Yatin Suneja

Yatin Suneja asked about any particular considerations for Q1 dynamics, given typical industry patterns.

Answer

Karen Massey, Chief Operating Officer, acknowledged that argenx, like the broader industry, experiences Q1 seasonal dynamics such as reverifications and winter storms, which led to a slowdown in Q1 last year. Sandrine Piret-Gerard, Chief Commercialization Officer, emphasized healthy underlying dynamics, including new patient starts, prescriber expansion, and strong access, which are expected to drive consistent full-year growth despite Q1 seasonality.

Yatin Suneja inquired about any particular considerations or dynamics investors should be aware of for Q1.

Answer

Karen Massey, COO, acknowledged typical Q1 industry dynamics like reverifications and winter storms, which also affect argenx. Sandrine Piret-Gérard, CCO, emphasized healthy underlying dynamics, including new patient starts, prescriber expansion, and strong market access, which are expected to drive consistent full-year growth despite Q1 seasonality.

Yatin Suneja from Guggenheim asked about expectations for VYVGART in thyroid eye disease (TED) studies, including potential positioning and whether the gMG study could capture some of the TED patient population.

Answer

Tim Van Hauwermeiren, Chief Executive Officer, stated that argenx would not disclose specific positioning for TED until data is available, emphasizing the need for the data to speak for itself regarding differentiation from existing mechanisms. He highlighted the fundamental biological difference of VYVGART's mode of action and noted that the company is increasing efforts in the thyroid space by venturing into Graves' disease.

Yatin Suneja inquired about the expectations and potential positioning for the thyroid eye disease (TED) studies. He also asked if there was a strategy to capture some of the gMG patient population within the TED study framework.

Answer

Tim Van Hauwermeiren, Chief Executive Officer, stated that the company would not disclose specific positioning for TED until data is available, emphasizing the need for the data to speak for itself. He highlighted ample room for improvement in efficacy and safety in TED and noted that venturing into Graves disease expands their efforts in the thyroid space, as TED and Graves represent a spectrum of the same underlying biology.

Yatin Suneja from Guggenheim Partners asked for clarification on the evolution of the gross-to-net percentage, which reached 20% year-to-date, for the second half of 2025 and into the following year.

Answer

CFO Karl Gubitz explained that the bulk of the gross-to-net increase is now complete. He anticipates smaller future increases driven primarily by product mix as the prefilled syringe (PFS) gains share. Crucially, he emphasized that the net revenue per patient is not expected to change, as the PFS expands the market with incremental patients, driving overall revenue growth.

Yatin Suneja asked about the current penetration in the gMG target patient population, the consistency of quarter-over-quarter growth, and any observed impact from competition.

Answer

Chief Operating Officer Karen Massey reiterated that argenx is in the early stages of the gMG growth curve, especially given the updated TAM of 60,000 patients. She confirmed that VYVGART is leading the growth of the biologics market and maintaining its #1 share. CEO Tim Van Hauwermeiren added that growth is fueled by moving into earlier lines of therapy, with 60% of new patients coming from orals, a trend enabled by VYVGART's clean safety profile.

Yatin Suneja asked for an update on VYVGART's real-world discontinuation rates and the average number of treatment cycles patients are receiving.

Answer

CFO Karl Gubitz confirmed that real-world discontinuation rates remain in line with expectations, which account for the ~20% non-responder rate from the ADAPT study plus other factors. He also stated that the average number of cycles for the IV formulation has been consistent at around five.

Yatin Suneja asked about the gross-to-net dynamics for Auvelity in Alzheimer's disease agitation (ADA) compared to MDD, and the expected penetration of Auvelity within the primary care market segment versus the neuropsych segment for MDD.

Answer

Ari Maizel (Chief Commercial Officer, Axsome Therapeutics) reiterated that ADA gross-to-net is anticipated to be more positive than MDD, assuming 70%+ Medicare Part D channel penetration. He noted that primary care is the dominant specialty for MDD volume, while psychiatrists have greater volume per patient. Currently, about a third of Auvelity writers are in primary care and two-thirds in psychiatry, with primary care growing.

