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spk11: Greetings, ladies and gentlemen, and welcome to the Brainstorm Cell Therapeutics Second Quarter 2022 Conference Call. At this time, participants are in a listen-only mode. As a reminder, this call is being recorded. And I would now like to introduce your host for today's conference, Mr. Tom Galassi of LifeSciAdvisors. Mr. Galassi, you may begin.
spk14: Good morning, and thank you for joining us. Before we begin the opening remarks, we would like to remind listeners that this conference call contains numerous statements, descriptions, forecasts, and projections regarding Brainstorm Cell Therapeutics and its potential future business operations performance, statements regarding the market potential for the treatment of neurodegenerative disorders such as ALS and MS, the sufficiency of the company's existing capital resources for continuing operations in 2022 and beyond, the safety and clinical effectiveness of the Neurone Technology Platform, clinical trials of neuron, and related clinical development programs, and the company's ability to develop strategic collaborations and partnerships to support their business planning efforts. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond Brainstorm's control, including the risks and uncertainties described from time to time in its SEC filing. The company's results may differ materially from those projected on today's call. The company undertakes no obligation to publicly update any forward-looking statements. Joining me on the call today will be Chaim Leibovitz, Chief Executive Officer of Brainstorm, Dr. Stacey Lindberg, Executive Vice President and Chief Development Officer, Dr. Ralph Kern, President and Chief Medical Officer, and Alaa Patlas, Interim Chief Financial Officer. In addition, Dr. David Zeppelin, Executive Vice President and Chief Operating Officer, is also on the call and will be available to answer your questions during the Q&A session. Now, I would like to turn the call over to Mr. Leibovitz. Please go ahead.
spk15: Thanks, Tom, and thank you to all listening for joining us to discuss our second quarter financial results and corporate highlights. I expect most of you have read our press release by now, and you will be able to see that we have been working very hard behind the scenes. We've been extremely disciplined by remaining quiet until today about our intentions to submit a BLA for Neuron. We are very excited to have this Q2 earnings call and to provide you with an update. Before I share my prepared remarks, the right thing to do is to start by expressing my thanks. Some of you might not understand all that is required to prepare a regulatory dossier, especially the first DLA for brainstorm. We have been working diligently towards this goal for over a year. And this is a very important moment for us as a company. I want to thank each and every employee at Brainstorm. Many who have dedicated their entire careers to our mission to help ALS patients. Every person in our company has contributed to this moment. But I would be remiss if I didn't specifically highlight the leadership of a few people. I'll start with Yosef Levy, our Vice President of Manufacturing. but has been accountable for every product that has been manufactured. It serves as the basis for our application. Under his leadership, we have launched a new manufacturing site with our commercial partner, Catalent, a great partner, by the way, in preparation for commercial launch, and authored the CMC sections of the BLA. Next, I want to thank Stacy Lindbergh, Executive Vice President and Chief Development Officer, for her leadership in clinical development and as the overall leader for the entire BLA process. Stacey has not only been the key driver of analytics and insights we have gained from phase three, but has also authored key non-clinical and clinical modules of the FBLA. Of course, I would like to thank our president, the chief medical officer, Ralph Kern, and the entire medical affairs team. This is also an appropriate time to thank the California Institute for Regenerative Medicine for being our substantial financial partner for this trial, as well as IMALS and ALS Association for funding part of the biomarker study. There are a number of important items to cover on today's call, including an update regarding the published results from Neuron's Phase III ALS trial and our decision to submit a BLA to the FDA for Neuron. In addition, Ralph will be speaking about our progressive MS program, and reviewing some of the recent presentations we made to the medical community. As is our usual practice, we'll follow our prepared remarks by addressing questions we received from investors in advance, as well as taking live questions from those of you listening on the call today. Beginning with our Phase III results, which you may recall were peer-reviewed and published in the journal Muscle & Nerve in December 2021 and in print in March 2022. While performing routine quality control checks and preparations for upcoming BLA filing, we discovered an error in the statistical model utilized by a vendor in the analysis of a key secondary endpoint. This is now being corrected, and last Friday, Muscle and Nerve published an errata sheet to the original article. Though correcting the error resulted in a change that was relatively small numerically, it does have meaningful positive implications that reinforces and strengthens the conclusions of the Phase III study. With the correction, the Phase III data are stronger than originally thought as we have achieved statistical significance on a key, important secondary endpoint for multiple subgroups, including the trial's pre-specified efficacy subgroup. The endpoint I'm referring to is average change from baseline to week 28 in ALS-FRS-R score and the pre-specified subgroup in trial participants with baseline ALS-FRS-R scores of at least 35, which is indicative of patients with less disease progression. Let me be clear about the context of the trial. The underlying data has not changed. The primary and secondary endpoints for the overall trial are still not significant. And it's productive to also clarify that the RATM relates only to the pre-specified subgroup on the secondary endpoint, as mentioned in addition to sensitivity analysis with additional thresholds summarized in the original manuscript. Given Stacey's extensive expertise and experience, as an industry leader and relevant to this discussion, Stacey is specifically also a globally recognized medical statistician It's far more appropriate that I ask Stacey to lay out in more detail this data. Stacey.
