Joseph Thome

Joseph Thome inquired about Intellia's CMC readiness for lonvo-z's potential approval and launch, specifically asking about any manufacturing changes between Phase 2 and Phase 3, and alignment with ex-U.S. regulators on the sufficiency of the submission package.

Answer

President and CEO John Leonard stated that BLA preparation is well underway, with preclinical and CMC work completed robustly. He confirmed that the Phase 3 HAELO trial uses the same commercial-grade material, eliminating the need for comparability tests. EVP and CFO Edward Dulac added that their CDMO network, primarily in Europe, is long-established with validated commercial-scale processes, ensuring readiness for launch.

Joseph Thome inquired about the CMC readiness for lonvo-z's potential approval and launch, any manufacturing changes between Phase 2 and Phase 3, and alignment with ex-U.S. regulators regarding the sufficiency of the submission package.

Answer

President and CEO John Leonard confirmed that BLA preparation for lonvo-z is well underway, with preclinical and CMC work robustly completed. He stated that the Phase 3 HAELO trial uses the same commercial-grade material, eliminating the need for comparability tests. EVP and CFO Edward Dulac added that they have an established network of CDMO providers, primarily in Europe, operating at commercial scale and well-equipped for launch.

Joseph Thome asked about Intellia's commercial strategy to ensure a favorable reimbursement environment for its HAE gene therapy, especially given challenges faced by other gene therapies in chronic conditions with established standards of care.

Answer

CMO David Lebwohl differentiated Intellia's gene editing from AAV gene therapy, emphasizing its straightforward outpatient administration. He stated that the drug's ability to provide a 'functional cure'—freedom from attacks and ongoing therapy—is what patients desire and will drive uptake. He also noted that payer engagement is already underway.

Joseph Thome asked if Intellia could analyze serum TTR in the MAGNITUDE-2 study before the 18-month primary endpoint and whether the polyneuropathy (PN) submission is dependent on the cardiomyopathy (CM) study's success.

Answer

CEO John Leonard clarified that the PN and CM programs are independent for efficacy, though safety data will be shared between them. He confirmed the study will remain blinded, so no premature TTR data will be released. CMO David Lebwohl added they are confident in TTR reduction based on prior experience.

Joseph Thome inquired about the potential risk of episodic pruritus in PSC patients affecting the upcoming volixibat trial compared to PBC, and what measures Mirum Pharmaceuticals has implemented in the study design, patient enrollment, or monitoring to mitigate variability.

Answer

CEO Chris Peetz highlighted that patient and advanced practitioner feedback indicates more persistent pruritus than some KOLs suggest. CMO Joanne Quan added that the study design specifically enrolls patients with persistent pruritus and tracks their response, based on prior research demonstrating the significant impact of pruritus on PSC patients' daily lives.

Joseph Thome inquired about potential risks in the upcoming PSC trial due to the episodic nature of itch in PSC patients, and what measures were taken in the study design to limit variability.

Answer

CEO Chris Peetz noted that patient and advanced practitioner perspectives suggest pruritus can be more persistent than some KOLs perceive. Chief Medical Officer Joanne Quan added that the study enrolls patients with persistent pruritus and tracks response, based on prior work showing significant pruritus impact on daily life for PSC patients.

Joseph Thome asked about the baseline criteria of patients enrolled in the fully enrolled PSC study, particularly how they compare to the interim analysis population. He also questioned the importance of quality of life measures and bile acid reductions alongside pruritus, and whether these secondary endpoints would be included in the Q2 2026 top-line data release.

Answer

CEO Chris Peetz stated that specific baseline criteria are not planned for presentation at this point but confirmed that patients were selected for elevated baseline pruritus scores and are representative of the PSC population in terms of background disease and medications. He emphasized that the regulatory focus is solely on the pruritus endpoint, though the company expects and is excited to see movement on fatigue and bile acids, which are important secondary measures.

Joseph Thome asked about the most important outcomes to anticipate from the Ralinepag data, such as PVR, six-minute walk distance, or time to worsening event, and what factors are expected to most resonate with physicians to drive adoption.

