Ami Fadia

Ami Fadia asked about acquired alterations post-Diraxonrasib monotherapy, their potential impact on durability in first-line combination with chemotherapy, and whether the company would consider exploring combinations with other mechanisms to increase durability.

Answer

Mark Goldsmith, Chairman and CEO, confirmed that the company is actively exploring combinations with other compounds targeting resistance mechanisms to increase durability. He noted they prioritize these efforts based on scientific data and are open to expanding them.

Ami Fadia inquired about the impact of acquired alterations post-Diraxonrasib monotherapy on durability in first-line PDAC and whether Revolution Medicines would consider exploring combinations with other mechanisms to address this.

Answer

Mark Goldsmith, Chairman and CEO, confirmed that the company is already actively considering and exploring combinations with other compounds that target potential resistance mechanisms to enhance durability. He noted that they evaluate many such opportunities, prioritize based on scientific data, and receive numerous inbound requests for combinations.

Ami Fadia asked about NBI-770, specifically what absolute level of change in the primary endpoint (CRIA score) would be considered successful, given the study is not powered for statistical significance, and if the company is considering studying it in PRD or NDD.

Answer

Sanjay Keswani, Chief Medical Officer, expressed hesitation to provide a specific effect size for success due to the high unmet need. He confirmed that NBI-770 is currently aimed at adjunctive treatment in major depressive disorder but acknowledged the potential to pursue treatment-resistant depression (TRD) or other indications, with the decision to be made based on data later this quarter.

Ami Fadia asked about NBI-770, specifically the level of change in the primary endpoint that would be considered successful (given the study isn't powered for statistical significance) and whether the company is considering studying it in PRD (Psychotic Depression) or NDD (Neurodevelopmental Disorders).

Answer

Sanjay Keswani, Chief Medical Officer, noted the small size of the study and hesitated to give a specific effect size for success due to high unmet need. He confirmed that NBI-770 is currently aimed at adjunctive treatment in major depressive disorder but could also target treatment-resistant depression, with the decision to be made based on data later this quarter.

Ami Fadia asked if the conservative INGREZZA guidance was primarily due to increased prior authorization hurdles and requested color on the initial 11 CRENESSITY patient forms, such as patient type and prescriber setting.

Answer

CEO Kyle Gano explained the INGREZZA guidance reflects a balance of factors, including competitive and payer pressures and the Q4 sales force disruption, weighed against long-term growth drivers. Chief Commercial Officer Eric Benevich described the initial CRENESSITY patient forms as very diverse, coming from both community endocrinologists and centers of excellence, and including both pediatric and adult patients.

An analyst on behalf of Ami Fadia from Needham & Company asked how NBI-845 is expected to fit into the current MDD treatment paradigm and what the expectations are for the upcoming FDA meeting.

Answer

CMO Eiry Roberts stated the FDA meeting will provide clarity on the Phase III strategy, enabling a program start in H1 2025. She explained that since the Phase II data was generated in patients with inadequate response to current treatments, NBI-845 could potentially be used as either an adjunctive therapy or a stand-alone monotherapy, with both paths being explored.

Ami Fadia asked about the complementary nature of orexin and oxybate mechanisms for nighttime sleep and future study plans, as well as the full-year gross-to-net expectations for Aristada.

Answer

Richard Pops, CEO, noted the potential for clinical research to understand how orexin agonists coexist with nighttime sleep consolidation, especially with once-nightly and once-daily forms, and mentioned ongoing polysomnography data analysis. Todd Nichols, Chief Commercial Officer, stated that Aristada's full-year gross-to-net is expected to follow consistent historical patterns, approximately 53%.

Ami Fadia of Needham & Company asked about the importance of avoiding a dose with even transient visual AEs, whether such a dose would be advanced to Phase 3, and if this is considered an on-target class effect.

Answer

Richard Pops, Chairman & CEO, broadened the focus from just visual AEs to all potential on-target, dose-limiting AEs like insomnia. He emphasized that the six-week data provides a comprehensive view to inform Phase 3 dose selection. Marcus Yountz, VP of Clinical Development, added that complex modeling is underway to determine the optimal dose range based on efficacy, safety, and ease of dosing.