spk08: Thank you, Haim. As Haim just walked you through, the results from our Phase III study evaluating multiple doses of neurone and ALS were published in Muscle and Nerve last December. Although results showed the trials did not reach statistical significance on the primary or secondary endpoints, Prespecified and post-hoc analyses showed a larger treatment benefit with Neuron compared to placebo across both primary and secondary outcomes in patients with less advanced disease. In addition, data indicate Neuron had an important effect on a wide range of biomarkers from all participants in the trial, which were shown to be statistically important to the clinical outcomes observed. As Haim described, as we were performing standard quality checks on the data from the trials in preparation of a BLA submission, we discovered an error in the way the subgroup analyses for one secondary endpoint were conducted. Specifically, we discovered that analyses reported in the original publication utilized an efficacy model that unintentionally deviated from the trial's pre-specified statistical analysis plan. by erroneously incorporating interaction terms between subgroup and treatment in subgroup analyses for the specific endpoint. Other subgroup analyses for endpoints, such as the primary endpoint, were conducted correctly and published accordingly. The newly published results employ the efficacy model as pre-specified in the analysis plan, correcting the analyses and the corresponding results. While the original publication noted that the treatment difference observed with Neuron in the pre-specified subgroup of participants with a baseline score of at least 35 was more pronounced compared to the analysis of all trial participants, it also indicated the difference in this pre-specified subgroup was not statistically significant. With the correct statistical model applied, the magnitude of the absolute difference or the average difference between neuron and placebo in disease progression on the ALS-FRS-R in this pre-specified subgroup only increases slightly as I referenced. It goes from 2.01 points to 2.09 points, so in the second decimal place. But importantly, applying the correct model also results in this difference becoming statistically significant with a p-value of 0.05. Moreover, We now see a statistically significant benefit from Neuron versus placebo on this endpoint for all subgroups with baseline ALS-FRS-R scores of at least 26 through the pre-specified subgroup of 35. In general, this benefit is maintained or increases to a treatment delta as high as 2.86 points across these baseline thresholds. I want to offer one other comment regarding the importance of these analyses, which might not be obvious. It's common to pre-specify subgroup analyses in large trials in the industry. However, in this trial, efficacy subgroup analyses play an important role in the evaluation of neurons treatment effect because of the higher number of participants enrolled in this clinical trial with advanced ALS at baseline. which is a distinguishing feature of this trial compared to other registration trials. Given the insensitivity of the ALS-Separate SR to measure disease progression in these study participants, analyses of trial participants less likely to be impacted by the ALS-Separate SR floor effect are critical to the evaluation of neurons treatment effects. Subgroup analyses are one strategy to do this. To reiterate a point made earlier, we believe these corrected analyses reinforce and strengthen the conclusion from neurons phase three trial. They are consistent with other analyses from the study, both pre-specified and post-talk, which, as I mentioned, also suggests a clinically meaningful treatment effect with neurons in patients with less advanced disease. We would like to thank the editors of Muscle and Nerve for working closely with us and our lead principal investigators from the trial to get these correct analyses published so the medical community can have a full and transparent view of our clinical data. Going through this process has provided us with even a more thorough understanding of our trial results, which is being pulled through as we now revise and finalize the relevant regulatory documents. For those interested in learning more, a link to the Erratum can be found in the press release issued today, and the Erratum is also available on our website. I would encourage you to read it. Before I turn the floor back to Haim, I want to mention an important presentation that took place at the European Network to Cure ALS or INCALS meeting, which was in Scotland in June of this year, because it ties into this discussion. This presentation was delivered by Dr. Jonathan Katz of California Pacific Medical Center and summarized the clinical response on the primary endpoint of our phase three trial after applying two methods to gain a better understanding of neurons treatment effect after minimizing the impact of participants data most impacted by the floor effect of the ALSFR-SR scale. One of them leveraged the published NCALS model. This result provides further evidence that those patients who had been enrolled in the phase three trial and who had advanced and rapidly declining ALS were subject to floor effects which resulted in reduced sensitivity on the primary insulin. We believe this is an important finding as it increases our understanding of neurons phase three results. I'll now turn the call back to Hein.
