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spk02: Third quarter 2023 conference call. An audio recording of the webcast will be available shortly after the call today on Diametica's website at www.diametica.com in the investor relations section. Before the company proceeds with its remarks, please note that the company will be making forward-looking statements on today's call. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these statements. More information, including factors that could cause actual results to differ from projected results, appears in the section entitled Cautionary Statement Note regarding forward-looking statements in the company's press release issued yesterday. and under the heading Risk Factors in Diomedica's most recent annual report on Form 10-K and current year quarterly reports on Form 10-Q. Diomedica's SEC filings are available at www.sec.gov. and on its website. Please also note that any comments made on today's call speak only as of today, November 14th, 2023, and may no longer be accurate at the time of any replay or transcript rereading. Diomedica disclaims any duty to update its forward-looking statements. Following the prepared remarks, we will open the phone lines for questions. I would now like to introduce your host for today's call, Mr. Rick Pauls, Diomedica's President and Chief Executive Officer. Mr. Pauls, you may begin, sir.
spk04: Thank you, Paul. Hello, everyone, and welcome to our third quarter conference call. I am joined this morning by Scott Kellan, our Chief Financial Officer. Before we begin this morning, I want to take a moment to welcome Dr. Ambar Shah as our Chief Technology Officer. Dr. Shah has over 25 years of experience in advancing biopharmaceuticals from early stage to commercialization, where he has had key contributions to over 50 drugs and multiple successful drug approvals. He was previously the Vice President and Head of Global Vaccine Development at CSL Securus, where he was accountable for end-to-end chemistry, manufacturing, and control in the development of vaccines. Prior to that position, he was Executive Director, Head of Drug Product Development at Bristol Myers Squibb's, formerly Celgene. His prior experience comprised increasingly impactful roles at AstraZeneca, formerly MedImmune, GlaxoSmithKline, formerly Human Genome Science, and Pfizer, formerly Wyeth. Ambrose consulted with us for five months before joining us in a permanent role. We are thrilled to have Ambrose as part of our team. Turning to our phase two updates, as we've discussed, our clinical operations have been working tirelessly to assemble the team, update procedures, and prepare the tools to properly support the physician investigators and the clinical study sites. During this time, we have also been speaking with study sites, key opinion leaders, industry experts, our scientific advisory board, and our new interim chief medical officer, Dr. Jordan Dubois, to ensure that the Remedy2 protocol is as clear and executable as possible by study sites while generating the data required for the FDA and other regulatory bodies. More than that, we want to give DM-19 the greatest possible probability of clinical success. We will focus today on discussing these protocol amendments. In addition to issuing our quarterly earnings press release yesterday, we provided a slide deck presenting more detailed information. This information is available on both the Diomedica website at www.diomedica.com and the SEC's website, www.sec.gov. The amendment protocols were submitted to the FDA in early October, and the FDA did not have any comments as of the end of the 30-day review period, which expired on November 3rd. Given this, we are able to and are moving forward in conducting Remedy 2 with this amended protocol. In its totality, we believe the amended protocol significantly increases our probability of achieving clinical success and will accelerate site activation. Furthermore, if we increase the performance improvement of DM-109 versus placebo at the interim analysis, we can reduce the total required number of patients for the trial, which is our quickest and most cost-effective path to completing the trial and getting our drug to stroke patients. The most significant change in the protocol centered around the inclusion and exclusion criteria for the trial. Specifically, we modified the baseline National Institute of Health Stroke Scale, or NIHSS, inclusion score to focus on ischemic strokes of moderate severity. This is defined as patients presenting with a baseline NIHS score of 5 to 15. We conducted a post hoc review of a Remedy 1 Phase 2 stroke trial focusing on those participants that did not receive mechanical thrombectomy prior to enrollment in a Remedy 1 trial. This is a subset of that trial that most closely aligns with the target patient population for the Remedy 2 trial. In these patients, there was a 15% greater absolute improvement in participants reaching an excellent outcome, defined as a score of 0 to 1 on the Modified Rankin Scale, or MRS. This group comprised of 45 participants, 25 active, and 21 placebo. These participants were enrolled based upon a baseline NIHSS score of 6 to 24. Scores above 15 represent moderate to severe and severe strokes. When we look at the results from just a moderate severity strokes in this trial, those in the NIHS scores of 6 to 15, which includes 34 participants, 19 on DM-19 and 15 on placebo, the improvement in excellent outcomes increased to 18%. And if we go one step further and look at just the strokes with the baseline NIHS score of 6 to 10, the improvement in excellent outcomes is even higher, where we had 35%, based on 26 participants, of which 14 were on DM-19 and 12 placebo. Let me add the caveat here and recognize that this post-hoc analysis includes a small number of patients, but it is key to point out there were no study participants in the non-mechanical thrombectomy subgroup with a baseline score of 15 that achieved an excellent outcome, an MRS of 0 to 1. It is a high clinical bar to take a patient with a baseline NIHSS score above 15, a moderately