This meeting is being recorded.
Following the publication of its annual results, I am joined for this webinar by Thomas Kuhn, CEO of Poxel, Anne Renevot, CFO, and David E. Moller, CSO of the company. During this webinar, management will review its financial results and will be available to answer your question following the presentation. Please submit your questions in writing in the Q&A tab at the bottom of your screen. I will now hand over to Thomas.
Thank you very much, Nicolas. Thank you for joining us today. I'm Thomas Kuhn, the CEO of Poxel. After my introductory comments, I will hand the call to Anne Renevot, our CFO, to review the full year 2021 financial results. Then David E. Moller, our Chief Scientific Officer, will provide an update on our clinical pipeline. Before we begin, let's review 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. On the next slide, 2021 has been a particularly important year in Poxel's history as it marks the first approval and launch of one of our drugs.
Indeed, in June 2021, we received, with our partner, Sumitomo, a leading company in the diabetes field in Japan, approval for TWYMEEG in Japan, and this was followed by its launch in September 2021. During the year, we also strengthened the company financial position through the milestone payment of roughly JPY 1.75 billion, representing EUR 13.2 million, received from Sumitomo in July for the approval of TWYMEEG, and the final tranche of EUR 13.5 million of the IPF loan, which was contingent on the successful approval of imeglimin in Japan. Now that imeglimin is commercialized, Poxel is entitled to receive sales-based payments and escalating 8%-18% royalties on product sales. We are immensely proud to have brought TWYMEEG to patients in Japan through our fruitful partnership with Sumitomo.
We achieve a significant milestone during 2021 in NASH, with the completion in September of the enrollment in DESTINY-1, a dose-ranging phase II trial evaluating PXL065 for the treatment of NASH. To recall, PXL065 is a novel, proprietary, deuterium-stabilized R-stereoisomer of pioglitazone. Additionally, following a thorough review of the company's program, Poxel has embarked on a new chapter to drive shareholder value. We made the strategic decision to advance and expand our portfolio of clinical assets in rare metabolic diseases, which represents the intersection of high unmet medical need, promising pre-clinical and clinical data, opinion leader enthusiasm, significant commercial opportunity, and attractive term results. Our first rare disease development program targets X-linked adrenoleukodystrophy, that we call ALD, a serious disorder with no approved pharmaceutical therapies. Our recent technical data with PXL065 and PXL770 demonstrate that both approaches have substantial efficacy potential.
The team has been preparing for the initiation of two identical phase IIa studies, which will enroll adult male with AMN, the most common form of ALD. Poxel mission and vision remains to discover, develop, and commercialize innovative therapies for patients suffering from serious chronic and rare diseases with underlying metabolic pathophysiology. To fulfill our mission, we are focused on NASH and rare metabolic disorder, starting with ALD. The aim over the coming period of time is to advance into pivotal trials with one program in NASH and one program in ALD. We also envision to strengthen our pipeline, leveraging our two small molecule-based platform and also through partnerships, through partnering, sorry, additional external programs. We will be able to apply our strong R&D capabilities to deliver novel medicines to patients with even stronger potential to create significant value for the benefit of our shareholders.
As you can see on the next slide, the chart represents our pipeline and is indicative of continuing progress. Our clinical pipeline continues to advance. In September, we announced the completion of the enrollment in the phase II DESTINY-1 trial for PXL065 with 123 biopsy-proven patients. We look forward to the result in the third quarter this year. David will walk you through our development plan for NASH and ALD and how this can be positioned as to potentially initiating pivotal trials in ALD in 2023. We also intend to further strengthen our existing metabolic pipeline with additional internal and/or external opportunities. Looking at the next slide with the TWYMEEG launch in Japan. TWYMEEG approval and launch in Japan represents a major milestone for us.
This major accomplishment resulted from the submission of a Japanese new drug application for imeglimin in July 2020, based upon an extensive pre-clinical and clinical program, including positive results from the phase III TIMES program in over 1,100 patients in Japan. The TWYMEEG approval in Japan represents the accumulation of several years of clinical development work and a strong validation of our R&D capabilities, as well as international footprint. Sumitomo Dainippon Pharma has made significant progress establishing high awareness of TWYMEEG among prescribing physicians, thanks to its comprehensive launch activities and ongoing promotional activities. Sumitomo has mobilized its full sales force of roughly 750 sales representatives to promote TWYMEEG.
