Eledon Pharmaceuticals, Inc. (ELDN) Earnings Call Transcript & Summary

Greetings, and welcome to the Eledon Pharmaceuticals ALS Phase IIa Clinical Trial Update Conference Call. [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Paul Little, CFO. Please go ahead, sir.

Good morning, and thank you for joining Eledon's conference call. I'm joined on today's call by David-Alexandre Gros, Chief Executive Officer; Steve Perrin, President and Chief Scientific Officer; and Jeff Bornstein, Chief Medical Officer. Earlier this morning, Eledon issued a press release announcing top line results from a Phase IIa clinical trial of tegoprubart in ALS. You may access the release and download today's presentation under the Investor tab on our company's website at eledon.com. I would like to remind everyone that statements made during this conference call relating to Eledon's expected future performance, future business prospects or future events or plans may include forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995. All such forward-looking statements are intended to be subject to the safe harbor protection provided by the Reform Act. Actual outcomes and results could differ materially from these forecasts due to the impact of many factors beyond the control of Eledon. Eledon expressly disclaims any duty to provide updates to its forward-looking statements, whether as a result of new information, future events or otherwise. Participants are directed to the risk factors set forth in Eledon's reports filed with the U.S. Securities and Exchange Commission. Now I would like to pass the call to Eledon's CEO, Dr. David-Alexandre Gros, DA.

Thank you, Paul, and thank you all for joining the call today. We are excited to discuss our Phase IIa top line results. At Eledon, we are building a company focused on patients for whom anti-CD40 ligand therapeutics may provide a potentially life-extending treatment option. Particular, as you can see on Slide 3, we are concentrating on 3 therapeutic areas: transplantation, focusing on kidney and islet cell; autoimmunity, focusing on IgA nephropathy; and neurodegeneration, focusing on ALS. Today's update marks an important milestone for Eledon and for our ongoing clinical programs, since our ALS study helps elucidate the safety and tolerability of tegoprubart, provides insights into the role and potential impact of tegoprubart in ALS and helps furnish some potential read-throughs to other indications through some overlapping biomarkers as well as safety. Moving on to Slide 4. Our first indication, ALS, is a disease that affects approximately 30,000 people in the United States with about 5,000 new cases each year. It's characterized by gradual progressive muscle weakness causing patients to lose the ability to ambulate, swallow and breathe on their own. Although there are 2 approved treatments for ALS, morbidity and mortality remain high, with about half of ALS patients dying within only 3 years of diagnosis. I will now turn over the call to our President and CSO, Steve Perrin, to walk through the pathophysiology of ALS, explain the role we believe tegoprubart has in addressing that pathophysiology and to review the just announced top line data. Steve?

