Hello. Good afternoon. Good evening, everyone. Welcome to this webcast. Thank you for joining us today.
I'm Thomas Kuhne. I'm the CEO of Boxel. 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 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 introduction highlighting our strategy. Then I will hand over to Mark Engelin. And to begin with, I'd like to thank very much Mark Engelin to participate to this call. Mark is the MD PhD pediatric virologist from Amsterdam, specifically being very close to this pathology, local dystrophy, and he's heading the Amsterdam local dystrophy center.
Then we'll hear from Ben Lanier. Ben will give his patient perspective. Ben is the co founder and a board member of ALD Connect and so a patient and it would be very interesting to hear from Ben. David Muller, our CSO, will then present you the science professional and data related to our 2 product as well our development plan, and then we'll have some closing remarks. So 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. Really 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 3MIG in Japan and the associated revenues that we'll get really from TriMEG, 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 deteriorated TAD platform as well as our AMP Kinase Activated 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 of concepts, 1 with PEGSEL65, 1 with 770 is the same design with the aim 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 provide 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, DESTINU I, 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'll have the readout from PEXELS65 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 IMEI Limon or the approval of IMEI Limon in Japan and the associated future revenues that it will trigger. As a reminder, we could draw the 3rd and last tranche, €13,500,000 from the IPF loan when we got really the approval of Imiglieline.
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 €13,200,000 As a reminder as well, Sumitomo is expected to launch the product mid September, early October. And following this commercialization, OXXEL 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 DPP4 inhibitors. This is the leading class in Japan. Sumitomo, they have their own DPP4, and the goal will, of course, be to combine imeglinine on top of their own DPP-four. We'll get back to you once the launch will be done, so effective in couple of weeks as I've just mentioned. So as you can see, this launch really opened a new chapter for PoXell to drive shareholder value.
With the additional funding from TwiML, 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 expedited delivery of novel medicine to patients with even stronger potential to create significant value for the benefit of our challenge. So you've got here a snapshot of our pipeline, which I think have a good mix of justifications there. 1, 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 hemoglobin in Japan and close really in additional countries where SImmetim was the right 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 PIXEL770 and PIXELO65 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 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 to 6 minutes, I will try to give an overview of X linked adrenoleukodystrophy. That's what 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. And it causes even though it's an X Men disease, it causes symptoms in men and women, but with clear difference in symptomatology. Can I have the next slide, please?
Biochemically is characterized by 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 external degeneration. Can I have the next slide please? So because this very long chain fatty acids accumulates, this has been a very convenient diagnostic method because determining C260 or more recently a complex lipid C26, Lysol PC 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, adrenal X linked adrenalukodystrophy was separated into distinct phenotypes, but it's actually more accurate to see it as a progressive neurodegenerative disease that 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. And the penetrance of this spinal cord disease is virtually 100% if patients are old enough.
And also, it can cause leukodystrophy, so 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, which the colored lines is a survival graph with 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 3rd or 4 decade of life and then the older men become, the more are affected.
Cerebral disease can already occur in early childhood, often in preschool, often in what you 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 chart on the left in your screen and it occurs at a later age, pretty rare before 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 adrenalukodystrophy 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 our late adulthood.
And then superimposed on that, male patients can get the progressive leukodystrophy, the cerebral ALD, 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 add 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 AUD, 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.
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 are transplanted in childhood will still develop 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 deaths within a few years after onset. So for the spinal cord disease, like I said, there's only supportive care, so treatment of spasticity, etcetera, 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 treatments 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, etcetera, 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 adrenal myeloneuropathy is slowly progressive, but over a lifetime causes severe and disabling 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. And then there's the cerebral ALD, the leukodystrophy, which does not affect all male patients, but if it strouts, is rapidly progressive and causes disability and death within 2 to 3 years, if not treated by hematopoietic stem cell transplants. 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, Martin. I think it was extremely interesting. Ben, do you want to leave the floor on our own and share your perspective?
Yes. Thank you very much. So I'm Ben Lanai. I'm a Frenchman established in the U. S.
For the past 35 years. And my story with ALD starts around age 40. I'm 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 Mark explained, it's a relentlessly progressive disease. I would say the 5 things that are a burden in our daily lives.
So number 1 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 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.
