Joining us at the 9th Health Tech Conference, one of the biopharm analysts here, Nirali Shahasvilli from the team, Eloxx Pharmaceuticals team, Sumit Aggarwal, and John Woolford, and so much for both of you joining us.
Thanks for having us.
Happy to. Maybe today, I think as a starting point, for people not as familiar with Eloxx's story, if you can give a little bit of the background.
Sure.
Because it's been a little bit of a journey to get to where we are now.
Sure.
And then we will talk about your asset and-
Yeah, sure.
What is going forward.
We have been public now for almost eight years, when we went through a bit of a cathartic time three years ago. But last, in June, we raised money to prosecute both our programs. We are focused on rare kidney diseases, and we have two programs, one in Alport syndrome and the other in autosomal dominant polycystic kidney disease, ADPKD. We are targeting nonsense mutations, which are a subset of these diseases, with our lead asset, ELX-02. We have learned a lot about our drug. The drug has been trialed in 145 subjects. We have almost 90 patients, month subject months of exposure. So very good safety profile so far. And we have had data that showed we could reverse the structural damage that is associated with Alport syndrome, which is really a functional cure if you can see it extend over a longer period of time.
Okay, great. Let's talk about ELX-02, and maybe just before getting into the two different indications, just the product itself, the mechanism
Sure.
And how it is working under them.
The mechanism of the drug is PTC read-through. When you have a nonsense mutation, a nonsense mutation is a mutation in the gene where instead of a regular ATCG, you have a stop, and it causes a formation of a premature termination codon. What this drug does is it reads past that premature termination codon and inserts an amino acid that results in full-length proteins getting formed again. This was a mechanism first described about 30 years ago when observed with gentamicin. It is an aminoglycoside, like gentamicin, which was specifically engineered to not have the two liabilities that gentamicin antibiotics have, which are, one, antibiotic activity, and second, mitochondrial toxicity. The drug has almost no antibiotic activity and has almost a two log, two orders of magnitude lower mitochondrial toxicity.
What that means is you do not see the kidney tox or the hearing loss that would normally be expected to be seen with aminoglycoside antibiotics. We have taken this molecule and really applied it to the kidney space, and having learned a lot from our earlier program in cystic fibrosis, both we learned about safety, we learned about the thresholds of exposure we need for efficacy. In the kidney, like aminoglycoside antibiotics, the drug gets taken up in a much larger exposure in the kidney itself. At the doses we are treating these patients, we have a 43-fold exposure in the kidney relative to plasma. Just for contrast, the lung exposure to plasma is only one to one. We can get about 30, 35 micromolar of exposure if you look at the AUC over 24 hours in the kidney versus only one micromolar in the plasma.
That helps us achieve the PKPD that we need to have for efficacy in all our programs.
Okay. You touched on this, but you do have some biopsy data that kind of-
Yes, if I double-click into the Alport data that we have, we treated three patients that had an Alport nonsense mutation, a collagen IV gene. Alport is a disease that is caused by mutations in one of three collagen IV genes, collagen IV A3, A4, or A5, and these patients had a mutation in collagen A4. After eight weeks of treatment, all the three patients, when looked at under the microscope in the biopsies, we saw a remodeling of the kidney. The two main elements of the kidney filtration structure are the glomerulus and the proximal tubules. The glomerulus is where the bulk of the filtration occurs. In Alport syndrome, the glomerular basement membrane gets irregular and becomes leaky, and then you have foot processes that attach to the glomerular basement membrane that start to efface or flatten out.
After eight weeks, we saw the glomerular basement membrane become more normal, and the foot process effacement reached about 80% of normal, starting with about 50% of normal.
Okay. Great. That has now led you obviously to, you did the raise, and you are starting the EXACT study. You can just talk about that, the development, following the biopsy results, how you planned out
Yeah.
phase II.