To strengthen the product positioning in patients with limited treatment option, such as the elderly and renal impaired ones, Sumitomo recently initiated a phase IV study targeting Type 2 diabetes patients with chronic kidney disease, CKD 3b, 4, and 5. Sumitomo has also began preparation to commercialize in other Asian countries. As expected, TWYMEEG initial net sales in Japan have been limited following its recent launch six months ago. TWYMEEG initial commercial uptake has been impacted by prescribing restriction for any new product during the first year of sales and substantial COVID-19 conditions. This has impacted the frequency of physician visits and delayed the significant market education effort required for a new product with a new mechanism of action. We believe that TWYMEEG is an important addition to Sumitomo existing diabetes franchise through differentiated dual mechanism of action and favorable efficacy and safety profile.
Indeed, TWYMEEG is a first-in-class product with a new, unique dual mechanism of action. TWYMEEG has a broad approval for use across the therapeutic continuum as a monotherapy with insulin or in combination with all other classes of diabetic products. Of note, it is especially efficacious when combined with DPP-4 inhibitors, which is the most widely prescribed therapeutic class for Type 2 diabetic patients in Japan. Moreover, given its robust efficacy and favorable safety durability profile, TWYMEEG offers strong potential for the patient with limited treatment option, including elderly and patients with renal impairment. Thus, TWYMEEG provides patients with Type 2 diabetes the opportunity for greater flexibility in their treatment. Throughout 2021, Poxel and Sumitomo have continued to pursue strong patent protection for imeglimin. The patent status for imeglimin will extend to 2036, including a potential five-year patent term extension, with other patent applications ongoing.
To date, we have received JPY 7 billion, roughly EUR 53 million of upfront payments, clinical and regulatory milestones from our partner, Sumitomo. In accordance with our license agreement, Poxel is entitled to receive escalating royalties of 8%-18% on net sales of TWYMEEG, as well as sales-based payments of up to JPY 26.5 billion, roughly EUR 200 million. In parallel, as part of our Merck Serono licensing agreement, Poxel will pay Merck Serono a fixed 8% royalty based on the net sales of imeglimin, independent of the level of sales. Given the immediate post-launch headwinds I've just described, the current forecast predict that Poxel receipt of royalties will be cash neutral through Sumitomo full year 2022, so through March 2023.
After that point, we expect that TWYMEEG will achieve the next commercial threshold, and the royalty rate will increase to double digits, with Poxel retaining all net royalties above 8%. I will now hand over to Anne, our CFO, to present the 2021 financial results. Anne?
Thank you, Thomas. Good evening, everyone. I will then review our financials for the full year 2021, starting with the revenue. Poxel reported revenues of EUR 13.4 million for the year ended December 31, 2021, as compared to EUR 6.8 million in 2020. This revenue mostly reflects the JPY 1.75 billion milestone payment from Sumitomo Dainippon Pharma that was triggered by the June marketing approval of TWYMEEG in Japan. Additionally, Poxel recognized JPY 7.5 million in royalty revenue, which represents 8% of TWYMEEG net sales in Japan in 2021 since its launch on September 16. Moving to the next slide.
As we've just seen, our revenue in 2021 mostly reflects the EUR 13.2 million milestone payment that was paid by our partner, Sumitomo, following the approval of imeglimin in Japan. It also includes the 8% royalty revenue of TWYMEEG net sales in Japan. As mentioned by Thomas earlier, as part of the Merck Serono licensing agreement, Poxel will pay to Merck Serono a fixed 8% royalty based on the net sales of TWYMEEG. This is reported in cost of sales. Moving to operating expenses. As a biotech company, the majority of our resources are allocated to research and development activities. In 2021, the R&D expenses amounted to EUR 27.5 million as compared to EUR 29.2 million in 2020.
R&D expenses in 2021 primarily reflected the clinical study costs incurred for the phase II DESTINY-1 study evaluating PXL065 in NASH. To a lesser extent, they also reflected some preparing costs of the proof of concept studies for PXL065 and PXL770 in AMN/ALD, as well as the regulatory costs incurred over the period of imeglimin for which the company obtained the marketing approval in June 2021. Taking R&D tax credit into account, that resulted in an income of EUR 2.3 million in 2021 as compared to EUR 2.5 million in 2020. The net R&D expenses amounted to EUR 25.2 million in 2021 as compared to EUR 26.7 million in 2020.
