Hello. Good afternoon. Good evening, everyone. Welcome to this webcast. Thank you for joining us today. I'm Thomas Kuhn, I'm the CEO of Poxel. You can see here before we begin, our forward-looking statements. Forward-looking statements are subject to inherent risks and uncertainties beyond the company's control that could cause the company's actual results or performance to be materially different from the expected results or performance expressed or implied by such forward-looking statements.
Further information can be found in our most recent regulatory filing. Here you can see the agenda for the call today. I will give brief introductions highlighting our strategy. I will hand over to Marc Engelen. To begin with, I'd like to thank very much Marc Engelen to participate to this call.
Marc Engelen is the MD PhD pediatric neurologist from Amsterdam, specifically being very close to this pathology, leukodystrophy, and he is heading the Amsterdam Leukodystrophy Center. We'll hear from Ben Lenail. Ben will give his patient perspective. Ben is the co-founder and board member of ALD Connect, and so a patient, and it will be very interesting to hear from Ben. David Moller, our CSO, will present you the scientific rationale and data related to our two products as well our development plan.
We will have some closing remarks. As you know, to begin with, Poxel is known to really develop and commercialize innovative therapies for patients suffering from serious chronic and rare disease. We've been successful in diabetes, we've been successful in NASH. Now we believe that it's a good timing to also target rare disease indications. How will we do that?
That's here on this slide. Following the recent approval of TWYMEEG in Japan and the associated revenues that we'll get from TWYMEEG, Poxel would like to accelerate and expand our focus on rare metabolic disease. As a first step, we would like to really leverage our internal platform, the dTZD platform, as well as our AMPK activator platform.
Our plan will be to advance one program in ALD into a pivotal study. As a first step, we will initiate two clinical trials, phase II clinical proof of concepts. One with PXL065, one with PXL770, with the same design, with the aim to assess the potential of the disease in the target population. These studies will be initiated early 2022. It's roughly a one-year trial, the data will be expected at the end of 2022.
This opportunity in ALD provides a faster to market strategy that will enable us really to strengthen and to expand our pipeline beyond what we currently have. As you can see here, we remain fully committed to NASH. We have the plan to advance 1 program in NASH into a pivotal study. As you know, we have a phase II ongoing, DESTINY-1, which is currently underway. We've just completed screening the patients, the enrollment of this phase II trial should be ended in Q3 this year, so that we could expect to have the results 1 year later in Q3 2022.
As a consequence, the future development of PXL770 in NASH will be reevaluated later on when we have the readout from PXL065 DESTINY-1 phase II trial in NASH, when we'll have as well the results of the phase II clinical proof of concept study in ALD. At that point of time, we make a decision which molecule to pursue in NASH and which molecule to pursue in ALD. As I said initially, the trigger point really for this new strategic directions is really the launch of imeglimin, of the approval of imeglimin in Japan and the associated future revenues that it will trigger.
As a reminder, we could draw the third and last tranche of EUR 13.5 million from the IPF loan when we got the approval of imeglimin, and so we could draw this tranche at the end of June, and we're expecting a milestone payment from our partner, Sumitomo, in Q3 of roughly EUR 13.2 million. As a reminder as well, Sumitomo is expected to launch the product mid-September, early October, and following this commercialization, Poxel will be entitled to milestone payments, sales-based payments, as well as double-digit escalating royalties. As for information, Sumitomo is actively preparing for the commercialization of the product in Japan.
As you know, Sumitomo is the leader in diabetes in Japan, and the goal will be to prescribe the product to a large population in Japan, but more specifically as an add-on therapy to existing agents available in Japan and more specifically to patients currently treated with DPP-4 inhibitors. This is the leading class in Japan.
Sumitomo, they have their own DPP-4, and the goal will of course be to combine imeglimin on top of their own DPP-4. We'll get back to you once the launch will be done, so effective in a couple of weeks as I just mentioned. As you can see, this launch really opened a new chapter for Poxel to drive shareholder value. With the additional funding from IPF Partners, we are willing to invest this funds to accelerate and expand our clinical pipeline of rare metabolic programs.
By developing product in rare metabolic disease in addition to NASH, we will be more efficient with our resources, more expedited delivery of novel medicine to patients with even stronger potential to create significant value for the benefit of our shareholders. You got here a snapshot of our pipeline, which I think have a good mix of justifications there.
One, in terms of indication, type 2 diabetes, NASH, rare metabolic indication. In terms of stage of development, there is a good balance between late-stage approach, even commercial approach with imeglimin in Japan, and close really in additional countries where it's written towards the right, and in phase III in U.S. and Europe. You have NASH, where we have phase II products.
Now this rare metabolic indication where both PXL770 and PXL065 could go directly into phase II, leveraging our existing preclinical data as well as the clinical data that we have gathered on other indications. With that, I will now leave the floor to Marc Engelen. Again, thank you very much, Marc, to be with us today. Marc will specifically give his perspective in terms of presenting really this disease, the pathophysiology, the unmet need, and the clinical feature. Thank you very much, Marc, for being with us today.