Answer

Leigh Peterson, Executive Vice President of Product Development and Xenotransplantation, highlighted Ralinepag's potency, tight IP receptor binding, and long half-life, which enable once-a-day dosing and improved tolerability. She emphasized the importance of demonstrating a statistically significant and clinically meaningful benefit in clinical worsening versus placebo, specifically mentioning reductions in hospitalizations and mortality.

Joseph Thome from TD Cowen & Company asked about the most critical outcomes to anticipate from the Ralinepag data, such as PVR, six-minute walk distance, or time to worsening event, and what factors would most influence physician adoption beyond the dosing convenience.

Answer

Dr. Leigh Peterson (EVP of Product Development and Xenotransplantation) highlighted Ralinepag's potency, tight receptor binding, and long half-life, enabling once-daily dosing and improved tolerability. She emphasized looking for statistically significant and clinically meaningful benefits in clinical worsening, including reductions in hospitalizations and mortality, with unblinding expected next week.

Joseph Thome asked for more details on potential large pharma partnerships related to the recent Tyvaso IPF data, including the ideal partner profile and implications for European rights.

Answer

Martine Rothblatt, Founder, Chairman, and CEO, explained that prior skepticism about Tyvaso in IPF has likely diminished due to the strong TETON 2 data, which was accurately predicted by their digital lung model. She indicated that while United Therapeutics is primarily US-centric, there is interest in partners for ex-US markets, particularly Europe, to bring Tyvaso's benefits to patients globally.

Joseph Thome asked for more details on potential large pharma partnerships related to the recent Tyvaso IPF data, including the ideal partner profile and whether it pertains to European rights.

Answer

Martine Rothblatt, Founder, Chairman, and CEO, explained that prior to the data release, there was skepticism about Tyvaso's efficacy in IPF, despite internal computational biology models predicting strong results. She noted the TETON 2 digital trial's accuracy in modeling the disease. Martine indicated that while United Therapeutics is primarily a U.S.-focused company, the strong IPF data could attract international partners, particularly for regions like Europe, to help bring Tyvaso's benefits to patients globally.

Joseph Thome from TD Cowen asked about the historical variability in FVC decline in placebo arms of IPF studies, how United Therapeutics attempted to standardize this in the TETON trial, and the potential translatability of ex-U.S. data to the U.S. trial.

Answer

Dr. Leigh Peterson, Vice President of Product Development, explained that to minimize FVC variability, the company employed central readers for all results and implemented extensive, standardized training at clinical sites for pulmonary function testing procedures, aiming for more consistent and true results.

Joseph Thome of TD Cowen asked about the xenotransplantation programs, inquiring if the UTHYMOKIDNEY trial will enroll a similar patient population as the 10-gene kidney program and what learnings were gained from the recent explant procedure.

Answer

Dr. Leigh Peterson, EVP of Product Development and Xenotransplantation, confirmed the UTHYMOKIDNEY study will target a nearly identical patient population. She explained that the recent explant was due to an unrelated infection requiring a reduction in immunosuppression, which led to rejection. Key learnings involve better management of immunosuppression during such events, and the experience is viewed as a positive step forward.

Joseph Thome asked for context on the baseline disease severity for patients in the xeno-transplant trial and whether their progress would be publicly reported like compassionate use cases.

Answer

Dr. Leigh Peterson, EVP of Product Development and Xenotransplantation, clarified that due to patient privacy in a formal clinical study, individual progress will not be publicized. She detailed the two eligible patient populations: those medically ineligible for the transplant list and those on the list but not expected to receive a transplant for at least five years.

Joseph Thome asked about the trend of patients de-escalating from Remodulin to Orenitram, whether the expedite protocol leads to higher Orenitram doses, and the potential impact on revenue.

Answer

Michael Benkowitz, an executive, responded that de-escalation from Remodulin to Orenitram is not yet a widespread trend. He confirmed that the expedite protocol is expected to result in higher average doses for Orenitram, as patients can reach a therapeutic dose much faster (within 1-2 months versus up to 6 months), which should cause the average dose to increase over time.