So patients have to take a lot of anti spasm medications to be able 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 specimens and ability to go to sleep. And then finally, kind of a general issue around energy and fatigue. Again, with kind of a 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 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. 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. Thank you for sharing all this. With that, I leave the floor now to David. We've heard about 3 of the unmet needs, so David will present you what we've developed at Boxel and what's our plan going forward. David, you wanted to cover?
Sure. Thank you, Thomas. I'm David Moller. I'm the Chief Scientific Officer at Boxel. It's a pleasure to speak to you today.
And I also want to thank both Mark 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, PXL-seven seventy 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, PXL-sixty five and related deuterium modified thiazolidinediones or dTZDs as we call them, they lack significant PPAR gamma action, but they do retain activities that are mediated by these non genomic pathways that also have the potential to produce similar metabolic and the 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 is what Mark 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 PXL-sixty five and 770. So 65, as you heard from Thomas, is the deuterium stabilized R stereo isomer of piaglitazone. And just to remind you, this is a widely prescribed medicine for type 2 diabetes, but unlike PO, 65 lacks significant PPAR gamma activity and mediates the efficacy through the non genomic pathways in several diseases including ALD.
But fortunately, given the relationship to PO, we can leverage the 505(2) regulatory pathway, which in other words accessing a large safety database for the parent molecule, and we also have an open IND for 65 in ALD in the U. S. More than 130 people so far have been exposed to 65 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 stereo isomer 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 had 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 and 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, piaglitazone has been shown to confer neuroprotection in other contexts. Secondly, one of the key non genomic mechanisms that's modulated by PO as well as our DTCDs, 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 65 and PO normalize elevated BLCFA levels in patient derived cells as you can see on the left panel and that this increase 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, then the middle panel.
In the ABCD1 null mouse, 65 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 PO even though these compounds were studied at the same dose. A recent event that also further sparked our interest in 65 and the DTZDs for ALD comes from clinical results that were recently reported by Menorix with their related molecule called liraglitazone in a long term Phase IIbIII trial with AMN patients. Here, there were actually very encouraging results obtained, especially with the postural body sway test that Mark referred to and a substantial reduction in the occurrence and progression of cerebral disease. But unfortunately, their primary endpoint, the 6 minute walk test, was not met. Comparing liraglitazone in the center of this table, which is also the M4 metabolite of p aglitazone to the parent compound on the left and 65 on the right reveals that liraglitazone is a potent PPAR gamma agonist that produces even greater weight gain plus edema versus that typically seen with peaglitazone in diabetes trials.
In contrast, 65 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 65 versus either PO or liraglitazone. 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 PXL-seven seventy 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 compensatory transporter ABCD2 as you see in the middle panel. As shown on the right, 770 treatment of ABCD1 null mice also suppressed elevated BLCFAs 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 neurobehavior with both 65 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 65 and PO as well as by 770, which isn't shown here. On the right are 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 aren't shown on this slide, it's of interest to compare our profiles with those reported by Menorix with their preclinical findings and also reported by Viking and Audobon with each of their thyroid hormone receptor agonists. Not only are the mechanisms of action distinct for our and from reviewing aggregate results obtained using the in vivo disease model.
And from reviewing aggregate results obtained using the in vivo disease model, where both 65 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, 1 with 65 and 1 with 770. The study design was developed with substantial input from Mark Engelin 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 PKPD modeling. The study readouts will include PK safety measurements at several time points and biomarkers, BLCFA 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. 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.
Plan to further finalize our Phase 3 plan with FDA interactions and further discussions with experts, but also importantly with patients. And 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.
Thank you very much, David. So before moving to the Q and A session, I'd like to highlight really a few conclusion words there. First, as we can see on this slide, now for the next 12 to 18 months, we have a number of near term milestones to drive our growth, including readout from our 65 Phase II in NASH. The 2 proper concepts, biomarker studies that David just described, and of course, the launch of TRIMAG in Japan. This launch of TRIMAG in Japan has actually opened a new chapter for pork cell, and we provide a structured footing stream to pork cell that we are willing to reinvest to accelerate and expand our clinical pipeline in rare metabolic diseases, first, leveraging our internal platform.