Well, thank you, Thomas. The next 5 - 6 minutes, I will try to give an overview of X-linked adrenoleukodystrophy that I hope will be complete and also clear. Adrenoleukodystrophy is a rare disease that is actually not so rare. There are tens of thousands of patients in Europe and the U.S. and hundreds of thousands worldwide.
It is a monogenic neurodegenerative disorder that is characterized by a defective very long-chain fatty acids degradation. Even though it's an X-linked disease, it causes symptoms in men and women, but with clear difference in symptomatology. Can I have the next slide, please? Biochemically, it's characterized by a deficiency of ALD protein encoded on the ABCD1 gene, and ALD protein is important for the transport of so-called very long-chain fatty acids into the peroxisome where they are degraded.
Deficiency of this protein causes a disbalance between the synthesis of very long-chain fatty acids from long-chain fatty acids and degradation, it causes accumulation of these very long-chain fatty acids in all tissues. For reasons that are not completely understood, this causes damage to the adrenal glands, but also to the nervous system, causing axonal degeneration.
Can I have the next slide, please? Because these very long-chain fatty acids accumulate, this has been a very convenient diagnostic method, because determining C26:0 or more recently, a complex lipid C26:0-lysoPC in, for instance, readily accessible tissues and plasma can readily demonstrate the diagnosis. Of course, the diagnosis can be confirmed by ABCD1 mutation analysis, and these metabolites can also be used for newborn screening, which has now been implemented in large parts of the United States and recently also in the Netherlands.
This will mean this is an entire opportunity for early and complete diagnosis. Can I have the next slide, please? Well, clinically, traditionally, X-linked adrenoleukodystrophy was separated into distinct phenotypes, but it's actually more accurate to see it as a progressive neurodegenerative disease that is characterized by, on the one hand, adrenal insufficiency that occurs often in childhood, or later in life, or the most common symptom is spinal cord disease, causing a gait disorder and incontinence, and this is kind of the core phenotype that occurs in both adult men and women.
The penetrance of this spinal cord disease is virtually 100% if patients are old enough. Also it can cause a leukodystrophy, so it's a cerebral white matter disease, which has a very distinct MRI pattern and which is usually rapidly progressive, causing severe disability or death.
This affects only about 60% of male patients, is unpredictable, and virtually never affects women. Can I have the next slide? If you plot symptoms over time in the right graph, which the colored lines is a survival graph for the different symptom groups in male patients. You can see that the spinal cord disease, the green line, is something that occurs in male patients from the third or fourth decade of life, and then the older men become, the more are affected.
Cerebral disease can already occur in early childhood, often in preschool, in what we call elementary school children, but can also still occur later in life. Adrenal insufficiency is something that also often occurs early in life but becomes more prevalent with age. For women, it's a little bit different.
Women virtually never have adrenal insufficiency or cerebral disease, but do get spinal cord disease, as you can see in the other bar charts on the left of your screen. It occurs at a later age. It's pretty rare before 30-40, but still affects most women, especially above 60. It is much less progressive over time. Can I have the next slide, please?
If we put it all together, all men and women with X-linked adrenoleukodystrophy are born completely healthy and asymptomatic and will develop symptoms during life. Those symptoms in men are generally adrenal insufficiency. Usually, almost 80% will develop adrenal insufficiency before the age of 18. Especially the spinal cord disease in men and women, but in adulthood or late adulthood. Superimposed on that, male patients can get the progressive leukodystrophy, the cerebral ALD, but not all of them.
Except for the ALD, there needs to be some modifying factor, some epigenetic factor, or some environmental factor to trigger the leukodystrophy. Can I have the next slide? Treatment is unfortunately very limited at this time. The adrenal insufficiency, of course, is readily treatable with hormone substitution therapy.
Cerebral ALD, the leukodystrophy, if detected in a very early stage, can be successfully treated by allogeneic hematopoietic stem cell transplant or now with the ex vivo gene therapy that has recently become available. Unfortunately, the spinal cord disease is at this point untreatable. There is no treatment to prevent it and no treatment to slow it down. Even patients who are transplanted in childhood will still develop spinal cord disease.
If cerebral ALD is discovered in a later stage, as is usually the case if patients are not screened regularly, there is no curative treatment possible anymore and will generally cause death within a few years after onset. For the spinal cord disease, like I said, there is only supportive care, so treatment of spasticity, et cetera.
Unfortunately, this is a great unmet need for both male and female patients because this is something that we cannot alter the disease course of. Can I have the next slide, please? A big problem with developing treatments for ALD is that it's a very slow disease. This means that the outcome measures we generally use in clinical trials, like the six-minute walk test, et cetera, are not very sensitive in trials that last one or two years.