Yatin Suneja asked about the gross-to-net (GTN) dynamics for Auvelity in Alzheimer's disease agitation (ADA) compared to MDD, and the expected penetration of Auvelity within the primary care physician (PCP) segment versus the neuropsychiatry segment for MDD.

Answer

Nick Pizzie, Chief Financial Officer, reiterated that ADA's GTN is expected to be more positive due to the Medicare Part D channel. Ari Maizel, Chief Commercial Officer, explained that while PCPs are dominant for overall MDD volume, psychiatrists have greater per-patient volume. Currently, about one-third of Auvelity writers are PCPs and two-thirds are psychiatrists, with primary care being the fastest-growing segment for new writers and patient starts in Q4.

Yatin Suneja asked about the expected growth inflection for Auvelity from the sales force expansion and upcoming DTC campaign, and also inquired about the current duration of therapy.

Answer

Chief Commercial Officer Ari Maizel clarified that a national DTC campaign is planned for later in the year and is not yet driving demand. He noted the sales force expansion is already showing an inflection in new patient starts. He stated the average duration of therapy is currently around six to seven prescriptions per year.

Yatin Suneja from Guggenheim Partners asked about the clinical path forward for solriamfetol in ADHD, including the rationale for the 300mg dose used in the adult study. He also questioned if Auvelity's payer coverage was plateauing and what an ideal coverage level would be.

Answer

Herriot Tabuteau, CEO, stated the next step for ADHD is a Phase III trial in pediatrics. He explained the 300mg dose was exploratory, with the 150mg dose being the primary focus that showed a clear effect. Ari Maizel, CCO, addressed coverage, noting that while stable, they are actively negotiating and expect access to expand, without specifying a target percentage.

Yatin Suneja asked for Axsome's perspective on the narcolepsy market opportunity for AXS-12, considering its SNRI mechanism and the potential future impact from orexin agonists.

Answer

Executive Darren Opland expressed optimism for AXS-12, acknowledging the need for education around its unique mechanism. He highlighted the large market of 185,000 patients and high dissatisfaction with current treatments as a significant opportunity, stating more details on the commercial approach would be shared closer to filing.

Yatin Suneja asked how the POWER3 study for vormatrigine will facilitate its move to a first-line setting in focal onset seizures (FOS) and sought clarification on the NDA review timelines for both ulixacaltamide and relutrigine, specifically regarding priority review.

Answer

President and CEO Marcio Souza explained that POWER3 aims to position vormatrigine as a first-line treatment for the majority of FOS patients, though not required for registration. He noted that priority review was requested for relutrigine due to its rare indication and smaller data set, but not for ulixacaltamide, citing broader business reasons related to maximizing long-term revenue and navigating the Inflation Reduction Act for a heavily Medicare Part D population.

Yatin Suneja asked how the POWER3 study for vormatrigine will help move the drug towards a front-line setting in focal onset seizures, and sought clarification on the review timelines for both ulixacaltamide and relutrigine NDAs, specifically regarding priority review status.

Answer

CEO Marcio Souza explained that POWER3 aims to address the needs of the majority of focal seizure patients who are not well-controlled, potentially positioning vormatrigine for first-line use, though it's not required for initial registration. Regarding review timelines, he stated that priority review was requested for relutrigine due to its smaller data set and rare indication, but not for ulixacaltamide, citing broader business reasons related to launch timing, revenue maximization, payer dynamics, and the Inflation Reduction Act's impact on Medicare Part D.

Yatin Suneja of Guggenheim Partners inquired about the kinetics of patient responses and the potential for further benefit in a 12-week study, the read-through from this data to the generalized epilepsy cohort, and the company's confidence in the safety of the planned 40mg dose.

Answer

President & CEO Marcio Souza stated there was a clear and significant deepening of efficacy between the first and second months, which is expected to continue in the longer 12-week POWER-1 study. He affirmed the company is very comfortable with the 40mg dose's safety profile, attributing tolerability issues more to background medication management than to vormatrogene itself. He also noted that exposure-response data suggests the potential for even greater efficacy at the higher dose.

Yatin Suneja asked for an update on the current enrollment status for the two essential tremor studies and requested details on the potential range for a sample size increase and the time that would add to the study.