severe stroke, and expect many to get to an MRS score of 0 to 1. It is important to note the average NIHSS baseline In most Calicang studies, this is the human urinary form of KLK1 in China, ranged from 8 to 8.5. In contrast, Remedy 1 was 10.9. By targeting moderate strokes, we anticipate aligning more closely with the Calicang range. Just to tie things out, we're also including stroke patients having a baseline NIHS score of 5, which represents approximately 20% of all moderate strokes. As mentioned, we saw the highest treatment effect in the NIH scores of 6 to 10, and by including NIH scores of 5, we hope to capture more of these patients. Our new range of 5 to 15 also fully aligns with the official NIH assess definition of moderate ischemic strokes. The net effect of the change in the NIH inclusion range does reduce the number of potentially eligible patients in the Remedy 2 trial. However, we believe that by focusing on moderate strokes, we have the highest probability of clinical success and generating the largest possible improvement relative to placebo, the latter being important for both reducing the number of participants we need in the trial and generating greater statistical significance, and perhaps equally as important, eventually driving commercial adoption and favorable pricing assumptions after the FDA marketing approval. The second change we want to discuss is the exclusion of ischemic strokes occurring in the posterior circulation of the brain or PC strokes. These can be problematic strokes for clinical trials. The NIH stroke scale predominantly evaluates neurological deficits created by strokes occurring in the anterior or front circulation of the brain. As a result, PC strokes are often underscored by the NIH stroke scale. Our chief business officer, Dave Wombeck, was recently on a business development trip in China where he was able to capture greater perspective on the clinical use of Kalkang, the human urinary-derived form of KLK1. In his various discussions, it became clear that PC strokes were excluded from the primary Kalkang studies due to the issues with the NIH stroke scale properly evaluating these patients. Obviously, this issue has the potential to create uncontrollable variability in a clinical trial, which we prefer not to introduce in Remedy 2. Here again, this may also reduce the number of eligible patients for the trial, but we expect the impact to be minimal. Only 20% of all strokes originate in the posterior circulation, and approximately 70% of those have an NIHS score less than 5. meaning the vast majority of this already small pool of patients would not meet the bottom end of our baseline inclusion criteria. The last change I want to address is the one that has the least potential to affect the overall timing of the trial, but is more technical. It is our removal of the overwhelming efficacy assessment during the interim analysis. An interim assessment of efficacy comes with a penalty in the statistical analysis of the overall trial. This penalty is significantly larger than the penalty for re-estimating sample size. By removing this penalty, we believe we further increase the probability of study success. Additionally, from a practical perspective, our projected future enrollment rates suggest little benefit in conducting an interim analysis. It is key to remember that we will not stop enrolling patients once the 144th patient is recruited. During the period encompassing the enrollment of the 144th patient through their 90-day follow-up and subsequent data analysis of the interim analysis, we anticipate enrollment nearing 240 patients. This 240 number represents the lower threshold of our re-estimated sample size range. Should our interim results demonstrate overwhelming efficacy strong enough to warrant halting the study, we would likely already be at or very near that point. It is key to point out that we will not stop enrolling patients once the 144th patient is recruited. With a now effective amended protocol that we believe gives us the highest probability of clinical success, our focus is solely on site activation and patient recruitment. Our team is energized and working closely with our global CROs. We have reached out to over 600 sites in 23 countries, and we are conducting extensive feasibility and site selection and narrowing down to what we believe will be the best sites for our trial, with a target still of up to 100 sites globally. Our protocol is also currently in review by the Canadian and Australian stroke consortiums. The first three sites of our trial are on track to be reactivated in November and December, then 20 fast track sites to follow in the US. We are working with our CRO and Scientific Advisory Board in the selection process. The majority of US sites should be activated in the first half of 2024. We'll provide more information on the timing of sites at our next conference call. Also, as we discussed in our last earnings call, based upon enrollment rates in recent stroke trials and discussions with multiple CROs, we believe that full enrollment for the interim analysis can be completed in 2024. But ultimately, this will depend upon the actual enrollment rates. Before handing it over to Scott, I'd like to emphasize we have received significant interest from key opinion leaders and investigators. DM-109 is designed to enhance collateral circulation, a method we consider superior to neuroprotectants and more like other established revascularization treatments like TPA and mechanical thrombectomy. They are also attracted to DM-109's potential safety profile, particularly its lack of increased bleeding. Additionally, we believe that the revised trial design with a higher potential to demonstrate an improvement in excellent outcomes also contributes to this interest. We believe that we are at a pivotal moment in the treatment of ischemic stroke, now at over a quarter century since the approval of TPA for stroke. Our strategy represents a potential landmark advancement in stroke treatment since then. I'd like to now turn the call to Scott Kellan to review this quarter's financial results.
