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

This meeting is being [Audio Gap]

[Audio Gap] communication of annual its results. I am joined by [indiscernible] CEO of Poxel; and Renevot, CFO; and David Moller, CSO of the company. During this webinar, management will review its final results and will be available to answer your questions following the presentation. [Operator Instructions] I will now hand over to Thomas.

Thank you, [ Nicolas ]. Thank you for joining us today. I'm Thomas Kuhn, I'm 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. And then David Moller, our Chief Scientific Officer, will provide an update on our clinical [ buyback ]. 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 filings. So on the next slide, 2021 has been a particularly important year in Poxel history as it marks the first approval and launch of our -- 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 approved in June and TWYMEEG in Japan, and this was followed by its launch in September 2021. During the year, we also strengthened the company's 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 a sales-based payments and escalating 8 to 18 royalties on product sales. We are immensely proud to have brought 2 patients in Japan through our fruitful partnership with Sumitomo. We also achieved 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. For the [indiscernible], PXL065 is a novel, proprietary, deuterium stabilized air stereoisomer R-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 preclinical and clinical data, opinion leader enthusiasm, significant commercial opportunity and attractive final results. Our first rare disease development program target X-linked adrenoleukodystrophy that we call ALD, a serious disorder with no approved pharmaceutical therapies. Our recent preclinical data with PXL065 and PXL770 demonstrate that both approaches have substantial efficacy potential. The team has been preparing for the initiation of 2 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 sinus, chronic and rare diseases with underlying metabolic pathophysiology. To fulfill our mission, we are focused on NASH and rare metabolic disorder, starting with ALDs. The aim over the coming part of time is to advance into pivotal trials with 1 program in NASH and 1 program in ALDs. We also envisioned to strengthen our pipeline, leveraging our 2 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 results in the third quarter this year. David will walk you through our development plan for NASH and ALD and how this can be positioned us 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 TWYMEEG launch in [ Japan ]. TWYMEEG approval and launch in Japan will present 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 preclinical 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 culmination 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 higher awareness of TWYMEEG amongst prescribing physicians, thanks to its comprehensive launch activities and ongoing promotional activities. Sumitomo has mobilized its full sales force of roughly 750 sales representative to promote TWYMEEG. To strengthen the product positioning in patients with limited treatment options, 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. And Sumitomo has also begun preparation to commercialize in other Asian countries. As expected, TWYMEEG initial net sales in Japan have been limited following its recent launch 6 months ago. TWYMEEG initial commercial uptake has been impacted by prescribing restriction for any new products during the first year of sales and substantial COVID-19 conditions. This has impacted the frequency of physician visits and delayed the significant market [ relation efforts require on innovative new product with a new mechanism of launch ]. We believe that TWYMEEG is an important addition to Sumitomo existing #1 diabetes franchise through differentiated [indiscernible] action and favorable efficacy and safety profile. Indeed, TWYMEEG is a first-in-class product with a new unique development of action. TWYMEEG has a broad approval for use across the therapeutic continuum as a monotherapy with insulin in combination with all other classes of diabetes 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 tolerability profile, TWYMEEG offers a strong potential for the patients with limited treatment option, including elderly and patients with renal impairment. Thus, TWYMEEG provide patients with type-2 diabetes, the opportunity for greater flexibility in their treatments. Throughout 2021, Poxel and Sumitomo have continued to pursue strong patent protection for imeglimin. The patent estate for imeglimin will extend to 2036, including a potential 5-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 milestone from our partner Sumitomo. In accordance with our license agreement, Poxel is entitled to receive escalating royalties of 8% to 18% on net sales of TWYMEEG as well as sales base payment of up to JPY 26.5 billion roughly approximately EUR 200 million. In parallel, as part of our [indiscernible] 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 trading 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. So 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. Initially [indiscernible] 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. So as we've just seen, our revenue in 2021 still 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, 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. So moving to operating expenses. The 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 clinical study cost incurred for the Phase II DESTINY study, [ determinating ] the PXL065 in NASH. To a lesser extent, they also reflected some recurring cost of the proof-of-concept studies for PXL065 and PXL770 in AMN [ ALD ] as well as the regulatory costs into period of beginning for which the company obtained the marketing approval in 2021. Taking R&D tax credit into account resulted in an income of EUR 23 million in 2021 compared to EUR 25 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 2 million in 2020. These result primarily reflected interest to the [indiscernible]. 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. So moving to the next slide. Intangible assets amounted to EUR 16.6 million at 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. So 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 further our operation and chemical expenditures requirements through at least 12 months from the reporting date. This is based first on our cash position at December 31, 2021 but also on our current development plan, on our cash for cash for 2022 that does not include any net royalties from Imeglimin in Japan, as a conservative approach handling a strict control of our operating expenses. However, Poxel is subject to certain financial covenants related to its debt with IPL partners, which could be potentially bridged at the end of Q3 this year. We are today actively pursuing several financing options, which would extend our cash runway and avoid a bridge of financial covenants through at least 12 months from the reporting period. These financing actions included dilutive and non-dilutive sources as well as discussion with our lender [ IPL ] partners, and we reasonably expect that is one [indiscernible] options would be completed before Q3 this year. So moving to the next slide, is liabilities. So 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. This mostly reflects the net loss for 2021. Total financial liabilities amount 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 for PGE. And 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. So 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 from the stock of repayment of the first tranche. So I will now over back to Thomas to review the latest developments from the first few months of 2022.