General and administrative expenses amounted to EUR 10.6 million in 2021 as compared to EUR 9.9 million in 2020. The financial loss amounted to EUR 1.3 million in 2021 as compared to EUR 4 million in 2020. These results primarily reflected the interest attached to the company indebtedness. Lastly, the net result in 2021 was a net loss of EUR 23.8 million as compared to a net loss of EUR 31.8 million in 2020. Moving to the next slide. Intangible assets amounted to EUR 16.6 million December 31, 2021, which is a similar level to December 31, 2020, and mostly reflects DeuteRx portfolio acquisition in 2018.
Cash and cash equivalents amounted to EUR 32.3 million at December 31, 2021, compared to EUR 40.2 million at December 31, 2020. The change in cash, which is a decrease by EUR 8 million, reflects EUR 9 million coming from financing activities and EUR 17 million cash burn from operations. We have just reported in our press release, we expect that our resources will be sufficient to fund our operation and capital expenditures requirement through at least 12 months from the reporting date. This is based first on our cash position at December 31, 2021. It's also on our current development plan on our cash forecast for 2022 that does not include any net royalties from imeglimin in Japan as a conservative approach. Finally, the strict control of our operating expenses.
However, [Poxel] is subject to certain financial covenants related to its debt with IPF Partners, which could be potentially breached at the end of Q3 this year. We are today actively pursuing several financing options which would extend our cash runway and avoid any breach of financial covenants through at least 12 months from the reporting date. These financing options include dilutive and non-dilutive sources, as well as discussion with our lender, IPF Partners, and we reasonably expect that at least one of the pursued options will be completed before Q3 this year. Moving to the next slide. Key liabilities. Total shareholders equity amounted to EUR 8.2 million for the year-end 2021, as compared to EUR 27.1 million at December 31, 2020. It mostly reflects the net loss for 2021.
Total financial liabilities amounted to EUR 35 million compared to EUR 24 million at December 31, 2020, mostly reflecting the EUR 29 million of the IPF loan and EUR 6 million from PGE. Last comment, the litigation with Merck has been settled and the provision that was reported at December 31, 2020, has been fully reversed accordingly. Now moving to the last financial slide, which is a statement of cash flow. The cash burn from operating activities amounted to EUR 17 million in 2021 as compared to EUR 26 million in 2020. The cash flow from financing activities amounted to EUR 9 million in 2021, compared to EUR 29 million in 2020. It mostly represents the drawdown of the third tranche of the IPF loan for EUR 13.5 million and the start of repayment of the first tranches.
I will now hand it back over to Thomas to review the latest developments from the first few months of 2022.
Thank you very much, Anne. In parallel to our activities to progress our pipeline, as we have understood, we are actively pursuing various financing option to extend our cash runway, including dilutive and non-dilutive sources, prioritizing non-dilutive initiatives. We are in advanced discussion with several parties, and we are confident that we'll close the financing in a reasonable timeframe to execute our strategic plan. We continue to prepare for the launch of two identical phase IIa clinical proof-of-concept biomarker studies in ALD. Subject to additional financing, these studies are planned to initiate mid-2022, followed by data readouts in 2023. We announced a few weeks ago that the FDA granted Fast Track designation to PXL065 for the treatment of ALD, designed to expedite development of pharmaceutical products, which demonstrates the potential to address unmet medical needs in serious or life-threatening conditions.
Drugs with Fast Track designation are eligible to apply for accelerated approval and priority review at the time of a new drug application submission, which may result in a faster product approval. During the year, we evaluated internal opportunities from our AMPK and deuterated TZD platform. This included completing the pre-clinical assessment of PXL770 and AMPK kinase activation for another panel of cases of Autosomal Dominant Polycystic Kidney Disease, ADPKD, which demonstrated a robust effect to attenuate disease in established model systems. David, sorry, will get back to this later. In addition to our clinical stage programs, we continue to evaluate external opportunities with a focus on chronic and rare metabolic disease to expand our pipeline.
Overall, our priorities in 2022 remain the top-line results of DESTINY-1, our phase II study in NASH for PXL065, expected in the third quarter, and finalizing financing to initiate the proof-of-concept studies in ALD. I now hand over to David to provide an update on our clinical programs.