spk05: Thanks, Rick, and good morning, everyone, and thanks for being part of today's call. Our total cash equivalents and investments were $56.2 million at the end of Q3, up from $33.5 million as of December 31, 2022. This increase was due primarily to the $33.8 million of net proceeds from our June and April private placements conducted earlier this year. partially offset by cash used to fund operating activities during the nine months ended September 30, 2023. Net cash used in operating activities for the nine months ended September 30, 2023 was 14.9 million compared to 8.7 million in the prior year period. The increase in cash usage relates primarily to increased net loss in the current year period over the prior year period and increased amortization of discounts on marketable securities. partially offset by non-cash share-based compensation and the effects of changes in operating assets and liabilities in the current year period. We believe that our current capital will support the clinical development of DM-199 and our operations into 2026. Our research and development expenses increased to $3.3 million for the three months ended September 30, 2023. up from $1.6 million for the three months ended September 30, 2022. R&D expenses increased to $9.4 million for the nine months ended September 30, 2023, up from $5.6 million for the nine months ended September 30, 2022. The increase for the nine-month comparison was driven primarily by costs incurred for the in-use studies performed to address the recently lifted clinical hold on the company's Remedy2 AIS trial, Costs incurred for the Phase 1c study determining the DM-199 blood concentration levels achieved with the IV dose of DM-199 using PVC IV bags and increased manufacturing and process development costs. Also contributing to the increase were higher personnel costs associated with expanding the clinical team. These increases were partially offset by decreased costs incurred for the Phase 2-3 Remedy 2 AIS trial as activity was limited prior to the June 2023 lift of the clinical hold. Our general and administrative expenses were $1.9 million for the three months ended September 30, 2023, up from $1.5 million for the three months ended September 30, 2022. G&A expenses were $6 million for the nine months ended September 30, 2023, up from $4.5 million for the nine months ended September 30, 2022. The increase for the nine-month comparison was primarily due to increased legal fees incurred in connection with our lawsuit against PRA Netherlands and increased personnel costs incurred in conjunction with expanding the team. Higher costs for patent prosecution and non-cash share-based compensation also contributed to the increase. Before I turn you over to Rick, let me share that the hearing for the PRA lawsuit is currently still on track for December 7th of this year. PRA recently filed a counterclaim alleging that our enforcement of the April 2023 judgment affirming our ownership of all study records violated Dutch procedural laws. We disagree with their counterclaim and we don't currently anticipate that this will change the December 7th hearing date. We very much look forward to presenting our case against PRA. Now let me turn you back over to Rick.
spk04: Thanks, Scott. With that, we would like to open the call for questions. Operator, if you could please open the lines for questions.
spk02: If you would like to ask a question, please press star 1 on your touchstone keypad now. You'll be placed into the queue in the order received. Please be prepared to ask your question when prompted. Once again, if you have a question,
spk01: please press star 1 on your touchstone keypad now. And our first question comes from Thomas Flatton of Lake Street Capital.
spk02: Your line is open.
spk07: Good morning. Just a couple quick questions, Rick. If you think about the total patients as a funnel, so you're excluding patients Mechanical thrombectomy, TPA, so conservatively we call that 20% of patients. Then you're removing about 20% of patients for the posterior circulation. Can you just walk us through how you see that all working, especially if you include the NIH SS score as well?
spk04: Yeah, thanks, Thomas. So as we see this, the bigger picture here is what's most important for us is getting to the we think the greatest clinical effect with this drug. And so we think commercially, the larger delta we see, so improvement of DM-19 versus placebo, we think the greater commercial value. And so as we're initially going to be targeting here, so we anticipate the initial label will be in the moderate severity stroke patients, which would be in kind of that 35 to 40% of all strokes. And then commercially, though, as we talk to neurologists and commercial people, We think that if a patient has a mild or a moderate to severe or severe stroke, that they'll most likely be getting our treatment.