Answer

CEO Marcio Souza declined to provide specific enrollment numbers but stated the company can confidently randomize 20-30 new patients per week. He explained that a hypothetical increase of 100-200 patients could be accrued in approximately 3-6 weeks, which would be followed by the 12-week study completion period for those patients.

Yatin Suneja sought details on the Essential3 interim analysis, including the sample size trigger, mADL11 delta target, and potential alpha loss. He also asked about the definition of a clinically meaningful mADL11 change and the nature and timing of the interim analysis disclosure.

Answer

CEO Marcio Souza clarified the interim analysis uses a 'promising zone' approach and is scheduled for Q4. He emphasized that clinical meaningfulness on the mADL11 endpoint is anchored to patient function, where even a small change is significant, though the study is powered for more. The company plans to communicate the decision from the analysis, which will likely be an update on the final readout timing and any potential sample size adjustment.

Yatin Suneja requested details on the Essential3 interim analysis, including the sample size trigger, the target mADL11 delta, and any alpha loss. He also asked what is considered a clinically meaningful mADL delta and for clarification on the interim analysis's nature, disclosure plans, and timing.

Answer

Executive Marcio Souza explained the interim analysis uses a 'promising zone' approach and a decision to resize would be based on IDMC recommendations, with the base case being no change. He defined a clinically meaningful mADL11 change as being anchored to patient function (e.g., drinking from a cup), which can be less than one point, though the study is powered for more. He confirmed the efficacy analysis is scheduled for Q4, and the company will communicate the decision and updated timeline for the full readout afterward.

Yatin Suneja inquired about expectations for further deepening and separation of Brepo's efficacy curves beyond 16 weeks, and the scope and size of the Phase 3 study, specifically if it would be similar to the DM trial.

Answer

CEO Matt Gline stated that while the data is still being explored, replicating the Phase 2 results in a Phase 3 program would be a significant win. He reiterated that specific Phase 3 design details, including scope and size, would be finalized after discussions with the FDA.

Yatin Suneja, Senior Managing Director at Guggenheim, inquired about the expectation for further deepening and separation of brepocitinib's efficacy curves beyond 16 weeks, and the scope and size of the phase 3 study for cutaneous sarcoidosis.

Answer

Matt Gline, CEO of Roivant Sciences, stated that while the data is still being explored, the current results are already exceptional, and replicating them in phase 3 would be a significant win. He reiterated that specific phase 3 study design details, including scope and size, would be finalized after discussions with the FDA, but Roivant is prepared to run a sizable study.

Yatin Suneja asked about the continued deepening of efficacy curves over 16 weeks for brepocitinib in cutaneous sarcoidosis, expectations for further deepening with longer treatment, and the scope and size of the phase 3 study.

Answer

Matt Gline, CEO of Roivant, reiterated that phase 3 design details would follow FDA discussions, but they are prepared for a sizable study. He highlighted the significant cushion from phase 2 data, noting that replicating close to it in a phase 3 program would be a huge win.

Yatin Suneja inquired about the continued deepening of the brepocitinib cutaneous sarcoidosis curves over 16 weeks, asking how to think about further deepening with longer treatment, and the scope and size of the Phase III study.

Answer

Matt Gline, CEO of Roivant, reiterated that Phase III design specifics would be shared after discussions with the FDA, but confirmed they are prepared to run a sizable study. He noted that while the data is still being explored, replicating the Phase II results in a Phase III program would be a significant achievement, suggesting ample room for success.

Yatin Suneja requested an update on the enrollment progress for the IMVT-1402 registrational studies in CIDP, myasthenia gravis, and Graves' disease. He also asked about the company's expected spend rate, particularly for R&D and G&A, heading into late 2025 and 2026.

Answer

CEO Matt Gline reported that Roivant feels good about enrollment across all IMVT-1402 trials and is on track to meet its publicly stated timelines. On spending, he reiterated guidance that the current cash balance is sufficient to reach the Graves' data readout. He noted that while R&D spending will increase due to the numerous ongoing registrational studies, the overall spend should remain 'pretty stable.'