Joseph Thome asked about the anticipated adverse event (AE) profile associated with the split dosing strategy for alixorexton in the Phase 3 trial, inquiring if it would reduce or potentially increase AEs while boosting efficacy.

Answer

Richard Pops, CEO of Alkermes, explained that alixorexton's orexin 2 receptor agonists have generally shown a favorable and well-tolerated AE profile. He noted that the split dosing is modeled to extend wakefulness in later hours with a similar AE profile, leveraging extensive Phase 2 data to optimize dosing and minimize side effects.

Joseph Thome asked about the anticipated AE profile for alixorexton's split dosing strategy in the phase III trial, questioning whether it would reduce or potentially increase adverse events while boosting efficacy.

Answer

Richard Pops, CEO of Alkermes, explained that orexin 2 receptor agonists generally have a favorable AE profile. He noted that split doses are modeled to extend wakefulness with a very similar AE profile, leveraging phase II data to maximize duration while minimizing side effects.

Joseph Thome inquired about the importance of showing ESS benefit in the NT2 data for regulatory bodies and the company's expectations for ocular monitoring in the phase three programs.

Answer

Richard Pops, CEO, explained that both MWT and ESS are primary endpoints for the NT2 study, capturing different aspects of sleepiness. Regarding ocular monitoring, he referenced Vibrance I data showing generally mild, well-tolerated ocular AEs with no structural issues, expressing hope for minimal monitoring in phase three, pending discussions with regulators.

Joseph Thome from TD Cowen asked about the translatability of elixorexant's safety profile to Alkermes's follow-on orexin compounds and whether their different properties might lead to a different adverse event profile.

Answer

Marcus Yountz, VP of Clinical Development, explained that while similarities are expected, the follow-on molecules have different structures and pharmacokinetic profiles that could lead to different outcomes. Richard Pops, Chairman & CEO, added that Alkermes hypothesizes a tolerability shift between NT1 and NT2 patients, which is being explored in the clinical program.

Joseph Thome inquired about the ALKS 2680 narcolepsy type 2 (NT2) study, asking for the rationale behind elevating the Epworth Sleepiness Scale (ESS) to a dual primary endpoint and whether the trial design allows for flexible dosing.

Answer

Dr. Craig Hopkinson, Chief Medical Officer, explained that ESS was elevated to a dual primary endpoint to align with the competitive landscape and global regulatory expectations. He clarified that while doses are fixed during the double-blind phase, the open-label extension allows patients to titrate their dose, which will provide valuable data for planning the Phase III program.

Joseph Thome asked about the potential competitive threat of GLP-1 drugs on VIVITROL's alcohol dependence business and whether abuse potential studies would be required for the orexin pipeline.

Answer

Chief Commercial Officer Todd Nichols stated that Alkermes is monitoring GLP-1s but does not currently see an impact on VIVITROL, which saw strong demand driven by the alcohol dependence indication. CEO Richard Pops confirmed that abuse potential studies for the orexin program are anticipated as a matter of course for CNS-active compounds.

Joseph Thome inquired about the JZP3507 (formerly ONC206) trial in pheochromocytoma and paraganglioma (PCPG), asking about the market size for PCPG relative to Modeyso's H3K27M market. He also asked about Jazz's comfort with leveraging its balance sheet for future M&A and the potential size of such transactions.

Answer

Rob Iannone, EVP of Research and Development, explained that JZP3507 is a follow-on to Modeyso, potentially offering greater potency, and the PCPG trial serves as a proof-of-concept for this next-generation molecule in rare neuroendocrine tumors. Phil Johnson, EVP and CFO, stated that Jazz has substantially deleveraged to 1.5x EBITDA and has the capacity to lever up for compelling transactions, though the long-term expectation is for capitalization to be more equity-weighted.

Joseph Thome inquired about the JZP3507 (formerly ONC206) trial launched in pheochromocytoma and paraganglioma (PCPG), its market size relative to Modeyso for H3K27M, and Jazz's comfort level with leveraging the balance sheet for M&A, including the potential size of such transactions.