What was very clear in Alport syndrome, when we were just thinking about the design of the study, functionally, you need to see a change in proteinuria. However, when you look at the natural history of the disease, the progression of proteinuria occurs at a much more rapid pace. The median age at kidney failure in these patients is 23 years old. We needed to look at an endpoint that was aligned with the drug's mechanism of action and could minimize the risk of a false negative. We chose, therefore, to use a biopsy endpoint rather than proteinuria as our primary endpoint.
Proteinuria is a secondary endpoint in the study, and the two things that we wanted to do in the next study, which is the EXACT study, it is a phase II study, was to trial the drug in more patients over a longer duration, and maybe three things. The third was to have a placebo group, because of the progressive nature of the disease, without a placebo group, it is really difficult to interrogate how significant of an impact you have had on the disease, right? Because if you had in most clinical trials in Alport, you see up to a 50% increase in proteinuria in 16 weeks. In our study, initially, we saw no change, but if you overlay that with a 50% increase, then that would be a very significant improvement in proteinuria as well.
Okay. Now maybe touch on the progress you are making here in terms of-
Sure.
Site activation, getting this.
Yeah. We have announced that we dosed our first patients in September. We continue to screen patients and activate more sites. We hired a new chief medical officer coming out of Novartis last couple of weeks back, and that has helped us kick into high gear our U.S. site activation. We are also opening sites in France and India, where we just recently got approval. Right now, we think we are tracking to a mid-year 2027 for the data readout for the primary endpoint, which is at 16 weeks. We will be able to give an update in January of how that is going. Next couple of months are pretty critical for us to make sure we can put our foot on the pedal and get that recruitment up and going.
We are working with Natera in the U.S., working with registries, data in the U.K. and Europe and India to find patients. These are roughly, Alport syndrome is about 60,000 patients in the U.S., and 7% of those are nonsense mutations, about 4,000 patients. So it is an ultra-rare segment of a rare population. So it is a lot of work to find patients, and we are doing our best to work with the sites that do genotyping and are able to find patients.
Okay, perfect. Maybe you can talk about what you're still on track for mid-next year. What do you hope to see at 16 weeks?
Yeah.
Does that sort of lead to potential discussion with the FDA about some sort of accelerated path, or is it really then kind of seeing the 32-week data later?
Yeah. So, like I said, the primary endpoint is a change in filtration slit density, which is a quantitative measure of foot process effacement. We then have secondary endpoints of UPCR and other biopsy endpoints. We saw a 50% increase in FSD in our phase II-A, and when we look at the relationship between UPCR and FSD, that should translate to a robust improvement in UPCR. So our operating assumption is that from a clinical trial perspective, this trial is oversized for a 25% increase in FSD. So we only need about 12 patients to have at least a 25% increase in FSD, and that's sort of our 20%- 25% is what we're targeting as an increase. Why that much?
All the prior work that has been done in looking at foot process effacement across diseases has shown that even a 10% improvement in FSD can have a material impact on the progression of disease.
Okay. What about proteinuria?
Yeah. You asked also the question of FDA. We would go to the FDA at the end of the primary endpoint readout. We have a very constructive relationship, a dialogue with the FDA. They want to see proteinuria and FSD correlations. They don't have to be stat sig. We have run a fair number of We've done a fair amount of modeling looking at the relationship between FSD and proteinuria based on published literature in Alport syndrome and other diseases. What we see is about a doubling of FSD leads to a 70% reduction in UPCR. Obviously, that's got high variability, but that's the general trend. You would expect to see that, because think of what we're essentially doing is closing a hole that has formed in the kidney.
As you close the hole, you go from a fully open hole to 50%, you should expect to see a significant reduction. We've not been able to Because of the variability in UPCR, we don't really have a bogey for UPCR. Our bogey is on FSD, because the bogey on UPCR depends on what happens in placebo as much as what happens on the drug side and how much variability you have in proteinuria. We are doing a lot of things to make sure we minimize the variability. We're taking three proteinuria readings, first morning void. The FDA hasn't told us that we need a bogey. One thing that folks may not be aware of is there is a working group called ASSENT that's been put together by the Alport Syndrome Foundation in the U.S.