Thank you very much, Thomas. Before briefly updating you on our specific programs, let's review the key features of our two lead molecules on this slide. PXL065 is the deuterium-stabilized R-stereoisomer of pioglitazone, a widely prescribed medicine for Type 2 diabetes. Unlike pioglitazone, PXL065 lacks significant PPAR gamma activity and mediates its efficacy predominantly through non-genomic TZD-related pathways, such as modulating the mitochondrial pyruvate carrier and inhibition of acyl-CoA synthetase 4, both of which are implicated as targets to attenuate inflammation, modulate lipid metabolism and prevent tissue degeneration. Strong efficacy was documented in four preclinical model systems for NASH and ALD without specific PPAR gamma side effects like weight gain and fluid retention.
More than 130 humans exposed to PXL065 confirm the expected clinical safety, and we've also validated that selective oral exposure to the preferred R-stereoisomer translates to humans. Given its relationship to pioglitazone, the 505(b)(2) regulatory pathway can also be employed, leveraging a large safety database for the parent compound. PXL770 is our novel direct AMPK activator, the first such molecule to be studied in any human disease. It produces substantial efficacy in several preclinical model systems, including those for common cardiorenal disorders, NASH, diabetes and ALD. Most recently, we've seen compelling benefits in polycystic kidney disease models, which I'll share with you shortly. Clinical development to date has demonstrated target engagement and translation of several disease-related efficacy parameters to humans, suggesting the likelihood of broader translation for this mechanism.
Preclinical and clinical safety have also been very favorable, with more than 200 humans exposed for 12 weeks. Moving on to adrenoleukodystrophy. X-linked ALD is a monogenic inborn error of metabolism due to mutations in the ABCD1 gene, which encodes a key cellular fatty acid transporter. This defect results in accumulation of Very Long-Chain Fatty Acids (VLCFA), with damage to several tissues, in particular neurons. As an X-linked disease, males are more severely affected, but many homozygous females have symptoms as well. ALD is also increasingly being diagnosed based on recent and broad-based adoption of newborn screening. Thus, the prevalence of ALD is similar to that of hemophilia or spinal muscular atrophy, about 25,000 in the U.S. alone. The clinical features of this disease are such as adrenal insufficiency or Addison's disease, but this can be managed with glucocorticoid supplements.
In contrast, most males and many females develop progressive spinal cord degeneration called adrenomyeloneuropathy, AMN, which is a serious and disabling. Well, fortunately, bone marrow transplantation can be used to treat cALD. However, it is only effective with very early onset disease and is not typically employed in adults. In the absence of any approved drug therapies for AMN or cALD, there's a huge level of unmet medical need and an opportunity for impact. Both of Poxel's platforms, shown on the next slide, deuterium-modified TZD and AMPK activators, have strong therapeutic potential in ALD. The case for dTZDs is supported by literature showing benefits of pioglitazone in ALD, as well as implicating non-genomic TZD-driven pathways for neurodegeneration. Similarly, there's a significant body of literature supporting the utility of AMPK as a target for ALD. Given this background, we studied both lead molecules in classical ALD model systems.
The example data shown here pertain to both PXL065 and PXL770. Both approaches strongly reduced toxic VLCFA levels in tissues from the established animal model, the ABCD1 null mouse. The left panel shows PXL065 data, and both could also normalize elevated VLCFA in patient-derived cells. The right panel shows PXL770 data. In addition, as shown on the next slide, longer-term experiments that were conducted in the ABCD1 null mouse were also shown to demonstrate an improvement in neural histology and neural behavior with both PXL065 and PXL770, and some examples of these data are shown here. The images to your left and the graph below show that distorted axonal morphology is improved, in this case by PXL065 and by PXL770.
On the right, quantitative results from balance and coordination tests using a balance beam test in this case. You can see that the disease mice exhibit impaired performance versus wild type, and that treatment with 770 was able to reverse this defect. Based on all the preclinical and clinical data we have for both platforms, we're now planning to initiate two parallel phase IIa studies, as shown on the next slide. These are biomarker-driven POC studies, one with 065 and one with 770. We have open U.S. INDs for both molecules, and as Thomas mentioned, Fast Track designation was granted last month for PXL065. The study design was developed with substantial input from several disease experts in the U.S. and Europe. Each trial will enroll 12 or 24 adult male patients with AMN.