Answer

Renée Galá, President and CEO, directed Rob Iannone to cover PCPG. Rob Iannone, EVP of Research and Development, explained that JZP3507 is a follow-on to Modeyso with greater potency, and the PCPG trial serves as a proof of concept for this next-generation molecule in rare neuroendocrine tumors. Phil Johnson, EVP and CFO, stated that Jazz has substantially deleveraged to 1.5x EBITDA and has the ability to lever up for compelling transactions, though the long-term expectation is for capitalization to be more equity-weighted, with leverage potentially fluctuating with M&A.

Asked about the confidence in the GEA trial data reading out in late Q4 2025, the performance of the control arm, and the timing of the next OS analysis.

Answer

The company has greater confidence and precision in their data maturity projections now, leading to the refined late Q4 timeline. While blinded, they noted the control arm in this setting has historically performed consistently across studies, similar to KEYNOTE-811. They did not provide specific timing for the second OS analysis but confirmed the study is powered for multiple looks.

Joseph Thome of TD Cowen asked for an update on the Dordaviprone Phase III ACTION study, including whether enrollment has restarted, and sought reassurance on the PDUFA date timeline.

Answer

Rob Iannone, Head of R&D, clarified that the enrollment pause was limited to the U.S. to prevent data confounding post-approval and that the trial is enrolling well. He affirmed that the FDA review is proceeding as expected, with no indication of a delay to the August 18 PDUFA date, and noted they may adjust the trial's analysis plan to ensure it is well-powered.

An analyst on behalf of Joseph Thome asked about the zanidatamab GEA study, questioning the importance of hitting on both the doublet and triplet arms and requesting a walkthrough of potential readout scenarios.

Answer

EVP, Global Head of R&D Robert Iannone explained the trial has 'two shots on goal.' For approval, either the doublet (zani + chemo) or triplet (zani + chemo + PD-1) arm must show benefit over the control arm. He noted the triplet arm would need to demonstrate an incremental benefit over the doublet. He expressed confidence in the doublet arm's potential for success.

An analyst on behalf of Joseph Thome at TD Cowen asked about the zanidatamab GEA trial, specifically the importance of success in both the doublet and triplet arms for a path forward.

Answer

EVP, Global Head of R&D, Rob Iannone, clarified that the trial has 'two shots on goal.' Approval could be based on either the zanidatamab-plus-chemo arm or the zanidatamab-plus-chemo-plus-PD-1 arm demonstrating superiority over the control. He noted the triplet arm would need to show an incremental benefit over the doublet. Management is confident in the doublet arm's potential for success regardless of PD-L1 status.

Joseph Thome asked about the anticipated launch timeline for Auvelity in Alzheimer's disease agitation (ADA) post the April 30th PDUFA date, and what specific metrics Axsome plans to provide to monitor the launch's progress, including potential revenue separation from MDD.

Answer

Ari Maizel, Chief Commercial Officer, confirmed that Axsome expects to be ready to launch ADA within a quarter of the April 30th PDUFA date. Regarding metrics, he stated they plan to share approximate percentages of scripts originating from the ADA space as they gather more data, acknowledging that standard IQVIA or Symphony data does not break out by indication.

Joseph Thome asked about the launch timeline for Auvelity in Alzheimer's disease agitation (ADA) after the April 30th PDUFA date, and what metrics Axsome anticipates providing to monitor the launch, specifically if product revenues would be separated between MDD and ADA.

Answer

Ari Maizel (Chief Commercial Officer, Axsome Therapeutics) confirmed that Axsome will be ready to launch Auvelity for ADA within a quarter of approval, with the team preparing all aspects for readiness. He stated that Axsome expects to share the approximate percentage of scripts coming from the ADA space as they learn more, acknowledging that typical IQVIA/Symphony data does not break out by indication.

Joseph Thome requested details on the pediatric ADHD trial design for solriamfetol, the basis for confidence from the adult data, and the certainty of the Q4 trial initiation.

Answer

Chief Executive Officer Dr. Herriot Tabuteau described the trial as a standard parallel group design using a pediatric scale. He said confidence is based on the fact that other ADHD drugs work in both populations and the diagnosis requires childhood onset. He acknowledged the complexity of pediatric trials requires 'perfect alignment' with the FDA.

