Good morning, everyone. Thank you for joining NeuroSense Investor Webinar, which will include live Q&A at the end. Before we start, we'd like to note that we may have forward-looking statements today, and we refer you to our filing with the SEC.
Thank you all. Just if you can move one slide back. I cannot control the slides for whatever reason, and we'll start. Thank you. Okay, so good morning, everyone, and thank you for joining us. I'm Alon Ben-Noon, Co-founder and CEO of NeuroSense Therapeutics. It's great to be here with you today and provide you with important updates about our near-term milestones and catalysts. I'm joined today by two key members of our extended leadership team, Dr. Shiran Zimri, whose expertise spans the various phases of product development and has been deeply involved in our clinical and regulatory efforts, including leading our plans in Canada, and we have also Michael Rabinowitz, our Strategic Advisor, who brings many years of experience in business development in pharma and biotech, and is spearheading our partnership efforts with the executive team.
On today's call, we will give you a clear, up-to-date view of where NeuroSense stands, what's coming next, and how we are thinking about execution and about value creation throughout 2026. As most of you know, NeuroSense was founded with a simple but ambitious goal: to change the trajectory of devastating neurodegenerative diseases such as ALS. Over the past few years, we have moved from concept to clinical evidence, and today our focus is on transforming that evidence to support registrational efforts and a de-risked, highly efficient confirmatory phase III study. In this call, we will focus on four key topics. First, ALS phase III, the PARAGON trial. Our intention is to initiate this pivotal study in mid-2026.
We have been working hard to take into account everything that we have learned from previous studies and to harness the expertise of our esteemed advisors so that we have the greatest odds to confirm and expand previous findings and support the future success of PrimeC. With recent FDA clearance of our study, we are fully committed to meeting our timelines. The second topic is the pre-NDS meeting with Health Canada. Following productive discussions with the agency, I'm glad to share that we are now back on track and believe we can advance the submission for conditional approval in Canada with the new data that we have generated. The third topic is the proof of concept phase II program in Alzheimer's disease.
We have recently completed the database lock of our proof of concept study, which we just announced today, and we anticipate top-line results in the first quarter of 2026. We look forward to assessing the data to better understand if we may be able to address unmet needs in Alzheimer's. And the last topic for today is the partnership discussions. We recognize the importance of providing our investors and supporters with a clear update on where our partnership discussion stands, and we will do so today, respecting, of course, the confidential nature of the discussions. At the end, we will, of course, leave some time for Q&A. Shiran will start with a strategic overview of our pivotal phase III study in ALS, the PARAGON study.
Thank you, Alon. Hello, everyone. My name is Shiran Zimri, and I'm a neurobiologist specializing in the neurodegenerative space. At NeuroSense, I serve as the VP R&D of the company and the country lead for our activities in Canada. Today, I'm delighted to join you and walk you through the latest scientific and clinical development across our programs, including the recent clinical insight, key regulatory processes in the United States and in Canada, and an update from our Alzheimer's disease program. Before we dive in, let me begin with a brief introduction to Prime C, our flagship therapy for ALS. Prime C is a fixed-dose combination assembled of two FDA-approved drugs in a unique extended-release formulation that synchronizes their pharmacokinetic profile. This enables us to have a synergistic targeting to chronic inflammation, iron accumulation, and dysregulation of microRNA.
PrimeC has demonstrated consistent biological activity across preclinical and clinical studies that allows us to PARADIGM a phase II-B study. The PARADIGM study consists of a six-month double-blind period followed by 12 months of open-label extension. As typical to phase II studies, safety and biomarkers were a primary endpoint, with clinical efficacy as secondary. When looking at the overall survival, as you can see here, oh, sorry, when looking at the double-blind stage, we observed early and steady separation between treatment arms, with participants on PrimeC maintaining to be higher and to have better functionality compared to the placebo. And this becomes even more clear when we are analyzing the 18-month data set, where you see that participants who remained on PrimeC demonstrated over a 30% advantage compared to those who began on placebo before switching into the active treatment.