That means that you need large numbers of patients and long follow-up time. It makes clinical trials, especially in diseases like this, difficult. We've been working intensively the last few years on developing all kinds of plasma biomarkers, quantitative MRI techniques, and other methods to more reliably quantify disease severity to allow for better outcome measures in clinical trials.
Can I have the next slide, please? To summarize, the spinal cord disease, the adrenomyeloneuropathy, is slowly progressive, but over a lifetime causes severe and disabling disease in most men and women with ALD and is not treatable. We definitely need a treatment to delay the progression of this disorder and prevent some of the debilitating symptoms.
It's important to summarize again, a few years ago, X-ALD was always considered a disease of men, but women, especially for the spinal cord disease, are also very much patients and not just carriers. There's the cerebral ALD, the leukodystrophy, which does not affect all male patients, but if it strikes, it is rapidly progressive and causes disability, and that's within 2-3 years if not treated by hematopoietic stem cell transplant.
The problem here is that for the first boy or man in the family who is not monitored for disease, usually by the time the diagnosis is made, the disease is already too progressed for hematopoietic stem cell transplant. That is one of the main rationales for the newborn screening. Can I have the next slide, please? That was the very brief summary of X-ALD.
I hope that at least gives a fair overview of this very complicated disorder. Thank you very much.
Absolutely. Thank you very much, Marc. I think that's extremely interesting. Ben, do you want to lead the floor now and share your patient perspective?
Thank you very much. I'm Ben Lonergan. I'm a Frenchman established in the U.S. for the past 35 years. My story with ALD starts around age 40. I'm now 55 years old. I started experiencing the early symptoms around gait. After years of playing tennis and mountain climbing and skiing, I suddenly started having issues with my ability to walk and urinary urgency as well.
I went through a two -year diagnostic odyssey, and was finally diagnosed in 2011, so exactly 10 years ago. I started a foundation, ALD Connect, which is now the premier patient-driven research collective in the U.S., and that's been in operation for eight years and has achieved really wonderful results, such as lobbying for newborn screening and creating a lot of infrastructure for clinical trial readiness.
My perspective is one of living with the disease for 10 years, as Marc explained, it's a relentlessly progressive disease. I would say the five things that are a burden in our daily lives. Number one is definitely gait and balance. These are things that are very impactful because they affect mobility, autonomy, quality of life.
You're very worried about safety, falling, breaking something, and then taking a huge step back. Really having things that help postural stability, help counter sway, and also maintain the ability to walk and conduct our normal activities every day would be absolutely wonderful. Another issue is adrenal function. For the patient, that manifests itself in terms of the onset of adrenal issues.
Typically, either a crisis that could be catastrophic or more an onset of pain, nausea, migraine, low energy, and that can be remedied with daily supplementation of steroids such as hydrocortisone. That's a regimen you have to maintain for the rest of your life. Bladder and sometimes bowel and sexual function issues are very tough because they affect, of course, how you plan your day.
Of course, if you're close to a bathroom. They also impact, of course, self-esteem and dignity and are pretty crushing burdens for patients. Spasms, so spasticity, but sometimes going all the way to really violent spasms and jerking movements in the legs can be a very big issue. They impact not only daily living but also sleep.
Patients have to take a lot of anti-spasm medications to be able to get restorative sleep and get very woozy and you can easily go into a downward spiral of taking a lot of drugs to be able to sleep and then really being woozy during the day, exercising less, moving less, and of course, having even more trouble with spasms and ability to go to sleep. Finally, a general issue around energy and fatigue.
Again, with the cascade of symptoms, you can feel fatigue, low energy. Anything to help turn around the flywheel and really get the symptoms under control, stop the progression, even maybe reverse some of the symptoms and get back to better health. I would say another general landscape of the patient community is that we are organized. We have a registry. We understand natural history.
We're in centers of excellence that are very well organized. We are mobilized, and we are hungry for treatments. We're coming out of years of better understanding the disease, but we have no treatments to help with our symptoms, to give us hope for disease-modifying therapy or even for a cure. You have the patient community is hungry, mobilized, and extremely ready to try treatments in this window of opportunity that we have today. Thank you.
Thank you very much, Marc. Thank you for sharing all this. With that, I leave the floor now to David. We've heard about David's unmet needs, so David will present to you what we've developed at Poxel and what's our plan going forward. David, do you want to take over?
Sure. Thank you, Thomas. I'm David Moller. I'm the Chief Scientific Officer at Poxel. It's a pleasure to speak to you today, and I also want to thank both Marc and Ben for their incredible insights and help in bringing this forward for us. Let's go to the next slide. I'm going to just sort of try to frame this.
Throughout the last year or so, we've continued to expand our pipeline and emphasizing more and more on orphan indications with our two small molecule platforms. Just to remind you, PXL770 and related molecules are direct allosteric activators of AMP kinase, which is the master cellular energy sensor. Activation of AMPK modulates several metabolic pathways as well as having key effects to attenuate inflammation and support cellular functions.