Thank you very much, Anne. So in [indiscernible] activities to progress our pipeline, as we have understood, we are actively pursuing various financial options to extend our cash runway including dilutive and non-dilutive sources prioritizing non-dilutive initiatives. We're in advanced discussions 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 2 identical Phase IIa clinical onset biomarker studies in ALD. Subject to additional financing, these studies are planned to initiate mid-2022 followed by data readout 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 integrated [ CT ] platform. This included completing the preclinical assessment of PXL770 and AMP kinase activation for [ a non-orphan in disease called autosomal ] dominant polycystic kidney disease, ADPKD, which demonstrated a robust effect to attenuate disease in established model systems. David will get back to this later. In addition to our clinical set programs, we continue to evaluate external opportunities with a focus on chronic and rare metabolic diseases to expand our pipeline. Overall, our priorities in 2022 remain the top line results of Deuterium, our Phase II study in NASH for PXL065 expected in the third quarter and finalizing financing to initiate a proof-of-concept studies in ALD media. I'll 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 2 lead molecules on this slide. PXL065 is the deuterium stabilized R-stereoisomer of pioglitazone, a widely prescribed medicine for type 2 diabetes. But unlike PO, 065 lacks significant PR gamma activity and mediates its efficacy predominantly through non-genomic TZD related pathways such as modulating the mitochondrial pyruvate carrier and inhibition of [ ASIL Coasiphitase ] 4, both of which are implicated as targets to attenuate inflammation, modulate lipid metabolism and prevent tissue degeneration. Strong efficacy was documented in several preclinical model systems for NASH and ALD without specific PPR gamma side effects like weight gain and fluid retention. And more than 130 humans exposed to 065 confirm the expected clinical safety, and we've also validated that selective dose proportional exposure to the preferred R-stereoisomer translates to humans. Given this relationship to PO, 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 damaged dissevered tissues in particular neurons. As an X-linked disease, males are more severely affected but many hemizygous 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 20,000 in the U.S. alone. The clinical features of this disease are shown [ on the next slide, summarizing that most patients develop ] 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 [ disable addition. Cerebral ALD, C-ALD is an even more severe problem leading to incapacitation and death in children but also in adults. ] Fortunately, bone marrow transplantation can be used to treat C-ALD. 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 C-ALD, there's a huge level of unmet medical need and an opportunity for impact. Both of Poxel's platforms shown on the next slide, [ Nutria-modified ] TZDs and AMPK activators have strong therapeutic potential in ALD. The case for D-TZD is supported by literature showing benefits of pioglitazone in ALD as well as implicating nongenomic TZD driven pathways for neuro degeneration. Similarly, there is 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 pertains 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 065 data, and both could also normalize elevated VLCFA in patient-derived cells. The right panel shows 770 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 neuro histology and neuro 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 065 and by PO. On the right, quantitative results from balance and coordination tests using a balanced beam test in this case, you can see that the diseased 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 2 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 opened U.S. IDs 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. And following a run-in period, patients will be treated for 12 weeks with 1 or 2 daily oral doses of either molecule. The readouts include PK, safety and measurements at several time points of key disease-related biomarkers, VLCFA and neurofilament light chain, both of which are validated as disease associated. Additional exploratory biomarkers will also be assessed. And following the analysis 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. And 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 work in drugs with similar prevalence, and we can expect clinical development to be expedited. The ALD community is very engaged, and we have 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. And 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 770 produced strong suppression of cyst formation in 3D vitro assays shown on left panel and in an established in vivo rodent model with an activation of PKD1, the main causative chain 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 wanted to underscore that given the unmet need and given the fact that there are still no treatments available for patients, we believe that our innovative approach with either 770 or 065 would 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 770, both 065 and 770 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 7 independent trials. For PXL770, our recent Phase Ib and Phase IIa results have also yielded prominent efficacy signals. This includes readouts from the [indiscernible] 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 and 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 meet -- 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 3 closely related, closely separated dose levels. Based on the Phase I data and PK/PD modeling, we believe that PXL065 is predicted to achieve the efficacy equivalent of 45 milligrams of pioglitazone without significant PPR gamma-driven weight gain or edema. The results from this trial will enable the selection of 1 or potentially 2 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 ground-breaking for patients afflicted by NASH. I'll now turn the presentation back to you, Thomas.