Yatin Suneja of Guggenheim Partners asked for clarification on the plans for the batoclimab study in Thyroid Eye Disease (TED), given it's described as potentially registrational, and requested guidance on the R&D spending outlook for 2026.

Answer

CEO & Director Matt Gline stated that Roivant remains data-driven and will make final decisions on batoclimab in TED after seeing the data, while emphasizing the company's primary focus is on IMVT-1402. CFO Richard Pulik added that cash use will ramp up slightly with the IMVT-1402 program and that positive DM data would lead to increased pre-launch and SG&A spending, but no other significant changes are expected.

Yatin Suneja questioned the timing of Roivant's recent investment in Immunovant ahead of key data and asked why the company didn't acquire the asset entirely. He also probed whether superior efficacy is necessary for commercial success.

Answer

CEO Matthew Gline explained the investment was made because the opportunity was attractive and it ensures Immunovant is funded through its Graves' disease data, a powerful message to the market. He noted a full acquisition would be a very large investment and Roivant's stock is not at a price where they are keen to issue billions in shares. Gline agreed that superior efficacy is not required for commercial success in MG, given IMVT-1402's other benefits like its auto-injector and dosing, but acknowledged higher efficacy would likely lead to greater market share.

Yatin Suneja sought clarification on the 14-week dynamic for INGREZZA and inquired about the inventory levels for CRENESSITY.

Answer

Matt Abernethy, Chief Financial Officer, confirmed that the 14-week dynamic primarily pertained to INGREZZA, representing almost a full week of impact on the Q3 quarter. He advised normalizing Q3 to a 13-week basis for Q4 trajectory modeling. CRENESSITY's inventory build for the quarter was approximately $7 million.

Yatin Suneja sought clarification on the 14-week dynamic (extra ordering week) for INGREZZA and asked about CRENESSITY's inventory for the quarter.

Answer

Matt Abernethy, Chief Financial Officer, confirmed that CRENESSITY's inventory build was about $7 million for the quarter. He clarified that the 14-week dynamic primarily pertained to INGREZZA, representing almost a full week of impact, and advised normalizing Q3 to a 13-week basis for Q4 trajectory modeling.

Yatin Suneja from Guggenheim Partners asked about the long-term implications of the Inflation Reduction Act (IRA) for INGREZZA and what the company's end goal for market access will be once its competitor has a negotiated price.

Answer

CEO Kyle Gano emphasized that INGREZZA is 'incredibly sticky,' meaning the primary competition post-IRA will be for new patients. CCO Eric Benevich added that the company's strategic goal is to maintain broad access and parity. He stated that the recent investments in payer contracts are intended to position INGREZZA strongly for 2026 and beyond, regardless of the evolving IRA landscape.

An analyst on behalf of Yatin Suneja from Guggenheim asked about the pivotal program strategy for NBI-845 in major depressive disorder and when the Phase II data might be presented.

Answer

CMO Eiry Roberts explained that the specific number and design of the pivotal trials will be determined after the end-of-Phase II meeting with the FDA, with trial initiation planned for next year. She also confirmed that the company plans to release the Phase II program data in the latter part of 2025.

Yatin Suneja from Guggenheim Partners asked for specifics on where costs are being cut, the potential impact on growth, and whether the Q4 2025 cash OpEx target of below $55 million should be considered a steady state for 2026.

Answer

Steven Basta, President, CEO & Director, detailed that major cost savings stem from eliminating the direct-to-consumer (DTC) program, a modest restructuring, and reducing third-party vendor costs, which he believes will not harm revenue. He clarified the $55 million Q4 OpEx is a target, not a committed 2026 run rate, as some incremental investments may be made, though 2026 spending will remain substantially lower.

Yatin Suneja from Guggenheim inquired about the recent flat trend in weekly VOQUEZNA script data and asked for an update on the gross-to-net (GTN) discount expectations for the remainder of 2025.

Answer

President and CEO Steven Basta advised against over-interpreting week-to-week script variability, noting the company's strategic changes are based on long-term financial discipline. CFO Molly Henderson confirmed the Q1 GTN was 53% but reiterated the full-year guidance range of 55% to 65%, attributing potential fluctuations to payer mix.