Ami Fadia from Needham & Company inquired about the annualized net revenue per patient realized in Q2 and any impact from inventory changes. She also asked for the implied year-end patient count and net price evolution embedded in the updated guidance.

Answer

CFO Tom McHugh reported an annualized net revenue per patient of approximately $92,000 in Q2, with no material impact from inventory stocking. CEO Gregory Divis added that the price improvement was also due to execution initiatives, not just seasonal gross-to-net changes. Regarding guidance, McHugh indicated the low end implies a similar level of net patient adds as Q2, and both executives suggested the current net price is a reasonable proxy for the second half of the year.

Ami Fadia of Needham & Company asked for color on the evolution of patient discontinuation rates and their impact on guidance. She also inquired about the new offensive lawsuits against Jazz, the timeline for the remanded court case, and the development timeline for the low-sodium formulation.

Answer

CEO Gregory Divis noted that the discontinuation rate improved from ~14% in Q4 to a lower rate in Q1, and CFO Thomas McHugh confirmed this improvement was a factor in raising guidance. Divis explained the new lawsuit asserts that Jazz's IH label infringes on five of Avadel's patents. Regarding the low-sodium formulation, he stated that more updates would be provided later in the year.

Bona, on behalf of Ami Fadia from Needham, asked about the key drivers for the low and high ends of the 2025 guidance range, the expected relationship between Q1 and Q4 sales, and recent trends in the patient mix between switches and new-to-oxybate patients.

Answer

Executive Gregory Divis explained that achieving the higher end of the guidance range would be driven by stronger overall patient demand, an increased proportion of switch patients, and improved therapy persistence. He noted that early Q1 trends suggest a stabilization and potential reversal of the declining switch patient trend seen in late 2024. Executive Thomas McHugh reiterated confidence in the full-year guidance while highlighting that Q1 is typically the highest quarter for gross-to-net deductions, which impacts sequential revenue comparisons.

Ami Fadia inquired about the current mix of new patient starts between completely new patients and switch patients. She also asked for color on the source of switch patients (e.g., high-sodium vs. low-sodium oxybates) and how the overall oxybate market's growth rate has evolved since the launch of LUMRYZ.

Answer

CEO Gregory Divis stated that while switch patients remained the largest source of new starts in Q3, the new-to-oxybate segment is a rapidly growing portion. Executive Richard Kim added that the majority of switches come from mixed-salt oxybate products. He also noted clear indicators of overall market growth, citing the ~150 prescribers new to oxybate therapy and increased prescribing from lower-volume physicians.

Ami Fadia of Needham & Company asked for more color on the preclinical work that provides confidence in the safety profile of the NMRA-861 molecule, given it is different from the earlier M4 PAM.

Answer

Joshua Pinto, President, reiterated that all M4 PAMs are structurally distinct. Nicholas Brandon, Chief Scientific Officer, then provided specifics, stating the critical preclinical data comes from in vivo rabbit studies. He explained that with NMRA-861 and NMRA-898, the company dosed the animals and achieved exposures that surpassed the levels where the previous molecule (NMRA-266) caused convulsions, without observing any similar safety signals. This work gives them high confidence that they have de-risked the new molecules.

An analyst on behalf of Ami Fadia asked if Neumora is planning any interim analyses for the ongoing KOASTAL studies and whether there have been discussions with the FDA about a potential regulatory path based on gender-specific efficacy.

Answer

President Joshua Pinto confirmed that no interim or futility analyses are planned for KOASTAL-2 and 3, citing the short 6-week duration of the studies. Chief Operating and Development Officer Daljit Aurora declined to comment on specific regulatory interactions but noted the company is evaluating the gender-based findings from KOASTAL-1 and will comment on potential paths at a later time if appropriate.

Ami Fadia asked about the drivers of NUPLAZID's continued strength, seeking color on growth across channels. She also inquired about Daybue's persistency in the open-label study for patients treated outside of COE settings.

