Eliana Merle

Eliana Merle asked about the potential for KT-621 to show efficacy improvements over dupilumab, based on both clinical and preclinical data, and requested a comparison of respiratory preclinical model data to atopic dermatitis preclinical data.

Answer

Nello Mainolfi, Founder, President, and CEO, stated that in preclinical asthma models, KT-621 consistently performed at least as well as, and often better than, dupilumab. He noted that preclinical AD models are less robust and 'mostly useless.' Clinically, KT-621 demonstrated robust activity, comparable to or numerically exceeding injectable biologics in biomarkers (IL-31, eotaxin, FeNO) and clinical endpoints. He emphasized that the primary goal is to deliver an oral drug with biologics-like activity, safety, and convenience, which would transform the treatment paradigm regardless of exact head-to-head superiority.

Eliana Merle asked about the potential for KT-621 to demonstrate efficacy improvements over dupilumab, based on both clinical and preclinical data. She also requested a comparison of KT-621's respiratory preclinical model data with its preclinical performance in atopic dermatitis.

Answer

CEO Nello Mainolfi cautioned against direct comparisons of early-stage KT-621 with dupilumab but noted that preclinical asthma models showed KT-621 performing at least as well, and often better. He stated that preclinical AD models are less robust but highlighted KT-621's strong clinical biomarker and endpoint activity in early studies, consistently matching injectable biologics. He emphasized the program's goal to deliver a convenient oral drug with biologics-like efficacy and safety.

Eliana Merle of UBS Group AG inquired how Kymera is thinking about the doses it will study in the Phase IIb trials for atopic dermatitis versus asthma, and whether STAT6 expression differences could affect dosing.

Answer

CEO Nello Mainolfi clarified that preclinical data shows STAT6 expression levels do not impact the drug's degradation kinetics. CMO Jared Gollob added that since preclinical models for both indications show optimal activity at similar degradation levels (90%+), they expect to use similar doses in both the AD and asthma Phase IIb studies.

Eliana Merle raised questions about the safety profile of the IRF5 degrader, citing literature suggesting IRF5 can act as a tumor suppressor, and asked if the company would explore lower degradation levels for long-term safety.

Answer

President and CEO Nello Mainolfi and Senior Director of Immunology Veronica Campbell addressed the concerns. Nello Mainolfi highlighted that IRF5's safety is supported by its cell-specific expression and activation only in disease contexts. Veronica Campbell added that broad genomic analysis shows little evidence for a tumor suppressor role and that the initial report has not been replicated. She noted that other IRF family members critical for immune surveillance remain intact.

Eliana Merle asked for a more in-depth view on the tafamidis IP situation, BridgeBio's base case for generic entry in the U.S., and why this debate is considered irrelevant for Attruby's uptake. She also followed up on the evolving use of serum TTR in clinical practice and its potential to demonstrate differentiation for physicians.

Answer

SVP of Strategic Finance Chinmay Shukla explained that Pfizer's EU patent withdrawal limits precedential value, and BridgeBio's EU base case remains 2030 generic entry due to Orphan Drug Exclusivity. For the U.S., he noted Dexcel conceded infringement of a polymorph patent and U.S. law has a higher invalidity bar. He reiterated confidence in Vyndamax's protection into the 2030s, potentially 2035. Shukla emphasized that the IP debate is a 'sideshow' as Attruby's uptake is driven by differentiated clinical data, and a less efficacious generic product won't displace a superior therapy, citing historical patterns. CEO Neil Kumar discussed recent JACC papers correlating serum TTR elevation with mortality reduction (5% relative risk reduction per 1 mg/dL increase). He highlighted Attruby's 3 mg/dL increase over tafamidis in OLE, suggesting a 15% relative risk reduction, and expects serum TTR to become a more important marker for therapeutic choice.

Eliana Merle followed up on the evolving use of serum TTR in clinical practice and its potential to differentiate Attruby for physicians.

Answer

Neil Kumar, CEO, referenced recent JACC papers correlating serum TTR elevation with reduced mortality (approximately 5% relative risk reduction per 1 mg/dL increase). He highlighted Attruby's significantly higher serum TTR elevation, noting a 3 mg/dL increase when patients switched from tafamidis to acoramidis in the OLE of ATTRibute, suggesting a 15% relative risk reduction in mortality. He anticipates serum TTR becoming an increasingly important marker for drug action and therapeutic choice.