This reflects a clinically meaningful and statistically significant slowing of the functional decline. On the right panel, you can see when we are looking at the survival, we can clearly see a 58% reduction in the risk to death and statistically significant 64% reduction in ALS complication-free survival, which includes death, respiratory function, and ALS-related hospitalization among the participants who started with PrimeC earlier. The PARADIGM study has also a very extensive biomarker program, which accompanies these findings that we just saw in terms of the clinical. This finding demonstrates a clear mechanistic engagement with stabilization of the iron-related mechanism and consistent modulation of the ALS-associated microRNAs, which reinforce PrimeC's multi-target biological activity and support the clinical outcome that was observed. Across functional outcomes, survival signals, and biomarkers, the evidence converged.
PrimeC was shown to be safe, well-tolerated, biologically active, and demonstrated consistent evidence of its potential in clinical benefits. These findings also form the foundation for the PARAGON pivotal phase III study. PARAGON is a multinational randomized double-blind placebo-controlled study with 48 weeks of double-blind phase that is followed by 48 weeks of open-label extension, in which all participants received PrimeC. The trial is designed to enroll approximately 300 participants randomized two-to-one across the United States, Europe, and Israel. The study incorporates the Bayesian adaptive design with up to two interim analyses, and it is powered to over 95% to detect the anticipated treatment effect. The enrollment is expected to begin in the second and third quarter of 2026, with patients anticipated to be out in mid-2027 and less patients out in 2028.
We gained tremendous experience in working with trial sites during the phase II study and plan to continue working with many of the same high-performing sites to meet the timeline and further de-risking our trial. This timeline reflects the global scope of the study and supports the comprehensive evaluation of PrimeC in future regulatory submission. As we move forward from clinical advancement to execution, it is important to highlight that the regulatory processes enable our phase III study to proceed globally. Yeah. All right. Sorry, so I'm glad to share that the FDA has recently formally authorized the initiation of PARAGON, and the operational preparations are now underway. In Canada, we are preparing for our pre-NDS meeting in April 2026, with cross-functional teams aligning PrimeC's submission strategy under the NOC/c pathway.
While ALS remains our primary focus, PrimeC's multi-mechanistic approach also provides a strong rationale for exploring its potential in other neurodegenerative diseases such as Alzheimer's disease. This brings me to talk about our RoAD study for Alzheimer's disease. So RoAD is a proof of concept phase II study that evaluates the potential of PrimeC combination in AD through randomized placebo-controlled design. The study has recently reached database lock, confirming that all clinical data have been collected, cleaned, and finalized. The study has reached sufficient maturity with eight participants enrolled and with a broad and diverse biological data set. We are now able to proceed with the analysis without further extending the enrollment. We are entering a pivotal stage that includes the. Sorry, switched too fast.
We are now entering the pivotal study, which actually includes advancing PrimeC towards the phase III, executing the regulatory strategy, and exploring the potential of PrimeC in Alzheimer's disease. We have a meaningful momentum, and we are extremely excited about what is coming ahead, and now, I will hand it over to Michael to present our partnering opportunities, so Michael, the floor is yours.
Thank you so much, Shiran. I'm fortunate I just have one slide, but let me back up to it. There we go. As Alon mentioned, I am Michael Rabinowitz and have been the Strategic Advisor to NeuroSense for about two years. I am the founder and principal of Entelluvia LLC, a boutique firm advising biotech and med tech CEOs on strategy, business development, and commercialization. I have over 30 years of leadership experience, with about 25 of those for the global pharmaceutical company Merck, leading in areas of marketing, finance, and business development, including negotiating and executing outlicensing, in-licensing, and acquisition deals. Our global business development efforts for PrimeC were quite successful and generated multiple partnership opportunities, culminating in the signing of a binding term sheet with a large pharmaceutical company.
Given that timelines in large pharma processes can naturally extend, we have proactively broadened our engagement with additional potential partners to ensure that NeuroSense maintains strong strategic optionality as we advance toward phase III while continuing constructive, transparent dialogue in good faith with the existing party. There are, of course, no guarantees in business development negotiations. What I can assure you is that we are doing everything possible to maximize the long-term value of PrimeC for the benefit of our shareholders and, most importantly, for people living with ALS, where the unmet need remains profound. I will now turn the call back over to Alon before we begin the Q&A. Alon?
