Poxel S.A. (POXEL) Earnings Call Transcript & Summary

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. So I will give a brief introductions highlighting our strategy, then I will hand over to Marc Engelen. And to begin with, I'd like to thank very much Marc Engelen to participate to this call. Marc is the MD PhD pediatric neurologist from Amsterdam, specifically really being very close to this pathology, leukodystrophy, and is heading the Amsterdam leukodystrophy center. Then we'll hear from Ben Lenail. Ben will give his patient perspective. Ben is the co-founder and a Board member of ALD Connect and also a patient, and it would be very interesting to hear from Ben. David Moller, our CSO, will then present to you the scientific rationale and the data related to our 2 products as well as our development plan, and then we'll have some closing remarks. So as you can -- 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. And we've been successful in diabetes. We've been successful in NASH. And now we believe that it's a good real timing to also target rare disease indications. So how will we do that? That's here on this slide. So following the recent approval of TWYMEEG in Japan and the associated revenues that we'll get really from TWYMEEG, Poxel would like to accelerate and expand really our focus on rare metabolic disease. And as a first step, we would like to really leverage our internal platform, the deuterated TZD platform as well as our AMP kinase activator platform. Our plan will be to advance 1 program in ALD into a pivotal study. As a first step, we will initiate 2 clinical trials, Phase II clinical proof concepts, one with PXL065, one with 770 with the same design with DM to assess the potential of this disease in the target population. These studies will be initiated early 2022. It's roughly a 1-year trial. And so the data will be expected at the end of 2022. This opportunity in ALD provides a faster-to-market strategy to -- that will enable us really to strengthen and to expand our pipeline beyond what we currently have. However, 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, and 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 770 in NASH will be reevaluated later on when we have the readout from PXL065 DESTINY Phase II trial in NASH and when we'll have as well the results of the Phase II clinical proof-of-concept study in ALD. And at that point of time, we'll 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 these new strategic directions is really the launch of Imeglimin or 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, EUR 13.5 million from the IPF loan when we got really the approval of Imeglimin. And so we could draw this tranche at the end of June. And we are 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. So as you can see, this launch really opened a new chapter for Poxel to drive shareholder value. With the additional funding from TWYMEEG, we are investing -- we are willing to invest these 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 expediently delivery of novel medicine to patients with even stronger potential to create significant value for the benefit of our shareholders. So you've 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 next-stage approach, even commercial approach, with Imeglimin in Japan and close really in additional countries where Sumitomo has the rights. And in Phase III in U.S. and Europe, you have NASH where we have Phase II products. And then 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. And again, thank you very much, Marc, to be with us today. Marc will specifically give his perspective in terms of presenting 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 to 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 in 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. And it causes -- 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. And deficiency of this protein causes a disbalance between the synthesis of very long-chain fatty acids from -- long-chain fatty acids and degradation and it causes accumulation of these very long-chain fatty acids in all tissues. And 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? So 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-lysoPC in, for instance, readily accessible tissues in the plasma can readily demonstrate the diagnosis. And 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. So this will mean this is an entire opportunity for early and complete diagnosis. Can I have the next slide, please? Well, clinically, traditionally, adreno -- X-linked adrenoleukodystrophy was separated in 2 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 system -- 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. And the penetrants of this spinal cord disease is virtually 100% if patients are old enough. And also, it can cause leukodystrophy. So it's cerebral white matter disease, which has a very distinct MRI pattern and which is usually rapidly progressive causing severe disability or death, but this affects only about 60% of male patients, is unpredictable and virtually never affects women. Can I have the next slide? So if you plot symptoms over time in the right graph with the colored lines with the survival graph for the different symptom groups in male patients. And 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. And 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 -- the bar charts on the left of your screen, and it occurs at a later age, pretty rare before 30 to 40 but still affects most women, especially above 60, but it is much less progressive over time. Can I have the next slide, please? So 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. And those symptoms in men are generally adrenal insufficiency, usually, almost 80% will develop adrenal insufficiency before the age of 18 and especially the spinal cord disease in men and women but in adults into late adulthood.And then superimposed on that, male patients can get to progressive leukodystrophy, the cerebral ALDs, but not all of them. So 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? A treatment is unfortunately very limited at this time. The adrenal insufficiency, of course, is readily treatable with hormone secretion therapy. And cerebral ALD leukodystrophy, if detected in a very early stage, can be successfully treated by allogeneic hematopoietic stem cell transplants or now with the ex vivo gene therapy that has recently become available. . But unfortunately, the spinal cord disease is, at this point, untreatable. There is no treatment to prevent it and no treatment to slow it down. And even patients who were transplanted in childhood will still develop the spinal cord disease. And 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. So for the spinal cord disease, like I said, there's only supportive care, so treatment of specificity, et cetera. But unfortunately, this is the 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? So a big problem with developing treatment for ALD is that it's a very slow disease. And that's -- this means that the outcome measures we generally use in clinical trials, like the 6-minute walk test, et cetera, are not very sensitive in trials that last 1 or 2 years. So that means that you need large numbers of patients and long follow-up time which makes clinical trials especially in diseases like this difficult. So 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? So 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. So we definitely need a treatment to delay the progression of this disorder and prevent some of the debilitating symptoms. And 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. Yes. And then there's the cerebral ALD, the leukodystrophy, which does not affect all male patients, but if it strikes is rapidly progressive and causes disability and death within 2 to 3 years, if not treated by hematopoietic stem cell transplant. And 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? So yes, that was the very brief summary of X-ALD. So I hope that at least gives a fair overview of this very complicated disorder. Thank you very much.