Eliana Merle of UBS inquired about commercial trends for Attruby since the approval of its competitor, AMVUTTRA, asking about the rate of new patient prescriptions and if Attruby has advantages in specific patient segments.

Answer

CCO Matt Outten responded that AMVUTTRA appears to be positioned for the mixed phenotype niche, which is about 10% of the market. He noted that BridgeBio is not seeing significant uptake of the competitor outside of that segment, citing AMVUTTRA's higher price and less compelling variant data. He also pointed to the financial challenges of its buy-and-bill model for community physicians as a competitive advantage for Attruby.

Eliana Merle asked about the European COVID vaccination market, including vaccination rates and pricing evolution, the pathway for a potential flu-COVID combination vaccine approval outside the U.S., and discussions around potential flu strain selection closer to the season start in Europe and Canada.

Answer

Stephen Hoge, President, discussed mNEXSPIKE's strong profile for the European COVID market, expecting it to be larger than current estimates and a meaningful driver of growth from 2027. He anticipates European approval for the combo product this year, with filings progressing in Canada. He confirmed strong international appetite for better, later flu strain matching, citing Moderna's mRNA technology's ability to tailor.

Eliana Merle asked for elaboration on the European COVID vaccination market, including vaccination rates and pricing evolution, the pathway for flu/COVID combination vaccine approval outside the U.S., and discussions with European and Canadian regulators regarding future flu strain selection.

Answer

Stephen Hoge, President, discussed the European COVID market, noting mNEXSPIKE's strong profile and the market's potential to be larger than the current $700 million 'shots in arms' estimate. He expects mNEXSPIKE to be competitive, driving growth from 2027. For the flu/COVID combination vaccine, international reviews are progressing, with European approval hoped for this year, potentially leading to a 2027 launch. He also confirmed discussions with European and Canadian regulators about later and more diverse strain selection for flu vaccines, similar to COVID, to improve matching and efficacy.

Eliana Merle inquired if a 2026 data readout for the INT (intismaran) Phase III trial is still a reasonable expectation and asked about plans for new trials for both INT and the newly prioritized Checkpoint program.

Answer

President Stephen Hoge confirmed a 2026 readout for the Phase III melanoma study remains possible, contingent on event accrual. He highlighted that the Phase II renal cell carcinoma study is now fully enrolled. For the Checkpoint program, he noted they are encouraged by early data and are advancing in first-line non-small cell lung cancer and metastatic melanoma, with plans to expand into more histologies.

Eliana Merle asked for a breakdown of Moderna's R&D spending, the flexibility for future cuts, and for more details surrounding the FDA clinical hold on the Norovirus program due to a single case of Guillain-Barré syndrome (GBS).

Answer

CFO Jamey Mock confirmed significant flexibility exists to reduce R&D spend from the guided $4.1 billion in 2025, noting over 50% of trial costs are for respiratory programs expected to wind down. President Stephen Hoge explained the Norovirus pause was a proactive measure for patient safety and transparency, and since enrollment for the season was complete, no impact on the study's timeline is expected.

Eliana Merle asked for characterization of the size of guaranteed ex-U.S. COVID vaccine contracts and the potential minimum sales outlook, as well as the expected time between the interim and final analyses for the CMV trial.

Answer

CEO Stéphane Bancel declined to disclose specifics on ex-U.S. contracts but stated that minimum purchase commitments would grow over time, despite a dip in 2025. President Stephen Hoge noted that CMV case accrual is steady and that the time to the final analysis, if needed, would not be a very long period and could happen quite quickly.

Tejas, on behalf of Eli Merle, asked for more details on the preclinical data for the KRAS program expected later in the year and how that might inform expectations for the Phase 1 trial of ARV-806.

Answer

CSO Angela Cacace detailed that upcoming preclinical data will highlight ARV-806's differentiation from inhibitors, its combinability with EGFR-targeted agents, and its ability to overcome resistance mechanisms. She also mentioned compelling data from the oral pan-KRAS program will be shared, including its potential for better combinability with immuno-oncology agents compared to pan-RAF inhibitors. This strong preclinical profile is driving investigator interest in the ongoing clinical trial.