Thank you, Michael. Thank you, Shiran, for those comprehensive updates. We hope that this overview has given you a clear sense of our progress and the opportunities ahead. With that, we would now like to open the floor for your questions. You're welcome to submit your questions.
Okay. Thank you, Alon, Shiran, and Michael for this presentation. The first question comes from Mr. Robert Le Boyer, an analyst from Noble, that asks, "What's the primary endpoint in the trial? Is the measurement acceptable for FDA approval? Is this endpoint acceptable to the FDA?" Shiran, I believe you can address that.
I will gladly take that. Thank you for the question. The primary endpoint of PARAGON is ALSFRS, the functional rating scale adjusted for survival after 12 months of treatment. That's a great question, and we were happy that you are asking that because, as I updated just recently, the FDA accepted our primary endpoint, and this is fully aligned with the regulatory.
Thank you. Another question, Alon, I believe it would be for you. Why do you think PrimeC has strong potential to succeed in phase III?
Thank you, so actually, I'll refer to what Shiran just said regarding the PARADIGM study. First, we build upon the foundations of the PARADIGM study, so PARAGON, our pivotal phase III study, which is the most important trial that we can execute and will do it diligently, is actually similar to PARADIGM, just with an extended period of dosing, and what we did in the inclusion-exclusion criteria is to narrow down the time from disease onset to 18 months from 30 months because we see even more substantial effects in patients in earlier stages in their disease. The study is powered to over 95% power to show the success of PrimeC, and I believe that, again, based on the consistency across all the clinical and biomarker outcomes in the PARADIGM study, we are set for success.
Thank you. And now a natural continuation for this question, the same one for you. Is NeuroSense fully financed for phase III initiation?
We are doing everything we can now in preparations towards making sure that we can finance the study. As Michael mentioned, we are working in multiple directions with regards to partnership. We do believe that this can mature soon. In any case, we are not staying indifferent to other opportunities, and we are looking at potential work with the leading VCs, they showed lots of interest in what we are doing. We maintain all the opportunities open to ensure that we can execute the PARAGON study soon.
Thank you. Michael, we have also a question about the partnership. How are you managing the partnership process to protect shareholders' value?
Thank you, Orazio. That's a good question. You know, we remain proactively managing the process. And I think it's important to remind everyone that we are still in good faith discussions, transparent discussions with the existing counterparty. However, to maintain or to ensure that we have optionality, we broaden those discussions to other parties who have indicated interest, and we're actively engaging with those other parties. So at the end of the day, we maintain all the strategic flexibility that we can to maximize the opportunity for PrimeC.
Thank you, Michael. Shiran, where does PrimeC fit relative to other emerging ALS therapies?
Oh, wow. That's a great question, so ALS, as we know, is a multifactorial complex disease that actually underlies multiple pathways and mechanisms, and this is exactly why we believe that there isn't no silver bullet, and the effective treatment will come from combination therapy, and Prime C does exactly that, so Prime C targets actually key of these pathways in terms of the iron accumulation, the regulation of microRNA, and also the neuroinflammation, which play a critical path actually in the disease pathophysiology and pathophysiology, and this is why we strongly believe that by targeting multiple fronts, we can create a meaningful benefit for the patients.
Thank you, Shiran. Alon, this one is for you. If you can elaborate about the key value inflection points that investors should anticipate soon.
True. Actually, we touched on that during this presentation. I think that the most important one is the phase III study initiation, the PARAGON trial. And we do plan to execute it according to what we just mentioned, according to our timelines. The pre-NDS meeting with Health Canada is obviously of great importance. And there were other topics, such as the Alzheimer's disease, that is, of course, of interest when we'll see the results, the readouts. The partnership is something that we did mention. I think it's, of course, it can create great value, unrelated, of course, to what I just mentioned about the actual execution and moving PrimeC forward with regards to the pivotal study, Health Canada, and on a different front, the Alzheimer's.
