There we go. Hi, everyone. My name is Joshua Fleischman. I'm a research associate on the team of Senior Analyst Ritu Baral. Today we're joined with Steve Uden, the CEO of Rallybio. Steve, please take it away.
Thanks very much. Thanks, Joshua, for the invitation. Thank you, everybody, for coming to join us. I'm going to talk to you about our company, Rallybio. I'm joined today by John Lieber, our CFO. Rallybio, this is us. We're a rare disease-focused company. We're built around the team that we put together in about 2018. We have an exciting year ahead. We're expecting readouts in three different programs this year. Our lead program for the prevention of a rare disease due to the mother mounting an immune response against her own foetus while it's still in the mother's womb and destroying the baby's platelets. If you have heard of Rhesus disease of the newborn, the red blood cell mismatch, much more prevalent, very similar to that, both in terms of pathology and treatment, though this is a much rarer syndrome.
We have a complement Factor V inhibitor, which we think will be sort of best in class in terms of being able to treat everything that's out there already, all the indications out there already, but also open up other opportunities to us due to the way that it will be presented as sort of the Wegovy of complement inhibitors. A first-in-class, best-in-class ENPP1 inhibitor for an oral treatment for hypophosphatasia. This is in partnership with Recursion, formerly Exscientia. You can see our financial position remains strong. We have over $65 million in cash at the moment, which will take us well into the second half of next year. This is the pipeline we've built. We built it around the team. With the team, we raised the financing, and we brought together these programs here.
I'm going to focus today primarily on the top three, the FNAIT program, which is now in phase II, the complement Factor V inhibitor, which is in phase I, getting ready for phase II. We've got some additional work we want to get completed this year and talk a little bit about this oral treatment for hypophosphatasia. With our current cash position, the other programs, whilst we remain very excited about them, they're currently having very little capital allocated to them, but we're looking forward to changing that at some time in the future. FNAIT, this is an interesting approach. What we're looking to do here is to prevent a disease from ever happening rather than treat it. It is potentially devastating. What happens is that the mother and the baby have different platelet types. The mum has a rare mutation.
Only about 2% of the world have this mutation, such that if the normal platelets from the foetus get into her circulation, she mounts an immune response to them. This produces alloantibodies, IgG, that cross into the baby and destroy the baby's platelets. Even though the baby is wrapped up in the mother's womb with no platelets, any bleed could be spontaneous or due to the mum tripping up on a rug or something, will bleed and bleed and bleed. Of course, that can result in miscarriage, intracranial hemorrhage, complications with delivery, bleeding into different organs. Because it is an immune response, once that first pregnancy is affected, so will all future pregnancies be affected. Now, we estimate that there are 30,000 at-risk pregnancies. At-risk means, number one, the mum has this mutation and the baby does not.
You can test to see whether the baby has the mutation with cell-free DNA. Number two, the mum has the HLA type DRB3*01:01. If she has those two combinations and the baby has the normal platelets, she's at high risk of having the immune response, and that's the 30,000 we talk about. This is a preventative, not a treatment. We are in a collaboration with Johnson & Johnson and are looking to see whether their FcRn antibody could be used to treat the mums who sadly already had an immune response. We hope that that opportunity will gradually diminish if our drug works. We estimate that with pretty conservative rare disease pricing, this would be a $1.6 billion opportunity. I'm just going to sort of toot our horn here.
As far as we've not been able to find, and I'm sure there is one, but we haven't been able to find it, a therapeutic where the first use in patients was in pregnant mothers. Lots of drugs are tested in pregnant mothers, late in development, often after they're approved. I'm blessed with a really, really experienced team with decades of drug development and preclinical experience. This is a sort of checklist of all of the things that we've done. We are literally writing the playbook for taking drugs into pregnant mothers as the first use, whether that's developing the monoclonal itself. It was originally a polyclonal approach, a license to a model that could be used in toxicology. This is a little mouse that's got the human antigen on its surface.
We've done this epidemiological study interrogating a large genomic database to get a fix on this 30,000 at risk, partnering with J&J, a big natural history study that will act as our historical control. We've done a proof of concept, and we're now going into phase II. phase II started at the end of last year, and I'm pleased to announce that the first mother has been recruited into this clinical trial. This trial will de-risk three things from our perspective. Number one, will the regulators actually let you go into a study in pregnant women? Obviously, we've been talking about this for a long time with them. Whilst we were delighted, we weren't hugely surprised. We've done everything they asked. Number two, would a pregnant mother actually agree to take part? I'm pleased to say that a pregnant mother in Norway has agreed to take part.