Answer

Chief Commercial Officer Thomas Garner attributed NUPLAZID's strength to an uptick in referrals and prescriptions across all channels, including community and long-term care settings. For Daybue, he noted that the current real-world 18-month persistency of 45% aligns well with prior data. EVP, Head of R&D, Elizabeth Thompson, added that real-world persistency has consistently tracked slightly better than what was observed in clinical trials.

Ami Fadia inquired about the future trajectory of gross-to-net percentages for both DAYBUE and NUPLAZID, and also asked about the potential peak sales for DAYBUE.

Answer

CFO Mark Schneyer explained that DAYBUE's gross-to-net is expected to stay in the low 20% range, while NUPLAZID's will gradually increase over the next few years as the small manufacturer benefit under the IRA unwinds. He stated that while the company does not provide specific peak sales guidance for DAYBUE, they anticipate meaningful growth from current levels.

An analyst on behalf of Ami Fadia of Needham & Company sought clarification on the company's statement about achieving a $1 billion annualized sales run rate, asking about the expected growth mix between Daybue and NUPLAZID in 2025.

Answer

CFO Mark Schneyer clarified that the $1 billion figure represents the current annualized run rate based on Q3's $250 million in sales, not a formal 2025 guidance. He stated that the company is not yet providing 2025 guidance but confirmed that they expect growth in both franchises next year.

Asked follow-up questions on the ZANI GEA trial, including whether the data will be mature enough for an OS analysis, the bar for a positive OS trend, and what would constitute an incremental benefit for the arm containing tislelizumab.

Answer

The company stated that the first of three planned OS analyses will occur with the final PFS analysis, and the extended time to reach the PFS endpoint improves the statistical power for this OS look. The totality of data will be considered for approval, citing precedent in the space. For the tislelizumab arm, it would need to be 'meaningfully contributing' with a favorable benefit-risk profile.

Ami Fadia of Needham & Company requested an update on the JZP-441 study in narcolepsy type 1 and asked how the company's business development priorities have evolved with recent market changes.

Answer

Rob Iannone, Head of R&D, confirmed the JZP-441 trial has been initiated but gave no guidance on data timing. Phil Johnson, CFO, stated that BD priorities are unchanged, with a focus on rare and orphan diseases. He affirmed Jazz is in a strong financial position to pursue deals, though policy uncertainty might lead to a slightly more conservative capital structure.

Ami Fadia of Needham & Company inquired about the market dynamics of the oxybate franchise, including the competitive impact on the business, the source of patient switches to Xywav, and the expected payer landscape once true generic versions of Xyrem launch.

Answer

Renée Galá, President and COO, highlighted Xywav's strong performance, with patient adds coming from both new-to-oxybate patients and switches from all high-sodium oxybates. She noted that when full generics launch (anticipated in 2026), they will require their own REMS, and Xywav's value will be driven by its low-sodium differentiation, supported by strong payer coverage and ongoing data generation. Bruce Cozadd, CEO, added that the high-sodium business now represents less than 10% of total revenue.

Ami Fadia from Needham & Company asked about the competitive dynamics in the narcolepsy market, the impact of new entrants, patient switching behavior for Xywav, and future payer dynamics with potential generic entry.

Answer

President & COO Renée Galá highlighted Xywav's strong performance, with patient adds coming from both new-to-oxybate patients and switches from all high-sodium oxybates. She noted that for 2026, with potential full generic entry, Xywav's differentiation on low sodium and its lack of AB-rating to generics will be key. She emphasized strong payer coverage and continued data generation to support its value.

Ami Fadia from Needham & Company, LLC asked about the PD-L1 status of patients in the zanidatamab Phase II GEA study and the strategic goals of the new pan-tumor basket trial.

Answer

EVP, Global Head of R&D, Rob Iannone, responded that they have not analyzed the GEA data by PD-L1 status and do not believe it affects zanidatamab's efficacy. He explained the pan-tumor trial is designed to efficiently generate data across a variety of HER2-expressing tumors, including in patients naive to HER2 therapies and those previously treated with other HER2 agents, to potentially support a broad, tumor-agnostic label.

Ami Fadia asked about zanidatamab in GEA, specifically the PD-L1 status breakdown in the Phase II study and any efficacy differences. She also inquired how the new pan-tumor trial is broader than previous studies.