spk15: Thank you, Stacey. With regards to our next update, I am pleased to formally announce today that we have decided to submit a biologic license application to the United States Food and Drug Administration. In making this decision to move forward, we have carefully considered the totality of evidence from Neuron's clinical studies, as well as the valuable feedback we received from ALS experts world-renowned statisticians, and leaders from the clinical and patient communities. We've also been monitoring the regulatory environment carefully. We believe that finding a BLA represents the optimal path forward to facilitate broad access to neurons for ALS patients who are our primary source of inspiration and motivates us all at Brainstorm. Regarding the timeline of disclosures, we intend to provide updates on whether the FDA files our submission. As always, we look forward to working closely with the FDA with the hope of bringing Neuron to patients as quickly as possible. I'll now turn the call over to Ralph Kern. I'll give you the latest updates in our PMS program, progressive MS program. Ralph.
spk07: Thank you, Chaim. As you know, we're developing Neuron as a treatment for progressive MS. And in the fall of 2021, we announced the results from our Phase 2 trial. This trial, which was open-label, evaluated three repeated administrations of neurons, each given two months apart. The study met the primary endpoint of safety and demonstrated improvement in tests of neurological function and cognition, as well as important changes in CSF biomarkers that reflect neurons' mechanism of action on important MS disease pathways. The results were shared with the broader neurology community at the ECTRIMS conference last October, where they were delivered in an oral presentation by Dr. Jeffrey Cohn, Director of Experimental Therapeutics at the Cleveland Clinic Mellon Center for MS. We're pleased to say that the manuscript with the Phase II data has been accepted by a leading multiple sclerosis journal. We'll make a further announcement in the near future once we're notified of the publication date and availability of the online manuscript. We also had the opportunity to present new data from our MS program at the recent CMSC meeting, which took place in Maryland in June. At this meeting, I presented new data from the phase two trial, looking at the impact of neuron therapy that demonstrated improvements at week 28 in monocular and binocular low contrast letter acuity, or also known as LCLA, which is a standard outcome used to assess visual disability in MS. At the same meeting, Dr. Christopher Locke from the Stanford School of Medicine presented data from the Phase II trial that demonstrated consistent reductions in CSF inflammatory biomarkers that may be relevant to disease progression and treatment response. Currently, patients with progressive MS have limited therapeutic options to address their progressive loss of neurological function and the resulting clinical progression and disability accumulation. We believe that the clinical and biomarker results we have generated with Neuron in the Phase 2 trial provide strong rationale for its potential to address the unmet clinical needs of progressive MS patients. We plan to present additional biomarker data from this trial later this year at the ECTRIMS conference in Amsterdam. And along with the published manuscript, look forward to additional feedback from MS experts and regulators, which will eventually inform our plans to advance Neuron in this disease. I'll now turn the call over to Ella, who will review our financials.
spk01: Thank you, Roz. It is my pleasure now to discuss our financial results for the second quarter and June 30, 2022. Brainstorm's cash, cash equivalents, and SHRM 10 bank deposits were approximately 12.2 million as of the end of June. This compares with approximately 22.1 million on the end of December 2021. Our research and development expenditures net in the second quarter of 2022 were approximately $5.1 million compared to $3.6 million for the comparable period in 2021. General and administrative expenses for the second quarter of 2022 and 2021 were approximately $2.5 million. Net loss for the second quarter was $7 million or $0.19 per share as compared to a net loss of $6.3 million or $0.17 per share for the comparable period in 2021. Back to you, Haim.
spk15: Thank you so much, Alla. Tom Galassi from Lifesign will now read questions we have received from investors. And we did receive questions also after Thursday because of the Ratham. Thank you, Tom. Please, this is yours.
spk14: Thank you, Haim. Our first questioner asked why there was a lack of communication for so long about your plans forward. Any specific reason?
spk07: Ralph? Thank you. Out of respect for the ALS community and regulators, we thought it was prudent and responsible to wait until we were able to share meaningful information. Today, as time communicated, we're pleased to break the silence and share our decision to proceed with the BLA submission. Thank you.
spk14: The next question asks, what regulatory pathways are being pursued?
spk02: Yes.
spk07: Key elements on our regulatory strategy, including the regulatory pathway, will be decided on in consultation with the FDA, and it isn't an appropriate topic for discussion at this time.
spk14: Thank you. The next question asks, what has been the sentiment of the FDA lately?
spk15: Thank you. We have interacted with the FDA across a variety of topics, and their actions consistently show they care about ALS patients, and their actions express urgency. This is exemplified in the action plan the FDA released earlier this year for ALS, a five-year strategy for improving and extending lives of people living with ALS by advancing the development of safe and effective medical products and facilitating patient access to novel treatments. We've also seen this urgency directly with Neuron in both phases of our expanded access program, where the FDA worked collaboratively with us to help patients get access to Neuron quickly. In short, we see them prioritizing and acting with urgency.
spk14: Thank you. The next questioner asks, is there anything patients, advocates, or investors can do to help?