Thank you very much. We have some more. Shiran, for you.
Yay.
Can patients continue standard of care, Riluzole, or Radicava in phase III?
Yeah. So the answer is yes, definitely. It is permitted, and it also will be balanced between the arms. And I think it's really important because it's actually reflecting the real-world practice and supporting the patient's community of care. So yes.
Thank you. Alon, with respect to the FDA, what's the current status of the PARAGON trial?
With regards to the FDA, the FDA cleared the PARAGON protocol, gave us a green light to proceed and to start the study. Now what we are doing is actually all the operational work in order to ensure we can enroll the first patient in around mid-year, opening sites and such.
Thank you. Shiran, with respect to Canada, what is the purpose of the pre-NDS meeting with Health Canada?
So it's basically to align on the content strategy of PrimeC, new drug submission, and ensuring basically optimized regulatory pathways and reducing the future review handling. So the short answer is alignment.
Thank you. Alon, will you also pursue accelerated pathways?
Of course, this is an option that we are considering carefully, and we'll see according to the robustness of the data as we progress if this is something that we intend to execute, such as, of course, a breakthrough designation, fast track. I think that everybody knows that we have, of course, orphan drug designation, but accelerated approval with the FDA is definitely something of interest, of high interest, and we will consider it once we agree that the robustness of the data can allow that.
Thank you. We keep getting also a few questions about the partnership. So Michael, what level of inbound partner interest are you seeing? And also, how would phase III success affect partnering strategy? If you can please address these two questions.
Thanks, Ora. You know, consistent when a company hits milestones, you see more confidence as well in interest levels. And clearly, as Alon has laid out and Shiran also expressed, the company has moved meaningfully through phase IIB with excellent results. And that allows them to move forward into phase III to confirm those results. And after the FDA recently cleared the phase III study, you know, we've seen, even though it's been relatively recently, we've seen an increase in interest level. And this is all should be expected because as a company continues to deliver, the interest levels also accelerate consistently with that. And a successful phase III study would certainly increase global interest, but that's not our biggest interest. Our interest is to make sure that in advance of phase III, that we give the greatest optionality to the company.
And so we're pursuing, as we said, continuing discussions with the party that had countersigned the binding term sheet and also, you know, talking to companies that engage with us subsequently, all in good faith and all in transparency, but all to ensure we're maximizing the opportunity for NeuroSense Therapeutics.
Thank you, Michael. A question that comes from Mr. Jim Malloy, analyst from AGP. Could you clarify the start of the phase III trial? Is it Q2, Q3, 2026?
True. So basically, mid-year, it could start in Q2, might start in Q3 as well. We are, according to our assumptions, we do believe it's feasible for Q2, but we don't want to state it, and we can commit for mid-year, basically.
Thank you, Alon. One more question comes from Mr. Boobalan from Roth Capital. What specific new data elements are being included in the Health Canada submission beyond the updated long-term survival database?
I'll take it. So first, thank you, Boobalan. Much appreciated. And yes, you are correct. It's the long-term survival data. This is one piece in it, but there is also an element of biomarkers that we intend to submit, additional new biomarkers that we are going to submit to Health Canada. And by that, we believe that Health Canada will be satisfied and will be able to proceed forward. That's according to our discussions. We think that with the new data, it will be possible.
Thank you. When do you expect to agree on the partnership terms as currently is heavily affecting the shareholders' belief of the company's ability to survive and keep developing? Alon?
Thank you for whoever submitted this question. So with regards to survival, that's, in my view, it's not a question. We have several tools that keep us not just alive, but also move forward and progress. And we do think, again, we have the partnership option. We have other options as well. But we do think that the partnership could mature sometime early or up to mid next year. It might not. Again, we are working on multiple pathways, and survival is not a question. But again, we have the tools, and we are progressing.
Thank you. And another one from Boobalan asks, what effect size assumptions are driving the phase III powering model?
We use the 30% effect size in the ALSFRS, which is relatively conservative according to our findings in the PARADIGM study.
Okay. Thank you. Shiran, I think this one goes to you. How does the adaptive design impact timelines?