Answer

EVP, Global Head of R&D Robert Iannone explained that PD-L1 status was not analyzed as it's not believed to affect zanidatamab's efficacy. He described the new pan-tumor study as a way to efficiently extend experience into rare, HER2-treatment-naive tumors and gather more data in HER2-agent-experienced patients, potentially supporting a broad pan-tumor indication.

Ami Fadia of Needham & Company asked for details on the placebo response from the CONNECT study and the assumptions for the RECONNECT trial. She also questioned if Harmony has considered a prospective study to evaluate the synergy between Wakix and orexin agonists.

Answer

Chief Medical & Scientific Officer Dr. Kumar Budur provided specific placebo response figures from the published CONNECT data and confirmed the RECONNECT study is over 90% powered to detect a one-point placebo-adjusted difference. President & CEO Dr. Jeffrey Dayno acknowledged they have contemplated the synergistic opportunity with orexins, but the current focus remains on advancing their next-generation pitolisant programs and growing the Wakix business.

Ami Fadia asked how market dynamics might evolve with orexin agonists entering the market and whether polypharmacy will persist. She also asked about the potential for exploring EPX-100 in a broader DEE population.

Answer

Dr. Kumar Budur, CMSO, responded that despite strong orexin data, narcolepsy will likely remain a polypharmacy market due to its multiple symptoms. He noted pitolisant HD is targeting fatigue, a key unmet need. Regarding EPX-100, he confirmed that pursuing a broader DEE indication is an option under evaluation, but the current focus is on the ongoing Dravet and LGS trials.

Ami Fadia asked for a definition of success for the ZYN002 trial, whether the prior CONNECT study would be accepted by the FDA, and what beyond trial design is needed to demonstrate Pitolisant HD's benefit in IH.

Answer

Dr. Kumar Budur, Chief Medical and Scientific Officer, defined ZYN002 success as a statistically significant and clinically meaningful result on the social avoidance subscale, noting a 3-point change is meaningful. He confirmed the CONNECT study data would be part of the NDA package. For Pitolisant HD in IH, he stated the INTUNE study provided a good understanding of the necessary duration and endpoints.

Ami Fadia inquired about the safety differentiation of EPX-100 compared to competitors and asked about the clinical development strategy for other Developmental and Epileptic Encephalopathies (DEEs) beyond Dravet and Lennox-Gastaut syndromes.

Answer

Chief Medical and Scientific Officer Dr. Kumar Budur highlighted EPX-100's established safety profile, noting its prior market history and favorable data from ongoing trials, which do not require special monitoring like some competitors. He stated that while preclinical data supports broader use in DEEs, the current focus is on completing the pivotal Dravet and LGS trials before potentially pursuing a broader or basket-trial approach. CEO Dr. Jeffrey Dayno affirmed this focused-to-broad strategy.

Ami Fadia of Needham & Company asked for clarification on why physicians were slow to adjust background therapies, the impact on efficacy and safety in the few patients who had adjustments, and what data is needed to convince physicians to enroll in the POWER-3 monotherapy switch study.

Answer

President & CEO Marcio Souza speculated that physicians are habituated to layering drugs and that it took time for them to adapt to a new approach. For the patients whose background medications were reduced, he confirmed that adverse events resolved without any negative impact on efficacy; in fact, efficacy was better in the long run. He stated that this result demonstrates the background therapy was primarily causing side effects, which builds strong confidence for the POWER-3 study, for which he reported incredible enthusiasm from physicians.

Ami Fadia inquired about the percentage of patients who have completed randomization in the Ulixa studies and whether a slowdown prompted the timeline shift. She also asked about the patient mix in the RADIANT study and the efficacy assumptions for relutrigine in the broader EMERALD study.

Answer

CEO Marcio Souza stated there was no slowdown in Ulixa enrollment and the timeline shift was a strategic decision. For the RADIANT study, he said the target is 50 patients with an expected mix of 70% focal and 30% generalized epilepsy. For the EMERALD study, he conveyed confidence that relutrigine's efficacy would be at or above the high bar set in the SCN2A cohort, given SCN2A is one of the most severe forms of the disease.

