BCEL actually had, like, a commentary in the New England Journal, like, last week or two weeks ago, which was interesting.
Oh, I didn't see that on FNAIT, or—
Yeah.
Oh, Dr. Dibben out. As I say, it's a bit of a bad memory at the moment, so we're still sort of post-traumatic stress.
Good afternoon, I guess, everybody. Jon Wolleben, Senior Analyst here at Citizens, and welcome to day one of our Life Sciences Conference. Pleased to have Rallybio and CEO Steve Uden joining us. Rallybio is a company we've been covering for many years now, going under a transformation focusing on new assets. Steve, thank you for joining us today and telling us about the story.
Oh, great. Thanks for inviting me, Jon.
You know, I think we should just hit it at the top, but maybe, you know, Rallybio focused on rare disease primarily. Your lead program, RLYB212, had some bad news, you know, just earlier this year. Can you give us kind of a, you know, a rundown about what happened?
Yeah, absolutely. It's really, really very sad for patients. We knew that the antigen that causes this problem in platelets is expressed on endothelial tissue. What we did not know is where it was expressed in the placenta. It appears that the antigen—it's a fetal antigen—and it appears that the fetus expresses the antigen on the surface of the placenta that is in direct contact with the mother's blood. It goes without saying we have done as much as we could to de-risk that and created the mouse model of the disease and saw no evidence of it. As you know, everybody will remind me, a mouse is a mouse and a human is a human. There are, you know, significant differences.
To cut a very long story short, because the antigen that drives this was exposed to the maternal blood as fast as we put the therapeutic in, it just attached itself to the fetal part of the placenta and the levels dropped to—they were barely measurable at Cmax and had gone at trough. We knew that we were not going to be able to maintain a plasma level through pregnancy that would have prevented FNAIT. Even if we tried, we would have been, quote, "flying blind," and a pregnant woman is not someone who you are going to just push the drug in as fast as you can. Maybe if this was an oncology indication, despite not having a model, you may have tried to do that, but clearly there is no margin for error in a pregnant mother. Very sad.
Difficult but prudent decision to step away from 212. Fortunately, you have other assets in the pipeline led now by RLYB116. Can you tell us a little bit about that program?
Absolutely. Just to remind everybody, our business model has been to find assets and bring them into the company where we believe they've got strong science to support what we expect to be a transformative impact in a disease. That's why we tend to, or we do lean towards rare disease, because they're typically monogenic and you can have these big impacts and really understand the science. We do, in fact, have three programs in the pipeline, but let's focus on the one that's in the clinic and we're just about to start another clinical trial, RLYB116. It's a Complement Factor 5 inhibitor, probably betraying Rallybio's heritage from many people from Alexion. We really do, you know, know the complement space very, very well. What's different about it? I mean, you know, we've already got SOLIRIS and ULTOMIRIS and Crovalimab and all the rest of it.
What's the difference? The first thing, it's on a different fundamental platform. It's based on something called an Affibody. These are these tiny 50 amino acid proteins that have an antigen binding surface that's equivalent to the CDRs, the complementarity determining regions, on a monoclonal. You can pack a huge amount of antigen binding in a tiny, in a tiny volume. This will be a 1 mL, 1.5 mL subcutaneous injection. Now, to stop this, this is a tiny protein, so in theory it should just drop straight out in the urine. It would be filtered immediately. The way we get around that is there is a small albumin binding attachment to the molecule, so it attaches to albumin. Albumin is processed, if you like, by the same system as monoclonals.
It just stays in the circulation as long as a monoclonal. We see the advantage of this is, number one, if you're going to go after the tried and tested indications, which is highly unlikely to be our strategy in the short term, obviously with time we would back into those more crowded spaces, but it would be like convenience, convenience, convenience. You would literally treat yourself once a week for 10 seconds and that's it, you're done. These are very stable molecules, so you don't have to refrigerate them. They could be kept in the bathroom cabinet and very low cost of goods, so a lot of pricing flexibility.