Eliana Merle inquired about potential patient enrichment strategies for the frontline vepdegestrant trial and the company's latest thinking on predictors of ESR1 mutations. She also asked a broader strategic question about expanding the platform into new areas like immunology and the current timeline from target selection to a development candidate.

Answer

Chief Medical Officer Noah Berkowitz stated that while the frontline trial will likely exclude certain rapid progressors, there are no plans for molecular enrichment, as vepdegestrant targets both wild-type and mutant ESR1. CEO John Houston and CSO Angela Cacace explained that the company's focus remains on oncology and neuroscience, though some assets are being explored preclinically for immune indications. The speed to a candidate now largely depends on the availability of a quality ligand for a given target.

Eliana Merle of UBS asked about the potential for success in the non-ESR1 mutant population in the VERITAC-2 trial and what the minimum PFS threshold would be to secure a broader label.

Answer

CEO John Houston acknowledged the biological challenge but believes a portion of the wild-type population will respond. CMO Noah Berkowitz stated that the base case for approval is the ESR1 mutant subpopulation, following regulatory precedent. He clarified the study is not powered for the non-mutated group alone but is powered for the overall ITT population.

Jasmine, on for Eliana Merle at UBS, asked about the topics for the upcoming pre-BLA meeting with the FDA, the number of U.S. sites capable of performing the AMT-130 procedure, and the estimated prevalence of eligible patients.

Answer

CMO Walid Abi-Saab said the pre-BLA meeting will cover top-line data and CMC updates to ensure the package is ready for submission, with an update to follow. CEO Matt Kapusta estimated 50-55 U.S. sites are capable of the procedure and stated that with 35,000 diagnosed patients, the 'overwhelming majority' are in Stage 2 or 3 and would be potentially eligible.

Eliana Merle inquired about the latest progress on CMC work and its timeline for BLA readiness, and also asked about uniQure's confidence in the composition of the natural history comparator after FDA discussions.

Answer

CMO Dr. Walid Abi-Saab stated that a detailed BLA submission timeline, including CMC updates, will be provided in the next regulatory update. He noted they are leveraging experience from HEMGENIX. Regarding the natural history control, he expressed confidence that the final agreed-upon comparator will not yield significantly different outcomes from what has been previously reported.

Jason on for Eliana Merle asked for clarification on whether patients could start sotatercept during the PROSERA trial, the potential commercial impact of a combination effect, and details on the target population for the CIRANATA (PH-ILD) study.

Answer

CEO Faheem Hasnain and CMO Dr. Richard Aranda clarified that patients could be on a stable dose of sotatercept for 6 months prior to enrollment but could not start it during the trial (no 'drop-ins'). Dr. Aranda detailed the CIRANATA population, noting it has more stringent hemodynamic criteria than the INCREASE trial and targets specific ILD subtypes, confirming they expect a greater treatment effect in this more severe population.

An analyst on behalf of Eliana Merle inquired about Emflaza's performance, specifically regarding volume trends, gross-to-net impact from generics, and the company's strategy to defend the brand.

Answer

CBO Eric Pauwels attributed Emflaza's resilience to strong brand loyalty built over eight years of providing 'white glove' patient services. He stated that since generic pricing has been similar, there has not been a significant impact on gross-to-net. While expecting some erosion, he noted the team continues to add new patients and maintain existing ones.

Eliana Merle asked about the size and centralization of the PKU prescriber base, which patient segments are expected to be the most rapid adopters at launch, and for clarification on potential premium pricing.

Answer

CEO Dr. Matthew Klein and CBO Eric Pauwels explained that the prescriber base is highly centralized within approximately 103 centers of excellence. They anticipate rapid adoption across all patient segments, driven by strong interest from physicians and dietitians, and are preparing for a significant bolus of patients at launch.

Eliana Merle of UBS inquired about the range of outcomes from the Huntington's Type C meeting, the path forward if a surrogate endpoint is not supported, and why the FDA combined two meeting requests into one.

Answer

CEO Matthew Klein expressed optimism for using Huntington lowering as a surrogate endpoint but stated the company is prepared to initiate an efficacy trial regardless of the outcome, having the capital to do so. He clarified that the FDA's decision to combine the two meeting requests was purely for logistical efficiency due to the significant overlap in topics and personnel.