But we are 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 our 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 to now move to the Q and 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 and 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. So we have the 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 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 further this question and maybe David you can elaborate further. So our goal will be really to quickly execute on our strategy for LD. 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 diseases. So as David mentioned, we will initiate really these two 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 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. 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 a really reasonable number of patients to be treated so that PoXell, 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, 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 Mark mentioned, on the greatest unmet medical need at the moment, which would be the spinal cord disease. But in the context of studying adults, adult men with AMN, there certainly will be cases as was the case with Menorix's experience of new onset or 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 part that's on the radar screen for sure. And if Mark Engelin 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 diseases 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. But and because for the cerebral ALD, there is an effective treatment. I mean, it's not a perfect treatment. It is highly invasive and 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. Next question?
Thank you very much for your answers. We have a second question from Jason Butler, Analyst at JMP. Can you discuss your thoughts on endpoints for clinical development? What are your views on VLCFA as a predictive biomarker? And how do patients prescribers think about clinical endpoints and how they speak to impacts on function?
Okay. David and maybe pass that.
Yes, let me maybe I can start and I'll also be interested to hear, Mark, your thoughts on this. So Jason, I think that's a very good question and we're still grappling with it 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 endpoints all the way from the BLCFA 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. 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 Mark and his team, as well as by others as being very sensitive, quantitative and also clearly a good way to follow progression because it's very tightly correlated with other more classical endpoints 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 endpoints?
No, 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 speeds 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, Mark. I hope that answered the question, Jason.
Thank you very much. So let's go to the next question from Andy Heich. Do you have any hypothesis as to why PXL-sixty five could induce expression of the compensatory ABCD2 transporter?
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 65 or 770 for that matter to the induction of ABCD2.
It is interesting to note that that's the common feature for some of the other mechanisms people are pursuing like the 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 Covington. Can you please remind us of the IP expiry for each of PXL-sixty five and PXL-seven seventy? 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, Lucie, for these questions on the characteristics of the 2 products. Again, David, do you want to start first?
Sure. So IP, I think we'll come back to that maybe. Noah, you could You
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 2a studies, we believe we have a good opportunity 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 Mark 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 post mortem 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 large in 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 that do influence disease expression. And we have some preliminary observations in an organoid cell model that there is 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 biochemical number. If you can normalize that, I'd be very surprised if there would be no effect on the
Yes. So thanks for the question, Lucie. So 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 2,040. 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 estate for both of these compounds and platforms.
Thank you very much. I'll come back to the rest of your questions from David Sinhaev. Why do you specifically target the AMD form and none of the other ex linked ALD forms? Would PXL-sixty five thousand seven hundred and seventy not be suitable for these indications? And the second question is, how do you competitively position both PXLs in comparison to gene therapies such as the bluebird deal therapy for cerebral ALD.
Okay. Thank you, David, for these questions. David and maybe Marc, you want to?
So I think what you were asking about was whether our technologies would also be suitable for other leukodystrophies, of which there are maybe 20. The reason we the reasons we really focused on X linked adrenoleukodystrophy in particular is because it's the most common of all the leukodystrophies by far, the most common peroxisomal disease as well as I understand it. And 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. So those are really the reasons. There is some potential that we could go after additional leukodystrophies, maybe the peroxisomal biogenesis disorders, for example, and that's something we're thinking about.
Then on the question of gene therapy, as Mark reviewed, and you can please comment Mark, the Bluebird product, which is not yet approved in the U. S, it's got a favorable review in Europe, so hopefully it 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. So 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. But of course, there is also companies interested in developing AAV gene therapy for ALD.
Yes. So there are some early stage efforts with Swan Bio, for example, going after AMN, the adult spinal cord disease with a locally administered spinal cord AAV expression system. And 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 65 and 710 0 in 1 or both NASH or ALD? How will you prioritize investment in the different programs?
Yes. So I can provide an answer. Thank you, Jason, for a good question. So very clearly, I like to make sure that, I mean, you understand that really we want to have different molecule for NASH and for ALD. Our plan is not to have the same molecule developed and commercialized for NASH and for ALD.
This is 2 such very different diseases that really we want to, for different reasons, only really target one disease with one molecule. And 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 2 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, 1st, that's a good problem to have. Let's say that this Pixel 65 will deliver very good results for NASH And for LD, we'll be pleased about this. And maybe you've seen that, but in our pipeline chart, we are continuously progressing our platforms and we are working on next generation products. And if that's the case, then we will take VX-sixty five forward in one indication and we'll move next generation product targeting the same pathways on the other disease. So that's our goal there.