Thank you, DA. Moving over to Slide 5. I'll give a brief overview of the schematic of the current understanding of the pathophysiology of ALS and the role that the immune system plays in that pathophysiology. We know from the genetics of the disease that ALS is a protein-folding disorder. There's aberrant genetic mutations and RNA processing and quality control genes that ultimately leads to the accumulation of misfolded proteins that end up being toxic to motor neurons. There's clearly compensatory mechanisms that helps motor neuron to deal with the buildup of misfolded proteins due to the fact that the disease typically starts later in life in the third or fourth decade. Once these compensatory pathways stop functioning as we age, one of the first things that happens is that there is a decrease in the speed in which communication happens between the nucleus of the motor neuron and the spinal cord and ultimately, where the axon process innervates muscle fibers in the muscle groups. And as that communication slows down, the neuromuscular junctions get weak, and the NMJ falls apart and the motor neuron pulls back. The pulling back of the neuromuscular junction is initially recognized by the immune system where macrophage and activated T cells infiltrate the muscle beds. They recognize these denervated nerves and they actually start to phagocytose them. As that cascade of pro-inflammatory activation increases, activated pro-inflammatory macrophage and T cells cross the blood-brain barrier and they activate the resident immune cells in the central nervous system called microglia and astrocytes. The activation of those innate immune cells in the CNS ends up creating a toxic environment that's the further demise of the motor neuron. So you get attack of the immune system on sick and dying nerves not only in the periphery but also in the central nervous system. Moving over to Slide 6. One of the most potent ways that activates pro-inflammatory signaling is the activation of co-stimulatory receptors and CD40 ligand and CD40 are a critical pair of these receptors that were identified back in the '80s, where initially, they were identified on immune cells where CD40 ligand is activated -- is expressed on activated T cells where CD40 is expressed constitutively on cells of the monocyte lineage, including B-cells, dendritic cells, NK cells and other cells of the monocyte lineage. When T cells are presented with antigen or foreign antigen via the MHC receptor to the T cell receptor, the activation of this second co-stimulatory pathway results in a pro-inflammatory cascade that results in clonal expansion of the T cell that's presented with the foreign antigen. Maturation of B-cell populations then make high-affinity antibodies to those antigens, and clinical expansion of both of these populations, resulting in pro-inflammatory signaling and increases in pro-inflammatory molecules like TNF alpha, IL-6 and others. Blocking this pathway has been shown to be very effective in slowing down and preventing disease progression in animal models of autoimmunity including multiple sclerosis, psoriasis, rheumatoid arthritis and others as well as in the prevention of acute and long-term transplant rejection. Moving to Slide 7. The macrophage infiltration into the muscle groups that I described was first identified in rodent models of ALS. And interestingly, it appeared to be mediated by CD40 ligand signaling. There are rodent antibodies that block CD40-ligand signaling and when scientists of the ALS Therapy Development Institute move these blocking antibodies into rodent models of ALS, they saw a very profound effects on ameliorating disease progression, which is shown on the graphs in these slides, where I'll focus on Panel B which is a delay in body weight loss that's apparent due to muscle atrophy in these animals. When you block CD40-ligand signaling, you see a statistically significant improvement in body weight loss. Similarly, down in Panel C, if you block CD40-ligand signaling in these animal models, you see a slowing down of disease progression that ultimately leads to an improvement in survival, which is shown in Panel D. Moving over to Slide 8. The initial observation and identification of macrophage infiltration was again identified in these animal models of ALS. In these animal models, unbiased gene expression profiling and proteomics experiments showed on the left-hand graph that multiple different immune cell pathways were activated at the time of onset in the muscle beds of these animals around day 70 and that these pathways became highly activated very quickly thereafter. Initially, the hypothesis was that inflammation occurs due to immune cells going into the atrophying muscle beds. However, when we did immunohistochemistry on the muscle groups from these animals much to our surprise, we show that the macrophages were actually specifically accumulating on denervated nerves. And the immunohistochemistry on the right-hand panels, the nerve itself is being labeled with a marker that shows up in red, which is the myelin coating that coats the nerve, infiltrating macrophages or CD68-positive cells are labeled in green, you can see prior to symptom onset of day 30, you don't see immune cells accumulating into those peripheral muscle beds but by day 60, you start to see them starting to accumulate and by day 100, the nerves are completely coated with macrophages that are phagocytosing those denervated nerves. Moving to Slide 9. As I mentioned, when you block CD40 ligand signaling in these animal models, you have profound effects on reducing pro-inflammatory amplification and the pro-inflammatory polarization of both T cells and macrophages. On the left-hand slide, what I'm showing here is immunohistochemistry again, shown CD68-positive macrophages labeled in green. And when you treat these animals through the blocking antibody to CD40 ligand, you can see in the immunohistochemistry that you have a significant reduction in those macrophages accumulating in the peripheral nerves and that data was quantitated in the box plots. On the far right-hand side is motor neuron counts in the spinal cord after treatment with the anti-CD40 ligand antibody. And even though the antibody doesn't appreciably cross the blood-brain barrier because it's a large molecule, you do see a nice translation into motor neuron survival, which accounts for the delayed disease progression and improved survival in these animals. Moving to Slide 10. As I mentioned, one of the prominent features of disease onset in these animals is denervation or loss of neuromuscular junctions. Immunohistochemically, that's shown in that top left-hand graph where you can see a neuromuscular junction should have a nice pretzel shape, if you will, where the green neuron that's coming into the myofiber will overlap with the postsynaptic side of the NMJ on the motor unit fiber. And if the immunohistochemistry for the postsynaptic side is in red, you see this nice yellow pretzel that means that the nerve is well attached to that myofiber innervating it and translating that electrochemical signal to cause muscle contraction. In ALS, those nerves get sick and they die back, and you can see the green nerve is fragmented in that middle neuromuscular junctions, and there's no overlap between that nerve and postsynaptic which is why the postsynaptic site is red and the motor neuron is dying back. The top neuromuscular junction, that motor neuron has completely died back, is not even