Eliana Merle of UBS asked for the company's latest thinking on its ex-U.S. commercial strategy and philosophy on partnering, and also requested more clarity on the timeline for FDA discussions and the public release of pivotal trial designs.

Answer

Dr. Mark Goldsmith, CEO, stated that the company does not provide timelines for regulatory interactions but will update when plans are definitive. On ex-U.S. strategy, he acknowledged strong interest from potential partners, creating significant optionality. He explained there is no rush to decide, and the company is using time to its advantage as its portfolio and organization mature. The recent hire of a Chief Global Commercialization Officer will help assess all options to best serve patients and the business.

Eliana Merle asked for clarification on SYFOVRE's net price per vial, noting a potential decline based on reported revenue versus vials shipped. She also inquired about gross-to-net variability and the sustainability of the 4% injection demand growth.

Answer

Executive Timothy Sullivan clarified that revenue is recognized when doses are shipped to distributors, not to physicians, so net price cannot be calculated from the disclosed vial shipments. He confirmed the Q1 gross-to-net was in the low 20% range and reiterated guidance of low-to-mid 20s for 2025. Executive Cedric Francois added that quarter-over-quarter injection volume growth is expected to continue as the market is still in the early stages of adoption.

Eliana Merle of UBS inquired about patient adherence and discontinuation rates for SYFOVRE, as well as expectations for sample usage beyond Q1.

Answer

CEO Dr. Cedric Francois stated that SYFOVRE adherence levels are similar to anti-VEGF therapies, which is a positive trend. EVP of Commercial David Acheson added that increased sample use is a sign of demand and that while the funding gap issue is temporary, its resolution timing is uncertain. Apellis will continue to supply samples to ensure patient treatment.

Eliana Merle from UBS requested clarification on SYFOVRE's volume trends, asking if the guided 'gradual' sales ramp implies Q4 vial growth similar to Q3's, and sought more detail on volume trends seen in October.

Answer

CFO Timothy Sullivan directed the question back to the prepared remarks, reiterating the company's guidance for 'low to mid-single-digit' percentage vial growth for the remainder of 2024. He declined to provide more specific intra-quarter guidance beyond that.

Eliana Merle asked for the latest expectations on a potential ELEVIDYS label update, including its timing, and what proportion of patients who delayed dosing in late March have since rescheduled.

Answer

President and CEO Douglas Ingram stated he did not have specific data on rescheduling but noted the delays were due to patients needing more information after the safety event. Head of R&D Dr. Louise Rodino-Klapac added that a labeling supplement was submitted in April to include the patient death, and the FDA has set a target completion date for the review no later than Q4 2025.

Eliana Merle from UBS asked for details on the limb-girdle muscular dystrophy (LGMD) Type 2E market, including prevalence, the number of diagnosed U.S. patients, the ambulatory vs. non-ambulatory mix, and potential revenue contribution.

Answer

CEO Douglas Ingram explained that while LGMD Type 2E is an ultra-rare disease, the three upcoming sarcoglycanopathy programs (2E, 2D, 2C) collectively represent a market opportunity about 25% the size of the Duchenne opportunity for ELEVIDYS. Chief Scientific Officer Dr. Louise Rodino-Klapac added that due to improved genetic diagnosis, the patient mix is now roughly an even 50-50 split between ambulatory and non-ambulatory.

Eliana Merle from UBS requested more details on ELEVIDYS site capacity, asking how many of the approximately 75 sites had dosed patients in Q3 and how concentrated the dosing has been across these centers.

Answer

Chief Customer Officer Dallan Murray stated that the vast majority of the 75 certified treatment centers have dosed patients. However, he and CEO Doug Ingram clarified that the company does not provide specific details on dosing concentration per site, preferring to focus guidance on overall net product revenue.

Eliana Merle asked about JOURNAVX's retail pharmacy stocking, inquiring about the target number of locations. She also asked about the expected trend in the mix of retail versus hospital scripts and the average duration of prescriptions being written.

Answer

CCO Duncan McKechnie stated that the goal is broad retail availability, and at launch, JOURNAVX was in about 95% of U.S. retail locations. He confirmed the initial script mix is heavily weighted toward the hospital discharge setting, as expected, and this trend should persist for the year. He noted the average prescription duration is about 14 days, which is in line with expectations for moderate to severe acute pain.