Following a run-in period, patients will be treated for 12 weeks with one or two daily oral doses of either molecule. The readouts include PK, safety, and measurements at several time points of key disease-related biomarkers, the VLCFA and neurofilament light chain, both of which are validated as disease-associated. Additional exploratory biomarkers will also be assessed. Following the analyses of these results, we should be able to choose the preferred molecule for further advancement into a pivotal trial to begin later in 2023. In parallel, we also intend to finalize our phase III plan with regulatory agencies. Depending on the treatment duration and the final selection of endpoints, our pivotal trial could lead to an NDA filing as early as the end of 2025.
To summarize the opportunity in ALD on the following slide, we remain excited to pursue treatments in ALD, as this represents an area of very high unmet medical need. It also provides substantial commercial opportunity, given premium pricing for orphan drugs with similar prevalence, and we can expect clinical development to be expedited. The ALD community is very engaged, and we've established relationships with key opinion leaders and collaborations with important patient advocacy groups such as those listed on this slide. Let me now discuss some newer data in kidney disease, beginning on the next slide. During the past year, we also completed the preclinical assessment of AMPK and PXL770 in autosomal dominant polycystic kidney disease, ADPKD. Here we've seen compelling benefits. ADPKD is an inherited orphan disease, and its prevalence is about 140,000 in the U.S.
ADPKD has very high unmet medical need. More than 50% of patients develop end-stage renal disease, usually in the prime of life, and only one drug, tolvaptan, is approved, and it's associated with significant safety and tolerability challenges. The pathophysiology also involves altered kidney metabolism and specific activation of growth-related pathways that AMPK is known to inhibit. In the studies we performed, PXL770 produced strong suppression of cyst formation in 3D in vitro assays shown on the left panel and established in vivo rodent model with an activation of PKD1, the main causative gene. We saw robust reductions in kidney size and cyst area in the middle and right panels, along with other improvements in kidney histology and in kidney function. These new results add value and create optionality for our AMPK platform.
We're not yet positioned to trigger development activities, but we are currently assessing clinical strategies. Moving now to NASH on the next slide. I want to underscore that given the unmet need and given the fact that there are still no treatments available for patients, we believe our innovative approach with either PXL770 or PXL065 will enable Poxel to have a significant role in the NASH arena. The next slide summarizes that in addition to strong potential in ALD for both lead molecules or in polycystic kidney disease for PXL770, both PXL065 and PXL770 have evidence to support their development in NASH. We have clinical validation that supports both molecules. For PXL065, a wealth of clinical data in NASH with the parent molecule, pioglitazone, has demonstrated substantial efficacy at this point in seven independent trials.
For PXL770, our recent phase Ib and phase IIa results have also yielded prominent efficacy signals. This includes readouts from the STAMP-NAFLD study, which revealed beneficial effects on liver fat content, liver enzymes, and glycemic parameters with an intriguing profile where patients with coexisting Type 2 diabetes, almost half of the enrolled subjects, were better responders. Both molecules are also first in class in daily oral approaches, and innovative development approaches can be pursued with both molecules as well. On the next slide, I'll summarize the status of our phase II ongoing trial in biopsy-proven NASH patients. As we announced last fall, the DESTINY-1 trial is fully enrolled, and the trial is on track to lead to yield results in Q3 of this year.
By leveraging the 505(b)(2) regulatory path, we've also designed a streamlined single phase II study with three closely related, closely separated dose levels. Based on the phase I data and PKPD modeling, we believe that PXL065 is predicted to achieve the efficacy equivalent of 45 milligrams of pioglitazone without significant PPARγ driven weight gain or edema. The results from this trial will enable selection of one or potentially two doses for advancement into phase III. Overall, we continue to maintain that the opportunity to provide an important treatment option to capture the benefits of pioglitazone without the burden of side effects would be groundbreaking for patients afflicted by NASH. I'll now turn the presentation back to you, Thomas, to conclude.
Thank you very much, David. I would now like to conclude on the 2022 upcoming milestones, as this will be an important year for Poxel again. The launch of TWYMEEG in Japan has opened up a new chapter for us, and will provide a future funding stream to Poxel that we intend to reinvest to advance and expand our clinical pipeline in rare metabolic diseases, first leveraging our internal platforms. We are confident that our partner, Sumitomo, is actively pursuing efforts to raise awareness and knowledge of TWYMEEG amongst prescribing physicians, and we'll have quarterly feedback on the sales trends. Results from the PXL065 phase II DESTINY-1 that David highlighted in NASH are anticipated in Q3 of this year. Subject to additional financing, the two studies in AMN/ALD are planned to initiate in mid-2022, with data expected in early 2023.