close to its neuromuscular injunction. When you block the CD40 ligand, you have 2 profound effects. On the bottom left, you can see that you start to preserve those large-caliber motor neurons. They're surviving longer. They're well myelinated and they have great structure. What that translates to is the far right-hand box plot. You can see, as I said, around day 70, there's a significant loss in neuromuscular junctions and when you treat these antibodies with a vehicle, you lose a significant amount of neuromuscular junctions between day 70 and 85 around the time of symptom onset. When you block with an anti-CD40-ligand antibody, you pretty much bring that neuromuscular junction occupancy back to normal. It's why you have better muscle function, it's why you slow down disease and it's why you improve survival. These observations have also been translated into adult patients with ALS and this table here moving over to slide 11 shows that there's a long history of pro-inflammatory molecules that have been reported in adults with ALS. And in some of these studies, they were longitudinal in nature, showing that inflammatory markers like TNF alpha and MCP-1 are associated with disease progression. In addition to that, CD40 ligand has been shown to be a prominent feature of ALS as well. Shown that it's up-regulated in about 56% of patients with ALS and a soluble CD40 level, soluble CD40 ligand levels actually correlate with disease progression as well. Moving to Slide 12. This is a schematic of our ALS Phase II study that we'll be presenting today. Now the study was a 12-week open-label study with multiple ascending doses of tegoprubart. There was 4 sequential dose escalations from 1 to 2 mg per kg up from -- in low doses 1 to 2 mg/kg in dose-escalating in higher numbers up to 4 and 8 mg per kg. In the lower 2 cohorts, we enrolled 9 subjects per group as we were primarily interested in safety and as we dose-escalated, we moved to 18 subjects per cohort. Tegoprubart was administered by IV infusion every 14 days. So each subject received 6 infusions. We collected biosamples at screening just prior -- in addition just prior to first infusion for each subject so that each subject can serve as their own control in the study. The primary endpoint of the study was safety and tolerability, and we also wanted to further understand pharmacokinetic parameters as well as antidrug antibody responses. We did include secondary endpoints that were really critical to the mechanism of action of the drug, and these were biomarker studies. The first one being target engagement because of the fact that CD40 ligand expressed on the cell surface of activated T cells. And because the communication induces the maturation of B cells, we wanted to look for target engagement in blood. And we could do that by looking at biomarkers of both T cell and B cell activation that we'll describe. The second biomarker endpoint that we're interested in looking at was the pro-inflammatory signatures of chemokines and cytokines that have been elevated in ALS that I just reviewed previously. Blocking CD40 ligand should have an effect in reduced pro-inflammatory chemokines and cytokines based on its mechanism of action. So we wanted to look at the impact on inflammation in circulation with exposure to tegoprubart. And then finally, we wanted to look and see if there was any association with target engagement in the induction of pro-inflammatory signatures with clinical outcomes such as ALSFRS. So if you move over to the next slide, on Slide 13, I'll overview the demographics of the study population. We enrolled 54 subjects into the study. As is typical for an ALS population, the majority of the subjects were male Caucasian. We did define enrollment criteria for subjects at time of enrollment, who have an aggregated ALSFRS-R score of 35 or greater at screening and who have less than 24 months since diagnosis. The ALSFSR or ALSFRS is a functional rating questionnaire with 12 questions focused on motor skills, respiratory function and bulbar function with 4 points qualifying each question. Thus, a perfect score for the 12 questions is 48. The average ALSFR -- ALSFRS at baseline in our study was 39.5. However, 3 subjects had an ALSFRS of less than 35 at time of first infusion with 2 of those subjects decreasing by 4 to 6 points during the -- 1 to 4 weeks between screening and their first infusion, whereas an average person with ALS would typically only decrease 0.8 to 1 point per month. In addition, there were 3 questions focusing on bulbar function, measuring a patient's ability to speak, swallow and salivate. There were 4 additional subjects who at the time of first infusion had a score of 4 for less in the bulbar subdomain, suggesting a lack of ability to speak or swallow and thus predicting a very first fast progression rate for these subjects. So moving to Slide 14. This is an overview of what we'll review in the data. We'll review the outcomes of safety and tolerability, pharmacokinetics and ADA responses, and as I mentioned, biomarkers of target engagement, changes in pro-inflammatory markers and exploratory endpoints, including changes in disease progression as measured by ALSFRS and changes in neurofilament light chain approaching that appears to be a prognostic biomarker of disease progression in ALS. As we have stated since initiating this Phase II study back in 2020 we consider these final endpoints as exploratory since we expected the trial to be too short and lacking enough subjects to achieve them. As such, we considered any positive data related to the exploratory endpoints to be potential upside. We did also include a couple of key sub-analysis. We actually looked at it and compared subjects who did not achieve target engagement as defined by changes in CXCL13 and we then compared subjects who have target engagement but different in changes in pro-inflammatory markers, in other words, high versus low responders. So moving to Slide 15. This is an overview of the safety and tolerability of the study. An external data safety monitoring committee met to review the data prior to each dose escalation. And after 1/3 of the subjects in the highest dose cohort had completed 6 infusions to ensure the safety of the continuing -- of continuing that ongoing last cohort. As you can see, 35% of the patients reported drug-related adverse events. However, there were no serious or severe adverse events related to study drug. The occurrence of adverse events were not dose-related and the occurrence of treatment-related adverse events was balanced across the dose cohorts. Two subjects withdrew from the study, one subject for worsening depression at the 1 mg per kg cohort, and one subject with formulations in the 2 mg per kg cohort. Importantly, there were no signs of platelet activation or thrombosis in the participants. And the pharmacokinetic profile of tegoprubart continues to be as expected and predicted with nice dose proportionality across the subjects. And in addition to that, we only had 9 of 215 samples that we collected had positive signals for antidrug antibody responses, but these were very low. They were at the cut point of the assay with very low titers, and they did not impact the exposure levels of tegoprubart study population. So moving to Slide 16. This is our first biomarker end points that I described to you. And as we've discussed previously, it'd be really important to demonstrate reductions in CD40 ligand with exposure to tegoprubart. CD40 