Eliana Merle requested more detail on new ALYFTREK patient starts, particularly from the segment that had previously discontinued other CFTR modulators, and asked what drives Vertex's confidence in recapturing these patients.

Answer

COO Stuart Arbuckle attributed the company's confidence to ALYFTREK's strong clinical profile, including its efficacy and convenient once-daily dosing. He explained that these patients want to be on the best possible therapy and ALYFTREK provides a compelling new option, though he did not provide specific data on the reasons for prior discontinuation.

Eliana Merle asked for early feedback on the YORVIPATH titration process for patients and physicians, and for any initial data or anecdotes regarding patient refill rates.

Answer

President and CEO Jan Mikkelsen responded by highlighting two key metrics that indicate success: patient adherence is extremely high, consistent with clinical trial levels, and the patient dropout rate is exceptionally low at under 1%. He summarized the strong retention by stating, 'If you start on YORVIPATH, you stay on YORVIPATH,' implying the treatment is chronic and highly valued by patients.

Eliana Merle asked about the utilization of the QuickStart free drug program versus patients going directly to paid therapy. She also inquired about pricing dynamics and whether formulary inclusion for cardiomyopathy was affecting the price for the polyneuropathy indication.

Answer

Chief Commercial Officer Tolga Tanguler confirmed a single price exists for both indications. He stated that the use of the QuickStart program is "very limited," consistent with the experience in polyneuropathy. He emphasized that patients are converting to paid therapy effectively across all payer types, with the majority having a zero dollar co-pay, indicating strong access.

Eliana Merle asked for a characterization of the growth mix in the TTR guidance between polyneuropathy and cardiomyopathy, and for more detail on how value-based agreements would work for cardiomyopathy.

Answer

Chief Commercial Officer Tolga Tanguler declined to break down the guidance further but reiterated that growth is expected to accelerate in the second half of the year. Regarding value-based agreements (VBAs), he noted they cover a significant portion of PN lives and are based on clinical outcomes. He anticipates this successful model will carry over to the cardiomyopathy indication.

Eliana Merle inquired about Alnylam's progress in developing RNAi delivery to new tissues like adipose and muscle, asking about initial target indications and the platform's competitive advantages.

Answer

Chief Medical Officer Pushkal Garg explained that Alnylam is leveraging human genetics to guide its pursuit of new tissues, noting the platform's favorable tolerability and infrequent dosing profile. He deferred a substantive update to a future R&D Day for competitive reasons. CEO Yvonne Greenstreet added that expanding to extrahepatic tissues is a key innovation driver for the company.

Eliana Merle inquired about the expected growth trajectory for Rezdiffra, particularly considering the potential market entry of semaglutide for MASH.

Answer

CEO William Sibold stated that with only 5% penetration in their 315,000-patient target market, there are years of growth ahead. He believes a competitor's entry will expand the market by accelerating diagnosis, and Rezdiffra's strong profile will ensure continued growth. CFO Mardi Dier added that Madrigal expects robust quarter-over-quarter and full-year 2025 sales growth.

Eliana Merle from UBS asked if the FibroScan benefits in the F4 data were consistent across different baseline liver fat levels and which patient subgroups showed greater VCTE reductions. She also inquired about the potential for further long-term data cuts from the study.

Answer

CEO William Sibold indicated that more detailed data would be shared at a future medical meeting. Dr. Michael Charlton, Head of Clinical Development, emphasized the clinical predictivity of the results, noting that a 25% decline in liver stiffness in similar patients has been shown to project a 30-40% decreased likelihood of liver-related clinical events.

Eliana Merle asked about the cadence of new patient starts for Rezdiffra and whether Madrigal anticipates payers will require a step-through with GLP-1s if Novo Nordisk's ESSENCE trial shows a strong fibrosis benefit.

Answer

CEO William Sibold explained that patient additions are steady and the company has not yet reached a steady state. Regarding potential competition, he noted that payers have not required a GLP-1 step-through to date and emphasized that real-world practice differs from controlled trials, highlighting Rezdiffra's strong product profile and established payer relationships.

Eliana 'Ellie' Merle from UBS requested more detail on the upcoming functional data for the DMD program, asking what to look for and what would be considered differentiating. She also asked about the statistical analysis plan for the pivotal study's functional data, including any use of natural history comparisons discussed with the FDA.