We are actively pursuing a number of funding initiatives in parallel to extend our cash runway, including dilutive and non-dilutive sources, prioritizing non-dilutive options. We are in advanced discussion with several parties, and are confident that we can close at least one transaction in a reasonable timeframe to execute our strategy. To summarize, we're 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 cards on multiple studies in the next 12 months that may allow us to initiate pivotal trials in 2023. All the work and success we have accomplished this year would not have been possible without the incredible energy from our talented employees, and I want to thank them for all that we accomplished during these very challenging times.
I'm also grateful to patients and physicians who take part in our clinical trials. Lastly, I would like to thank you for your continuous support as a shareholder. We look forward to updating you on our progress. That close our presentation, and I think we can now move to the question and answer session. Thank you very much for your attention.
Thank you very much, Thomas. Before starting this Q&A session, we remind you that you can submit your question in writing in the Q&A tab at the bottom of your screen. We have a first question from David of Degroof Petercam. Can you remind me about the annual treatment cost of TWYMEEG per patient? And in that context, when will you provide guidance on the expected annual or biannual reduction in TWYMEEG price?
TWYMEEG has been priced basically similarly to the leading class in Japan, the DPP-4 inhibitors. Actually, it has been priced at the same price of the market leader in Japan, which is sitagliptin, Januvia from Merck & Co. Overall, per year, it's roughly, you know, $500 a year annual cost for the treatments there. As you said, in Japan, there is now an annual price reduction, which is basically in place for any new treatments there. We haven't received, you know, any guidance from our partners, Sumitomo.
Of course, this is things that we intend to discuss in the coming year. We'll get back to the market as soon as we know more. In parallel of this, of course, the priority for Sumitomo is really to, as I said, really expand the awareness of the product. I think they've done a terrific job so far on this. As a new molecule, a new entity with a new mechanism of action, it requires, of course, a lot of promotional effort, but we are fully confident that Sumitomo really will really do all the activities needed so that TWYMEEG can become a real product leader in Japan and in the other territories in Asia.
Thank you, Thomas. We have several questions from Jason Butler of JMP Securities. The first one is, has the initial use of TWYMEEG been as expected, mainly in combination with the DPP-4 inhibitor?
It's a good question. Based on the feedback that we received from our partners, Sumitomo, yes, I can confirm that really most of the prescription was really in combination with other treatment. We mainly anticipate that this is in combination with DPP-4 inhibitors, because this class is prescribed in roughly, you know, 80% of the market. As a reminder, we saw an extremely robust efficacy and a really good safety during our phase III program there. We're also receiving information from our partners, Sumitomo, that the product is also well prescribed as a monotherapy. Again, we saw really good evidence in terms of efficacy and safety during our phase III program.
We know that down the road, Sumitomo has in mind to really promote the use of imeglimin as a monotherapy. Given the mechanism of actions, and we believe that the earlier it is prescribed to newly diagnosed patients, the better it is for the patients. It's a broad label as we mentioned, and even after a couple of months on the market, we can see that the product is not only prescribed as a combo, but also as a monotherapy.
Thank you. The second question from Jason is, beyond funding, are there any other gating items to initiation of proof of concept studies in ALD?
Yeah, I can maybe start and David I'm sure will weigh in there. We are really actively, you know, preparing the studies. The regulatory activities are ongoing in both U.S. and Europe to really support the trial initiation. Of course, you know, we are working as well with the CROs to identify really the best clinical sites there. We are also working on the supply. David, maybe you want to say a word on this other gating items.
Yeah. We're pretty close to ready to go. The site selection and qualification has been completed more or less. The CMC material available, waiting for final IRB approvals at the sites. There really isn't anything else that's significant that would slow us down on that front, Jason. Do you wanna move to the next question?
Yeah, sure. If the phase IIb results for PXL065 are positive, is the next step an end-of-phase II meeting with FDA?
Yeah. Maybe David, you wanna answer that for NASH?
Yes. The answer is yes. There would obviously be a lot of work leading up to that, in terms of planning the phase III program and looking for sources of funding or partnership to enable that. Yes, that would be the major inflection point. We've completed the chronic tox studies, the studies that we believe are necessary under the 505(b)(2) path. The CMC work should support initiation of phase III, sometime, you know, within a few months after the completion of the DESTINY-1 trial.