Absolutely. Thank you very much, Marc, and I think that's extremely interesting. Ben, do you want to lead the floor now and share your perspective?

Yes. Thank you very much. So I'm Ben Lenail. I'm a Frenchman established in the U.S. for the past 35 years. And my story with ALD starts around age 40 and now 55 years old. And I started experiencing the early symptoms around gait. After years of playing tennis and mountain climbing and skiing, I suddenly having -- started having issues with my ability to walk and urinary urgency as well. And so I went through a 2-year diagnostic odyssey and was finally diagnosed in 2011, so exactly 10 years ago, and 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 8 years and has achieved really wonderful results such as lobbying for newborn screening and creating a lot of infrastructure for clinical trial readiness. And so my perspective is one of living with the disease for 10 years and, as Marc explained, it's a relentlessly progressive disease. I would say the 5 things that are a burden in our daily lives. So number one is definitely gait and balance. So 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 and 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. So for the patient, that manifests itself in terms of the onset of adrenal issues. So 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, but 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 and of course, if you're close to a bathroom. And they also impact, of course, self-esteem and dignity and are pretty crushing burden 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. So patients have to take a lot of anti-spasm medications to be able to get restorative sleep and get very, 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. And then finally, kind of a general issue around energy and fatigue. Again, with kind of the cascade of symptoms, you can feel fatigue, low energy. So anything to help kind of 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 take another general landscape of the patient communities that we 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. And so you have the patient communities hungry, mobilized and extremely ready to try treatments in this window of opportunity that we have today. Thank you.

