because it's the same therapy, that the indication is even larger than ischemic heart failure. It's sister indication of chronic myocardial ischemia. Yeah, I'm very bullish about taking this forward when we get the chance to in a larger study. Right now, this data is primarily to enhance partnering opportunities, and we will be coming back to this pretty aggressively as we continue to advance the ischemic heart failure program in Japan and in the United States.
Well, we're down to our last three minutes. I want to touch briefly on BCDA-03 CardiALLO, allogeneic NK1R+ receptor, and BCDA-02 CardiAMP CMI for chronic myocardial ischemia. I'm sorry, 04, allogeneic NK1R+ receptors. Then how are 04 and 03 progressing, what's the status there?
Absolutely. This is our allogeneic mesenchymal stem cell therapy. Here we've treated 48 patients to date in threee trials. This program, these are off-the-shelf cells that are essentially culture expanded from a single donor into many dosages. Although many view this as the superior cell therapy from a business perspective, in fact, the autologous therapy I just detailed has potential to have 90% margins and relatively straightforward logistics at a relatively modest price point for society. These cells will be at a higher price point. For the cardiac indication, they will use the same delivery paradigm. And fundamentally, the data that we have has been great in all three trials. We have been working on non-dilutive funding to accelerate this.
The same team that is involved in manufacturing these cells at our facility, which you can see here in the bottom right-hand corner, this team also does all the biobanking for the CardiAMP trials and also is involved in a lot of the cellular analysis there. It's sort of a redundancy on our system. For the pulmonary indication, and this is new news I'll share with you today, we have been focused historically in acute respiratory distress syndrome, but here we are now migrating towards another pretty compelling indication with that data set, which is pulmonary fibrosis. We'll see where that goes ahead, and that may be tied into some interesting opportunities in the future. Our peer, Healios, is actually going to be approved in acute respiratory distress syndrome in Japan, and so we'll be watching that closely as well.
How would you, in our last minute here, how would you characterize the partnership environment, h ave you seen high levels of interest?
Let's just say that having PMDA say, yes, they're interested in approving CardiAMP is a pretty big deal out there, w e're having conversations. The data I shared with you previously has been described as interesting by the FDA and intriguing by some very large cap groups that are involved in heart failure therapies. Partnering takes time, and these conversations are active. We will see where this all evolves to ahead. There's partnering in Japan, there's partnering worldwide, and these two indications for CardiAMP really present it as a franchise for this mechanism of action in broader cardiovascular ischemic cardiomyopathy.
Well, excellent. With that, we're at the end of our Fireside Chat. I'd like to thank you, Peter, BioCardia, for joining us today, and thank all of you for listening in. Again, please stay tuned for our next Fireside Chat coming up right after this. Thank you, Peter.
Thank you kindly, Jim. Truly appreciate it. Be well.
Welcome to our next Fireside Chat. Again, my name is James Molloy, biotech and specialty pharmaceutical analyst here at A.G.P. In this chat, we are talking with another of my coverage companies, Barinthus Biotherapeutics, which we have buy rated with a $6 price target. Barinthus has three interesting compounds of development, VTP-1000 for celiac disease in phase I trials, and CLY-101 and CLY-201 for diabetes that are expected to be part of the repertoire should the ongoing merger with Clywedog Therapeutics finalize, which is expected this summer. Obviously it's not final yet. With us today from Barinthus is CEO Bill Enright. Thank you for joining us here today, Bill.
I appreciate it, Jim. Thanks for having me.
Pleasure. Would you please give us a sort of brief overview of Barinthus for our listeners and a little background on the Clywedog merger and how that all came to be?
Sure.
Potential Clywedog merger.
Barinthus Biotherapeutics is a company originally started in the U.K. It was a spin-out of University of Oxford. Initially focused as a vaccine company, but we've transitioned and pivoted to an autoimmune specialty with a new platform that we call SNAP-TI. Our main focus right now is in the autoimmune space, and our lead program is a potential cure for celiac disease that you mentioned, called VTP-1000. The merger with Clywedog, to answer the second part of your question there, we're in an enviable position to have a nice cash cushion that we managed to get when we IPO'd several years ago, and looking for potential new assets to add to our portfolio. We came across Clywedog Therapeutics.
They have a couple of interesting assets as you mentioned, in the diabetes space, a menin inhibitor, CLY-101, and a TYK2 inhibitor, CLY-201. These are proven products. The menin inhibitor is approved in a different indication in oncology, a lot of the safety risks and things are taken out of the equation there. We think it has an interesting opportunity in the diabetes space. We're really looking forward to getting this merger closed and moving these programs forward.
Well, let's touch on those in just a little bit. Let's go back to VTP-1000, which you have in-house with celiac, and then we'll go back to the Clywedog and the potential there. Could you walk us through the SNAP-TI technology that sort of underpins this compound, please?