Thank you. The last question from Jason is it possible to compare your preclinical results for PXL770 in ADPKD to any data for tolvaptan in the same models?
Yes. Great question. Thank you for asking. In the in vitro cyst 3D cyst assays, which we've done in human as well as dog, we did compare that to tolvaptan and showed we have the same effect and a fairly good potency as well. In the in vivo model, we did not do an active comparator with tolvaptan. However, the data that we generated was in the exact same model that's been published with tolvaptan, where we have really, I'd say, the same degree of efficacy on all the major parameters, including kidney weight, cyst index and kidney function. So it looks very comparable. It's a different pathway, quite a distinct pathway, so there could be additive benefits in adding an AMPK activator to tolvaptan as well.
We also know that tolvaptan, I mean, suffers from-
Yeah.
-challenging tolerability and safety profile with the black box warning. As we've seen, PXL770 so far, you know, has showed a good safety and a favorable tolerability profile, so which could further differentiate it from tolvaptan.
Thank you. Now we have a question from Lucy of Jefferies. Please, can you expand on the IP estate? I was under the impression the composition of matter expired 2026, so we have five-year PTA out to 2031.
Yeah. Maybe Noah, do you wanna answer this one?
Sure. Thanks for the question, Lucy. You're referring to the imeglimin patent estate. In Japan, there are a series of patents, the latest which expires in 2031. Unlike in the U.S., where you can only extend a single patent, in Japan, you can request to extend multiple patents. We, together with Sumitomo, have pursued that and have selected several patents to extend, which if successful, would take us out to 2036. We also have a series of new patents that we filed that are still being prosecuted, and that's not considered in the current estimate, but it could be in the future.
Thank you very much. We have another question about ALD. Can you please describe the addressable markets for PXL065 ALD treatment? The total addressable market in dollar sales.
Maybe I can just say what I've been shown, and then I will let David really complement that. I think the two main disease in ALD are really, you know, the adrenomyeloneuropathy that affect really the young adults there, male and female. By the way, that David will really detail, which we believe is the most, you know, attractive commercial opportunity, you know. It's a slowly progressive disease and there is an urgent need really for treatments there. There is another disease, which is very important to treat given the very, very high unmet need, which is the cerebral ALD, and David, you know, talk about it.
We believe that PXL065 as well as PXL770, and by the way, could be really interesting for these two diseases. We will start, of course, you know, with AMN, not only because it's better in terms of clinical strategies to start by that. At the same time, I mean, we believe that going into cALD could also be a really interesting opportunity for us. Maybe David, do you wanna complement that?
Yeah. Just to remind you, as I mentioned on one of the slides, there are approximately 20,000 or so patients in the U.S. That's the best estimate that we have today. The number's increasing based on newborn screening as well. Given that the majority of patients have or do or will develop AMN, the main spinal cord disease, there's, you know, the potential population would be probably on the order of at least 10,000 in the U.S., and you can extrapolate to Europe for a similar number. As Thomas mentioned, you know, that would be for men who are more severely afflicted, and then we would potentially wanna expand into women, over the course of time, and potentially also target the really severe phenotype of cerebral disease.
The population could be as up to maybe 20,000 overall. Then in terms of pricing, it's hard to gauge, but based on analogy with other diseases like hemophilia or SMA that I alluded to, this could be a multi-billion-dollar opportunity.
Knowing that there is now a diagnostic which is more and more used, and that's anticipated to be more and more used in newborn screening, so which would help to expand really the population, and of course, identifying as early as possible the patients that need treatment.
Thank you very much. Another question. How should we think about the go, no-go decision regarding polycystic kidney disease opportunity? Are there more preclinical studies to be conducted, additional regulatory feedback from the FDA?
Well, I think, I mean, as we've always said, we have two interesting platforms, and with which we can target different indications, and specifically in this rare metabolic disease space. So for AMPK, we have explored, you know, different indication. As David mentioned, I think there is a lot of literature showing the potential of activating AMPK for the treatment of the disease. We wanted basically to demonstrate that, you know, in a few model. David highlighted, you know, some of that there. We are of course very focused on initiating this ALD study for PXL770, and so this is really a priority for us.