But that's basically how we will do the thing. As a consequence, that's why basically for Pachel770 in NASH, we want to make sure to benefit from the results for O65 in NASH as well as the one for ALD for both 65 and 770, hence, the consequence of this product.
Thank you very much, Thomas, for your answer. We now have another question from Lucie about the cash of the company. Does the current cash along with the IPF loan? And does the SDP milestone cover the 65 NASH trial and the ALD proof of concept studies?
Yes. Thank you, Lucie, for this question. Anne, do you want to take this one?
Yes, Doctor. Lucy. Hi, Lucy. Thank you for your question. So I can confirm that our cash runway extends through 2022 and fully fund the ongoing Phase II study for NASH for 65.
So as it relates to IMN, we can start the preparation of the initiation of the 2 proof of concept studies. However, the proof of concept studies in themselves is not included in our cash run rate. So we'll have to fund this. But as a global comment on that this is rare disease. So the cost of these studies is quite reasonable.
Thank you, Anne.
And if I answered your question, Craig, you see?
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?
Mark, do you want to take a shot at that one?
Yes. Purely hypothetical. I mean, gene therapy is, of course, very attractive treatment option, but I haven't seen any specific results yet. I mean, there's a lot of technical hurdles still that needs to be resolved. So I have no idea how feasible that will be in the short term, but there's a lot of work going on.
But like David said, I mean, in the end for the foreseeable future, it might actually be complementary.
Thank you, Marc, for your answer on this.
Thank you very much, Mark. Yes, so now we have another question. This one from Difei Yang. Do you expect the duration of efficacy measurement to be longer than 1 year in ALD?
Yes. No, absolutely. No, no, that is just even 2 years is touch and go. I mean, this is a very slow disease. And to get a meaningful signal with the tools we have at this time, 2 years is the bare minimum you need to make any kind of meaningful observation.
And so we are working under different scenarios going forward. Maybe David, you want
to give Yes. I just want to emphasize what we said earlier, which is that we agree with Mark that for definitive proof of clinical benefit, we're going to need to do studies of minimum 2 year duration. But we also believe that there's going to be a very likelihood that we can do shorter clinical trials for accelerated approval, potentially even including even those that might be based exclusively on circulating biomarkers. And we also think that based on the experience with Menorix that we show that I showed you where they have a clear benefit that they did see in 2 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, 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.
And maybe we have time for a last question.
We do indeed. We have another question from a participant. There does not about PXLs and there does not appear to be a control group in the plan Phase IIa trials for 770 and OC5 in ALD, why not choose a design that would allow compression to either placebo or positively active compound?
Yes, that's a good question. Maybe David and Marc?
Yes, I can start with that. Maybe Marc, you were even very involved in advising us on this point. But, well, first of all, there is no active comparator, right, except potentially liraglitazone, but we understand that liraglitazone did not affect these biomarkers at least at least ELCFA levels. So based on all the input that we've received from a number of experts, including Mark, 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. So 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 the point where we can really start the more important pivotal trial.
So that's the rationale really. Marc, do you want to comment further on this question of
placebo? Exactly that for screening to see if there is something there before you go for the at a full blown trial. I think that biochemical proof would be enough to move forward. And for that, for just the biochemical effect, you don't really need placebo. You can I think with this design, you can quickly see if your compound does what you think it does?
And then of course, if it's clinically efficacious, that's a much more difficult question. And then you definitely need placebo and long follow-up, but this seems like a reasonable first step.
Yes.
As it will be a 12 weeks study duration, there will be also several time points to assess the biomarker, so you can really see on different endpoints several times.
Thank you, Pascal. And 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. And in this pivotal program, of course, not only there will be placebo arm, but also different endpoints as we refer with the goal to really assess carefully the efficacy as well as the sector of the product. But the goal is really to quickly before this quickly assess the potential of each of our products. So hence the strategy to move quickly with these
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 presenting you really our update on this. I'd like to thank again very much Mark and Glenn and Ben for really having shared really all the knowledge about this pathology. We'll continue working with Mark and Ben going forward.
And of course, we'll update everyone on our plan. But so for now, I wish you all really a good evening or a good afternoon. And again, thank you very much for your attention. Bye bye.