We also see it as a great opportunity to open up indications, which we explored at Alexion as part of our medical affairs IIT strategy, indications where Complement Factor 5 inhibition has been shown to have, you know, transformative benefit, but for various reasons companies have not pursued it. We have been very public. One of the indications we are really intrigued with and we are doing more work on, and I will get back to, you know, when we will, how we will settle on the indications, is something called antiphospholipid syndrome. Antiphospholipid syndrome, it is what it says on the tin, the patients raise antibodies against phospholipids, which are expressed on the endothelium, and they then undergo recurrent arterial and venous thromboses. Believe it or not, in my youth, I used to treat patients with APS, and the treatment was Warfarin.
I won't say how long ago that was, but just suffice to say that even today there is no other therapy than Warfarin. So from what we saw with SOLIRIS, this would be a great preventative.
They're having like Xarelto today instead of Warfarin, or they're not on the new?
No, they've tried the DOACs and on something they've, if anything, they make the syndrome worse.
Interesting.
In fact, there were two reasons why we did not go into APS when we were at Alexion. Number one was that the belief was that the DOACs were going to save the day. The second thing for a preventative, you know, you do not really want to have somebody going into the hospital every, you know, two weeks or eight weeks, just because they might get something. Whereas if the idea of just a quick shot once a week.
Circling back on that, if you're targeting once a week self-subcutaneous, you know, how does that compare to what's out there today? Because I think people probably hear SOLIRIS from years ago and may not be familiar with the burn of treatment.
Yeah, the monoclonals are largely intravenous. Crovalimab, the Chugai monoclonal, can be given subcutaneously. It's given in the physician's office. We believe that some patients are sort of trained, quote, "off label" to treat themselves at home, but it's a significantly larger volume. It's just given with a syringe. Ours will be given with an autoinjector. Again, they've gone over after the same old indications, PNH, and I believe they're going to start to look at gMG. Alexion, I think I told you in the past, Jon, actually, we diligenced this asset at Alexion, and at the time there were these problems in phase I. In fact, it was my team, we worked on 1720, which is based on the camelid antibody from camels, basically llama was raised in.
It's still a significantly larger molecule, so it has to be given 3 mL or 4 mL every couple of weeks. We could give our therapeutic once every two weeks, but we strongly believe that with complement you need 100% compliance with treatment. You do not want anything that's complicated. Every two weeks, did I do it last week or this week? It's literally every Saturday morning, clean my teeth, give the shot. We are deliberately focusing on once a week therapeutic, small volume, 1 mL, 1.5 mL . Certainly in the first instance, we want to go after indications that have just been left on the table.
Can you talk about potency and then also can you review the data you've shown and then kind of changes you've made to the program for the upcoming study?
Yeah, so people will probably recall that we took it into a phase I MAD study. We pushed the dose, you know, way above 200 milligrams and showed, you know, rapid and complete and sustained knockdown of C5, or what appeared to be. So we certainly knew, but the problem was that as we went above 100 milligrams, we began to see whispers of the side effects that had stopped development when it was in Sobeys' hand at 10 milligrams. And we suspected and have confirmed that it was, these are almost certainly due to residual bacterial proteins getting through into the bulk drugs. It's not unusual. So in treating complement diseases, the majority of patients would almost certainly respond to 100 milligrams once a week, and certainly for something like mg that would be more than adequate. However, you know, not every patient is the same.
There are, as we learned with ULTOMIRIS and/or SOLIRIS first, and later with ULTOMIRIS, that there are some patients who need to be given higher doses. For example, the labeled dose of SOLIRIS is 900 milligrams. Many patients are on 1,200 milligrams or higher because they get breakthrough. What we want is to not only have a drug that's a dose that's going to work in the vast majority of patients, 100, 100, around that, but also the ability for these more resistant patients or when patients, you know, get sick, to be able to push the dose higher without adverse events. We're going back into the clinic with an improved bulk drug. We now know that we've eliminated virtually every residual protein. There's just a small amount of one left.
You'll see that on our webcast that we did when we got to the bottom of that. We've added additional biomarkers to really, you know, double that to confirm that, you know, what we saw with our assay also is underpinned with things like hemolysis. That study will start before, you know, during this quarter with readouts in 3Q and 4 Q demonstrating that we can get complete, rapid, and sustained inhibition of complement and be able to push the dose for those patients who do need that higher dose.