So basically, it can shorten the involvement if strong safety appears, futility boundaries to avoid unnecessary continuation. The adaptive design is basically accelerating the efficacy without compromising rigor.
Thank you, and a follow-up question. How will you manage variability across global sites?
So that's a really good question. And we definitely did a lot of work, you know, learning from the field, from previous studies that were conducted by other companies, and consolidated all of these conclusions into our study design for PARAGON. And this is why we are aiming for reducing the number of sites and having many patients in the sites and actually balancing and reducing the variability between the sites and also the number of separation that we have.
Thank you.
Oh, I see. Sorry to interrupt you, but I do see more questions regarding financing. I want to remind everyone here in the call that in the last three financing that we did, we did it with premium, taking lots of care about our shareholders and stakeholders in order to ensure that we create the maximum value for them. And I do hope and believe that we will be able to maintain and create more value throughout the way. So that's something else that I wanted to emphasize given the multiple questions regarding financing.
That's a very important one. Thank you. Michael, is the primary partner's timeline extend further? If and how are you protected?
Like I said, you can only control what you can control. What we've done is we've engaged with other parties in order to protect NeuroSense and to ensure we maximize the opportunity. We've done all in good faith, transparency, and good discussions with all involved. Recently, some of the positive news has increased even the inbound engagement that we've had. We continue on the path of continuing discussions with our original potential partner and at the same time, broaden the scope so that we are talking with multiple companies and ensuring that whatever environmental or other factors occur, we will have the optionality for NeuroSense to make the right decision for PrimeC.
Thank you. Thank you, Michael. Shiran, I'm combining here two questions for you. Why do biomarker results matter so much? And will we incorporate biomarkers into phase III?
Wow. So definitely the person to ask. So I'm a huge fan of biomarkers because basically, I think that's the best way that you can actually demonstrate the biological activity of the drug and its actual target engagement. So here in the PARADIGM study, for example, we were actually able to demonstrate the biological activity that we are seeing in the microRNA and also in iron. And not only that, that just as an example, when we looked on the effect on the iron homeostasis, we actually also saw a clear correlation to the clinical function to the ALSFRS. So you can see clearly that the functional and the biomarkers actually go hand in hand.
To the question if we are taking that to PARAGON, so of course, yes, we truly believe that by looking on biomarkers such as our target engagement, such as neurofilaments, that's definitely enhancing the clinical credibility and also the regulatory confidence that we have in the study.
Thank you, and one more. I participated in another ALS trial. Can I join PARAGON?
Okay. So generally, yes. It's depending on the washout and also obviously meeting the eligibility criteria. The final decision is always the study PI at the site who is taking basically the decision if they enroll a person into the study.
Thank you. Alon, when would you anticipate top-line data for PARADIGM? Should it start in mid-2026? And whether any interim looks expected?
So officially, we can expect top-line data from the PARADIGM study in 2028. Although, as mentioned, we have an adaptive design with the interim analysis. So if we have an interesting or very substantial finding in this interim analysis, it can come much earlier. So this is also something that, of course, we consider during the study, not just to have the option to compensate if one of the assumptions wasn't correct, but also to have the option to conclude the study early for futility or for success, for substantial efficacy. So this could be very exciting if we get there to this point. And I think that with that, I would like to thank those who submitted the questions. And thank you, Shiran and Michael, for the clear and thoughtful answers. And I would like to summarize this webinar.
As we look forward or we look ahead to 2026, our mission remains unchanged: to execute with discipline, advance our programs with scientific and regulatory rigor, and to create meaningful value for our shareholders. We have achieved a great deal to date, and we have the plans and team in place to deliver on the important milestones ahead of us. As always, this is not just our work, but also our collaborators, the LS community, clinicians, LS families, and many others, many other stakeholders and shareholders that support us, like you, believe in us, believe in the cause, believe in the science, in our achievements, and are counting on us. And we are fully committed to make you proud. Our success is your success. And I appreciate your continued support and engagement. And of course, I look forward to updating you as we further advance. Thank you very much, all.
Thank you.
Thank you.