On the other hand, PXL065 and related deuterium-modified thiazolidinediones, or dTZDs as we call them, they lack significant PPARγ action, but they do retain activities that are mediated by these non-genomic pathways that also have the potential to produce similar metabolic and cytoprotective effects. Recently we've generated a swath of preclinical data in models of ALD as well as in several kidney diseases, including polycystic kidney disease.
From these efforts, ALD has really emerged as our first rare metabolic disease development program. Going to the next slide, here's the similar slide as what Marc had presented to you. As you heard from his nice review, increases in the very long-chain fatty acids, or VLCFAs, and specifically saturated C26, are really the primary driver of disease, with downstream pathologies leading to axonal degeneration for both the cerebral and the spinal cord disease.
Interestingly, we've developed evidence that I'll show you that both AMPK activation as well as the dTZD approach can be leveraged to address the pathophysiology, both to correct the primary effect by suppressing VLCFA levels, but also potentially by ameliorating downstream mitochondrial dysfunction, inflammation, and cell death.
Before we go into the specific data, on the next slide, I just want to remind you of the characteristics of our two lead molecules, PXL065 and PXL770. PXL065, as you heard from Thomas, is the deuterium-stabilized R stereoisomer of pioglitazone. Just to remind you, this is a widely prescribed medicine for type 2 diabetes, but unlike Pio, PXL065 lacks significant PPARγ activity and mediates the efficacy through the non-genomic pathways in several diseases, including ALD.
Fortunately, given the relationship to Pio, we can leverage the 505(b)(2) regulatory pathway, which, in other words, accessing a large safety database for the parent molecule. We also have an open IND for PXL065 in ALD in the U.S. More than 130 people so far have been exposed to PXL065 per se, to confirm the expected clinical safety, and we've also validated in clinical trials that we have selective and dose proportional exposure to the preferred R stereoisomer that's translated to humans.
With PXL770, the novel direct AMPK activator, I just want to remind you that this is the first such molecule to be studied in any human disease, and the clinical development to date has demonstrated target engagement as well as translation of several diabetes and NASH-related efficacy parameters to humans, which suggests to us the likelihood of broader translation for this mechanism in general.
The preclinical clinical safety have been very favorable to date, with over 200 people exposed for up to 12 weeks. Going first to the data that we have for dTZDs. At the top of the slide, you'll see that the rationale for considering dTZDs in ALD is summarized. First of all, pioglitazone itself has been demonstrated to produce strong efficacy in the classical ALD model, which is the Abcd1-null mouse. In addition, pioglitazone has been shown to confer neuroprotection in other contexts.
One of the key non-genomic mechanisms that's modulated by Pio as well as our dTZDs, the mitochondrial pyruvate carrier, MPC, is also implicated as a target for neurodegeneration in general. Turning to the data that we've generated in collaboration with academic partners.
The examples shown here demonstrate that PXL065 and Pio normalize elevated VLCFA levels in patient-derived cells, as you can see on the left panel, and that this decrease occurs in conjunction with an increase in the compensatory transporter ABCD2, which can fill in potentially for the missing ABCD1 function in the middle panel. In the ABCD1 null mouse, PXL065 also produced substantial reductions in elevated VLCFA levels in plasma, brain, and in the spinal cord, which is what is illustrated in the right panel.
The effects were greater than that observed with Pio, even though these compounds were studied at the same dose. A recent event that also further sparked our interest in PXL065 and the dTZDs for ALD comes from clinical results that were recently reported by Minoryx with their related molecule called leriglitazone in a long-term phase II-B/III trial with AMN patients.
Here, there were actually very encouraging results obtained, especially with the postural body sway test that Marc referred to and a substantial reduction in the occurrence and progression of cerebral disease. Unfortunately, their primary endpoint, the 6-minute walk test, was not met.
Comparing leriglitazone in the center of this table, which is also the M4 metabolite of pioglitazone, to the parent compound on the left and PXL065 on the right, reveals that leriglitazone is a potent PPARγ agonist that produces even greater weight gain plus edema versus that typically seen with pioglitazone in diabetes trials. In contrast, PXL065 is designed to avoid significant weight gain and edema based on dialing out the PPARγ activity.
Importantly, our data also support the potential for superior efficacy with PXL065 versus either pio or leriglitazone. Turning to the AMPK platform, let me first describe several lines of published evidence that support this approach. Deletion of AMPK is deleterious in cells from the Abcd1-null mouse, even more importantly, AMPK activity is reportedly suppressed both in cells and in brain tissue obtained from patients.