Thank you very much, Marc (sic) [ Ben ]. Thank you for sharing all this. With that, I leave the floor now to David. We've heard about already the unmet need. 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 of 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. So 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 2 small molecule platforms. And just to remind you, PXL770 and related molecules are direct allosteric activators of AMP kinase, which is the master cellular energy sensor. And 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 thiazolidinedione, or dTZDs, as we call them, they lack significant PPAR gamma action, but they do retain activities that are mediated by these nongenomic pathways that also have the potential to produce similar metabolic and cytoprotective effects. So recently, we've generated a swath of preclinical data in models of ALD as well as in several kidney diseases, including polycystic kidney disease. And from these efforts, ALD has really emerged as our first rare metabolic disease development program. So going to the next slide, here's the similar slide, as what Marc had presented to you. And as you've 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. And 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. So before we go into the specific data on the next slide, I just want to remind you of the characteristics of our 2 lead molecules, PXL065 and 770. So 065, as you heard from Thomas, is the deuterium-stabilized R-stereoisomer of pioglitazone. And just to remind you, this is a widely prescribed medicine for type 2 diabetes. But unlike pio, 065 lacks significant PPAR gamma activity and mediates the efficacy through the nongenomic pathways in several diseases, including ALD. But 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. And we also have an open IND for 065 in ALD in the U.S. More than 130 people so far have been exposed to 065 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 770, 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 suggest 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. So going first to the data that we have for dTZDs. At the top of the slide, you'll see that the rationale for considering TZDs 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. Secondly, one of the key nongenomic mechanisms that's modulated by pio as well as our dTZD, the mitochondrial pyruvate carrier, or MPC, is also implicated as a target for neurodegeneration in general. Now turning to the data that we've generated in collaboration with academic partners. The examples shown here demonstrate that 065 and pio normalize elevated VLCFA levels in patient-derived cells, as you can see in the left panel, and that this increase in -- also occurs in conjunction with an increase -- decrease occurs in conjunction with an increase in the compensatory transporter ABCD2, which can fill in potentially for the missing ABCD1 function than the middle panel. In the ABCD1 null mouse, 065 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. And 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 065 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 IIb/III trial with AMN patients. Here, there are 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. But unfortunately, their primary end point, the 6-minute walk test, was not met. Comparing leriglitazone in the center of this table, which is also the M-IV metabolite of pioglitazone, to the parent compound on the left and 065 on the right, reveals that leriglitazone is a potent PPAR gamma agonist that produces even greater weight gain plus edema versus that typically seen with pioglitazone in diabetes trials. In contrast, 065 is designed to avoid significant weight gain and edema based on dialing out the PPAR gamma activity. Importantly, our data also support the potential for superior efficacy with 065 versus either pio or leriglitazone. Now turning to the AMP kinase platform, let me first describe several lines of published evidence that support this approach. Deletion of AMP kinase is deleterious in cells from the ABCD1 null mouse, but 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 then 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 mouse, we were very gratified to also see evidence of improved neural histology and neuro behavior 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, and this was improved by both 065 and pio as well as by 770, which isn't shown here. On the right, our quantitative results using a balance beam motor and coordination test. And here, you can see that the diseased mice exhibit impaired performance, in this case, a higher score versus wild-type mice and 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 and 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 065 and 770 have shown positive effects on all the parameters we've studied to date. We also have the benefit of being able to pursue 2 different approaches in parallel and using molecules that have been derisked based on extensive preclinical talks 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 will be future opportunities to combine 2 or 3 of these mechanisms or others with our molecules in order to maximize therapeutic benefits. And before turning it back to Thomas, I'd like to briefly describe our clinical plans in ALD. We plan to conduct 2 parallel and identical Phase IIa biomarker-driven POC studies, one with 065 and one with 770. The study design was developed with substantial input from Marc Engelen and from several other disease experts in the U.S. and Europe, and 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 we'll have additional exploratory biomarkers as well. The trials are scheduled to begin in early 2022 with data available later in the year. And then 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 but also, importantly, with patients. And depending on the treatment duration, the final selection of end points 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. So 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 065 Phase II in NASH; the 2 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 will provide the future revenue stream to Poxel that we are willing to reinvest to accelerate and expand our clinical pipeline in the rare metabolic diseases, first, leveraging our internal platform, but we're 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 with an increasing focus on rare metabolic diseases in addition to NASH has the potential to deliver significant value to shareholders as we turn over cash 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. So we will now move on to the Q&A session. [Operator Instructions] So we have the first question from [ David Chinez ]. Actually, we have a couple. I'll ask the 2 first. Do you plan to partner for clinical development and/or conversation in EU and U.S. in AMD? What year do you envision to reach the market? And will you target both the cerebral and spinal cord form of AMD?