ligand is expressed on the cell surface of activated T cells, as I mentioned. It modulates the pro-inflammatory signaling as well, we wanted to look at reductions in CXCL13 which is a potent chemokine that's involved in B cell maturation and antigen presentation. As you can see on the table in the left, we showed there was a statistically significant reduction in both CD40 ligand and CXCL13 in a dose-dependent manner. In addition, we observed an increase in the percent of subjects who showed a reduced level of these biomarkers in a dose-dependent manner as well. As we previously discussed as well, we wanted to look at the downstream -- important outcomes downstream of target engagement as this is important in the modulation of pro-inflammatory markers that are elevated in patients with ALS and we wanted to look if tegoprubart would modulate these pro-inflammatory markers in a dose-dependent manner. We identified 6 pro-inflammatory proteins from the literature that have been described to be elevated in people with ALS including TNF alpha, MCP1, IL-6, IL-1 beta, EN-RAGE and C-reactive protein. As you can see in the right-hand table, we observed statistically significant reductions in 4 of the 6 of these pro-inflammatory markers, including TNF-alpha, MCP1, EN-RAGE, and CRP at the highest dose. IL-1 beta was not detected in our study population, was below the limit of detection in the assay. In addition to that, we looked at other pro-inflammatory proteins given that we utilized a multiplex Luminex platform to look at protein levels in our study. In total, we observed the reduction in 23 of 32 pro-inflammatory proteins that we measured in the study, including the myeloid marker CXCL9 and CXCL10, as well as complement C3 in the B-cell markers IgA, IgM, IgG and others. The specific group of biomarkers is particularly important to our other disease and usage in such as -- our other disease programs such as IgA nephropathy since reduction in IgA, IgG, C3 and CD40 ligand have been associated with disease progression and proteinuria in patients with IgAN. While CXCL9, CXCL10, IgM and C3 have been associated with kidney transplant rejection. Moving to Slide 17. Finally, we look to see if there were any changes in ALSFRS associated with exposure to tegoprubart study. We utilized data from the PRO-ACT database to service a historical placebo group. The PRO-ACT database is a publicly available data collection from historical ALS clinical trials containing demographic data as well as clinical outcome measures, including ALSFRS. We built a cohort of ALS patients from the PRO-ACT database that were assigned to placebo groups in those studies and who had an ALSFRS of 35 or greater at time of enrollment. The database had approximately 1,500 patients fitting these criteria. As you can see, this cohort had a monthly decline of about 0.83%, which is a representative monthly decline of ALSFRS in broader ALS populations. For our analysis, we combined the Low and High Dose cohorts to increase power and because these groups have similar changes in target engagement. The All group includes all 54 subjects who enrolled in the study, the Low group consists of 18 subjects in the first 2 cohorts who received either 1 or 2 mg per kg of study drug, the High group consists of 36 subjects in the 4 and 8 mg per kg group. As you can see from the table, the Low Dose cohort had a monthly decline, very similar to the PRO-ACT database with a monthly decline of 0.89, which is about 7.2% higher than PRO-ACT. The High Dose in the All group cohorts had a faster monthly decline than the PRO-ACT cohort with monthly declines of negative 1.08 and negative 1.02, which is a 30% and 22% difference compared to PRO-ACT, respectively. This rapid decline was due to the inclusion of the subject to enrollment study who had ALSFRS that fell below 35 from the time of first infusion and who had scores of 4 or less in -- at the time of enrollment in their bulbar subdomains. As you can see in this second column called Baseline Criteria, if we remove these 7 subjects that were present in the 4 and 8 mg/kg cohort, we see that our study population now looks much more similar to the PRO-ACT database and is probably more representative of a typical ALS population. And in fact, as you can see in those cohorts, the actual slope was actually less than PRO-ACT, negative 0.66 in the High Dose and 0.75 in the entire cohort, suggesting that higher doses may actually be leading to therapeutic benefit. If we now focus on Target Engagement, which is the third column over on the table, at 4 and 8 mg per kg doses, there's a 100% target engagement as measured by a reduction in CXCL13 but approximately 40% of subjects in the 1 and 2 mg/kg cohorts did not show this target engagement. If we further exclude these subjects in the analysis, there's again an improvement in ALSFRS decline in the Low Dose group with a further reduction in decline from 0.89 to negative 0.68 points per month. For subjects who do not have target engagement also generally lacked pro-inflammatory changes seen in subjects with target engagement. Of note, subjects in the low-dose group who did not have target engagement progress with a delta of negative 1.4 points per month, which is 70% more rapid in terms of ALSFRS than subject who had target engagement. So finally, we looked at high dose response versus low dose responses as defined by the number of inflammatory markers that were decreased. High responders, you saw a minimum of 10% reduction in 75% or more of inflammatory markers show a greater slowing of ALSFRS slope in both the high dose as well as the overall population. These data taken together suggest the inhibition of CD40 ligand signaling by tegoprubart results in a decrease in pro-inflammatory biomarkers that may result in a slowing of disease progression. So in summary, on Slide 18, we continue to show a very favorable safety and tolerability profile for tegoprubart with 35% of patients having one or more drug-related adverse events. There was no serious or severe adverse events in the study and the occurrence of adverse events was balanced across the dose cohorts. In addition, the pharmacokinetic profile and very low ADAs that we're observing with exposure to tegoprubart was also very encouraging in the study. With biomarkers of target engagement, we showed a statistically significant reduction at the high dose at 4 and 8 mg per kg, with target engagement on both T cell showing reduction in CD40 ligand as well as on B cells with the chemokine CXCL13, respectively. In addition to that, we showed that there was a reduction in modulation of pro-inflammatory markers in a dose-dependent way with 2-dimensionality to that reduction; as one dose escalates, you see a larger increase in reduction of pro-inflammatory proteins in subjects with ALS but you also, as you dose escalate, see a higher percentage of patients in each cohort showing those types of reductions. We observed these types of behaviors in 23 of 32 biomarkers, including the ones that we had been talking about since 2020, where we would have liked to see a reduction, including TNF-alpha, MCP-1, EN-RAGE and C-reactive protein. For the exploratory endpoints, it appears that target engagement and level of reduction in pro-inflammatory biomarkers is associated with a trend in slowing down of disease progression as measured by ALSFRS slope when compared to a cohort from the ALS PRO-ACT database. Thank you for your time, and I'd like now to pass it back to DA.