spk15: Well, first, we sincerely appreciate the outstanding support from the entire community of people and their loved ones living with ALS, advocacy groups, and also our dedicated investors. With this in mind, we want and we need to be fully respectful of the FDA process, and we are confident they will act with the urgency that ALS demands.
spk14: Okay, and the next question asks, are you waiting for the analytics decision in September before proceeding?
spk15: No. We're moving as fast as we can, and we have full confidence that the FDA will also act with urgency. Thank you.
spk14: Next we have, where is your publication on the biomarkers?
spk02: Stacy, please.
spk08: Okay. I appreciate this question. Our biomarker data is an important part of our study and one that's already gotten a fair amount of airtime. For example, we included key biomarker data in our primary clinical publication in muscle and nerve, including sharing the statistically significant contributions of biomarkers in predicting clinical response observed with neuron in our trial. We've also shared biomarker data multiple scientific meetings, which can be found on the investor-related portions of our website, including a recent presentation at the American Academy of Neurology by one of our principal investigators, Dr. James Berry, Director of the ALS Clinic at Mass General Hospital. And while our resources have been devoted to finalizing the BLA, a publication dedicated to biomarker data is being worked on.
spk02: Thank you, Stacy.
spk14: As it pertains to the primary endpoint of those who had a minus 1.25 point change in slope, if the pre-specified endpoint had been 31 or the average of trial enrollees, is it correct that the data would have met its pre-specified primary endpoint as well?
spk15: Thank you. Stacy, please.
spk08: Yes. So the first, the negative 1.25 point change is our primary endpoint in the response criteria. So this statement is correction. Sorry, this question is correct. In fact, you can view it in Table 4 of the manuscript. You'll likely recall that we defined the efficacy subgroup threshold as a baseline score of 35 because we anticipated this would be the baseline average for the study. And as the person who asked this rightly points out, the actual or observed baseline average was 31. At this threshold, the response rate was more than double with Neuron compared to placebo, so it was 35.4% response with Neuron and 15.4% with placebo, and the p-value was 0.043. Thank you.
spk14: Next we have, if the trial had not enrolled anyone with a baseline ALS FRS below 27, Would the entire trial have met both its primary and secondary endpoints, as well as pre-specified primary and secondary endpoints?
spk15: Thanks. Stacy, take this, please.
spk08: Sure. What we can share is that based on participants who were in the trial, for those who had a baseline score of at least 27, so greater than or equal to 27, the primary endpoint and the key secondary endpoint averaged change from baseline. Both had p-values less than .05. Your question, though, asks if all 200 participants had been in the range of the ALS FRS score, what would have happened? And this requires speculation for participants that weren't included in the trial, so we can't comment further to the question.
spk13: Thanks, Stacey.
spk14: For our next question, regardless of whether the baseline ALS FRS was above or below 27, Is it accurate to say that participants in the neuron arm had biomarkers that trended in a favorable direction and no one in the placebo arm did not have similar favorable trends?
spk02: Sure.
spk08: When we've shared biomarker data at scientific conferences, in addition to what we published in the meth for nerve paper, It is really important to note that we've reported data from all participants in the trial and have not focused on data from a subgroup of participants. In the figures that we've published and shown, the data is at a treatment group level, and we can see that neuron favorably changes biomarkers across important pathways. While in these same biomarkers, placebo trajectories remain stable and generally unchanged. We have investigated differences in biomarker trends in participants with more advanced ALS at baseline compared to those with higher baseline values. And the general impact with Neuron and placebo across biomarkers are similar between subgroups. For example, if we look below 25 and above 25. We'll elaborate more on this in the biomarker manuscript that's being written.
spk14: Thank you, Stacey. And for this next one, I'll note we have a few questions layered in together. Bofersen is going for accelerated approval based upon neurofilament light, an invalidated biomarker. Dr. David Taylor stated that neuron only decreases at 18%, and that your error bars show you have no effect. What is an error bar, and is it true that you have little to no effect on neurofilament light? Are there other biomarkers that could be used for accelerated approval? Why didn't neurofilament light reach the statistical significance? And lastly, can you explain why the y-axis didn't include zero?
spk15: Thank you. Stacy, take this one, too. Thanks.