Joseph Thome asked about the clinically meaningful change on the AISRS scale that Axsome is looking for in the upcoming ADHD data for solriamfetol and how the product might be differentiated from competitors like Qelbree.

Answer

Chief Executive Officer Dr. Herriot Tabuteau explained that the primary goal is for the trial to be positive by meeting its primary endpoint, without targeting a specific magnitude of difference. He noted that comparisons to competitors like Qelbree would have to wait until the data is unblinded, which is expected very soon.

Joseph Thome of TD Cowen & Company asked how solriamfetol in MDD could be differentiated from Auvelity and where patients for the AXS-05 Alzheimer's agitation trials are being sourced.

Answer

CEO Herriot Tabuteau explained that solriamfetol offers a novel mechanism for MDD and is being studied in patients with and without excessive daytime sleepiness. For AXS-05, he noted patients are sourced from specialized clinical trial centers, and the program's focus on community-dwelling patients is a key differentiator.

Joseph Thome inquired about the Votoplam Huntington's program, asking if Novartis is now responsible for disclosures from the phase 1/2 program and if any data should be expected in May. He also asked if there's another planned FDA meeting to discuss the existing data package for accelerated approval and what triggers the interim analysis in the phase 3 study.

Answer

CEO Dr. Matthew Klein confirmed that Novartis will oversee the analysis and disclosure of the open-label extension data from PIVOT-HD once all subjects cross 24 months in the first half of 2026. He stated that a subsequent regulatory meeting would be needed to discuss accelerated approval potential after this analysis. The details for triggering the interim analysis in the phase 3 study have not yet been disclosed, but the aim is to assess efficacy after a sufficient number of subjects complete a significant treatment duration.

Joseph Thome asked about the Votoplam Huntington's program, specifically who is in charge of further disclosures from the Phase I/II program and the expected timing. He also inquired if there's another planned FDA meeting for the accelerated approval package and what triggers the interim analysis in the Phase III study.

Answer

Matthew Klein, CEO, explained that Novartis is overseeing the analysis of the open-label data from PIVOT-HD, which will occur once all subjects cross 24 months in the first half of 2026, with disclosure details to be worked out. He confirmed that the FDA is open to accelerated approval, and a subsequent regulatory meeting would be needed if the data supports it. Regarding the Phase III interim analysis, Klein stated that details haven't been disclosed, but the intent is to assess efficacy after a sufficient number of subjects complete a significant duration of treatment.

An analyst on for Joseph Thome at TD Cowen asked about the potential launch scenarios for vutiquinone: if approved, how quickly could it launch and what would be the initial target population? And if not approved, would PTC consider running another trial?

Answer

CEO Dr. Matthew Klein stated that the company is focused on success and is ready to launch vutiquinone immediately upon approval, leveraging its existing infrastructure. The initial target would be patients under 16, who currently have no approved therapies, a population served by pediatric ataxia centers PTC has long-standing relationships with. He affirmed PTC's commitment to patients and its belief in the drug's supportive data, implying they would continue to support the program.

Joseph Thome inquired about expectations for monotherapy weight loss in obese, non-diabetic patients with the ALK7 program, and sought clarification on whether the planned study expansions (including monotherapy diabetic populations and overall size) apply to both ARO-INHBE and ARO-ALK7 programs.

Answer

James Hamilton, Chief Medical Officer and Head of R&D, stated that there are no specific expectations for monotherapy weight loss, viewing these studies as hypothesis-generating. He confirmed that a monotherapy cohort was added to the Activin E study and would likely be added to the ALK7 study as well.

Joseph Thome asked about expectations for monotherapy weight loss in obese, non-diabetic patients for the ARO-ALK7 program, given its distinct biology. He also sought clarification on whether the planned study expansions, including monotherapy diabetic cohorts and increased overall size, applied to both ARO-INHBE and ARO-ALK7 programs.