Ami Fadia inquired about the gating factors for a pivotal program for PRAX-628 in generalized epilepsy. She also asked how age and severity might impact seizure reduction for PRAX-562 and its potential read-through to other DEEs.

Answer

CEO Marcio Souza explained that the RADIANT study, which includes generalized epilepsy patients, is a key step toward a potential pivotal program by providing experience and data in that population. For PRAX-562, he noted that patients are young with high seizure burdens, making any gains highly meaningful. He believes the results will be translatable to a large number of DEEs with similar characteristics, such as high seizure burden and poor tolerability to existing drugs.

Ami Fadia asked about the gating factors for initiating a pivotal program for PRAX-628 in generalized epilepsy and if RADIANT is meant to inform the dose. She also questioned how age and severity might impact PRAX-562 seizure reduction, the read-through to other DEEs, and if the ulixa interim analysis carries a statistical penalty.

Answer

Executive Marcio Souza explained that RADIANT is a key first step toward a generalized epilepsy program, designed to demonstrate maximum efficacy and collect crucial PK data before launching a formal pivotal study. For PRAX-562, he noted the young age and high seizure burden of enrolled patients make any gains highly meaningful and translatable to other DEEs. He did not directly address the statistical penalty but reiterated the interim analysis uses a 'promising zone' approach.

A representative for Ami Fadia at Needham & Company asked about OJEMDA's penetration within each priority center and the strategies being employed to increase adoption in accounts with lower usage.

Answer

CCO Lauren Merendino reported 100% penetration in Priority 1 accounts and 75% in Priority 2, stating the focus has shifted from breadth to depth of prescribing. The strategy involves encouraging use in a wider range of appropriate patients and promoting earlier, second-line use as physician confidence grows. CMO Dr. Elly Barry added that the conservative nature of pediatric oncologists, who weigh long-term effects, necessitates time to build this confidence.

On behalf of Ami Fadia, a representative asked what Priority 2 and 3 prescribers need to see to drive uptake and about the number of sales interactions required. A second question requested an overview of DAY301 and its differentiation from other PTK7-targeting ADCs.

Answer

Chief Commercial Officer Lauren Merendino explained that non-prescribing physicians are either waiting for the right patient or are later adopters who want to see peer experience first. CEO Jeremy Bender detailed that DAY301 is a PTK7-targeted ADC with an exatecan (TOPO1) payload, which he believes has first- and best-in-class potential based on its preclinical profile compared to other PTK7 ADCs in development.

Ami Fadia of Needham & Company attempted to clarify the number of new patients added in Q3 using prescription data and asked about the expected timeline for initial data from the DAY301 trial.

Answer

CEO Jeremy Bender declined to confirm patient-count calculations, reiterating the focus on the steady pace of new patient demand. Regarding DAY301, he confirmed the trial is set to begin in Q4 2024 or early Q1 2025 but stated the company has not yet provided guidance on a data release timeline for 2025.

Ami Fadia of Needham & Company asked about Axsome's strategy for managing operating margins and investment across its diverse portfolio, particularly in the context of potentially acquiring new assets and the return on investment (ROI) decisions that guide the company's path to profitability.

Answer

Nick Pizzie, CFO, responded that R&D spending is concentrated on late-stage programs with a high probability of success and high ROI. He also highlighted that the commercial infrastructure built for Sunosi and Auvelity provides significant operating leverage for future product launches, which is expected to enhance the ROI of those programs.

Ami Fadia inquired about the company's philosophy on operating margin evolution over the next few years and requested more granular detail on the 2025 operating expense outlook, especially with the upcoming launch of Symbravo.

Answer

Chief Financial Officer Nick Pizzie stated that the company will take a strategic, ROI-focused approach to the Symbravo launch, leveraging its digital-centric platform to ensure efficient SG&A spend. He reiterated that the launch costs are factored into the existing cash runway, which is expected to last until cash flow positivity, and that the overall strategy is to grow the top line faster than operating expenses.

An analyst on for Ami Fadia of Needham & Co. asked about expected Q4 prescription trends for Auvelity considering holidays, the timing of Q4 data readouts, and whether the EMERGE study impacts the AXS-07 regulatory decision.