Yatin Suneja inquired about the FDA's response timeline for the Citizen Petition, potential company actions if the petition is denied, and whether Q1 2025 revenue is expected to grow or decline from Q4 2024.

Answer

President and CEO Terrie Curran stated the FDA must respond within the 180-day period ending in June and confirmed Phathom would likely pursue litigation if the petition is denied, citing confidence in their legal position. CFO Molly Henderson indicated that Q1 revenue would be softer than Q4 due to industry-wide dynamics like deductible resets and wholesaler inventory adjustments.

Yatin Suneja asked about the expected duration of therapy, the gross demand discount implied by the retail vs. BlinkRx split, the potential impact of Q1 insurance changes, and the timeline for issuing financial guidance.

Answer

CCO Martin Gilligan noted that persistency is consistent with PPIs (140-160 days annually) and that the script mix has shifted to 70% retail as access grew. He acknowledged a potential Q1 dip is typical industry-wide but expects 2025 to be a big growth year. CFO Molly Henderson stated the company is comfortable with 2024 consensus but will wait for more NERD launch data before issuing formal guidance.

Yatin Suneja asked about ACP204, seeking to understand the specific pharmacology that is better addressed by this molecule compared to NUPLAZID in the Alzheimer's disease psychosis (ADP) population, and how the trial setup differs from the prior DRP study.

Answer

EVP, Head of R&D, Elizabeth Thompson, highlighted two key differences. From a molecule perspective, ACP204 lacks QT prolongation, allowing for higher dose exploration which could lead to greater efficacy. From a program design perspective, the ADP study is specifically focused on that disease, enrolls a more severe patient population, and uses biomarker confirmation—all key learnings from the previous DRP experience.

Yatin Suneja of Guggenheim asked for details on the statistical powering of the Prader-Willi syndrome study, specifically the effect size it is designed to detect.

Answer

An executive, likely Head of R&D Elizabeth Thompson, explained that the study is larger than the prior trial and is powered across several scenarios to achieve a statistically significant result with over 80% power. The powering assumptions are broadly consistent with historical data but account for a slightly longer trial duration.

Yatin Suneja of Guggenheim Partners asked for color on the COASTal program, including screen failure rates and site quality, as well as the male-to-female enrollment ratio. He also asked for expectations on the upcoming NMRA-511 data in Alzheimer's disease agitation.

Answer

Bill Aurora, Chief Operating & Development Officer, responded to both questions. Regarding the COASTal program, he noted that enhanced medical monitoring with partners like MGH and the use of Verified Clinical Trials (VCT) are helping ensure appropriate patient randomization. He confirmed that female enrollment is higher than male, consistent with MDD prevalence. For NMRA-511, Aurora clarified it's a signal-seeking study not powered for statistical significance, with the primary endpoint being change on the CMAI scale. The data will inform understanding of the drug's effect and guide future development.

Yatin Suneja from Guggenheim Securities asked how Neumora is tracking the prior antidepressant use of patients in the KOASTAL program, a key variable from the KOASTAL-1 study, and questioned if an interim analysis is planned for the ongoing trials.

Answer

Daljit Aurora, Chief Operating and Development Officer, explained that a partnership with the MGH SAFER clinical team provides enhanced oversight to ensure patients with appropriate treatment histories are enrolled. He stated definitively that there are no plans for an interim analysis for the KOASTAL-2 or KOASTAL-3 studies.

An analyst on behalf of Yatin Suneja asked for retrospective details on the baseline MADRS scores for patients with high placebo response in KOASTAL-1, the number of clinical sites being removed for KOASTAL-2 and 3, and the expected number of patients per site.

Answer

President Joshua Pinto declined to provide specific baseline score details but confirmed that some underperforming sites have been removed from KOASTAL-2 and 3. He stated that while the target enrollment remains approximately 332 patients per study, the company could not comment on the final number of sites or the average number of patients per site going forward.

Yatin Suneja asked about the final baseline mix of treatment-naive versus previously treated patients, the company's early commercialization strategy, and potential differences in rescue rates between the two patient groups.