What doses did you use before? What doses are you using now?
We got up to about 300 milligrams, but had to dial it back and settled at 100 milligrams as a well-tolerated dose with good pharmacology. We're going to go back in at 150 milligrams. It is a, what they call it, an adaptive design, so we can go back up to 300 milligrams. We've conservatively said that we'll go 150- 225, but based on the data, we may dial that up or even dial it down if we think that's the appropriate thing to do. Very common nowadays that, you know, you have these adaptive designs.
Sure. You want to see complete knockdown. The nice thing about complement healthy volunteer studies is you can see if the drug's working. You know, historically in PNH, that's, you know, half your answer there and then it's just running the trials. You know, how do you think about the subsequent development then and like what's the bar? You know, you say complete inhibition. Is that 100%? Does time matter? Does duration matter? I'm guessing yes.
Yes. I mean, you do certainly for something like antiphospholipid syndrome, you know, we would want to show that we are, you know, inhibiting hemolysis and within the limits of our, and with our assay showing complete knockdown of C5. mg, we know it's not quite so significant. Now, if we were, and at this stage we're not planning to go into PNH and we can, you know, it's incredibly crowded. Our view is if you put it into a PNH patient, people go, well, of course it works with PNH, you know, that's what it does. We are going to explore, certainly we're very intrigued with APS. We're just sort of working that up to settle on that. There's a couple of other indications that we're going to select. Within the next few weeks, we'll be going public with what they're going to be.
You've talked about having readouts in 3 Q and 4 Q, but are you going to pull them together now? Or like how are you thinking about actually?
I think as we get the data, we will, you know, 150 milligrams, we did this. Looking forward to data. I do not think we need to wait for a big, you know, we have not actually sort of formally settled on that, but now the current plan is that each time we get data from each cohort, we will share it. You know, the good thing about, as you touched on earlier, the good thing about complement therapeutics is that the endpoints, certainly in phase I, are totally objective. You have either knocked down the C5 or you have not. You know, the patient mood and what have you is not going to impact that. Furthermore, the ability to inhibit C5 is very predictive of how it is going to work in the clinic, as we demonstrated with SOLIRIS and then ULTOMIRIS back in our previous lives.
What are the safety events of interest that you're looking for?
I mean, it's really more of a toleration issue than a safety issue. As I say, 10 milligrams back in the very, very first variant of that caused sort of transient pyrexia, feeling of nausea, sometimes vomiting, lightheadedness. That's why it's safety, I guess, if you think about it. But, you know, we would hope to see none of that, you know, nothing like that at all. Very, very well tolerated with, you know, if you ask enough phase I volunteers, you know, what do you notice? You're going to get, you know, itchy eyes and scratchy throat and that sort of stuff. We would expect this to be a sort of completely well tolerated with no hint of these sort of side effects that are known to be, which have been well associated with bacterial contamination.
It sounds like antiphospholipid syndrome is the one that's kind of floating to the top. You know, for those not as familiar, myself included, talk a little bit about prevalence, you know, how it presents, how it's treated. You mentioned not really anything out there. What else in development?
Yeah, there's probably at any one time in, you know, somewhere like the United States, probably around 150,000-200,000 people with APS. The market that we, now in full disclosure for the people with the milder forms that have had one DVT, say a couple of DVTs over two or three years, they will remain well treated with, and they are well controlled with Warfarin. There is, however, probably in the tens of thousands patients who have, despite good anticoagulation, despite trying, often they have an underlying condition. Despite that, they're still having thrombosis two, three times a year. That segment is in sort of the tens of thousands. Again, it's a rare disease and we would go after those patients.
Is it diagnosed clinically after like recurrent thrombosis events? How does it?
Yeah, typically, yeah, so absolutely right. So typically, you know, patients had a couple of DVTs or whatever, older people, they're more often a stroke.
They go on Eliquis, it doesn't work.
Yeah, and then somebody sort of says, hey, we ought to test for antiphospholipid antibodies if they have not already done it. It is a sort of semi-clinical diagnosis. In other words, presence of antiphospholipid antibodies, recurrent thrombosis, or in younger women, recurrent miscarriages. I do not think we would, or despite our sort of passion around that space from the two-one-two days, I do not think we would go straight after that population for obvious reasons. You know, you would want to back into that population. It would be patients who are having these two or three thromboses a year despite good anticoagulation with positive antiphospholipid antibodies, possibly a history in the past of miscarriages.