spk08: Sure. Neurofilament light's an important biomarker for ALS, as well as many other diseases. I'll start with a comment around the impact of Neuron on neurofilament light, and I saw the exchange on Twitter. In reference to the talk given by Dr. Brown at MND last year, there was a comment made that the 82% reduction of neurofilament light values with Neuron compared to placebo at week 20 was a typo. This comment was an error and incorrect. Dr. Brown correctly stated that the neurofilament light values with Neuron were 82% lower than placebo at week 20. Just as a reminder, CSF was collected seven times across the trial, and the graph that shows neurofilament light values over time, which reported differences between treatments at the last time period on the slide at MND. The graph of neurofilament light values, though, show that the values for those treated with neuro decreased in a steady manner from week two all the way through the last measurement at week 20, while placebo values at the end of the study are very similar to baseline values. There, of course, are other questions that we can answer from the data, including how the changes from baseline to post-treatment compare between neuron and placebo. And we'll answer this and provide many additional insights in full detail in our upcoming manuscript. But it's very clear from the data already in the public domain that, number one, neuron lowers neurofilament-like values, while placebo remains similar to baseline. And number two, neurofilament light is an important biomarker, which plays an important role in explaining the treatment response observed in the trial with neurons. This statement is true across all analyses that we've done. And I'll separately talk about the last two parts of the question. So why weren't neurofilament light values significant? The significance level of tests are impacted by two things. the amount of variability observed, and the size of a treatment effect. Given the observed trajectory in neurofilament light values, the length of the trial, and in fact, the fact that the last biomarker measure was at week 20 instead of week 28, likely contributed to the lack of significance. But we also see larger variability in the neurofilament light assay compared to other markers. In fact, on the slide that Dr. Brown showed at MND, Death receptor 6 data was also shown on the same slide, and you can see by the error bars that there is a much smaller patient-level variability. One important thing to know is that neurofilament light is only part of neurons' biomarker story. It's an important part of understanding the clinical effect observed with neurons. But given neurons' broad mechanism of action, no single biomarker can capture the full effect of neurons. The last part of this question was why didn't the axis include zero? It's a very technical question, but if you look at the graph, you'll note that the data were reported in log scale. This is done because transforming the data to log scale is the correct way to analyze biomarker data because analyses assume data is distributed normally, yet biomarker data across the board tends to be skewed and it diverges from the normal distribution. The transformation in log scale takes care of this and ensures that The assumptions with your statistical analysis are not violated. From what's in the literature, neurofilament light values in ALS patients typically are in the 4,000 and above. In our trial, the average baseline scores of neurofilament light from this trial were above 5,000 in both treatment groups. So including zero on an axis, which would focus on range of values that were pretty implausible, we think would be misleading in the graph. So I'll close by saying I'm personally excited to see how neurofilament light and other biomarker data advances our ability to produce new treatments faster as we gain confidence in making decisions from them. And I'm confident the rich data set from Neuron's FACER trial will help accelerate this journey for the scientific community.
spk13: Thank you, Stacey.
spk14: Our next question we have, in Dr. Brown's presentation about biomarkers, over a dozen biomarkers were discussed. Which of the biomarkers are predictive of a clinical response, aligning with your primary or secondary endpoints?
spk15: Thanks, Ralph.
spk07: Sure. To continue Stacey's comments, we've collected and analyzed additional biomarkers that have not yet been presented in the public domain. And as shared earlier, we're currently writing a biomarker-focused manuscript that will address all biomarkers analyzed The muscle and nerve publication specifically provided the biomarkers that were identified by a stepwise regression model, which were statistically important for the primary endpoints. They included three inflammatory biomarkers, MCP1, a biomarker called Fetuin A, and MSR1, or macrophage scavenger receptor 1, a neurodegeneration biomarker, NFL, which you just heard about, and a very important neuroprotective biomarker, VEGF or VEGF. We'll be providing additional analyses, in other words, answering the question like what biomarkers are important when we look only at participants treated with neuron. I won't give this away today, but what has been true across the board as we've worked to assess the relationships between biomarker data and clinical endpoints is that we consistently see biomarkers that are statistically relevant the clinical endpoints covering all these three important ALS pathways. The broad mechanism of action and neurons' ability to lower markers of neuroinflammation and neurodegeneration, in addition to increasing markers of neuroprotection, all appear to be important in explaining the clinical response that we have observed.
spk02: Thank you, Ralph.
spk14: Next question. For the people in the Expanded Access Program, have you analyzed any of the biomarker data? And if so, what have you found?
spk07: Well, thank you. The second period of the EAP program is ongoing. Biomarker data will not be analyzed before the end of the trial. It's the best practice to analyze all samples collected at one time to avoid complications that could just add noise. For example, results that may be related to batch effect.
spk02: Thank you. Next question we have, can you explain CAFS and the significance of this endpoint? Please.
spk08: The CAVS is an endpoint that's referenced in the FDA's ALS guidance, and it was added to the trial as a secondary endpoint after discussing clinical endpoints in the trial with the FDA. If you're not familiar with it, CAVS stands for the Combined Assessment of Function and Survival. It was published in 2013 in a paper co-authored by three of our principal investigators, including the first author, Dr. James Berry. And it's an interesting endpoint, it's an important endpoint, because it allows for the assessment of clinical function in the context of survival data. Each patient's outcome in the trial is compared to every other patient's outcome and results in ranks. And the average rank score for each treatment group is then calculated, and the treatment group with the higher mean CAV score indicates a better group outcome. The question we received referenced a specific graph in the supplement information to the muscle and nerve paper, which was figure S3, and it was panel B, if you want to reference it. This graph has each of the efficacy endpoints for the subgroup of participants that were above 25 at baseline. And the CAVS data shows that at every time point, Neuron has a higher CAVS score compared to placebo, with a few time points being statistically different. This tells us in this subgroup that Neuron consistently has higher scores, meaning greater clinical outcomes on this endpoint.