I was visiting the site only last week. There is the technical issue that this study will need to resolve before we'll be ready for a registration program. That is, how do the changes in the mother's physiology during pregnancy impact the pharmacokinetics of this drug? Because the trick here is to keep sufficient blood in the mum's circulation to prevent the alloimmunization by removing fetal platelets, but not so much that it gets into the baby and starts to cause problems in the baby. That will be the technical thing that we have to de-risk as the mum's blood volume goes up during pregnancy and the presence of the foetus inside her that does, in fact, carry the antigen. We have got the first mum in the study, and we're looking forward to data readouts in 2Q and 3Q this year.
Originally, we thought it was going to be 3Q and 4Q, but luckily, we found the mother much more quickly than we'd expected, and she was, so the investigator tells me, so pleased to be taking part. As I said, it's a $1.6 billion market opportunity. In the background, we are doing a lot of work in terms of the trick here will, of course, be to get on the guidelines for the management of pregnancy, getting reimbursed. We're talking to payers. We're talking to prescribers. We're talking to physicians who write the guidelines, not only in the United States, but all around Europe, understanding how things get on screening in, say, Europe, which tends to be a government-driven thing compared to the U.S., where it's driven much more by the American College. A really exciting program.
This could absolutely transform the management of children during pregnancy and effectively eliminate a disease should it work. I'm now going to go on to a program that sort of betrays our heritage from Alexion. Many of us in Rallybio have worked together for many years. Many of us were at Pfizer together. From Pfizer, we all found ourselves at Alexion, and now we all find ourselves at Rallybio. This is a therapeutic for the treatment of complement-driven diseases. In full disclosure, it was a program that we looked at while we were at Alexion. It was developed in a collaboration between Sobi, who now no longer do R&D, and Affibody. It's a therapeutic based on something called the Affibody, shown here. It's a tiny protein, about 60 amino acids.
Compare that with the 1300 amino acids to 1400 amino acids in a monoclonal antibody. You can see that you can pack a huge amount of drug in a very small volume. Interestingly, the Affibody is the sort of red and yellow sort of structure shown on the left-hand side. As I always say, it's not really red and yellow. We just use that for illustration. The antigen binding surface shown in red is equivalent to the antigen binding surface in a monoclonal. In this 60 amino acid protein, you can get as much antigen binding activity as in a monoclonal. You stop it from dropping out in the urine by this small albumin-binding peptide that's attached to the back of it. We've been into phase I. This clearly is an effective complement Factor V inhibitor. It can be given once a week.
We've done some additional work to increase the amount of drug that we can give by improving the manufacturing processes, removing the last residual elements of small E. coli proteins that were in the original bulk we made. We're now going to just confirm that we can really push the dose. We think this is going to address not only existing therapeutics, existing indications such as PNH and gMG, but also could be used in preventative approaches such as something called antiphospholipid syndrome. Now, why are we excited? These are two bits of data to show you why we're excited about this molecule. This is some preclinical work that we did where we compared our drug with ravulizumab, the Alexion follow-on to Soliris. What we're looking at here is comparing the ability of our therapeutics, shown here as 112 and 116.
The difference between those two molecules is we substituted a couple of amino acids on that yellow backbone to improve stability. The original molecule is 112 that we received from Sobi. 116 is our slightly re-engineered molecule. We are comparing it with ravulizumab, called here ZB007. Interestingly, the inventor of ravulizumab now works at Rallybio. He was able to help us ensure that we got a very good sort of molecule of ravulizumab. What we are looking at here is the concentration of our therapeutic and ravulizumab in terms of preventing hemolysis. If you know complement biology, you know, excuse me, will know that the sort of gold standard test for inhibiting complement inhibition is the ability to prevent hemolysis of sheep or chicken red blood cells put into human serum. You can see that the curves completely overlie ravulizumab.
In other words, this molecule does everything that ravulizumab does, but in a much smaller molecule. That is the science. That is the sort of thing that gets me out of bed and what I really enjoy doing. Now look at this, really, what I think is really interesting market data. This is work that we commissioned in late 2023. It was based on work that we had done when we were at Alexion, originally diligencing this asset. The bottom line is that this message has not changed. What we are doing is asking patients, bearing in mind all of the ways that you could have your complement inhibitor administered, which is most attractive to you, which of the product profiles are most attractive to you. Of course, we have the way down, sadly, at the bottom, number five for PNH is, of course, Soliris.
