Vivoryon Therapeutics N.V. (VVY) Earnings Call Transcript & Summary

Thank you for joining us. My name is [ Leon Wang ], I'm a VP here covering SMid-Cap Biotech, and it's my pleasure to present Vivoryon -- Ulrich Dauer, the CEO. Ulrich, I'll pass it over to you.

Yes. Thank you very much for the kind introduction, and also thank you for making us part of the exciting program of Barclays Global Healthcare Conference. When I joined Vivoryon back in 2018, so 5 years ago, the perception towards the field of Alzheimer's disease was mainly dominated by a series of expensive late stage failures in clinical trials and lack of new approvals for almost 2 decades. Fortunately, this situation has changed with Abeta antibodies like lecanemab and donanemab, which are increasing the excitement in all the field, industry attention, and they are increasing the hope by patients for novel treatments that can make a true difference to them. I'm very pleased to have the opportunity today to explain why your attention should not only be centered around big Pharma's Abeta antibodies. By introducing Vivoryon, I want to show you why a small company like Vivoryon in particular, our differentiated small molecule-based approach, can shape the landscape of Alzheimer's treatments going forward. Just for completeness, our legal disclaimer. Now this is who we are and what we do. We are a small biotech company with 2 sites in Germany in Munich and Halle. And we are developing small molecule-based medicines. And we do that to block the misguided activity of certain enzymes that cause diseases or let them progress. And we have been very successful in leveraging this approach in Alzheimer's disease with our small molecule inhibitor varoglutamstat, which is currently subject of 2 Phase IIb trials in Europe and in the U.S., respectively. And varoglutamstat is representing a highly differentiated approach to the treatment of this devastating disease for a number of reasons. It's a small molecule, which is orally available and has already shown its clinical potential to be able to improve important disease parameters like working memory, which is an important cognitive ability, which is eventually heavily weakened in patients. Varoglutamstat is intervening upstream and through a dual mode of action, it's able to modulate all 3 important pathological hallmarks of the disease. And we have strong evidence supporting that we have a very favorable safety profile without any signs of ARIA, which is a limiting class-side effect of Abeta antibodies, which is essentially brain bleeding and brain swelling. Our shares are listed at the Euronext in Amsterdam and our operations are based on a strong balance sheet and on a strong corporate position. Despite a difficult financial year, we have been able to raise EUR 51 million last year where we brought in additional strategic investors like KKR. Our programs are protected by a strong IP estate providing us exclusivity beyond 2035. Now I don't need to convince anybody a few about the tremendous medical need in Alzheimer's disease. So 30 million people are affected worldwide, and this number is expected to double by 2015, driven by demographic changes in major territories. And recent advances with Abeta antibodies like lecanemab, which has recently been granted accelerated approval, and donanemab show promise. However, they come with substantial limitations. And I've already mentioned this ARIA class side effects, which needs to be closely monitored to patients getting this treatment have to be very closely monitored, especially in the first weeks of treatment. And this is something which can be done in any doctor's practice down the road but requires a specialized infrastructure. And specific infrastructure is only required to mitigate the risk of ARIA, but it's also important for the administration of the truck because Abeta antibodies obviously are infusion-based treatment, so they require the hospital setting for the administration. Now we are addressing these challenges with our small molecule-based approach with varoglutamstat that can conveniently be administered as an oracle at home -- and again, we have strong evidence supporting that it does not come with an increased risk of ARIA. Grounded in the discovery that the enzyme glutaminyl cyclase or QPCT is catalyzing the formation of a neurotoxic Abeta variant, N3pE-Abeta, we are pioneering small molecule-based approaches to block this pathological pathway. Now how does varoglutamstat work? And how is it differentiated especially from Abeta antibody approaches? We are targeting an enzyme glutaminyl cyclase or QPCT, which is overexpressed in the brains of patients and which is clearly associated with Alzheimer's pathology. So QPCT catalyzes the formation of the neurotoxic Abeta variant, N3pE, and N3pE correlates with the expression levels of the target enzyme QPCT, and is only present in the disease situation, not in healthy individuals. N3pE is present in all aggregation states of Abeta from monomeric forms into -- up to senile plaques and anything in between. So by inhibiting this target, we are addressing all aggregation states of Abeta. And there's a second element to the mode of action where the isoform of glutaminyl cyclase comes into play, QPCTL, which is stabilizing the pro-inflammatory cytokine or chemokine rather CCL2. So by inhibiting this enzyme, we have a direct anti-inflammatory effect. And moreover, CCL2 as well as N3pE are promoters of the downstream pathology. So by exiting this pair of enzyme, we are able to modulate all 3 important pathological hallmarks in Alzheimer's disease, which is the Abeta pathology, neuro inflammation and how pathology and thus protect synaptic function of patients. Now as can be seen in this cartoon on the right-hand side, varoglutamstat is acting very upstream. So we are preventing the formation of neurotoxic N3pE Abeta rather than taking it out of the system once it's established. And we were also interested in seeing whether we could leverage this mode of action in a combination setting. And to this end, we have done preclinical experiments where we combine varoglutamstat with the series of Abeta antibodies, and we have seen additive effects or in other words, we were able to substantially reduce the dose of antibodies and still preserving their activity. So this could be a mean to manage the class side effect, the ARIA side effect, which is clearly dose-dependent effect. However, at the first place, we are developing varoglutamstat as a monotherapy, and this shows our development strategy, starting with preclinical models where we have shown the target engagement in animals led to attenuation of N3pE production and attenuation of neuroinflammation, ultimately leading to significant improvement of cognitive parameters in animals. In a Phase I in over 200 elderly healthy volunteers, not only look on