Thanks, Steve. Today's results give us conviction that tegoprubart has the potential to treat ALS as well as a broader range of inflammation-related indications by targeting the CD40 ligand pathway. We remain focused on executing our ongoing trials and look forward to sharing an initial view of the collected data on each of our other 3 programs towards year-end. 2022 continues to be an exciting period for Eledon, marked by multiple value-creating opportunities and the emergence of potentially transformative treatment option for persons living with ALS, IgAN or undergoing kidney or islet cell transplantation. I'd like to conclude with how pleased I am with encouraging results we have just shared with you as well as with the entire Eledon team that has worked so hard in furthering our mission to help patients with ALS and other unmet medical conditions. I would also like to thank our investigators and most importantly, the patients and families who participated in this trial for their commitment to finding a novel therapeutic option for ALS. Finally, I would like to thank all of the patients and families who supported tegoprubart's early development as well as ALS TDI, Augie's Quest, the Muscular Dystrophy Association, the ALS Association and ALS one. With that, I will now ask the operator to please begin our Q&A session. Operator?

[Operator Instructions] Our first question today is coming from Pete Stavropoulos from Cantor Fitzgerald.

Good morning, DA and team. Nice to start the week off with some positive data. Congratulations. So first question I have, I know this is early data, but when you look at the patients that had a slowing in disease progression as measured by ALSFRS, was there -- were there any characteristics that could help inform a future study? You touched on earlier-stage versus later-stage patients, but known rapid progressors by genotype or patients with a higher pro-inflammatory signature or higher soluble CD40 ligand. And on specifically on Slide 17, there was a high -- there were high responders that you highlighted, was there anything about their baseline characteristics that could help enrich this patient population in a later-stage study?