You can see halfway up is ravulizumab, given eight weekly. In fact, additional work that we've done shows that many patients need to receive ravulizumab every five to six weeks, much to Doug, who invented ravulizumab, works for us, his annoyance. Subcutaneous administration with a device every couple of weeks, or what I would call the Wegovy of C5 inhibitors. In other words, that once-a-week quick one-and-a-half-million injection. The Affibody, because it's such a small protein, is very stable. You can store it in the bathroom cabinet. It doesn't need to be refrigerated. Saturday morning, clean my teeth, take my 116, and good to go. We have discussed, could you push the dose to make it every two weeks? We're personally of the opinion that let's stick with one week because it's much better from compliance. Saturday morning, take the drug.
I'm not sure that two weeks or three weeks really adds anything other than, did I take it last week or is it next week? Now, if all of this is delivered, this is the market opportunity that we think exists through our own market research. Two already approved indications, PNH and gMG, where we'd be taking market share in terms of now patients have been stabilized for three, four, five, 10 years. They're now looking for a much more easy way to give their therapeutic. They can travel. They don't have to get to the hospital. Modest market share there. And then this syndrome, antiphospholipid syndrome. This would be a preventative therapeutic. You can see for a preventative, the idea of having to go to hospital or whatever every few weeks for an infusion is not going to be attractive.
If it's a 10-second injection once a week, suddenly it becomes most attractive. Now, we did work when I was at Alexion for, and so what is antiphospholipid syndrome? It's a rare syndrome where the patient produces antibodies against phospholipids, particularly phospholipids that occur on blood vessel endothelium. It presents as multiple and recurrent thromboses, either in the venous system or the arterial system. It is also, interestingly, a cause of recurrent miscarriage, which sort of piqued our interest, bearing in mind our interest in FNAIT. I was a physician, or I guess I'll say I was a practicing physician. I did hematology for a few years a long time ago. I won't say quite how long ago. The only treatment we had for antiphospholipid syndrome was warfarin. Wind the clock forward many decades, the only treatment that we have for these patients is warfarin.
Despite the fact that in individuals who have thromboses two or three times a year, Soliris has been approved to be very effective, it's obviously not a convenient therapeutic. My point, and there's very, very good evidence that the complement system in general and C5 in particular is involved in the pathogenesis of APS. We're really excited to be able to get into another space where there is no therapeutic. A bit like FNAIT, this would be using a proven pharmacology to address a syndrome for which there's really no improvement after many decades other than anticoagulants that only work in a proportion of the patients. As I said, we're going back into the clinic later this year. We've done some work to improve the toleration of the drug, so we think we can get a huge excess.
We're already knocking down the complement system adequately to treat these syndromes, but having worked with ravulizumab and Soliris, having a bit of headroom for patients who are particularly resistant to therapy is always useful. Once we've done that, raise more money and then get into proof of concepts in these various indications, PNH, gMG, and of course, antiphospholipid syndrome. I'm now going to sort of talk a little bit about this very interesting collaboration that we have with formerly Exscientia, now Recursion. Exscientia was a U.K.-based medicinal chemistry company founded by some former Pfizer colleagues. There is always sort of human connection. It's an artificial intelligence platform that focuses on medicinal chemistry. At the end of last year, they were acquired by Recursion, who you probably know is an artificial intelligence-focused company-based company focused on biology, so it makes a natural fit.
Just as the deal was closed, we worked with Exscientia to produce an oral treatment for hypophosphatasia. Again, betraying our heritage in Alexion. You're probably aware that Alexion has the drug STRENSIQ. STRENSIQ is an enzyme replacement for this syndrome. What is hypophosphatasia? Hypophosphatasia is a rare syndrome where the patients either have no activity in the enzyme nonspecific alkaline phosphatase or markedly reduced activity. Now, alkaline phosphatase is the enzyme that is responsible for converting something called pyrophosphate. That's two phosphate molecules joined together, splitting it into phosphate and phosphate. The phosphate can then combine with calcium to calcify the bones. Now, patients with hypophosphatasia, at the top of these three radiographs is a normal child. You can see this baby's been born with ribs that are calcified.
Shown below are two patients where they've produced the cartilage template for the bone, but because they don't have alkaline phosphatase, they're unable to produce adequate phosphate to combine with calcium to mineralize the bones. It can present in a broad range of presentations. Children are born with complete absence of the enzyme, unlike the children shown here. You can see, in fact, the child at the bottom is being ventilated despite being over two years old. You can get a much milder form that's often not diagnosed until late childhood, teenage years, sometimes even adulthood. It presents a bit like rickets or osteomalacia, osteogenesis imperfecta, frequent fractures, and loss of teeth. What else can I say about this? You can see the prevalence. The very, very rare form is very, very rare. The children that are treated with STRENSIQ, it's one every 300,000.