Answer

James Hamilton, Chief Medical Officer and Head of R&D, stated that Arrowhead has no specific expectations for monotherapy weight loss with ARO-ALK7, viewing these studies as hypothesis-generating. He clarified that monotherapy cohorts were added to the ARO-INHBE study and are likely to be added to the ARO-ALK7 study as well.

Joseph Thone with TD Cowen asked about the proportion of SHTG patients currently on anti-PCSK9 treatment, whether this population is considered under-treated on both triglyceride and LDL sides, and the specific triglyceride and LDL cutoffs for patients enrolled in the early ArrowDiamond PA (dimer) study.

Answer

James Hamilton, Chief Medical Officer and Head of R&D for Arrowhead Pharmaceuticals, indicated that while many SHTG patients may be on statins, very few are on anti-PCSK9 inhibitors, suggesting an under-treated population. He specified that the early dimer study enrolls patients with mixed hyperlipidemia, requiring triglycerides up to 880 mg/dL and either a non-HDL of 100 or an LDL greater than 70, ensuring true mixed hyperlipidemia.

Joseph Thone asked about the proportion of SHTG patients already on anti-PCSK9 treatment and if this population is under-treated on both sides. He also requested the triglyceride and LDL cutoffs for patients enrolled in the early dimer study.

Answer

James Hamilton, Chief Medical Officer and Head of R&D, indicated that many SHTG patients may be on statins, fewer on fibrates, and very few on PCSK9 inhibitors, suggesting it's not commonly used in that population. For the early dimer study, he specified that patients with mixed hyperlipidemia are allowed with triglycerides up to 880 mg/dL, and either non-HDL greater than 100 mg/dL or LDL greater than 70 mg/dL, requiring true mixed hyperlipidemia.

Joseph Thome asked about the MIRROR III study, questioning if the patient population might have lower adherence, and inquired if the three SHTG-related trials would have a combined or separate data release.

Answer

Interim Chief Medical Scientist Bruce Given expressed confidence in trial adherence based on past experience and robust trial execution. Regarding the data release, he noted the results would be available close together, while CEO Christopher Anzalone added that his initial thought is to release them all at once, though a final decision has not been made.

Joseph Thome of TD Cowen asked about the company's confidence in derisking liver toxicity for its Kv7 pain program, whether any quality-of-life measures for Ezetucalner have captured pain-related data, and what level of detail, such as seizure freedom rates, to expect in the top-line data release.

Answer

President and CEO Ian Mortimer stated that the liver toxicity of a prior drug (flupertine) was likely not on-target and that Xenon has no current concerns with its candidate, XEN1101. He also confirmed the top-line release will be detailed, consistent with past disclosures. Chief Medical Officer Christopher Kenney noted that while they have strong QoL data, specific pain data is limited to migraine headache capture in the epilepsy trials, which did not enrich for that comorbidity.

Joseph Thome questioned the rationale for including both Bipolar I and II patients in the upcoming trial, particularly after negative data from a competitor in mania. He also asked if the dosing method in the Mount Sinai study (two 10mg pills vs. one 20mg pill) could have influenced its results.

Answer

Chief Medical Officer Dr. Chris Kenney clarified that Xenon is studying the depressive phase of the illness, where the underlying pathophysiology is considered similar between types. He noted the negative mania data is somewhat reassuring as it suggests the mechanism doesn't worsen mania. Both he and CEO Ian Mortimer confirmed the IST dosing was once-daily and the use of two pills versus one was due to supply and would not be expected to alter clinical outcomes.

Joseph Thome of TD Cowen asked for the rationale behind planning two Phase III studies for bipolar depression versus three for MDD, and also inquired about enrollment progress and challenges for the PGTCS epilepsy study.

Answer

CMO Dr. Chris Kenney explained that with two positive MDD studies potentially completed by the time the bipolar data is available, the regulatory bar for a bipolar indication could be lower, possibly requiring fewer studies. CEO Ian Mortimer addressed the PGTCS study, acknowledging that enrollment is challenging due to the lower prevalence of the condition and the tendency for immediate physician intervention, which often makes patients ineligible for clinical trials.