Answer

CCO Ari Maizel acknowledged a likely Q4 seasonality impact but expressed optimism for continued growth. CEO Herriot Tabuteau stated the Q4 readouts are 'right around the corner' and confirmed the EMERGE trial for AXS-07 is not required for the regulatory decision but will inform commercial strategy.

Ami Fadia of Needham & Company asked for more detail on the expected acceleration in ZURZUVAE growth following commercial expansion and requested quantification of any inventory changes that impacted revenue.

Answer

CEO Barry Greene and COO Chris Benecchi responded. Greene highlighted the over 20% Q1 growth and reiterated expectations for continued quarter-on-quarter growth, driven by new prescribers becoming repeat writers, but declined to provide a specific forecast. Benecchi added that inventory will fluctuate as wholesalers adjust to the product's growth trajectory and sales force expansion, emphasizing that patient demand is the most reliable indicator of performance.

Ami Fadia sought to quantify the increase in investments for DTC and other media efforts, asked if further sales force expansion is planned for later in the year, and inquired about the balance of investment between Sage and Biogen.

Answer

CEO Barry Greene confirmed the commercial plan is a 50-50 co-investment with Biogen, with both parties expanding their sales forces and other promotional efforts. COO Chris Benecchi added that the company is currently in the midst of these investments, including social media and connected TV campaigns, and expects them to have an impact as they are rolled out, but did not provide specific quantification.

Ami Fadia asked for clarity on the market dynamics for PPD treatment, specifically the split between OB/GYNs and psychiatrists, and if patient severity differs across these prescribers.

Answer

CEO Barry Greene stated that over 70% of Zurzuvae prescriptions come from OB/GYNs, which is the company's primary focus for early intervention. He clarified that Zurzuvae is being used for mild, moderate, and severe PPD across all specialties, emphasizing that PPD severity can fluctuate rapidly, making any diagnosis a trigger for intervention.

Asked about the underlying assumptions for the $2 billion guidance, including patient growth, market expansion, ex-U.S. sales, competitor entry, and whether the current commercial footprint will be expanded.

Answer

The $2 billion target is viewed as conservative, based on a large and growing diagnosed patient population with low current penetration. The main competition is symptom-directed therapy. The commercial field force is being expanded, with the impact expected in 2026 and beyond, while near-term investments focus on driving urgency to treat.

Asked about the development and differentiation strategy for elenestinib compared to AYVAKIT, and how the upcoming BLU-808 data will guide indication selection.

Answer

Elenestinib is positioned as a long-term follow-on to AYVAKIT, aiming to provide further clinical differentiation to extend the SM franchise's growth. For BLU-808, the initial data will inform dose-tuning for various type 2 inflammatory diseases, which will be explored in cohort studies before selecting a registrational path.

Asked about the spectrum of disease severity among ISM patients, how the threshold for treatment is evolving, and what biomarkers from the BLU-808 healthy volunteer study will indicate its broader potential.

Answer

The launch is seeing a broadening of treated patients from the most severe to those with fewer but still significant symptoms. The company also highlighted the progressive nature of ISM as a reason to treat. For BLU-808, the healthy volunteer study will assess a wide range of pharmacodynamic markers, but the broader strategy is to rapidly move into multiple clinical proof-of-concept studies to determine its applicability across various diseases.

Asked about the doses being evaluated for ITI-1284, the rationale for studying it as both monotherapy and adjunctive therapy in GAD, and the reasoning for choosing the BEHAVE-AD endpoint for the Alzheimer's psychosis trial.

Answer

The study designs, including doses and endpoints, were determined following discussions with the FDA. Testing two doses establishes a range, and the BEHAVE-AD scale was deemed appropriate for the psychosis indication. The company sees an opportunity for a well-tolerated and effective drug in GAD for both monotherapy and adjunctive use.

Asked for clarification on the regulatory filing strategy for MDD if trial results are mixed, and for an update on the path forward for the mixed features indication.

Answer

The company stated it is too early to define the regulatory strategy for a mixed trial outcome (one positive, one negative), as it would depend on the data. For mixed features, they are waiting for official minutes from a recent constructive FDA meeting before providing an update.