spk14: And for our next question, can you tell us the approximate date the final patient of the current expanded access program receives their final injections?
spk07: Rolf? Thanks for this question. The final patient dose for the expanded access program is planned for mid-September this year. We've collected data from both EAP treatment periods, including biomarkers.
spk02: Thank you.
spk14: Our next questioner asks if there are any updates on progressive MS.
spk07: Rolf? Thank you. As we've announced, the peer-reviewed manuscript describing results from our Phase II trial of Neuron in progressive MS has recently been accepted for publication in a leading MS journal and should be available soon. This is a very important moment as we consider next steps. As you know, patients with progressive MS have limited treatment options to address the progressive loss of neurological function and disability accumulation, and the data generated to date suggests that there is a strong rationale for the potential of Neuron to address the unmet clinical needs of progressive MS patients. As we've mentioned, we're continuing a very active dialogue with leading MS experts, the global MS advocacy community, and with regulators, all of which will inform and shape our plans to advance Neuron in this underserved disease.
spk14: Thank you. Our next question asks, Why there's no further trial for Parkinson's disease plan when prior studies showed all endpoints were met? Is this because of a lack of resources?
spk07: Well, yes. Our preclinical data in Parkinson's disease suggests that neurons have the potential to address the functional impairment and also the loss of dopaminergic neurons in this condition. Our focus now is to advance access of neurons to ALS patients as quickly as possible. and to fully evaluate next steps in the development of neuron in progressive MS. Certainly, the lessons we learn will inform our options in Parkinson's disease, and we continue to follow activity in this disease space very closely. Thank you.
spk14: And for our last pre-submitted question, our questioner asks, is there any update on the exosome program or any updates on another potential addition to your pipeline?
spk05: David? We are expanding our preclinical exosome program to include several respiratory indications, including COPD and ARDS. We, as well, are evaluating exosomes as protective agents for prevention of chemotherapy-induced lung complications. Furthermore, we're looking to explore additional inflammatory indications. Are missing the immunoinflammatory properties of neurons MSC's NTS derived exosomes.
spk02: Thank you. Thank you. Jenny?
spk11: Yes. If anybody would like to ask a question via the phone lines, please press star 1 on your telephone keypad. We ask that while posing your question, you please pick up your handset if listening on a speakerphone to provide optimum sound quality. Please poll while we hold for questions. Thank you. Your first question is coming from David Bouts of Zax Small Cap. David, please ask your question.
spk12: Hey, good morning, everyone. So I apologize in advance if you've gone over any of my questions. I lost my connection to the call a couple times. So first of all, did you cover what led to the reanalysis of the data from the paper? And then was the outcome of that new analysis what kind of tipped the scale in favor of filing a BLA? Or had you already decided to file a BLA prior to that And then lastly, have you shared this new data with the FDA, and can you share what their response to it was? Thanks.
spk15: Thank you so much, David. So actually, we did discuss part of your question. I'll start, and I'll hand it over to Stacey. So actually, it was opposite the way around. It's part of the routine QC while finalizing BLA documents. That's when we found this statistical small error. And that's when we went back, and we had to work with the journal. to get this read, and we thank them for that. We did share this with the agency, but we can't comment further at this time, even though I understand and just to know that. And please respect that. We are still to file the BLA. And I said before that we will update once we get feedback relating to the BLA submission from the agency. Stacey, you want to add something?
spk08: I think you covered the answers quite well. I don't have anything further to add.
spk02: Thank you.
spk11: Thank you very much. Your next question is coming from Jay Lemple, who is a private investor. Jay, please ask your question.
spk04: Thank you. Someone had mentioned a batch effect. Could you elaborate on what that means and how it impacts the investigation or trials?
spk15: Yeah, I think Ralph spoke to that, but it's not something that happened, but Ralph can explain.
spk07: Yeah, sure. It's just a technical point that when you analyze biomarkers, if you analyze them in groups, let's say in several small groups, you can have variation between assay results. When you analyze biomarkers at the same time in one batch, you lower that variability. So it's the best practice to limit the number of batches and to try to analyze the biomarkers all at the same time.
spk04: Okay, perfect. Thank you.
spk11: Thank you very much. Your next question is coming from Dennis Fairchild of Fairchild. Please ask your question.
spk06: Good morning. Congratulations to everyone. You have Really worked hard and everyone appreciates it. Are you filing for a unlimited approval or for approval as a subgroup?