Great. Thank you for the question, Pete. Appreciate it. Let me turn that over to Steve.

Yes. So obviously, it's a good question. We're obviously in the early days of thinking about how we can leverage this data for next study designs. But clearly, what the study showed is that if you demonstrated clear target engagement that appear to correlate to a decrease in pro-inflammatory signaling in a very large group of proteins that are associated with inflammation. And ultimately, that looks like it has a trend towards slowing down disease progression. I think the question that you have as far as genetics, demographics or other things, I mean, clearly, we know that some forms of the genetic forms of the disease are faster progressors than the sporadic population as a whole. And in addition to that neurofilament light chain is a biomarker, a prognostic marker of fast progression, we did see that in our study. We also saw that folks with bulbar onset at time of enrollment were also faster progressors, which is well described across ALS cohorts. I think the question that we need to understand as we think about our next study design is how we might want to leverage, for example, target engagement into that study design.

Okay. In terms of target engagement, you had a 4- and 8-milligram doses. Do you see the potential of actually expanding the window of dosing in the next study?

Steve?

Like I said, it's a great question. It's still kind of early days on how we might select a dose based on this data. We did show target engagement and knockdown of CD40 ligand at multiple doses as well as CXCL13 and those -- as we said, as we dose increase from 1 to 2 to 4 to 8 mg per kg, the percent knockdown in those proteins go higher. They got statistically significant for CD40 ligand at 2 mg per kg and were more significant at 4 and 8. For CXCL13, we saw statistical significance at 4 and 8. The question is, do you actually go to higher doses? Or do you select a dose from the study? And again, I think we're still looking into the data and understanding the best way that we might leverage this data for the next study.

Okay. Also for ALSFRS, it measures the patient's degree of functional impairment by assessing speech, swallowing and other measures. Were there any key drivers in the reduction of the ALSFRS slope? Or was the trend basically evenly distributed across the scale?

The biggest thing that seems to impact ALSFRS progression based on the ALSFRS scale is definitely bulbar onset. Patients that have bulbar onset tend to be faster progressors than people with peripheral limb onset, if you will. And that's been true for quite some time across broad ALS populations, and we certainly saw that in our study as well. About 30% of people with ALS typically present with bulbar presentation rather than limb onset.

And one last question. There were -- there was a reduction of IgA observed in the study. Can you speculate if these changes would result in clinically relevant reductions in IgA nephropathy patients? So will it translate to clinical benefit? And do you think -- okay. That's it.

It's a good question. Obviously, we weren't studying an IgA nephropathy population here, and it's in what can compare to different diseases across the population. But we did note that we saw a reduction in certain biomarkers, including IgA, IgE and complements and that those same biomarkers have been implicating disease progression of IgA nephropathy. It also just reinforces the mechanism of action of tegoprubart and the fact that at least in this patient population, we saw biomarker movements that were -- that we would have expected based on the biology.

The next question today is coming from Thomas Smith from SVB Securities.

Congrats on the data. Just a couple on the biomarker data, I just wanted to clarify, were the -- were the reductions in the pro-inflammatory biomarkers dose-dependent between the high doses 4 and 8 mg per kg? And then separately, did you see any trends on changes in neurofilament light chain?

Thanks, Tom. Appreciate the question. Steve, let me turn that over to you.