Sure. The SNAP-TI is a platform technology. It is a nanoparticle technology, i t's a self-assembling peptide nanoparticle. This is a really cool chemistry that was developed out of the NIH and Johns Hopkins University. We can control the size of these particles, w e can control the number of peptides, g ives us a real advantage in being able to add multiple antigens to go after these diseases. Some of the issues with the current platforms are that you cannot get enough antigens, you cannot get enough of the antigen in there such that you have to do IV administration. Because the peptides are the particle, well, that allows us to get enough antigen in there that we can actually do IM or subq dosing. You can imagine in some of these autoimmune diseases, you may have to repeat administer.
There's a potential for doing auto-injectors and those kind of things as we move along. Really interesting technology that we think has a lot of applications in addition to the celiac program.
It's in phase I, the AVALON trial in the U.S. Could you walk us through the SAD portion? Single ascending dose portion has been completed end of last year, right?
Correct.
The multiple ascending dose portion is expected to complete this year. What does that trial look like?
As you said, it was a two-part study. The single ascending dose study had 18 patients. This is a double-blind, placebo-controlled study in patients. It's a pretty stringent phase I study. The single ascending dose portion had 18 patients, so three doses, six patients in each dose. Again, looking at safety, and looking at in patients that have diagnosed celiac disease that's confirmed with a biopsy. We're looking at changes in baseline of the transglutaminase antibodies and also at a cytokine profile because IL-2 in particular is a reasonable biomarker for this disease. In that phase I, in the SAD portion of the study, we announced top-line data at the end of the year and showed that there's actually a dose-dependent response even with the single dose, which was quite surprising to us.
We weren't sure that we were actually going to see a reasonable signal with just a single dose. The MAD portion of the study is enrolling. Enrollment is going well. We're on track to have data from the MAD portion, which is 24 patients, and we'll have those data in the second half of the year, we expect. Again, these patients will get three doses at each dose level, two weeks apart. There's a gluten challenge at the end. We can get a hint of efficacy here. It's not powered for statistical significance, but we should be able to look at the cytokine profile and the transglutaminase antibodies to see a hint of efficacy here. That's going really well. Obviously, safety is the key thing here.
One of the interesting things that I forgot to mention about this technology is we can actually incorporate immunomodulators into these nanoparticles. In this study in particular, we're incorporating rapamycin into the particles. Now, that gets co-delivered with each particle, and it's important for a couple of reasons. The rapamycin is actually important in helping to change the T cell balance, which is what we're trying to do here. We're really trying to impact the disease, going after the root cause by changing the T regulatory ratio. It also helps blunt the initial response that you see in many of these other studies, where we know we're giving antigens that people are reactive to. All right? That immunomodulator actually helps dampen that response, and so you don't see the reactogenicity profile that many of these other studies are seeing with these initial doses.
Okay, e xcellent. I think everyone listening knows someone who has celiac disease. This is a fairly-
It's a huge disease. It's about 1% of the global population is now diagnosed with celiac disease. That's not talking about celiac or gluten sensitivity or those kind of things. This is diagnosed celiac disease, and it's growing at about 7.5% a year, which is significant. Mainly due to better diagnostics, to be honest, but it's unclear why the rest of that growth is there.
Obviously, this isn't colorectal cancer, but it's certainly not something you want to have anyway, and it's a real suffering. People have celiac. There's no getting around it.
Yeah, absolutely. The only treatment right now is a gluten-free diet, and that's not 100% effective. Right? There's lots of people that, even on a gluten-free diet, have issues that remain, and they're always worried. Every time you go out to eat, every time you go to a friend's house, every time you're on an airplane, is there going to be cross-contamination? Am I going to end up in the bathroom for a couple hours here? It's a real problem.
What does the development landscape beyond VTP-1000 look like? There isn't much out there.
No. There's a couple of other technologies that are out there looking at this again, this antigen-specific approach. There's B-cell depleters and things like that people are also trying. In this kind of a situation, it's like you're using a sledgehammer to pound in a nail.
Right. As sell-side analysts, of course, everything's a billion-dollar opportunity, but t his is a legitimate multi-billion dollar opportunity should you guys get across the finish line.
Yeah. Absolutely.
it's a wide-open field.
It's a wide-open field.
What would phase II or the rest of the clinical development timeline look like for this?
Yeah. We're looking at this. Obviously, we need to see the data from this phase I study. This will help us determine the potential dose here. We may look to expand this study and add more patients to ensure that we're actually seeing the kind of efficacy that we think we're seeing at the particular dose. We move into a phase II study. Larger study, a couple of 100 patients, at the preferred dose here. We also need to look at duration of response, right? How long is this going to last in patients? Are we going to have to repeat dose on a monthly basis or a quarterly basis or an annual basis? That remains unclear at this point.
There's been some changes, some moving parts at the FDA, some good, some bad. One thing that seems to come through is moving away from the two-trial dogma. I know in particular in CDFA Seal, one of the other companies I follow, they just put out guidance just last Friday about only one trial for CDFA Seal. Any communication you guys had with the FDA on what a phase III program might look like should you get there, or could a big phase II get this through?