I'm guessing managed by internist. How is awareness? How easy is it to test for antiphospholipids?
Oh, I mean, it's, you know, it's a check the box. It's, you know, it's often, well, certainly, but I'm, you know, dating myself down. I can't imagine it's changed. It's sort of picked, you know, you run a sort of an immunological screen. You've got somebody who've got, so let's just check for, you know, anti-nuclear antibodies and it just comes back and somebody says, oh, look, the antiphospholipids are positive. Most sort of even sort of interns would have learned about it in medical school simply because it's the sort of underlying pathology is very, it's one of these syndromes that sort of by teaching about antiphospholipid syndrome, you can teach about a lot of other, you know, SLE is a similar sort of syndrome. Certainly, you know, I was aware of it when I graduated.
Has anything tried to be developed? What does kind of a regional path look like? What are clinical endpoints? What would next steps look like?
Yes, we are, and that's one of the, we're just sort of keeping our powder a little bit dry and, you know, we're really intrigued with that and we'd like to get there. We're working with a couple of KOLs. The sort of the potential issue is that as you got into sort of phase II, big phase II and phase III studies, you would need to start towards moving towards outcomes, you know, have you actually prevented. However, we're working with a couple of groups who have, who are, you know, this is their focus, their life's work, and they are developing a series of biomarkers and assays.
What we would hope to do is select, you know, I'm making these numbers up at the moment, Jon, but 10-12 patients with these recurrent thromboses, measure the biomarkers, treat them for a period of time, and then demonstrate that we're knocking the biomarkers down. That would give you the sort of the strength of will or whatever to then start to get into sort of smaller, well, bigger, but not too big sort of outcome studies. Treat, you know, a number of patients, follow them for a year, looking at historical data saying, look, they've had, you know, two or three thromboses a year up until now, and lo and behold, as we saw with SOLIRIS and the ability to completely prevent that in the vast majority of patients.
You know, thinking back 10 years, probably due to SOLIRIS's success, you know, in ourselves included, we're very high on the complement biology as solving a lot of different diseases. I'm not sure if the promise has kind of borne out, and I think there's been a lot of failures for maybe target specific or mechanism specific reasons. You know, do you, when you look at the complex cascade, and there's so many different things, and my eyes go cross, I try and figure it out again. You know, is C5 still, you know, the best option out there, or do you think there's other kind of greener pastures, and, you know, do you think the complement biology is caught up to where, you know, the promise is?
I think the quick answer is yes. I mean, back to your original point, it is multifactorial. It's not, you know, you've Complement Factor 5, you know, it's one of nine different complement targets. There is no doubt. The first thing is in terms of Complement Factor 5, that has got the broadest sort of history of successful outcomes, either in diseases where there are indications or where it's been explored in IITs. It's not surprising because C5 is the point at which the enzyme cascade reaches a point where it's now releasing both, you know, the pro-inflammatory mediator C5a plus initiating the membrane attack complex, which then actually starts to destroy cells.
Now, it has been shown that there are a number of syndromes where complement associated, where in fact targeting other parts of the complement pathway for whatever reason works particularly well. Classic is cold agglutinin disease and ENJAYMO, a Sanofi product that works as a C1 inhibitor, C1s inhibitor. It looks certainly C3 inhibition seems to have worked in the eye. You know, we're still of the belief that our competitors are other C5 inhibitors. There are other syndromes where, you know, the physician may be reaching for other therapies, you know, Alexion have explored adding factor D to SOLRIS to sort of treat the breakthrough patients. Novartis have been looking at iptacopan, their factor B inhibitor, and it's certainly shown promise in things like C3 glomerular nephropathy and what have you. They've got it approved in PNH.
Our work, as we've really worked through what are the indications, is that yes, it definitely works. The uptake's not brilliant, and I think I personally don't think for PNH where you've got to maintain 100% knockdown day in and day out, an oral treatment's a good place to go because it's twice a day, and if you forget and go on holiday, you're going to get breakthrough. Things where they're more indolent and over many years, C3 glomerular nephropathy and IgA nephropathy probably will be a very interesting therapeutic.