It's a global working group looking at surrogate endpoints for approval of drugs in Alport syndrome, just like you had PARASOL with FSGS. The first cut of data that they showed was that even a 10% improvement in UPCR leads to clinically relevant reductions in or improvement in hard endpoints of kidney failure or reduction in 50% eGFR.
Okay. Maybe last couple ones on Alport, then I will turn over to Arseniy on the ADPKD side. You touched a little bit on the commercial, the size of the market at least. What do you see as sort of the commercial opportunity? If you talk about any sort of.
Yeah.
Other products that might be in development.
Sure. We are very focused on nonsense mutation Alport syndrome because the drug's mechanism is very specific to that. We do not see any competing products in that area, and there are a few competing trials, but none of them have shown robust preclinical data that would suggest very large effect sizes. We do not really see any competition there. We are working on some pricing work on our own, but this is, given the ultra-rare nature of the population, if you just take the global market is about 7,000, 8,000 patients between Europe, the U.S., and Japan. We are doing some work to start the regulatory process in Japan as well. You would expect to get pricing in this $500,000-$700,000 per patient per year, so that translates to about a $4 billion TAM opportunity in Alport globally.
Okay. All right, let me turn it to Arseniy.
Yep. To help frame the ADPKD discussion, maybe you could help us understand how that disease is different from Alport, how the unmet need is different, and then it is the same mechanism.
Sure.
How-
Sure
All of that. Sorry.
Yeah. It's the largest genetic kidney disease. It's obviously different in a couple of different ways. One, the disease is caused by different genes, two genes, PKD1 and PKD2. They code for the polycystin-1 and polycystin-2 protein that together form a complex that's an ion channel transport, just like you have in other diseases. The progression of the disease is relatively stable. These patients develop cysts in the kidney, and the kidney expands over time as the cysts grow. The cysts usually are formed because the patients have a germline mutation, and then they develop a spontaneous second mutation in the second allele. So it's what's known as haploinsufficiency plus a second hit hypothesis. On average, they're about in the mid-30s to low 40s at the age of diagnosis, and they progress. The eGFR slope is pretty stable in these diseases. So, now, that's sort of the disease.
It's treated, there's only one drug that's approved, it's called tolvaptan, and it's very difficult to tolerate. It's got polyuria and liver safety issues, but it showed a 50% reduction in the rate of growth of kidney volume, which is the endpoint that the FDA looks at for accelerated approval. Now, there are similarities between Alport and ADPKD as we think about it. They're both caused obviously by a protein. In both diseases, there's very broad and robust evidence showing that when you restore the protein, you can reverse the disease. In animal data, and critically in ADPKD now, farabursen, the drug that Regulus was developing and now is being developed by Novartis, showed that even in three months, you can increase protein that leads to a differential change in the TKV growth.
In that regard, it's very similar because we're changing the structure of the kidney with an Alport, and here too, the disease is a structural disease because you're trying to change the size of the kidney.
Okay. You mentioned in Alport there are 7,000 patients globally.
Yeah.
4,000 in the U.S. is your target. How are you thinking about the opportunity in ADPKD?
There are about, depending on which reports, there's about 26%-30% of ADPKD patients that have a nonsense mutation. In the U.S., the range of estimates is between 140,000 and 200,000 all ADPKD patients, and globally, you mostly double that number. As we think about the total ADPKD market globally, we think it's closer to about 100,000 patients globally. Again, if you look at IgAN as a proxy for the BAFF and the APRIL drugs as a proxy for the pricing you can get on a disease-modifying agent it's about $400,000. That's obviously a huge number, just 100,000 patients times $400,000 is a huge number in TAM, right?