In addition, metformin, which is known as a weak and indirect AMP kinase activator, was shown to induce ABCD2 in ALD model systems. Based on these observations, we studied PXL770 in both the in vitro and in vivo models of ALD. 770 nearly normalized elevated VLCFA levels in patient-derived cells, as you can see in the left panel, and this was also associated with an increase in the compensatory transporter, ABCD2, as you see in the middle panel.
As shown on the right, 770 treatment of Abcd1-null mice also suppressed elevated VLCFAs in the spinal cord and also in brain and plasma, which aren't shown on this slide. In more recent experiments that were also conducted using the Abcd1-null mouse, we were very gratified to also see evidence of improved neural histology and neurobehavior with both 065 and 770.
Some of the examples of these data are shown on the slide. In the images on your left in the accompanying graph, you can see that there's distorted axonal morphology as assessed using electron microscopy of the sciatic nerve, this was improved by both 065 and Pio as well as by 770, which isn't shown here.
On the right are quantitative results using a balance beam motor and coordination test, here you can see that the diseased mice exhibit impaired performance, in this case a higher score, versus wild-type mice, that chronic treatment with 770 was able to reverse this neurologic defect. With this caveat that no head-to-head results are shown on this slide, it's of interest to compare our profiles with those reported by Minoryx with their preclinical findings, also reported by Viking and Autobahn with each of their thyroid hormone receptor agonists.
Not only are the mechanisms of action distinct for our molecules, but we believe that we have a compelling preclinical profile for each of our leads. This was apparent when comparing results from patient-derived cells and from reviewing aggregate results obtained using the in vivo disease model, where both PXL065 and PXL770 have shown positive effects on all the parameters we've studied to date.
We also have the benefit of being able to pursue two different approaches in parallel and using molecules that have been de-risked based on extensive preclinical tox and clinical experience. Finally, I want to point out that the pipeline for new therapies, as Ben highlighted, in ALD is really quite limited at this time. We also hope and we expect that there'll be future opportunities to combine two or three of these mechanisms or others with our molecules in order to maximize therapeutic benefits.
Before turning it back to Thomas Kuhn, I'd like to briefly describe our clinical plans in ALD. We plan to conduct two parallel and identical phase II-A biomarker-driven POC studies, one with PXL065 and one with PXL770. The study design was developed with substantial input from Marc Engelen and from several other disease experts in the U.S. and Europe, each trial will enroll approximately 12 adult male patients with AMN and exclude those with active cerebral disease.
Following a screening run-in period where we will confirm that fasting VLCFA levels are stable, patients will then be treated for 12 weeks with a single oral dose of either molecule. The dose selection for this study is based on prior preclinical and clinical results, including extensive PK/PD modeling.
The study readouts will include PK safety measurements at several time points and biomarkers, VLCFA and neurofilament light chain, and both of these are basically validated as disease-associated and will have additional exploratory biomarkers as well. The trials are scheduled to begin in early 2022 with data available later in the year. Following the analysis of these results, we should be able to choose which is the preferred molecule for further advancement into a pivotal trial.
This pivotal trial would then begin in 2023. We plan to further finalize our phase III plan with FDA interactions and further discussions with experts, also importantly with patients. Depending on the treatment duration, the final selection of endpoints, and the potential for accelerated approval, our pivotal trial could lead to an NDA filing in 2025. I'll now turn it back over to you, Thomas, to conclude the presentation. Thanks.
Thank you very much, David. Before moving to the Q&A session, I'd like to highlight really a few conclusion words there. First, as you can see on this slide, over the next 12 to 18 months, we have a number of near-term milestones to drive our growth, including readout from our PXL065 phase II in NASH. The two proof of concept biomarker studies that David just described, and of course, the launch of TWYMEEG in Japan.
This launch of TWYMEEG in Japan has actually opened a new chapter for Poxel, and we provide a future funding stream to Poxel that we are willing to reinvest to accelerate and expand our clinical pipeline in rare metabolic diseases. First, leveraging our internal platform, but we also committed to bring some additional programs going forward with the new programs as early as 2022.
To summarize, we are very excited that our new strategic direction is an increasing focus on rare metabolic diseases in addition to NASH, has the potential to deliver significant value to shareholders as we turn over cards on multiple phase II studies in 2022 that may allow us to initiate pivotal trials in 2023. We look forward to updating all of you on our progress. With that, I'd like to thank you all for your attention, and I suggest we now move to the Q&A session. Thank you very much.
Thank you very much, Thomas and all, for this presentation. We'll now move on to the Q&A session. To our participants, you have the possibility to ask your questions by writing them down in the chat or by raising your hands to ask them orally.
We have a first question from David Seneff. Actually, we have a couple, I'll ask the 2 first. Do you plan to partner for clinical development and/or commercialization in EU and US in ALD? What year do you envision to reach the market? Will you target both the cerebral and spinal cord form of ALD? Okay.