We view, you know, this result as ADPKD as a good way to really expand our pipeline. As a reminder, we not only have seven seventy but also other AMPK activators there in our pipeline. We're looking at that as, you know, a good way we need to complement our pipeline. This is something that of course will continue working. As we said, currently, we are thinking about really what could be the best strategies, whether, you know, for PXL770 or for, you know, next generation components there. David, do you wanna
Yeah. I would just add that, you know, in principle, PXL770 could be advanced directly into a phase II study, which would be the typical path for ADPKD, something like a one-year study looking at kidney volume. We haven't initiated any development activities at this point, and we haven't filed an IND. We just recently got this data. We think it's quite compelling and, you know, maybe Noah could comment. There's been, you know, some significant interest from other parties as well in this indication, as well as in others that we're doing.
Yeah. We're obviously, as Thomas and David said, we're actively looking at next steps on this program, including developing a clinical strategy. In parallel, this is a very high value indication in the market. It's you know, an indication that only has currently really a single therapy, tolvaptan, which has a black box warning. Nonetheless, it's still you know, quite a successful product. It has attracted a fair amount of interest externally and you know, we'll keep the market apprised of that as things develop.
Thank you. Another question. In speaking with expert in the NASH field, it appears that there is a pretty significant inter-scorer variability in ballooning. As you think about a phase III program turning positive result of the DESTINY-1 study, are there any ways to mitigate that clinical risk?
Good question. It's basically a key topic currently in the field of NASH with really the pathology data and the difficulty for this, David. I mean that's a topic that we discussed a lot with our experts there.
This was a hot topic at the NASH-TAG meeting that I attended in January as well. This is one of the most difficult components of the NAS score, the NAFLD Activity Score that in the biopsy reads for pivotal trial in particular. We're very aware of that issue. You know, ways to mitigate that would include implementation of automated AI-assisted pathology reads, where there's increasing evidence that that could help to resolve some of the ambiguity that you can see between different pathologists. As well as the potential to have you know multiple pathology reads in a more systematic way.
Bear in mind also that based on what we know about pioglitazone, where there are several studies showing it also has an impact on fibrosis, that there could be a substantial benefit on fibrosis per se, which could be an independent path for approval as well as an improvement in the NAS score. It's a little too early to say exactly what we're gonna do. There are ways we believe things. We're learning as we go and learning from some of the failures and challenges others are experiencing.
Thank you. Another question. Are you expecting a significant ramp up in the TWYMEEG sales once the two-week prescription limit ends after one year? How much of an impact do you think this is having? Maybe I will add this question also. Please, could you repeat the annual price for TWYMEEG in Japan?
Basically the annual price is roughly, you know, around $500 a year. Yes, we expect of course a significant impact following this one year restriction there. Currently, as a really innovative product, we know that from our partners, Sumitomo, that the product is mainly, you know, prescribed by, you know, what they qualify as, you know, expert physician that really see the value of the product. This expert physician are mainly, you know, in hospital there. As you can imagine, in big hospital, seeing, you know, a patient every two weeks is very difficult, and it's more really, you know, the general practitioner that can do this.
That's why, having after this one-year period, the ability to only really see your patient every three months, every six months would help a lot. Of course, then it will transition more and more to a generalist practitioner as for any new anti-viral product. That's why, you know, this is a first effect, which we believe, you know, could really increase the ramp up of sales there. The second thing is, of course, COVID-19. It's difficult of course to predict anything with this pandemic there. Hopefully, you know, this is behind us in a reasonable timeframe.
As you can imagine, as I just mentioned, going to hospital either, you know, for the patients or for sales rep, is difficult under COVID-19. Of course, Sumitomo for the last two years have developed a lot of other ways to basically, you know, promote the product and facilitate, you know, a prescription of the product. Of course, it adds, you know, some complexity on top of that. That's why really following the expiry of this one year restriction, as well as hopefully, you know, releasing the COVID-19 regulation in Japan, could, we believe, you know, significantly help really for the ramp up of the product.
Thank you very much. I think that was the last question. I propose to close this Q&A session. Thomas, I leave you the last word.
Sorry. Well, thank you very much. Thank you for your attention and this question. I hope we share with you really where we stand on our developments there. As you have understood, 2022 is gonna be a very interesting year with significant milestones on ALD, with the first two readouts in NASH in 2023. And of course, we will keep, you know, all of you fully informed about our progress there. Looking forward to our next update. For the time being, well, have a good rest of your day, and we'll talk soon. Bye-bye.