Yes. So the first question about reduction in pro-inflammatory biomarkers, there was a consistent pattern of increase/decrease in pro-inflammatory markers as one dose escalated from 1 to 2 to 4 to 8 mg per kg. They typically became statistically significant for the 23 markers at 4 mg per kg doses. There were a few that we saw that at lower doses as well. And in addition to the greater decreases in protein expression as one dose escalates, there's other 2-dimensionality perspective that you have to keep in mind that we also saw an increase in the percentage of patients in the cohort that showed statistically significant reductions as we dose escalated. So we kind of got both of those, a reduction in the proteins themselves as well as an increase in the number of subjects that appear to be responding. For your second question, we did look at neurofilament light chains, as I described. It's a pretty well-validated prognostic biomarker that predicts disease progression at time of diagnosis. We didn't see changes in neurofilament light chain in the study. Much like many other companies have struggled to correlate a therapeutic change in NFL with a clinical outcome, we didn't see changes either. It was only a 12-week study. It's quite possible that we just are not looking long enough to show that a therapeutic will modulate NFL levels. In some other studies that I'm describing have gone out 6 months and have also not seen these types of correlations. It could be that we just have to go out longer than even 6 months to see a correlation between NFL and clinical outcomes. It's still kind of young days to understand if NFL is going to be more than just a prognostic marker and actually be a marker of therapeutic efficacy.

Okay. Understood. Great. And then one on Safety & Tolerability profile looks pretty clean, consistent with the Phase I experience. Just on the antidrug antibodies, I know it's a pretty small percentage, and you said it's kind of up against the limit of quantification within the assay, Steve. But were any of the ADAs neutralizing?

They were not. They didn't affect our exposure levels of tegoprubart. So no, they were not.

Okay. Okay. And maybe just lastly, just help us think through kind of the next steps here in ALS and maybe some of the timelines for laying out those next steps.

Sure. I'll take that question. So Tom, we're obviously very excited by the data that we presented today. In terms of next steps for ALS, we plan to present -- publish the data. We plan to work with KOLs, patient community and regulators on what a next trial could look like. As we recently reiterated in our quarterly earnings release, we currently have sufficient cash into 2024, based on our ongoing transplant and IgAN clinical studies. So we also plan to explore a range of potential sources of financing or we would advance into another ALS trial.

Your next question is coming from Matt Kaplan from Ladenburg Thalmann.

Congrats on the results. Can you give us a little bit more color in terms of the magnitude of change in the inflammatory biomarkers and also in terms of CXCL13 and CD40 ligand engagement that you saw?

Sure. Yes, do you want me to take that, DA?

Sure.

I mean they were highly variable, as you can imagine. The percentages reductions decreased as we dose-escalated, but even within a cohort, there was variability, but we saw reductions in target engagement markers 60%, 70% or more in 100% of responders in the higher dose cohorts for target engagement. So a very potent reduction in target engagement markers.

In others, we considered response to be a change of a minimum of 10%, that for us a minimum change would have been negative 10% to be considered a successful reduction.

Okay. And can you talk a little bit about the durability of the reductions that you saw between doses from a PK point of view?

I didn't hear the last half of that, I'm sorry.

Just from a pharmacokinetic point of view or from pharmacodynamic point of view, can you talk about the reduction in -- that you saw in the durability of it between doses?

So as I mentioned, the dose proportionality was really very consistent on what we had reported and published for the Phase I study with really nice dose proportionality. The exposure levels within a cohort were actually very, very tight. It appears to be that tegoprubart is a very well-behaved IgG1 monoclonal antibody based on the data that we're seeing. So the exposure levels from subject to subject were actually pretty close. We haven't completed all of the relationships between exposure levels and biomarker stuff, that stuff is still going on.

Okay. Your next question is coming from Rami Katkhuda from LifeSci Capital.

Congrats on data. As you mentioned, it's early days, but how does the change in the ALSFRS slope with tegoprubart compared to therapies like riluzole or edaravone ?

I mean, I guess I could take the first. I guess I could take a first pass at that, if you want, DA?

Please, I mean obviously, it's hard to compare across trials and across drugs. But Steve?

And Jeff, feel free to chime in as well. I mean, riluzole and edaravone are very different. I mean riluzole, obviously, is a drug that was approved 30 years ago. It had mixed results in the large Phase III trials that were conducted, which I believe there were 3 of them, 2 of them showed a positive decrease in ALSFRS slope, one of them did not. It's obviously been in the general population for a very long time. And I think that the data for riluzole would suggest that it does impact disease progression, but it's in a very small percentage of people with the disease. And as long as you're tolerating exposure to riluzole, people say to take it, but the percent changes were very, very small for riluzole. Edaravone, if you remember from the published data from Japan, because clinical trials were not conducted in the U.S., was approved based on data from Japan. The larger Phase IIb study that was highly powered did not show a statistically significant difference between the edaravone placebo group; however, a retrospective analysis identified a fast-progressing group of folks that looked like that they were seeing benefit and when they ran their smaller Phase III study, they showed a statistically significant change in ALSFRS in that population. In the general population since edaravone was approved back in 2017, there has been multiple publications globally that edaravone doesn't seem to have a very large impact, if any, on disease progression rates. For our study, as DA was alluding to, this is a pretty short study. It's only 12 weeks, and we did see a significant -- or a trend towards slowing of disease progression associated with tegoprubart exposure levels. But I think we need to get to a larger study to really understand how to qualify that and quantitate it.