Maybe I can answer for this question and maybe, David, you can elaborate further on. Our goal will be really to quickly execute on our strategy for ALD. You've heard about the high unmet medical need and really with a strong need for patients to have therapies to really slow down and control this disease. As David mentioned, how we initiate reading these two trials in 2022. We have the aim to really push the most promising molecule into phase III as early as 2023.
We believe, and we are finalizing now plan for the pivotal trial because there are a couple of options that we are specifically willing to discuss with the regulatory bodies, including the FDA. Potentially, we believe that we could be really having a plan that will allow really the product to be approved as early as 2025.
Clearly the plan will be to move this by ourselves to answer this first part of the questions. In this type of opportunity, there is a really reasonable number of patients to be treated, so that Poxel, with our experience, with our capabilities, we can progress this product until the finish line. That's really our goal to do this. David, you want to add anything?
Yeah, I guess another part of the question was related to cerebral disease versus spinal cord disease. Our initial thinking here is that we're focused, as Marc mentioned, on the greatest unmet medical need at the moment, which would be the spinal cord disease. In the context of studying adult men with AMN, there certainly will be cases, as was the case with Minoryx's experience of new onset or progressive cerebral disease.
We would be encompassing that as part of our later stage development. Potentially we would have the ability to also extend the development of our molecule or molecules into the pediatric population as well. That's on the radar screen for sure. If Marc Engelen or Ben want to comment further on their thoughts on that question, it would be useful as well potentially.
No, I think that makes sense, David, with what you said. I do think that the spinal cord disease is the greatest unmet need at this point because it just affects so many men and women and causes such a disability later in life. Because for the cerebral ALD, there is an effective treatment. It's not a perfect treatment. It's highly invasive, and there's only a narrow window of opportunity to administer that treatment, but there is a treatment. I think that the primary focus on spinal cord disease totally makes sense.
Thank you.
Next question.
Thank you very much for your answers. We have a second question from Jason Butler, JMP. Can you discuss your thoughts on endpoints for clinical development? What are your views on VLCFA as a predictive biomarker, and how the patient's prescribers think about clinical endpoints and how they speak to impacts on function?
Okay. David, maybe pass that.
Maybe I can start, and I'll also be interested to hear Marc Engelen your thoughts on this. Jason Butler, I think that's a very good question, and we're still grappling with a little bit. We have yet to have a detailed discussion with the FDA or other regulatory bodies. We're looking at it basically as a spectrum of endpoints, all the way from the VLCFA reduction that we expect to see in early clinical development to effects on other non-invasive biomarkers like neurofilament light chain, which are highly correlated as well with disease in this clinical syndrome, as well as in other diseases like MS, then to functional tests.
The one that we favor the most would be the postural body sway test because it has been recently validated by Marc and his team, as well as by others as being a very sensitive, quantitative, and also clearly a good way to follow progression because it is very tightly correlated with other more classical endpoints like six-minute walk test or disability scores.
Our potential options would include an accelerated approval based on VLCFA neurofilament light chain, and then an extended functional readout, for example, using the body sway test. It remains to be seen exactly how that is going to pan out. Marc, do you have further comments on endpoints?
No, completely agree. The only interesting thing is, of course, that now with those new tools, the wearables, there's a lot of ideas on developing even better outcome measures. For instance, walking speeds and things like that. Yeah, that remains to be seen if these are superior to, for instance, the balance and other measures. There's lots of stuff happening there.
Thank you, Marc Engelen. I hope that answered the question, Jason Butler.
Thank you very much. Let's go to the next question from Andy Hsieh. Do you have any hypothesis as to why PXL065 can induce expression of the compensatory ABCD2 transporter?
David, do you want to answer this one?
Andy, thank you for the provocative and interesting question. The answer is not really. This is a very recent observation, so we haven't had the chance yet to interrogate what potential pathways would link 065 or 770, for that matter, to the induction of ABCD2. It is interesting to note that that's a common feature for some of the other mechanisms people are pursuing, like the thyroid hormone receptor beta agonist. Again, I don't think it's quite clear what the direct connection there might be as well.
Thank you very much, David, for your answer. We have a question now from Lucy Codrington. Can you please remind us of the IP expiry for each of PXL065 and PXL770? Do you both penetrate the BBB to the same degree? It seems that the phenotype can vary widely between individuals. Does severity correlate with the VLCF levels?
Thank you, Lucy, for this question on the characteristic of the two products. Again, David, do you want to start first then?
Sure. IP, I think we'll come back to that maybe.
We can take that at the end.
We can take that at the end. As far as the brain penetration of our molecules, they both clearly do have some effects that penetrate the brain, and we've also looked at spinal cord exposure. Based on the doses that we're selecting for our phase IIa studies, we believe we have a good opportunity to have adequate tissue exposure.
We don't know the precise degree of brain penetration other than what's been demonstrated in lower species right now. On the question of VLCFA and the correlation with severity, it's not very well associated with severity. I'm sure Marc could comment further on this. However, as he showed in one of his slides, it is clearly higher in all men affected with this disease than it is in any control subjects. It's also higher in general in men than it is in women.