Obviously, addressable market will be lower because we don't address patients that have an eGFR below 30, so anyone kidney failure, and all these patients progress at different rates, so we likely will have upper cutoff on eGFR. We think that the addressable market is probably half of that. Still 50,000 patients times $400,000, still a $20 billion market.
Mm-hmm. Can we talk about your development program in ADPKD?
Yeah.
And what from your Alport experience
Yeah.
Would you be able to leverage in that program?
We have four sets of preclinical data that support moving into PKD. The first is data showing that when you treat organoids, kidney organoids that have been made from iPSC cells, you see a 50% of wild-type protein expression, and you see a significant reduction in the organoid volumes and the number of cysts, new cysts formed, as well as the growth in the existing cysts. Second, we have data from primary epithelial cells in patients showing we have a robust increase in transcripts of PKD1 and PKD2, and an improvement in the phenotype of the epithelial cells. The third is data from PKD cysts from patients that showed that when you treat those cysts with our drug, we see a reduction in the cyst volume and cyst growth.
The fourth is preclinical data in cells, in vitro preclinical data, where we see about a 3% protein expression leading to downstream regulation of the proliferation pathways. Those are the four things. Based on that, we've decided that it makes sense to go to include all PKD patients that have nonsense mutations, so PKD1 and PKD2. If you look at some of the trials out there, they're mostly focusing on PKD1. We don't think we need to do that. Second, we are including patients that have a slightly lower volume growth. These are patients that have an image MIC or Mayo Imaging Classification 1B. Most companies will focus on 1Cs, Ds, and Es because they're rapid progressors.
Given the mechanism, we don't need to do that. The third, we have the target engagement from our Alport study, and we know that the drug concentrates in the kidney, in the proximal tubules, and the cysts. That's where a lot of the megalin is found
which is the primary reason for uptake of the drug. We've taken the same PKPD from Alport and applied it to ADPKD. When you put it all together, the trial is designed to show an improvement in TKV. It is a one-year study, one-to-one placebo control. We chose one year because that gives you the opportunity to have a discussion with the FDA for breakthrough designation, as well as a path potentially to accelerated approval. 60 patients was really to ensure we had, while not the full safety data set that the FDA requires, which is 100 patient years of safety data, in the context of a rare disease, a robust safety data set.
Okay. What is the timeline?
We expect to start enrolling our first patient in third quarter of next year.
And with a 52-week study design, you would have data readout in the first half of 2029.
Understood. Let me turn it over back to Vamil for
Yeah, just a couple things more on the corporate side then. One, if you can share your current cash position and your runway going forward as we have these upcoming events.
Yeah, sure. We announced, we ended the second quarter with $62 million, and we have not yet provided our 3Q financials. They should be available shortly. We will update then, but we have announced in the second quarter we expect that cash to last into mid-2028. That is where we are from a cash perspective, which will give you the Alport data readout and initiation of the PKD study.
Okay. This mechanism, I guess, is there potential to look at other indications, whether it is kidney or-
Yeah. So, really, we have a very broad preclinical data set, including in the kidney. It works in pretty much every nonsense mutation. So yes, there is. How we sequence that development is still a TBD. I think our view is that something like a platform designation with the FDA is a more appropriate development path for the kidney. For other diseases, we have to understand the PK to ensure we get enough drug. But there was a study published in 2017 in DMD patients that showed robust protein expression in these patients that were treated with gentamicin twice a week. There is data showing robust restoration of these skin cells in RDEB and JEB patients. There is a lot to do.
I think the limiting factor for us beyond just bandwidth and cash is making sure we do the right preclinical studies to investigate the exposure PK of the drug in the relevant cells.
Okay. Perfect. I think we can leave it there. Thanks so much for joining us.
Thank you.
Obviously, congrats on getting. It's been a long time to get to where you are, so great to see the progress, and look forward to seeing the data.
Well, thank you for having us, and thank you for the questions.
Okay, great. Thank you.
Take care.