Not yet.
Okay.
Those are conversations that we'll be having once we have data in hand.
All right, f air enough. That'll be end of the second half of this year?
Correct.
All right. Well, maybe over to the Clywedog and the merger. You talked through some of the reasons through it. Can you walk us through CLY-101 and the menin inhibitor and the TYK2 inhibitor, how they differ from each other, and then I guess maybe you did mention obviously that the merger's not complete. What are the potential hurdles to it getting complete?
Yeah. We got a little bit delayed because of the government shutdown last fall into getting an SEC reviewer and getting that through our S-4 through the SEC. All that's behind us. Where right now, there's a proxy out there for our shareholders to vote for the merger, which is ongoing. Voting will conclude later this week. Hopefully, that's not a real hurdle. We've got to go through a scheme of arrangement with the U.K. court because we're moving to a U.S.-based company, a U.S.-headquartered company, and so there's some additional hurdles that we have to jump through. It's more procedural, so we don't anticipate any issues in bringing this to a close somewhere around mid-year, as you said, this summer. I'm not sure whether it'll be the end of the second quarter or beginning of the third quarter, but in that range.
CLY-101, that's currently in a phase I-B trial, or does that start out? Yeah.
Correct. Again, the menin inhibitors. Clywedog is a company that was started by OrbiMed and Torrey Pines. They have some interesting AI technology that they're using to design first-in-class or best-in-class molecules. Menin inhibitors I mentioned was an approved product in AML, in the oncology space. That has some safety issues, has had some cardiovascular issues, prolonged QTs. They specifically designed and screened for molecules that didn't have the safety issue. They were going after just to make a best-in-class molecule in oncology, and they were approached by a strategic that said, "Have you looked at this in diabetes?" They hadn't. They did some work with the strategic, some preclinical work. Data looked very interesting, and so they did do a phase I safety study, SAD and MAD portion in that.
They had done tox out to 28 days because it was an oncology study, which is a little short for diabetes. We decided to move it into a phase I-B with that 28-day tox to get an initial read in diabetes here. They are currently enrolling a 60-patient, double-blind, placebo-controlled study in patients in Australia. We're looking at a couple of different doses, three different doses. This is a one-to-one randomization. They'll be looking at safety, obviously, as the primary thing. Obviously, they're looking at cardiovascular issues to make sure that the preclinical screening matches. They'll also look at A1C and C-peptide from changes from baseline over that four-week period, as well as weight loss. Because the menin inhibitor actually has a dual mechanism of action. It increases beta islet cell mass, so you get increased glucose production.
It also increases GLP-1 receptor expression. Interestingly, one of the side effects of this may be weight loss. We'll look at weight loss and waist size decrease.
How does that compare or contrast with CLY-201, the TYK2 inhibitor?
Right. The TYK2 inhibitor is kind of on the other side. Again, the focus on that will be initially in T1D. Again, two mechanisms of action there. One is inhibiting IL-12 and IL-23, that signaling pathway that suppresses the cytotoxic T cells that destroy the beta islet cells. You're trying to stop the beta islet cell destruction in T1D. The other is, it also inhibits the interferon pathway, which again suppresses the stress-induced apoptosis, those beta islet cells. Again, two mechanisms of action here. Again, you could actually envision this as a pretty interesting one-two punch in a combination, but down the road. Right now, we're focused on the two as separate molecules.
Again, we're hoping to have this wrapped up, or the merger wrapped up by the summer. We're down to our last couple of minutes here. As you mentioned, Barinthus reported their first quarter, about $66 million in cash, an enviable position. Are there other assets you're looking at, or is that sort of on hold now with Clywedog coming to a close?
Yeah, that's on hold. We're going to focus on the three assets that we have, assuming this merger closes, as you mentioned. We've got milestones here, both in the VTP-1000, as I mentioned, coming up in the second half of this year. Data from the CLY-101 should be in third quarter. We've expanded that clintox as I mentioned, so we can actually extend the treatment time. We'll get that back into the clinic with a longer treatment regimen. We'll have more data from that in 2027, we'll get a phase I-B/II-A started on the TYK2 inhibitor to have data in 2027 as well. The cash that we have, we haven't guided on cash at the close because timing of the close has been uncertain.
Also we have a redemption feature for some of the existing Barinthus shareholders, and we're unclear how much of that will actually get redeemed. What we have committed to is to ensure that we have cash to get through these milestones. Get through the end of 2027.
That's the guidance. Orbi and Torrey Pines have committed to make sure that we have enough cash to get through the end of 2027, to get through these major milestones in all three programs.
Excellent. Well, with that, we're at the end of our Fireside Chat. I'd like to thank Bill from Barinthus Biotherapeutics for joining us and for all of you for listening in as well. This ends the Fireside Chat. Please stay tuned for our next one coming up right after this. Thank you, Bill.
Appreciate it, James. Thanks everybody.