In general, as you've heard, the men are afflicted with more severe and earlier onset disease than women. I believe there's some evidence as well that VLCFA levels in tissue, in particular in the brain, are higher in association with severe or severely active cerebral disease versus in other post-mortem studies in other patients who have less severe disease.
That's the extent of it. It's clearly the hallmark of disease and a proximal driver of disease, so we think it is a potentially valid marker for efficacy as well. Marc, do you want to further comment on that question?
No, that's basically it. I just wanted to add that in our male patients, there is absolutely no correlation with plasma very long-chain fatty acids levels and disease severity. Like you said, there are some studies on post-mortem material that do suggest that in the brain, very long-chain fatty acid levels do influence disease expression. We have some preliminary observations in an organoid cell model that there is probably also a correlation between C26 levels and disease expression. Unfortunately, in plasma, there is no clear correlation.
Yeah. However, if we bring levels down to normal, it would be a very good sign.
I'd say so, yeah. It's a very good point. If you can normalize that, I'd be very surprised if there would be no effect on the clinical parameters. Yeah.
Thank you, Marc, for sharing this. Noah, do you want to get back to the IP for Lucy?
Thanks for the question, Lucy. We have multiple patent families for each of these compounds. As it relates to the composition of matter patents, those should take us at a minimum from the mid to late 2030s, and we have strategies to extend that further beyond 2040. We also remember these are both NCEs, and to the extent that we're able to get orphan drug designation and other forms of additional exclusivity, we'll certainly pursue that. We feel very good about the overall IP estate for both of these compounds and platforms.
Thank you, Noah.
Thank you very much. I'll come back to the rest of the questions from David soon enough. Why do you specifically target the ALD form and none of the other X-linked ALD forms? Would PXL065/770 not be suitable for these indications? The second question is, how do you competitively position both PXLs in comparison to gene therapies such as the bluebird bio therapy for cerebral ALD?
Okay. Thank you, David, for these questions. David, and maybe Marc Engelen, do you want to?
I think what you were asking about was whether our technologies would also be suitable for other leukodystrophies.
Yeah
of which there are maybe 20. The reasons we've really focused on X-linked adrenoleukodystrophy in particular is because it's the most common of all the leukodystrophies by far. It's the most common peroxisomal disease as well, as I understand it. Really based on hints from the literature as I reviewed, that both of our approaches seem to be fairly well aligned with the pathophysiology in general principles, as well as based on the specific literature.
Those are really the reasons. There is some potential that we could go after additional leukodystrophies, maybe the peroxisome biogenesis disorders, for example, and that's something we're thinking about. On the question of gene therapy, as Marc Engelen reviewed, and you can please comment, Marc Engelen.
The Bluebird product, which is not yet approved in the U.S., it's got a favorable review in Europe, so hopefully will be approved, is really an alternative to hematopoietic stem cell transplant, which is really only indicated for very early onset cerebral disease, typically only in childhood. If you're an adult or you're diagnosed with more advanced cerebral disease, even that would not be an option, as I understand it. Marc, do you want to comment on that further?
No, that's absolutely correct. Of course, there's also companies interested in developing AAV gene therapy for ALD.
Yeah. There are some early-stage efforts with SwanBio Therapeutics, for example, going after AMN, the adult spinal cord disease, with a locally administered spinal cord AAV expression system. We think that's a really exciting opportunity as well, and it would also be complementary potentially to what we're doing.
Thank you.
Thank you very much for your answers. We have a second question from Jason Butler. Are there scenarios where you may want to advance both O65 and 770 in one or both NASH or ALD? How will you prioritize investment in the different programs?
Yeah. I can provide an answer. Thank you, Jason, for this question. Very clearly, I like to make sure that you understand that really, we want to have different molecule for NASH and for ALD, yeah. Our plan is not to have the same molecule developed and commercialized for NASH and for ALD. These two such are very different diseases that really we want to, for different reason, only really target one disease with one molecule.
The way we will prioritize is easy. We will, as David said, we will basically compare the results in ALD and really select the best product to move forward to the pivotal program for phase III. Although that's two different studies, it's exactly the same design, and so we'll be able to have indirect comparison to really select the best therapy to move forward in ALD.
If by chance, the same product will be the best really for NASH and for ALD, well, I would say that's a good problem to have. Let's say that if PXL065 deliver very good results for NASH and for ALD, we'll be pleased about this. Maybe you've seen that, but in our pipeline charts, we are continuously progressing our platforms, and we are working on next generation products. If that's the case, then we will take PXL065 forward in one indication, and we move next generation product targeting the same pathways on the other disease. That's our goal there. That's basically how we will do the thing.