spk02: I don't know if somebody's on mute, maybe.
spk15: I was on mute, sorry. That's okay. Thank you for that question, and the question did come up in the written Q&A also. We said that we are still discussing with the FDA these questions that you're asking, and we have to respect that, and we advise that we will update the community only when we get definitive feedback from the FDA on the submission. But thank you for that question, and thank you for congratulating us.
spk11: Okay, thank you very much. Your next question is coming from Mark Bedwell, private investor. Mark, please ask your question.
spk10: Well, it's more of a statement just saying thank you
spk02: to the entire team. We appreciate you so much. And that's it. Did you have a question, Mark?
spk10: I just wanted to say thank you to the entire Brainstorm team.
spk11: Okay, fantastic.
spk10: Thank you. You're very, very welcome.
spk11: Thank you. Your next question is coming from Daniel Walker from Ness Industries. Daniel, please ask your question.
spk09: Yes, thank you. I do have a few questions. First, Dr. Kern, one of the patient eligibility requirements of the pivotal phase through randomized double-blind placebo-controlled study with patients must be rapid progressors. Maybe can you please just quantify that a little more and what qualifies as a rapid progressor? And in the phase three, a change in disease progression post-treatment of greater than or equal to 1.25 points per month on the ALS functional rating scale to find a clinical response. In the now updated Wiley muscle and nerve pre-specified secondary endpoint, neuro and patients progressed on average two points less on the ALS FRS compared to placebo. And in some cases, this delta was as great as 2.86 points. Maybe can you just quantify the magnitude of these responses a little more? I believe you completed your neurology residency at McGill University back in 1987. Again, what is the significance and magnitude of these phase three data and results? And what does this mean for ALS patients and their treating neurologists relative to when you started in the field? How big of a milestone is this?
spk07: Sure, I'll take. So first of all, there were several questions. I'll answer the question of the eligibility requirements first. One point per month average rate of decline is about the average rate of decline for an unselected ALS population. This has been confirmed in very large population studies, but also in clinical trial databases such as PROACT. So that's about an average rate of decline. So The net effect of looking at rapid progressors is to ensure that the population is more homogeneous and there's a predictable rate of decline. The second question you asked me was around the primary endpoint, which is 1.25 points per month change. And I think that is different than the total difference between placebo and neuron or any treatment in neuron, any treatment in placebo at the end. So let's take that second one separately. 1.25 points per month over a period of a study can amount to several points difference for patients. And even one or two points difference or change in an ALS patient can mean the difference between being able to feed oneself independently or transfer in and out of a wheelchair or moving provide daily supportive care. So these are very large differences for ALS patients. And I think all the experts in the field and the ALS community is beginning to appreciate that these small changes really have huge impact. One example is that even a one-point change in the ALS FRSR can lead to a 7% increase improvement in quality of life. And this has been demonstrated. Finally, I'll make a very brief comment and maybe ask Stacey to add her views. The difference of two or more points between neuron and placebo is at the end of the study. So the difference from baseline to the end of the study. And as I mentioned earlier, this also relates to the comment I made about two-point difference being very significant in terms of quality of life and very meaningful clinically to an ALS patient. In terms of my own experience as an ALS doctor for several decades, these are very encouraging changes. And I think I share the views of our principal investigators that, you know, it's a long time coming, obviously, for ALS, for the ALS community. And we're very encouraged by these changes. And as I said, they're very meaningful. So Stacey, maybe I can get you to add your comments on top of mine.
spk08: Sure, Ralph. You know, the only thing I would add to this, because I think you characterized all of this extremely well. When we look at these subgroups that have just been published in the erratum, and when we look at any of the subgroups, which are allowing us to understand the the treatment effect from this trial once we've minimized the effect of the lower end of the aloeseprasol, the floor effect. What we have to remember is that the size of the trial, 200 patients, was what we believed was needed to see a statistical difference between Neuron and placebo based on what we knew before starting the trial. analyses in all of these subgroups really deliver the size or the magnitude of the treatment effect we expected, both with neuro and placebo. So that should give us a lot of confidence when the trial is returning treatment effects and also placebo effects that are similar to really what you expect based on the literature and all of the clinical data that we have on neuro and The second point is that you then don't expect necessarily, it's unexpected, to find subgroups that are in smaller number of patients that are significant. So power is impacted and your resulting key values, of course, are impacted by the size of your data. observing these clinically and statistically significant p-values are quite striking in that context.