Joseph Thome asked how Xenon's next-generation Kv7 development candidates are differentiated from azetukalner and whether they are covered by new intellectual property.

Answer

CEO Ian Mortimer confirmed that the new candidates are novel chemical structures with new, distinct IP. He clarified that the goal is not to fix a specific deficiency in azetukalner's already compelling profile, but rather to build a franchise with chemical diversity. Learnings from azetukalner on required plasma exposure levels for efficacy will be leveraged to guide the development of these new molecules.

Joseph Thome asked about the LUCIDITY trial design, specifically how patient diet is controlled to prevent self-liberalization, and the key determinants for the go/no-go decision on the AMX-35 program in PSP.

Answer

Chief Medical Officer Dr. Camille Bedrosian explained that patients receive extensive dietary training and are asked to maintain their run-in period diet, which is reinforced at every visit. For the PSP program, she stated the decision will be based on the totality of data, including the PSPRS clinical endpoint, biomarkers, and imaging, with a high bar set for advancing.

Joseph Thome of TD Cowen asked about the ideal structure for a potential business development deal and whether the SER-155 Phase II trial would include the EU.

Answer

Co-CEO Marella Thorell explained that the primary goal for any deal is to secure capital to advance SER-155, with various structures like partnerships or mergers being considered. Co-CEO Thomas DesRosier added that merger discussions are active with companies that could benefit from Seres' regulatory expertise. Regarding the trial, Thorell confirmed the Phase II study will be global, and SVP of Clinical Development Dennis Walling noted strong enthusiasm from European KOLs.

Joseph Thome asked about the impact of recent FDA changes on Seres' interactions with the agency, the level of confidence in securing a partnership by year-end, and whether a potential partner would have input on the Phase 2 protocol. He also followed up on the optionality of the Phase 2 interim analysis, such as expanding the study.

Answer

President and CEO Eric Shaff stated that despite general concerns about the FDA, Seres' own interactions have been 'highly constructive and regular,' possibly aided by SER-155's Breakthrough Therapy Designation. On partnerships, he confirmed progress and urgency but declined to give a specific timeline, noting potential partners are being briefed on the study design. Regarding the interim analysis, Eric Shaff and Dr. Dennis Walling confirmed it provides optionality but clarified the current expectation is that the Phase 2 study will inform a separate pivotal Phase 3 study, pending FDA discussions.

Joseph Thome of TD Cowen inquired about the SER-155 program, specifically asking if any manufacturing process changes are required between the Phase I and the upcoming clinical study, and whether the company anticipates altering the patient population for the next trial.

Answer

Eric Shaff, President and CEO, explained that while the company is preparing for either a standalone Phase II or a seamless Phase II/III, the immediate next step is submitting the clinical protocol to the FDA. He noted that a partner's input would be valuable in this decision. Lisa von Moltke, CMO, added that they believe they have the correct, broad patient population for the next study. Chris McChalicher, Head of Manufacturing and Quality, confirmed that recent FDA feedback was confirmatory, allowing them to proceed with the current manufacturing campaign for the upcoming trial.

Joseph Thome asked about the clinical trial strategy for expanding SER-155 into additional patient populations like auto-HSCT and cancer neutropenia, and inquired about the compositional differences between SER-155 and SER-147.

Answer

President and CEO Eric Shaff and Chief Medical Officer Dr. Lisa von Moltke explained that they would seek synergies in trial design, possibly through a basket study or adaptive arms, and would not need a new Phase I study due to established safety. Regarding the drug compositions, Chief Scientific Officer Matthew Henn clarified that while SER-155 and SER-147 are different consortia of bacteria, the specific strains are not disclosed. He noted SER-147 is optimized for the distinct pathogens and unique GI environment found in chronic liver disease patients.

Joseph Thome of TD Cowen asked about the rationale for drawing down $50 million in debt and the potential triggers for accessing the remaining tranches. He also questioned if the sales teams for both products are now considered right-sized.

Answer

CEO Mike Raab and CFO Justin Renz characterized the debt draw as a prudent move to strengthen the balance sheet at a favorable interest rate, providing flexibility. Regarding the sales force, both executives expressed confidence in the current team sizes for Ibsrela and Xphozah, noting they continuously assess optimization.