safety and tolerability, but we also got important information about the ratio between different doses and target engagement or target occupancy. We completed a first inpatient trial, a Phase IIa trial in 120 patients, 3 months trial. And this trial showed that varoglutamstat was able to improve a variety of important disease parameters and most importantly, working memory as an important positive domain, and that after only 3 months of treatment, which is a very short time in the development of Alzheimer's disease pathology. As we speak, we are running 2 Phase IIb trials. Our VIVIAD trial in Europe and VIVA-MIND trial in the U.S. in accordance to the draft guideline by the FDA for accelerated approval. We have received Fast Track designation in 2021. And that allows us to closely communicate with the authority and make sure that we are taking the most important regulatory boxes in our development strategy. Now this is what we do in our European VIVIAD trials in our European Phase IIb trial, a trial, which is currently fully enrolled with 259 patients. We are focusing on patients with mild cognitive impairment and mild Alzheimer's disease. And in the first 12 weeks of the treatment, we carefully uptitrated the dose, and then we randomized 1:1:1 placebo, and 2 dose groups 300 milligrams and 600 milligrams. After 24 weeks of treatment of the 91st patient, we asked an independent data safety monitoring board to give us a recommendation on the most appropriate final dose for this trial. They only look on safety signals, and they came up with a recommendation for the higher dose of 600 milligrams, which for us was the best possible outcome. And now we are completing this trial with a 1:1 randomization pattern, placebo and 600 milligram. We will end up with different treatment times, and this is because the first patient remains on treatment until the last patient has completed 48 weeks of treatment, with a maximum treatment time of 96 weeks. We expect an average treatment duration of 82 weeks. The primary endpoint of this trial is a composite of 2 cognitive domains, which is working memory and attention, those parameters with the most pronounced changes in our prior Phase IIa trial. So it's a truly informed trial. Of course, we are looking on all sorts of secondary readouts like EEG signals, the complete neuropsychological test battery activity of daily living, and we are looking into exploratory efficacy endpoints in the CSF, but also on the cognitive level. The [ true data ] office trial we expect in the first quarter of next year. Now where do we stand with respect to majority of the trial and the safety update? Again, as mentioned, the trial is fully enrolled with 259 patients, 14 patients already completed the trial with 96 weeks of treatment. We have seen now 19 discontinuations, but only 5% due to adverse events. I will talk about the treatment emerging adverse events in a minute. We have seen 0 deaths in this trial, 3.7% serious adverse events, 2% severe adverse events, 17% related adverse events and 0 ARIAs. Now in terms of treatment emergent adverse events. Except from COVID-19 infections where we had approximately 18%, but we lost no patient due to COVID-infections. They are mainly related to gastrointestinal disorders as can be seen in the bar graph of the right-hand side of the slide in purple. Now this is what we do in our U.S. trial, the VIVA-MIND trial, and this trial is being supported by an NIH grant of USD 15 million. So we are conducting this trial together with the Alzheimer's Disease Cooperative Study out of San Diego and led by Howard Feldman, and we feel really privileged to be able to work with such an outstanding team and such an outstanding organization in our first trial in the U.S. Now also here, we start with an adaptive dose-finding part of the trial where we even consider a lower dose, 150-milligram dose, 300 milligram dose, 600 milligram dose. We are focusing on the same patients, patients with mild cognitive impairment and mild Alzheimer's disease. Now the first place, the goal is to enroll 180 patients and treat them for 72 weeks. The primary endpoint is going to be the established and approval endpoint CDR sum of box score. Now what is special about this trial is that we built an optionality to really be able to upgrade this product into a full-blown Phase III trial should have been necessary, and we will take this decision based on the data from the European CDR trial. Also here, we look into all sorts of secondary endpoints and exploratory efficacy signals. Now we are focusing on Alzheimer's disease mainly, but we are also leveraging our approach in other important diseases like immuno-oncology, inflammatory and fibrotic indications. And this is the resulting pipeline. So the most advanced program, our European VIVA trial, again, which will read out full data presumably in the first quarter of next year. The second program before [indiscernible] start our U.S. trial, the VIVA-MIND trial. And we have the third clinical activity with varoglutamstat in China, where our partner Simcere has taken all responsibility to progress development of varoglutamstat in China. And here, we also get already regulatory clearance by the Chinese authority for the start of clinical trials. Although we are focusing on small molecule approaches, we do have an antibody in development, PBD-C06, which is working in a similar way like lecanemab, so it's binding to N3pE amyloid or N3pE Abeta. However, it's optimized with respect to the reduced immunogenicity potential and a reduced potential for ARIA side effects. And as mentioned before, we also leveraging our approaches, our technology, our know-how in other indications like in oncology, inflammation and fibrosis. Now this is the team that is making that happen, and all of us have more than 20 years of experience in growing value in the biotech industry. And with this slide, I want to reiterate that we are very well positioned for continued value generation. I've explained to you the unique and differentiated positioning of our small molecule approach, especially with respect to the fact that it's a small molecule, which is orally available, can be conveniently taken at home, it's intervening upstream and through its dual mode of action, is able to address all 3 important pathological hallmark of the disease. And very importantly, we have very strong and supporting evidence that we will have a very favorable safety profile without any signals of ARIA, which is bleeding and swelling of the brain. And with our approaches, we truly believe that we will be able to shape the future landscape of Alzheimer's disease treatments. And that concludes my presentation. Thank you for listening, and I'm prepared to take questions from the audience. Thanks.

Great. Thank you, and thanks for coming by. I really appreciate the presentation.

Thanks very much.