spk07: Got it. And then to get to the 144 patient enrollment by year end, how many sites do you need to have actively enrolling at your pacing to get to that number?
spk04: Yeah, so right now, you know, we're looking at, you know, and we're talking about up to 100 sites. really focusing on those first 75. So what we're looking at right now is about 40 in the U.S., potentially 10 in Australia, 10 in Canada, and then the remaining in Europe and other parts of the world. So looking at the enrollment rate, that's the first assumption. And then the second assumption is the patient enrollment by month. So right now what we're using is an enrollment rate target of 0.25. So having one patient per site every four months. And so this is based upon some of the analysis of some historical stroke trials. We've recently gone back and did an analysis of the last 20 or so stroke trials for acute eczemic stroke. Many of those were mechanical thrombectomy that had a smaller treatment window and targeting a smaller patient population. And on average, there was an enrollment rate of 0.5 So about twice in terms of the rate that we're targeting. But there's still a lot of variables here that we just don't know. So even with these changes that we've made, we're still using the assumption of the 0.25 enrollment rate. And, you know, getting into the new year as we start to get some traction here and we start getting the first sites up, we'll have better clarity of where that actual enrollment rate comes in at.
spk07: Got it. And then one final one, if I might. Any reason that we shouldn't see the interim analysis read out in the second quarter of 25? if everything goes to plan?
spk04: Right now, that's the plan. And again, there's lots of variables. But I'm hoping here, I'm hoping that this enrollment rate is conservative. In the past, we had some challenges with COVID. Also, part of these protocol changes, there were some aspects in there that weren't quite clear. So with our new interim chief medical officer, in particular, helping us with just revising and just making the trial protocol more clear. And I think that's going to help with recruitment.
spk07: Excellent. Appreciate you taking the questions. Thank you.
spk01: Thanks, Thomas. Our next question comes from Alex Nowak from Craig Hallam. Your line is open.
spk08: All right, great. Good morning, everyone. So the prior protocol made DM-189 available only when mechanical thrombectomy wasn't given. Now it's based more on the interior circulation, but is the goal still the same to reduce the mechanical thrombectomy to patients? Is that correct?
spk04: So the plan still is to be excluding patients that were previously treated with mechanical thrombectomy and to exclude those patients that have a large vessel occlusion. And we believe that's about 20% of the strokes today that have a large vessel occlusion.
spk06: And then the anterior circulation is being added on top of that. Yeah, Alex. Hey, this is Scott.
spk05: As we were laying out in the remarks, the NIHS score doesn't evaluate the posterior circulation strokes very well. And so the potential for getting miss-scored patients into the trial, scored low or high, creates variability that we just don't want to introduce. And keep in mind that of those 20% that are PCS strokes, 70% generally present with an NAHS score of four or less. So the effect on the addressable patient population for Remedy 2 is very minimal.
spk08: Okay, got it. And then the assessment of the anterior versus posterior circulation, how quickly can that be performed in the center? Is that just a real-time assessment? And then how many in Remedy 1 were anterior?
spk04: Yes, it's something that's a quick review by a neurologist. We don't have the data in front of us from a remedy one, but we can double check on that.
spk08: Okay, understood. And then I just want to confirm, so what will be reported now during the interim analysis? I understand you don't want to get hit with a penalty, but I just want to be clear on what we're going to see when that interim analysis hits.
spk04: Sure. So the interim analysis, if we're seeing a lack of efficacy, the study will be terminated. for lack of efficacy. Otherwise, there'll be a resampling size between 240 and 728 patients. So the only thing that's changed here is that we removed the option for stopping for overwhelming efficacy.
spk08: Got it. So there won't be any unblinding of the data. We won't necessarily see excellent outcomes in the interim piece. We'll just either know it's either going to be stopped for lack of efficacy or study size needs to be modified.
spk04: Yes, that's right. And basically what drove this change here as we're going through our forecasting and realizing that even if we achieve overwhelming efficacy at the interim analysis during that five-month period from when patient 144 is dosed and the interim analysis is conducted, we should be pretty close to that 240 patient anyways, in particular with now expanding with our trial side of the U.S., So we felt that there's no sense of taking that statistical penalty if effectively we're going to be there anyways at that point in time.
spk08: Yeah, makes total sense. And then all these recommendations to the study change, did they come internal? Did they come by KOLs out in the field or were they from the CRO?