Answer

CEO Curran Simpson outlined that the next functional data update will include longer-term follow-up for patients at both dose levels and initial data for new patients in the dose level 2 cohort. Chief Medical Officer Dr. Steve Pakola added that they will report on time function tests and NSAA. He confirmed they compare results to matched external natural history controls to provide context and that this methodology was part of their successful end-of-Phase II discussions with the FDA.

Eliana Merle inquired about the future revenue mix of VOXZOGO between U.S. and ex-U.S. markets and asked about the proportion of untreated eligible patients with achondroplasia in the U.S. and the reasons for non-treatment.

Answer

Chief Commercial Officer Cristin Hubbard stated that the U.S. revenue contribution for VOXZOGO, currently around 25%, is expected to increase over time. She attributed non-treatment to factors like awareness and access to prescribers, which are being addressed via increased commercial efforts. Chief R&D Officer Gregory Friberg added that they are continuously building the clinical data set on proportionality and quality of life to increase physician and family comfort with the therapy.

Eliana Merle requested more color on the drivers of growth in the Enzyme Replacement Therapy (ERT) business and the company's confidence in sustaining high single-digit growth, asking for details on the new initiatives mentioned.

Answer

EVP, Chief Commercial Officer Cristin Hubbard attributed the growth primarily to strong Palynziq uptake in the U.S., driven by new patient starts and re-engagement of discontinued patients. She outlined future initiatives including high-yield diagnostic efforts, adherence programs, and geographic expansion, noting that the new business unit structure will also drive urgency and accountability.

Eliana Merle inquired about the Livdelzi IDEAL study in partial UDCA responders, asking about enrollment progress and the potential for the study to expand the drug's label and eligible patient population.

Answer

CMO Dietmar Berger confirmed that enrollment is on track. CCO Johanna Mercier added that this partial responder population represents about one-third of patients, or 20,000-25,000 people in the U.S. and a similar number in Europe, highlighting a significant opportunity to expand Livdelzi's reach.

Eliana Merle asked about Amicus's pipeline strategy, specifically the balance between internal development and external business development, and the company's focus regarding therapeutic modalities and stages of development.

Answer

President and CEO Bradley Campbell outlined a strategy focused on acquiring de-risked, late-stage, or commercial assets within the next 12-24 months to leverage their existing infrastructure. Chief Development Officer Dr. Jeff Castelli and Chief Business Officer Sebastien Martel added that internal efforts are focused on next-generation therapies for Fabry and Pompe, while external BD targets adjacent rare disease areas like renal, cardio, and metabolic disorders.

Eliana Merle asked about the characteristics of U.S. patients switching from Nexviazyme to Pombiliti and Opfolda, particularly their average time on the prior therapy.

Answer

President and CEO Bradley Campbell stated that, as anticipated, most patients switching from Nexviazyme have been on that therapy for one to two years. He noted a large group of patients is now reaching this timeframe, creating a significant opportunity. He also observed that some patients switch earlier, often influenced by positive word-of-mouth, a trend the company hopes will grow.

Eliana Merle asked for an update on the flu-COVID combination vaccine program following a Phase III endpoint miss and inquired about the timeline for the second-generation program, especially in light of competitor progress.

Answer

Chief Strategy Officer Ryan Richardson stated that BioNTech is working with Pfizer on a next-generation flu-COVID combo vaccine. While it's too early for a precise roadmap, he expressed confidence that issues from the initial trial can be addressed through construct optimization, supported by early evidence. He indicated that updates and a more definitive roadmap are planned for 2025.

Eliana Merle asked for the latest thinking on the Phase II initiation timeline for ARO-RAGE in asthma, including key gating factors, and inquired about the timeline for seeing additional data from other preliminary clinical programs.

Answer

Dr. Christopher Anzalone, President and CEO, explained that plans for the ARO-RAGE Phase II study are currently in development as they evaluate patient types and treatment duration. He provided no new guidance on data timing for other programs, stating data will be presented once studies are complete and results are interpretable.

Inquired about the broader implications of the upcoming German patent ruling on other IP cases and whether certain patent families are more valuable for potential damages.

Answer

The company stated that the German ruling on one patent won't affect others, as each is judged on its merits. The potential value for damages is tied to the patent's grant date, with earlier patents being more valuable. They highlighted the strength of their broad IP portfolio.