Got it. And then just out of curiosity, were you surprised that IL-1 was not significantly detected in the study patient population?

Again, I didn't totally hear the question, DA. If you wanted to grab it.

The question was that whether we were surprised that we did not detect IL-1. It was something that we had expected to see based on the historical literature. We did not see it using our assays. It's -- it's tough to know whether it was tied to the assay that we used or to the underlying patient population. Steve?

Yes. No, I totally agree. I mean IL-1 beta was just not detected in the Luminex-based platform that we utilized. It has specific sensitivity thresholds and at least in our population, samples were not coming above the noise in that particular assay format.

Got it.

As we mentioned, we detected a wide range -- a wide range of inflammatory biomarkers.

Your next question is coming from Vernon Bernardino from H.C. Wainwright.

Congrats on the results. A couple of questions. In the Phase IIa study, you did have multiple -- looks like collections of samples through the study, the 12-week study. Could you at least characterize or do you have plans to perhaps show the progression of those biomarkers at those various time points? And as a follow-up to that, just wondering also about the progression and measurements of ALSFRS at any time during those time points?

Sure. Vernon, thank you for the question. So in terms of your question regarding from a time perspective, the progression of biomarkers, what we saw was that tegoprubart had quick onset of action and that we began to approach maximal reductions in about 4 weeks. With regards to ALSFRS, and the delta, Steve, let me turn that over to you.

So again, as you saw from I think it was Slide 17, across the entire cohort, we didn't see a big delta in ALSFRS and it was probably due to the 7 subjects that had significant disease progression in that 2- to 4-week period between screening and time of first infusion. Once you take those subjects out, including the ones that had the 4 points or less in the bulbar domain, the study population became closer to what you might describe as a more representative ALS population, albeit when you look at the high-dose cohort, in particular, you start to get some hints that high-level exposure might actually be slowing down disease even when you just remove those 7 subjects from the 4 and 8 mg per kg cohorts. Furthermore, as we started to investigate target engagement and not seeing full target engagement from the low-dose cohorts, if you start to remove people where you didn't see obvious target engagement, again, you start to show this flattening of the ALSFRS curve suggesting again, if you see good target engagement that appears to trend towards an improvement in disease progression. And then finally, obviously, if you're hitting target, one would predict that you should be knocking down pro-inflammatory markers. And as we described, we hit like 23 of 32 markers that sit downstream of CD40 ligand signaling and are associated with pro-inflammatory signaling both on T cells as well as cells of the myeloid lineage. And of course, if you correlate target engagement to a reduction in pro-inflammatory markers, again, you see this flattening of the curve, there's a trend towards it that appears to be slowing down disease progression, albeit that this is a 12-week study.

Yes, it's exactly that last part, where I wanted to go next. Slowing down on disease progression, it's only a 12-week study, so patients obviously want to see slowing down disease progression and with potential of your -- of tegoprubart to perhaps even improve the condition of these patients. Do you think that perhaps a follow-up to the study would require a higher dose or evaluation?

I mean, Vernon, I think to our point so far, we're kind of still in the early days of thinking about the next trial design, Obviously, if Jeff wants to jump in, he's been thinking a lot about what -- compared to whether -- what is the clinical development path, what's the regulatory path for improvement in ALS? And how do we leverage this data to get there. But Jeff, I don't know if you want to add any color to that.

No, I think -- it's DA. I think it's early days. We just got the data. So we need to finish interpreting the data, have discussions with regulators, with our KOLs and after that, we'll be able to come back with a more definite plan in terms of what the next steps from a development perspective could look like.

No, it's great results and very exciting because, obviously, the rapid response and the potential to not only slow but perhaps improve disease in these patients would make us even more excited if there is potential for greater effect at a higher dose. Congrats again on the results.

We reached the end of our question-and-answer session. I would like to turn the floor back over to DA for any further or closing comments.

Thank you very much, and thank you all for joining today's call.

Thank you. That does conclude today's teleconference. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.