spk04: So really good question. So it came really a combination. I mean, first off, Dave Wombeck, our chief business officer, was in China for a week in August. And speaking to, you know, the company that's currently marketing the Calicang, the urine form of KOK1, speaking to several other pharmaceutical firms and related. And based upon that, he got some pretty clear feedback on some of these changes we've made, like this posterior strokes. We'd be better targeting the moderates patients. So really leveraging the feedback really in China in terms of what patients that we believe will be better responders And then also having Jordan Dubar, our interim chief medical officer joining, taking another close looking at the protocol, getting some additional feedback here from the initial sites that we reached out to. So after coming off clinical hold, we reached out to numerous sites and there was a number of feedbacks to the protocol that could be done just to simplify it and reducing some of the steps that were perceived as complicated. And the point here right now, it's very important here that we make this protocol as simple as possible for the sites so that they don't look at this protocol and feel that it was overcomplicated. So although this is taking a small delay here, I'd call it, but really very minor in terms of the big picture. So we see this as that if we can increase the efficacy at the interim analysis by a few percentage, then the previous protocol you know, that could really make the difference in not having to go to a larger total sample size. So ultimately, we feel this should reduce the total number of patients, the time, and the cost for the trial.
spk08: All right.
spk06: That makes sense. Appreciate the update. Thank you. Yep. Thanks, Alex.
spk01: We have a question from Francois Griswold of Oppenheimer. Your line is open.
spk03: All right, thanks for taking questions. So just a couple here. In terms of the moderate severity, can you help us understand, you know, I guess you talked about the prevalence, but mechanistically, is there rationale for this to make more sense here? And how do we, you know, how do we get to feel comfortable that this won't, you know, having patients that are only moderately severe, is it easy to gauge who's moderate and how do we feel comfortable that that won't make enrollment quite a bit harder? Thank you.
spk04: Yeah, so thanks, Frank. So the premise here is if you take a stroke patient that's come in, and so first off, it's very clear. So the severity is scored by the NIHSS. So if the score is 5 to 15, that is a clear moderate severity stroke patient. And so when we take a step back and we look at this, if a patient has a moderate to severe, so above 15, the likelihood of that patient getting to a full recovery, an excellent outcome, is not very high. And so as we take a step back and we look at this, and as I mentioned on the prepared remarks from our Phase 2 trial, we didn't have a single patient on DM-109 who came in with a baseline above 15 that got to an excellent outcome. So I think what this does is just biases the opportunity here for a higher effect. And as we're looking at our Phase 2 data further, it's really in those patients that are, you know, frankly, that were in the six to the 10 that we saw the greatest impact in getting to a full recovery compared to placebo. So we think these changes, you know, will ultimately show a greater effect. And then furthermore, when we take a looking at the clinical use of the Kalkang in China, most of those trials are targeting a less severe, so targeting more of a moderate severity stroke scale.
spk03: Okay, thanks. And then lastly, can you help us understand the potential outcomes of this lawsuit that's coming up here? Thank you.
spk05: Oh, sure, Frank. Hopefully the outcome is that we get access to our data, we get access to the study site, we're able to finally audit that study and confirm what the actual results were. I mean, first and foremost, you know, we really, really would like to get a final study report that's accurate and fileable. Beyond that, we're going to ask, we're asking for damages. You know, that last proof of concept study that we believe was messed up, you know, would cost six or seven million dollars to re-perform today. So, we're asking for that. We're asking for a some damages related to a license, an opportunity that Diametica had at the time that was basically undermined by the errant reporting from PRA. And we're taking a chance on lost value of the company as well. So all in, we're asking for as much as $75 million in damages, and we'll see how much we can get through the court's process again. provided that they reaffirm their judgment from April that Diametica is the owner and that PRA has breached the agreement. Does that answer your question, Frank?
spk06: Yep, okay, thank you. All right, thanks, Frank.
spk01: And seeing no further questions, I'll turn the call back over to our host.
spk04: All right, thanks, Paul. So the refinements that we discussed today in the inclusion criteria and are intended to enhance Remedy2's probability of success on the primary endpoint, which also has the potential to reduce the total number of participants required to be enrolled in Remedy2 trial without significantly impacting the estimated enrollment rates. We'd like to thank everyone for joining us this morning and for your continued support. We are thrilled to be re-engaged with clinical study sites and hope to be enrolling participants soon. This concludes our call.
spk02: The meeting has now concluded.
spk01: Thank you for joining and have a pleasant day.
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