That's why basically for PXL770 in NASH, we want to make sure to benefit from the result for PXL065 in NASH as well as the one for ALD for both PXL065 and PXL770, hence the consequence in this product.
Thank you very much, Thomas, for your answer. We now have another question from Lucy about the cash of the company. Does the current cash along with the IPF loan, and does the SDP milestone cover the O65 NASH trial and the ALD proof of concept studies?
Yeah. Thank you, Lucy, for this question. Anne, do you want to take this one?
Yes, absolutely. Hi, Lucy. Thank you for your question. I can confirm that our cash runway extends through 2022 and fully funds the ongoing phase II study for NASH for PXL065. As it relates to AMN, we can start the preparation of the initiation of the two proof of concept studies. However, the proof of concept studies in themselves is not included in our cash runway. We have to fund this. As a global comment on that, this is a rare disease, so the cost of these studies is quite reasonable.
I don't know if I answered the question correctly.
Thank you.
Thank you very much, Anne, for your answer. We have another question from Andy now. How do you think about gene therapy's role in ALD, and how could different modalities coexist in the treatment paradigm?
Marc, do you want to take a shot at that one?
Yeah. Purely hypothetical. Gene therapy is, of course, a very attractive treatment option. I haven't seen any specific results yet. There's a lot of technical hurdles still that needs to be resolved. I have no idea how feasible that will be in the short term, but there's a lot of work going on. Like David said, in the end, for the foreseeable future, it might actually be complementary.
Thank you, Marc, for your answer on this.
Yep.
Thank you very much, Marc. Yes, Thomas, we have another question this time from Difei Yang. Do you expect the duration of efficacy measurement to be longer than 1 year in ALD?
Yes. No, absolutely not. Even two years is touch and go. This is a very slow disease. To get a meaningful signal with the tools we have at this time, two years is the bare minimum you need to make any kind of meaningful observation.
We are working under different scenarios going forward. Maybe, David, you want to-
Yeah, I just want to emphasize what we said earlier, which is that we agree with Marc Engelen that for definitive proof of clinical benefit, we're going to need to do studies of minimum two-year duration. We also believe that there's going to be a likelihood that we can do shorter clinical trials for accelerated approval, potentially even including those that might be based exclusively on circulating biomarkers.
We also think that based on the experience with leriglitazone that I showed you, where they have a clear benefit that they did see in two years on the postural body sway test, and given that that has now been basically better validated as a highly relevant way to measure function, that as an example, could be used as a more reliable and quantitative test in a study that would be relatively efficient, even if it requires a 2-year treatment period.
Okay, David. Maybe we have time for last question?
We do indeed. We have another question from a participant. There does not appear to be a control group in the plan phase II-A trials for PXL770 and PXL065 in ALD. Why not choose a design that would allow comparison to either placebo or possibly active compound?
Yeah, that's a good question. Maybe David, then Marc.
Yeah, I can start with that. Maybe Marc, you've been very involved in advising us on this point. First of all, there is no active comparator, right? Except potentially leriglitazone, but we understand that leriglitazone did not affect these biomarkers, at least not VLCFA levels. Based on all the input that we've received from a number of experts, including Marc, it's pretty clear that VLCFA levels, neurofilament light chain levels, these principal biomarkers are quite stable from day to day or week to week within any given patient.
It's a more efficient design to have each patient serve as their own control and just look at ensuring that the baseline is stable and then looking at a treatment effect in order to rapidly get to a point where we can really start the more important pivotal trial. That's the rationale, really.
Marc, do you want to comment further on this question of placebo?
No, exactly that. For screening, to see if there's something there before you go for the full-blown trial. I think that biochemical proof would be enough to move forward. Yeah. For just a biochemical effect, you don't really need placebo. I think with this design, you can quickly see if your compound does what you think it does. Of course, if it's clinically efficacious, that's a much more difficult question. You definitely need placebo and long follow-up. This seems like a reasonable first step.
Yeah.
It will be a 12-week study duration, there will be also several time points to assess the biomarkers, so you can really see on different end points several times.
Thank you, Pascale. Again, the goal is really to quickly assess the potential of our products there with the aim to then select the best one to move forward. In this pivotal program, of course, not only there will be placebo arm, but also different endpoints as with her, with the goal to really assess carefully the efficacy as well as the safety of the product. The goal is really to quickly assess the potential of each of our products. Hence the strategy to move quickly with these two small trials.
Thank you very much all for this question and answer session, which is now over. Thomas, I give you back the floor to end this webinar.
Well, thank you very much for all your questions. We hope that it has answered most of your questions. Of course, we'll continue and presenting you really our update on this. I'd like to thank again very much, Marc Engelen and Ben Lonergan, really having shared really all the knowledge about this pathology. We continue working with Marc and Ben going forward. Of course, we'll update everyone on our plan. For now, I wish you all really a good evening or a good afternoon. Again, thank you very much for your attention. Bye-bye.