Thank you very much, David. I would now like to conclude on the 2022 upcoming milestone as this will be an important year for Poxel again. The launch of TWYMEEG in Japan has opened a new chapter for us and will provide a future [ of 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 that David highlighted in NASH anticipated in Q3 of this year, and subject to additional financing, the 2 studies in AMN and ALD are planned to initiate in midyear 2022, with data expected in early 2023. We are actively pursuing a number of funding initiatives in pilot to extend our cash runway, including dilutive and non-dilutive sources prioritizing non-dilutive options. We're in advanced discussions 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 are 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 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 so grateful to patients and physicians who take part in our clinical trials. And lastly, I would like to thank you for continuous support as a shareholder. We look forward to updating you on our progress. That closes 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 [Operator Instruction] We have the first question from David of [indiscernible]. 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 the annual reduction in TWYMEEG price?

So TWYMEEG has been priced basically similarly to the leading class in Japan under DPP-4 inhibitors, and actually, it has been priced at the same price at the market leader in Japan, which are sitagliptin, [indiscernible], from Merck & Co. And so overall, per year, it's roughly $500 a year -- sorry, 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 any guidance from our partners Sumitomo, and of course, this is things that we intend to discuss in the coming year, and 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, will 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 have full confidence that Sumitomo will really do all the activities needed so that TWYMEEG can become a real product leader in Japan and in the other territories [ initially n].

We have several questions from Jason Butler of JMP Securities. The first one is, has the initial views of TWYMEEG being as expected, mainly in combination with DPP-4 inhibitor?

It's a good question. So based on the feedback that we received from our partner Sumitomo. Yes, I can confirm that really most of the prescription was really in combination with other treatment. And we mainly anticipate that this is in combination with DPP-4 inhibitors because this class is prescribing roughly 80% of the market. And as a reminder, we saw an extremely robust efficacy and a real good safety during our Phase III program there. But we're also receiving information from our partner Sumitomo that the product is also well prescribed as the monotherapy. Again, we saw a really good evidence in terms of efficacy and safety during our Phase III program. And we know that down the road, Sumitomo has in mind to really promote the use of TWYMEEG as a monotherapy. Given the mechanism of actions, and we believe that the early it is prescribed to newly diagnosed patients the better it is for the patients. So it's a broad level, 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 as well as a monotherapy.

The second question from Jason is beyond funding, are there any other gating items to initiation of proof-of-concept studies in ALD?

Yes, I can maybe start, and David, I'm sure, will weigh in there. So we are really actively preparing the studies. The regulatory activities are ongoing in both U.S. and Europe. -- to really support the training session. And of course, we are working as well with the CROs to identify really the best clinical sites there. We're also working on the supply. So David, maybe you want to say a word on these other gating items.

Yes. We're pretty close to ready-to-go. The site selection and qualification has been completed, more or less, the [ CMC ] materials is available waiting for final IRB approvals at the sites. So there really isn't anything else that's significant that would slow us down on that front, Jason. You want to move to the next question.

Yes, sure. If the Phase IIb results for 065 are positive is the next step an end of Phase II meeting with FDA?

Yes. So maybe, David, do you want to 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. But 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, and the CMC work should support initiation of Phase III sometime within a few months after the completion of the DESTINY trial.

Thank you. And the last question from Jason is, is it possible to compare your preclinical results for 770 in ADPKD to in data for [indiscernible] 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 was -- 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.