The milder forms, it is much more prevalent. There is a huge unmet need because STRENSIQ is incredibly expensive. It is a very complicated molecule and very burdensome. You have to give six injections every week in order to maintain levels. Our therapeutic would be one pill once a day. This is the market that we would be addressing. Right over on the sort of far left-hand side are the patients currently treated with STRENSIQ. These are the babies and children born with no calcium in their bones, unable to walk. Many, many of them die before they start receiving STRENSIQ. The problem is it is very burdensome. You get anti-drug antibodies. It is a sort of engineered molecule and typically denied late onset simply because of cost and burden. Shown on the right-hand side is this milder form, very debilitating.
The patients are typically in wheelchairs, multiple fractures, etc., etc. We would be addressing that market. There is even the possibility that could you use our drug with STRENSIQ to reduce the amount of STRENSIQ that needs to be given? This would explain why that would be. Just a little diversion in, so that's the opportunity, a little diversion into science. Shown at the top is a cartoon showing what's probably happening to everybody in this room as we sort of sit and stand here. What we're showing is shown in green on the far right-hand side is normal alkaline phosphatase, happily converting pyrophosphate into phosphate and mineralizing bone. Where does the pyrophosphate come from? The vast majority of it comes from the enzyme ENPP1. ENPP1 hydrolyzes ATP to AMP and pyrophosphate. Then the pyrophosphate passes on to the alk phos to make phosphate.
Now, the problem is that not only do the patients shown in the middle, these are the patients, so their alkaline phosphatase has turned all brown, as you can see. It's not really brown. We just use that for illustration. But it's not working. What happens is you get a buildup of the pyrophosphate substrate. These patients actually have two problems. Number one is they're not producing enough phosphate. Secondly, pyrophosphate is toxic to bone. It inhibits calcification. It's a sort of double whammy. Number one, you can't make phosphate. Number two, you get a buildup of the substrate, pyrophosphate. Our approach, shown at the bottom, will be to partially inhibit the activity of ENPP1, so there's less pyrophosphate. If you have residual tissue nonspecific alkaline phosphatase activity, you can probably cope and turn the pyrophosphate into phosphate.
Most importantly, you're preventing the buildup of this toxic metabolite. Here's some data from a preclinical model. These are some work that we did internally. There was a publication, the ASBMR, with a model of adult onset HPP, hypophosphatasia, with a probe molecule. What we're showing here is the ability of our drug, shown in blue on the left-hand side, to bring pyrophosphate levels down to normal in wild type, shown in yellow. In the middle, of course, is the model that is the mice with massively reduced alkaline phosphatase activity. You can see the effect on bone mineralization on the right-hand side. Really quite exciting program that could revolutionize the management of hypophosphatasia. This is what we're up to this year. Lots of milestones. We'll be reporting the initial PK data from this sentinel mum.
We will only be treating one mum to start with in the FNAIT program for an abundance of safety. There is no margin for error. Those data will be being reported in the second and third quarters of this year. We will be going back into studies with 116, so ahead of starting phase II work to show that we can really push the dose. We'll be sharing some natural history data from our FNAIT program, wrapping up the first pregnancy in 212, and looking forward to moving the ENPP1 inhibitor into preclinical work. Thanks very much for your attention. Happy to take questions. Thanks very much, Joshua. Thank you.
Okay. Thank you. Any questions from the audience? No?
Okay. Great. Thanks, Joshua.
Thanks for coming.
You've got a question?
Of course, we have a question.
I thought I was going to get an early coffee. Never mind.
To start off for 212, you mentioned the first sentinel patient has been dosed. We should be expecting interim data in 2Q, top-line sentinel patient data in 3Q. What does good data look like for this patient? How should investors think about these PK differences between the healthy volunteers and the pregnant mothers? How do you predict these PK differences may impact the PK-PD relationship?
That's a great question. We've done extensive modeling based on the work that was seen in phase I, the work that was seen in that APLDQ mouse. That's a mouse that has the abnormal, has the human, not the human, the human platelet antigen, plus big epidemiological studies showing the level of antibody that you need to avoid. We've set a target therapeutic range of between six and 10 nanograms per mil. We want to sail in between that.