spk09: That's great. And Dr. Lindborg, along those lines, can you please maybe just talk a little more about the pre-specified secondary endpoint p-values and how patients and investors should be thinking about these updated p-values? Maybe first, can you just explain the industry gold standard of 0.05? And then in the phase three, the updated p-values in the pre-specified secondary endpoint that met statistical significance and that were as low as 0.016 and ranged from 0.016 to 0.05 and successfully met the endpoint. Very few people have a PhD in statistics from Baylor University. So can you maybe just break down the statistical significance of these phase three pre-specified secondary endpoint p-values that met their endpoint? For instance, if you're a patient, what should these p-values tell you about Neuron as a treatment? And as an investor, how much confidence should these p-values give you? And then how should we be thinking about the p-values and how they correlate with so many of the very positive patient-reported outcomes and real-world evidence out there from patients treated with Neuron?
spk08: Thanks, Daniel. So in terms of pre-specified and our endpoints, our primary and secondary endpoints, it's always really critical that when we're conducting clinical research, and this is true in academia as well as in the industry, that we're thinking very carefully about the trial, the questions we want to answer, and then the appropriate ways to analyze the data and really bring forward evidence. So your question about pre-specified analyses is important. These were identified before any data was observed in the trial and they give therefore objectivity and a different level of rigor to being able to draw conclusions from the trial. And when we look at subgroups, For example, these are also carefully, as we focused on the participants that were 35 or above, this was a pre-specified threshold. So these analyses carry a different level of credence. And while it's important to always be able to do sensitivity and learn from trial, they're different than analyses that are generated post-hoc. We obviously did not anticipate a floor effect in the trial. Otherwise, that would have been a core part of the design, the learning that's come from this. And therefore, they are extremely important to help us understand the data. The relevance of a p-value of 0.05 or less. So in the regulatory statutes, you will see wording about substantial evidence. And there is nothing that defines what that means from a statistical standpoint, but a common threshold that is often employed is using 0.05 as a measure of minimizing the false positive risk from trial. What's important in diseases such as devastating nature, ALS, as we're looking at and trying to identify effective treatments is to look at substantial evidence but be able to balance benefit risk and that is the important dialogue which will now have to occur and certainly will be central to our regulatory submission. One of the most important things I think that come from our data, Daniel, if I remember the last question that you asked and what I would close with is really So we look at the variety of analyses that we've published very transparently, emphasizing the difference between pre-specified and post hoc. What's very important with our data set and what we've learned, when we see clinical endpoints that now we understand in the range of the ALS-Seprosar that has been widely studied and we're confident in its ability to measure disease progression, When we look at our biomarker data and we see changes that were anticipated going in the direction that we expected with neuron and stability, which we also expected with placebo, and we see very consistent conclusions across the ranges of the scale, the efficacy scale, that again, we're very confident in the scale's ability to measure progression we walk away with a set of data that we believe builds on each analysis and allows us to look at the trial results in total.
spk09: That's wonderful. Thank you so much. And then, Dr. Kern, maybe back to you just for my last question. You and Dr. Lindborg have touched on the ALS functional rating score and p-values. cerebral spinal fluid CSF from all participants in phase three are revealed large and also statistically significant CSF biomarker improvements from baseline with neuron treatment, particularly in biomarkers related to neuro inflammation and neuro degeneration while placebo remain unchanged. Can you maybe just talk a little bit about the biological responses and effects on biomarkers that were also seen in phase three? and how patients and investors should be thinking about the correlation and connection between these statistically significant biomarkers and statistically significant positive changes in ALS, FRS. How are all these connected, and how do all these tie together to prove neurons' mechanism of action and effectiveness?
spk07: Yeah, so I think this is potentially a very long conversation. answer, so I'm going to be very brief because I want to respect the clock and give other people a chance to ask questions as well. I just want to reiterate what we said, that we have a hypothesis of a neuron's mechanism of action, and we were able to confirm that in the study. So we know that neuron is interacting with pathways that are both important to the mechanism of action and to ALS. And I think as Stacy just said, and I'll just... just reiterate her comment that there's a very nice convergence of biomarker and clinical data in our experience. And I think it adds confidence to our data. And I think I'll leave it at that. And maybe we can go on to some other questions now. Thank you. Thank you both.
spk11: Thank you very much. If there are any remaining questions, please press star 1 on your phone handset at this time. Thank you. Your next question is coming from Michael Altman, who is a private investor.
spk03: Yes, thank you. You guys are doing a great job. My question has to do with, from a cash flow standpoint, is there any anticipation of another raise or a partner at this point to help improve the cash flow?
spk15: Thank you. Very good question. So, you know, we have an ATM with Lurink and Raymond and If the market will allow, we'll tap into it. No pressure for the moment. The last year, we didn't tap into it. So we'll see. But thank you. It's a very good question.
spk11: Thank you. There appear to be no further questions in the queue. I will now hand back to management for any closing remarks.
spk15: Thank you so much, Jeannie. Very good call. And thank you, everyone listening. And all have a wonderful day. Thank you.
spk11: Thank you, ladies and gentlemen. This does conclude today's conference call. You may disconnect your phone lines at this time and have a wonderful day. Thank you for your participation.
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