Answer

CEO Dr. Jay Duker confirmed the trials achieved the target ratio of approximately 75% naive and 25% previously treated patients. He stated that an early commercialization team is actively engaging with physicians and payers, with plans to expand later this year. He expects the naive population to require fewer rescue injections than the 'frequent flyer' patients studied in Phase 2.

Yatin Suneja from Guggenheim Partners asked about the final baseline patient mix between treatment-naive and previously exposed patients, the company's early commercialization strategy, and how to think about rescue rates between these two patient groups.

Answer

CEO Jay Duker confirmed the trials achieved the target mix of approximately 75% naive and 25% previously treated patients. He stated that an early commercialization team has been active since the Phase 2 trial, engaging with physicians, payers, and practices. Duker expects the predominantly naive population in Phase 3 to result in fewer rescue injections and better visual acuity outcomes compared to the heavily pre-treated population in the Phase 2 trial.

Yatin Suneja requested commentary on the screen failure rate, the mix of treatment-naive versus previously treated patients, and any available blinded safety data from the ongoing Phase III trials.

Answer

President and CEO Dr. Jay Duker stated that the screen failure rate is better than the historical average of 50%. He confirmed the patient mix is targeting 75% naive and that enrollment of previously treated patients was capped early on. He declined to release any masked Phase III data to protect trial integrity but reiterated DURAVYU's very good general safety profile.

Requested details on trial enrollment metrics, including screen failure rates, the mix of naive versus previously treated patients, and any available blinded safety data.

Answer

The screen failure rate is slightly better than the historical 50% average for wet AMD trials. The patient mix is targeted at 75% naive, and enrollment has remained strong even after capping the previously-treated cohort. The company will not release blinded data to protect trial integrity but reiterated DURAVYU's strong historical safety profile.

Yatin Suneja from Guggenheim Partners requested commentary on the screen failure rate, the mix of treatment-naive versus previously treated patients, and any available blinded safety data from the nearly-enrolled LUGANO study.

Answer

President and CEO Dr. Jay Duker stated that the screen failure rate is better than the historical 50% for wet AMD trials. He explained the patient mix is targeted at 75% naive, with previously treated patients enrolled early and now capped. He declined to release masked safety data to avoid compromising the trial but reiterated that DURAVYU's safety profile has been very good based on prior public statements.

Yatin Suneja inquired about the characteristics of patients recruited into the Phase III wet AMD trials, the potential design of the Phase III DME program, and guidance for modeling R&D expenses in 2025.

Answer

President and CEO Dr. Jay Duker noted that the cap for previously treated patients (~25%) has been reached in the LUGANO trial, with most new enrollees being treatment-naive. Chief Medical Officer Ramiro Ribeiro discussed flexibility in the DME trial design. CFO George Elston advised that Q4 2024 R&D spending is a good barometer for 2025 due to the ongoing trials.

The analyst asked for clarification on the development strategy for NPDR, questioning the rationale for moving forward with a 30-35% response rate when existing VEGFs show higher rates. He also asked about the role and expectations for Best Corrected Visual Acuity (BCVA) in the NPDR study.

Answer

The executive, Jay Duker, clarified that the 30-35% response rate is considered a viable floor based on KOL feedback, who value a safe, long-acting (9-month) therapy over the higher efficacy of frequently injected current treatments. He noted the low uptake of current therapies supports this view. Regarding BCVA, it is not a primary endpoint, and significant changes are not expected as most NPDR patients have relatively good vision.

Asked how the endpoint for the broad DEE indication would be harmonized across different subsets and inquired about a potential food effect for LP659 and the key objectives for the upcoming MAD study.

Answer

The primary endpoint for the DEE study will likely be 'countable motor seizures,' which is considered harmonizable globally. A food effect for LP659 has not been analyzed yet. In the MAD study, the company will focus on continued safety, sustained lymphocyte reduction, and the absence of broad immune suppression.

Yatin Suneja of Guggenheim Partners asked about the observed differences in frataxin level increases between skin and buccal cells, whether patients with robust skin increases also showed similar increases in buccal cells, the potential for further study of the 25mg dose, and details regarding the allergic reaction.