You think there's still plenty of white space for C5 inhibitors and other conditions?
Absolutely, yeah.
I want to spend a few minutes on the earlier stage pipeline. Can you give us a run-through about, you know, where you are? You have multiple programs. We've got a few minutes, but maybe talk on kind of where they are, what you're targeting, and what next steps could be.
Yeah, I'll go to paradoxically the earliest, but we think that, actually it's beginning to sort of creep ahead actually, which is our ENPP1 inhibitor, which we are developing in partnership with now Recursion. A little bit of history, again, betraying our heritage at Alexion. If people know Alexion, they'll know that they've got STRENSIQ for the treatment of hypophosphatasia, a very burdensome enzyme replacement, six injections, you know, a week subcutaneously, and all the sort of baggage that goes with that, and only used in severe onset. Now, one bit of work, something that intrigued us at Alexion was this, what they call a double knockout mouse.
There is a model of hypophosphatasia where you knock out the enzyme that causes it, alkaline phosphatase, but there is also a model where you knock out both the alkaline phosphatase enzyme and the enzyme that makes the substrate, something called ENPP1. It is the substrate. It makes the substrate for Alphos . Lo and behold, these little mice have normal skeletons or almost normal skeletons. The question is, hang on, in a patient with hypophosphatasia, if you were to knock out ENPP1 and prevent the buildup of the substrate, pyrophosphate, and pyrophosphate itself is inhibitory of bone mineralization, maybe certainly for patients with the milder adult onset forms, this could be a great treatment. Who knows, it could even be added to something like STRENSIQ to lower the drug burden.
We've worked with [exine geno Recursion] to make a small molecule inhibitor of ENPP1. It's in IND- enabling studies as we speak. Over the next few days, we will be sort of starting to share some of the data that we've generated in two different mouse models of hypophosphatasia, obviously working with the KOLs and what have you to, you know, they want to publish and we're being thoughtful about how much we can share. I think you're going to, I'm looking forward to sharing some, you know, in the next few days, high-level data showing in models of both, you know, neonatal onset HPP and, you know, adult teenage onset HPP. This drug prevents the, you know, the symptoms or in the model of hypophosphatasia.
A little teaser today. Okay.
Absolutely. Yeah, something to look forward to. We're obviously having to coordinate with our colleagues at Recursion. They want to, you know, we don't want to sort of front-run them and also being very respectful of the KOL who ran one of the models for us. You know, he wants to, obviously his PhD student wants a sort of really good publication, but he's a super collaborator. We still have the Matriptase 2 antibody, which we re-engineered. It would be used in iron overload syndromes. It's good to go. We've got the cell banks, but we just have it, you know, like everybody, being very, very thoughtful about our capital. And so sadly at the moment, that is sort of sitting on the shelf, either till we can capitalize it or find someone else who can work with us to move that forward.
How's the partnership with EyePoint?
That is sort of on hold at the moment. They are having to, I think they're focusing at the moment. I think we're going to be in the process of, you know, gradually sort of pulling back from that, you know, at least having the optionality, but at the moment they're really having to focus on their lead programs like a lot of companies.
Makes sense. We have the ENPP1 preclinical data coming next few days. I'm guessing concurrent with your first quarter update. We'll have data from 116, 3Q, 4Q, probably rolling out as you get data from each cohort. Can you remind us of your current cash position and runway that you have?
Yeah, our current runway is into second half of 2026. And as John says, that's not the second of July. He's in the audience. That's your joke, John, so I'll tell it for you.
We'll get an update in a few days.
We're going to get an update, you know, any day now. You know, we've obviously reviewed our expenditure around 212 and, you know, pulled as many levers as we can to, you know, extend the runway as far as we can. We'll be up, you know, I don't want to front-run that, but we will be updating over the next few days.
We have things to look forward to in this calendar year, which is enough to say. Steve, thank you again for joining us.
Thank you
for the rundown.
We'll look forward to catching up here in just a few days.
Yeah, look forward to it.
Thank you very much.
Thanks a lot. Thank you.