Now, it's possible that when we treat the first mum, we're not quite there. There it might be, well, okay, we're lower than that, but we can, through the models, and we've published these, by the way, and you can get access to them on our website. We know that by making this up, giving 1.5 times the dose, we can stay in that window. Success would look like a dose that can either is already in the therapeutic range, if we're really lucky, or we can predict how the dose would be adjusted for the next cope. We're doing a sentinel mum now. We'll then be looking at three more mums, and success would be able to say, right, the dose that we need to take in is 1.5 what we've given already. Does that make sense?
It does. Yeah.
As a follow-up to that, in the real world, do you anticipate that 212 will require active therapeutic monitoring to maintain a trough within a certain concentration?
One would hope not, a bit like the use of RhoGAM during pregnancy. This is a very well-behaved monoclonal. It's a human monoclone. It was derived from a plasma cell of a mother who'd had FNAIT. The PK variability was only about twofold in phase I. So we're pretty confident that this will not require therapeutic monitoring during pregnancy.
You mentioned this is just the first patient. There's three more in cohort two, four more in cohort three. I know in the past we've spoken about 2027 phase III initiation, right?
Yeah.
What factors may potentially accelerate or gate that phase III initiation?
It's going to be the speed with which we can find women with this rare mutation.
One of the sort of, because this is prevention rather than treatment, we have to screen many, many mums to find the high-risk ones. We've built sort of statistical models as to when one would expect to see the mum. In fact, the guidance we gave at the end of last year was based on such a model. Yet we turned the card much more quickly. I think that what could speed up is that our luck remains and we find these mums more quickly. We're obviously going to high-prevalence areas. I was in this particularly prevalent in Norway and Sweden. I was there last week and the Netherlands. What could slow it would, of course, be if we just were unlucky and we don't find mums for a while. The problem is that the biggest physiological changes in the mother occur at that last trimester.
This is not something where one can do an interim analysis after 25 weeks of pregnancy and then you're good to go. You've really got to follow it right out. Because only at the end of pregnancy is the blood volume at its greatest and the placentas and the babies are the biggest, etc., etc.
To pivot now towards 116. Earlier this year, there were some encouraging data talking about higher purity product, the analytical techniques to more accurately measure the free C5 levels. Compared to the other phase I study that was done, how should investors think about what good data would look like for the new ongoing phase I study?
Great question, Joshua. Number one is that we can push. Remember, we pushed beyond 100 mg in the previous phase I.
We were getting to see whispers of the side effects that stopped the program dead in its tracks with Sobi back in the day at 10 mg when the volunteers were very sick. Clearly, it would be getting up to 150 mg-200 mg without any hints of these side effects caused by bacterial host cell proteins. Which, by the way, this is not an unusual story. Many forms of insulin have been through exactly this cycle. Made in E. coli, they take it into the clinic and you need to improve the manufacturing. There's a big long list of. It would be getting up to sort of 150 mg-200 mg.
With two other things, we'll be using both the recalibrated assay, so demonstrating that we are getting really rapid, complete, and sustained knockdown of free C5 with the new limits set with the updated assay. We're going to be backing that up with prevention of hemolysis, which is we didn't use it in the original phase I. It is a particularly difficult assay, but we found a really good lab that can do this for us. It would be getting well above up to 150 mg or higher, free C5 knockdown with the new limits set with our assay and inhibition of hemolysis.
Great. Thank you. One last question on my end. You know I had to ask about the medicinal chemistry. How should investors think about this second-generation ENPP1 inhibitor?
What do you hope to get that improves on top of that first data set from ASBMR?
Oh, absolutely. It was a probe molecule, and the issue was around bioavailability. As people are aware, if you've got poor bioavailability, you're much more prone to variations in drug levels, simply because if you absorb 50% more of a low, it's a much higher swing than if you're—so primarily, it was all around the drug properties. The fundamental pharmacology was more or less the same in terms of potency and target specificity and that sort of thing. It was all the drug-like properties that had to be smartened up: bioavailability, variability, microsomal stability, etc., etc.
Which is, for those of you who have not been involved in small molecule discovery, and Joshua will know this as well as anybody in this room, getting a molecule that inhibits the target that you're after is usually pretty straightforward. I'm not a chemist, so they'll probably be hijacked by chemists. The issue is typically, though, getting the molecule to be drug-like, stable in microsomes, no hERG signal, high solubility, all of these other things. That's actually, and it was that that the Exscientia wanted to get a top-class molecule. Remember, this is a drug that's going to be taken for the rest of a patient's life. So it's really got to be an incredibly well-behaved molecule. This isn't like an oncology product where it can be a little bit more rough around the edges because the patient's sicker and it's going to be given for a shorter time.
Does that help?
It does. Steve, thank you so much for coming. Thank you all for coming, everybody.
Great. Thank you.