Answer

Dr. Carole Ben-Maimon, President and CEO, explained that skin is a more stable tissue with naturally higher frataxin levels than buccal cells, which have a high turnover rate. She confirmed that patients with frataxin increases in skin generally also showed increases in buccal cells. Dr. Ben-Maimon stated that for the 50mg cohort, the plan is to maintain the current dosing regimen for comparability, but longer-term 25mg dosing could be useful. The allergic reaction was described as typical, resolving with standard therapy.

Yatin Suneja of Guggenheim Securities asked for characterization of target engagement for SZN-043 and whether the 0.5 mg/kg dose is sufficient for biological activity. He also inquired about target engagement for SZN-1326 and whether the observed liver-related adverse events could be ruled out as target-specific, questioning if a threshold effect exists given that damaged tissues might be more sensitive.

Answer

CEO Craig Parker, with CFO Charles Williams relaying, explained that SZN-043 target engagement was confirmed via ALP elevation. He expressed confidence that the 0.5 mg/kg dose is in a potentially therapeutic range, cautioning against direct extrapolation from animal models. For SZN-1326, target engagement will be confirmed via biopsy in UC patients. Parker noted the liver effect appears target-related as SZN-1326's target, Frizzled5, is also on hepatocytes. He hypothesized that damaged liver might show regenerative benefits without transaminase spikes, but this requires human data.

Yatin Suneja of Guggenheim Securities asked for characterization of the target engagement for SZN-043, questioning if the 0.5mg/kg dose is sufficient for biological activity, and also inquired about target engagement data for SZN-1326. He further questioned if the liver-related adverse events could be ruled out as target-specific and whether a threshold effect might exist, given that damaged tissues could be more sensitive.

Answer

CEO Craig Parker, with questions relayed by CFO Charles Williams due to audio issues, explained that SZN-043 target engagement was confirmed by ALP elevation, a result of blocking the ASGR1 receptor. He expressed confidence that the 0.5mg/kg dose is in a potentially therapeutic range, despite being lower than in animal models, cautioning against direct extrapolation. For SZN-1326, he stated there is no target engagement assay yet and it will require patient biopsies to measure the Wnt target gene Axin2. Parker confirmed the liver effect appears target-specific, as SZN-1326's target is also on hepatocytes. He hypothesized that damaged liver tissue might primarily show regenerative benefits without transaminase spikes, but this needs to be confirmed in human studies.

Yatin Suneja of Guggenheim Partners inquired about the upcoming Phase 1b data for CDX-0159, asking if it includes biologic-refractory patients and if the 4.5mg cohort data is needed for dose selection. He also asked about the hematology profile of the subcutaneous formulation and the potential for using biomarkers to select patients for the new eosinophilic esophagitis (EoE) indication.

Answer

SVP and Chief Medical Officer Diane Young confirmed that biologic-refractory patients are included in the study and that the 4.5mg cohort data is not required to advance, given the strength of existing data. SVP of Regulatory Affairs Margo Heath-Chiozzi described the hematology profile as consistent with IV dosing, showing only mild, transient decreases. Regarding EoE, Executive Director of Research Diego Alvarado and Diane Young explained that the initial study will enroll a broad, biologic-eligible population to first understand the drug's effect on mast cells before defining predictive biomarkers.

Yatin Suneja inquired about the dosing rationale for praliciguat in the HFpEF and diabetic nephropathy (DN) trials, the definition of a clinically meaningful change for the DN study's primary endpoint, the decision to add a higher dose to the olinciguat sickle cell disease (SCD) study, and the primary efficacy endpoints for that trial.

Answer

Chief Medical Officer Christopher Wright explained that the HFpEF study uses a single higher dose for efficiency, while the DN study uses two doses for better dose-ranging. He noted a UACR change of 20% or more is a reasonable target for the DN study. The decision to add a higher olinciguat dose was driven by favorable tolerability data from a separate clinical pharmacology study and blinded data from the ongoing STRONG SCD study. For the STRONG SCD study, the primary endpoint is safety, with secondary endpoints including biomarkers for anemia and vascular inflammation, as well as a patient-reported outcome (PRO) for daily symptoms like pain and fatigue. A significant impact on vaso-occlusive crises (VOC) is not expected due to the study's 12-week duration.