Okay. So maybe I can answer for this question and maybe, David, you can elaborate further. So 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 the disease. So as David mentioned, we will initiate really these 2 trials in 2022. We then have the aim to really push the most promising molecule into Phase III as early as 2023. And we believe and we have -- we are finalizing our 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. But potentially, we believe that we could be really having a plan that will allow really the products to be approved in -- as early as 2025. So 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 really a 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, and that's really our goal to do this. David, do you want to add anything?

Yes. I guess another part of the question was related to cerebral disease versus spinal cord disease. Our initial thinking here is that we would -- we're focused, as Marc mentioned, on the greatest unmet medical need at the moment, which would be the spinal cord disease. But 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 of progressive cerebral disease. So we would be encompassing that as part of our later-stage development. And then potentially, we would have the ability to also extend the development of our molecule or molecules into the pediatric population as well. So that's on the radar screen for sure. And 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, what you said that I think -- 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 disability later in life. But -- and because for the cerebral ALD, there is an effective treatment. I mean it's not a perfect treatment. It's highly invasive and it's -- there's only a narrow window of opportunity to administer that treatment, but there is a treatment. So I think that the primary focus on spinal cord disease totally makes sense.

Thank you very much for your answers. We have a second question from Jason Butler and he's with JMP. Can you discuss your thoughts on end points for clinical development? What are your views on VLCFA as a predictive biomarker? And how do patients' prescribers think about clinical end points? And how do they speak to impacts and function?

Okay. David and maybe...

Let me -- yes. Let me -- maybe I can start, and I'll also be interested to hear, Marc, your thoughts on this. So Jason, 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. But we're looking at it basically as a spectrum of end points all the way from the VLCFA reduction that we expect to see in early clinical development to effects on other noninvasive 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 and then to functional tests. The one that we favor the most would be the body -- postural body sway test because it's 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's very tightly correlated with other more classical end points like 6-minute walk test or disability scores. So 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, but it remains to be seen exactly how that's going to pan out. Marc, do you have further comments on end points?

No. I completely agree. And 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 speed and things like that. But yes, that remains to be seen if these are superior to, for instance, the balance and other measures, but there's a lot of stuff happening.

Thank you, Marc. I hope that answered the question, Jason.

Thank you very much. So let's go to the next question from [ Andy Heise ]. Do you have any hypothesis as to why PXL065 could induce expression of the complementary ABCD2 transporter?

David, do you want to answer that one? [ Andy ], thank very much for the question.

Andy, thank you for the provocative and interesting question. The answer is not really. We don't -- this is a very recent observation, so we don't have the -- 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 a thyroid hormone receptor beta agonist. And 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 both penetrate the BBB to the same degree? It seems that the phenotype can vary widely between individuals. Does severity correlate with the VLCFA levels?

Thank you, Lucy, for these questions on the characteristic of the 2 products. Again, David, do you want to start first? And...

Sure. So IP, I think we'll come back to that. Maybe, Noah, you could...

I can take that at the end.

You can take that at the end. Okay. So the -- as far as the brain penetration of our molecules, they both clearly do have some effects to penetrate the brain and we've also looked at spinal cord exposure. So 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. And 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 -- these are postmortem studies in other patients who have less severe disease, but that's the extent of it. But it's really -- 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 acid levels and disease severity. But like you said, there are some studies on postmortem material that do suggest that in the brain, very long-chain fatty acid levels are -- do influence the disease expression. And we have some preliminary observations in an organoid cell model that there's probably also a correlation between C26 levels and disease expression. But unfortunately, in plasma, there is no clear correlation.

Yes. However, if we bring levels down to normal, it would be a very good sign.

I'd say so, yes, it's the [indiscernible]. If you can normalize that, I'd be very surprised if there will be no effect on the clinical parameters.

Yes.

Yes.

Thank you, Marc, for sharing this. Noah, do you want to get back to the IP to Lucy?

Yes. So thanks for the question, Lucy. So we have multiple patent families for each of these compounds. As it relates to the composition of matter patents, that 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. So we feel very good about the overall IP state for both of these compounds and platforms.