Joseph Thome of TD Cowen inquired about XPHOZAH demand trends in the non-Medicare channel from Q4 to Q1 and whether current R&D and SG&A spending levels represent a new baseline.

Answer

CFO Justin Renz projected that SG&A would rise from Q1's $83.2 million to about $90 million by year-end, with modest growth in R&D from its $14.9 million base. CCO Eric Foster noted that the non-Medicare business (commercial and Medicaid) gained momentum throughout Q1 as the impact of one-time Medicare transitional fills from early in the quarter subsided, reinforcing their strategy.

Joseph Thome of TD Cowen inquired about physician awareness of XPHOZAH's reimbursement dynamics and the focus of the company's business development strategy.

Answer

CCO Eric Foster stated that while physicians are aware of the changes, the operational impact is primarily on dialysis organizations, allowing Ardelyx to maintain a simple 'prescribe as needed' message. President and CEO Michael Raab noted the BD strategy is focused on assets within their current therapeutic areas that fit the company's skill set.

Joseph Thome asked about the potential for different dynamics in Q4, such as stocking or prescription pull-forwards for XPHOZAH, the next steps if the court injunction is granted, and whether dialysis centers are preparing for the January 1 change.

Answer

President and CEO, Mike Raab, stated he doesn't anticipate stocking issues due to a continuity of care program. He noted it's premature to discuss next steps on a potential injunction. He also explained that the required infrastructure changes are debilitating for dialysis providers, which is a key reason many support the Kidney Patient Act to avert what he called a 'catastrophe.'

Joseph Thome from TD Cowen asked if recent regulatory events with other companies have altered uniQure's launch strategy for AMT-130 and whether a minimal striatal volume requirement is expected on the label, given the initiation of a new cohort for patients with smaller volumes.

Answer

CEO Matt Kapusta stated their launch plan has always prioritized patient safety with a 'centers of excellence' strategy and highlighted AMT-130's favorable safety profile due to local administration and the AAV5 vector. CMO Walid Abi-Saab added that the new fourth cohort is designed to generate safety data in patients with lower striatal volumes to potentially relax inclusion criteria, but it is premature to speculate on the final label.

Joseph Thome asked for clarification on the latest AMT-130 data cut seen by the FDA, whether the agency had reviewed Cohort 3 data, and if the proposed 2-week steroid regimen was used in earlier cohorts.

Answer

CMO Dr. Walid Abi-Saab clarified that the most recent data the FDA saw was from a June 2024 cut, which included 24 patients at two years, and they have not seen Cohort 3 data. He explained that Cohorts 1 and 2 did not have systematic perioperative immunosuppression, and the proposed 2-week steroid regimen is new but is a common, well-understood neurosurgical practice.

The analyst asked about potential risks from differing standards of care as the study expands to new geographies and whether the exclusion of bevacizumab from the study protocol poses a headwind to enrollment or the future commercial opportunity.

Answer

The company responded that they mitigate risks by only selecting highly qualified centers that meet specific standards for neurosurgery, radiation, and follow-up care. Regarding bevacizumab, it is not allowed in the study, but they do allow for concurrent Temozolomide with a required washout period.

Asked about the potential sales force expansion for an MDD launch, the focus on primary care, and whether current 2024 expense guidance accounts for this.

Answer

The 2024 SG&A guidance does not include a material sales force expansion. An expansion is planned post-approval to target the large primary care market for MDD. The size and timing will be determined closer to launch, making it a likely 2025 or later expense.

Inquired about the characteristics of enrolling sites in the RAISE study (strong enrollers vs. high screen failures) and the number of patients needed for an FDA filing beyond the interim analysis.

Answer

Recent enrollment has come from newer sites, broadening the participation base. High screening activity, even with screen failures, is seen as a positive sign of engagement. For filing, they will discuss the final number with the FDA after the interim analysis but expect to have an ample safety database from the continued study, the open-label extension, and RAISE II. The safety profile so far is consistent with Phase II data.