Luca Issi

Luca Issi pressed for further clarification on Ionis's confidence in Olezarsen's priority review, contrasting past statements with the current standard review assumption in guidance. He also asked about the absence of European sites (excluding the U.K.) for the Angelman syndrome program on ClinicalTrials.gov, questioning if it relates to regulatory preferences for sham-controlled trials.

Answer

CEO Brett Monia reiterated that the company cannot speak for the FDA regarding priority review, maintaining that assuming standard review for guidance is responsible, with potential adjustments if priority review is granted. Executive VP and Chief Development Officer Holly Kordasiewicz explained that Ionis has submitted to Europe for the Angelman program and plans to open sites there once approval is received.

Luca Issi sought further clarification on Ionis's guidance assuming standard review for olezarsen, asking if anything has changed regarding their confidence in priority review or if it's simply conservatism. He also inquired about the absence of European sites (excluding the U.K.) for the Obidutersen program in Angelman syndrome, asking if it relates to European regulators' preference for sham-controlled trials.

Answer

Brett Monia, CEO, reiterated that Ionis is in the FDA's evaluation period for priority review and that assuming standard review for guidance is the responsible approach at this stage, with adjustments to be made if priority review is granted. Holly Kordasiewicz, Chief Development Officer, explained that European sites for Obidutersen are pending regulatory approval, and Ionis plans to open them as soon as that approval is received.

Luca Issi questioned if the greater than $1 billion peak revenue opportunity for Olzarsen in SHTG was conservative, given the estimated 1 million patient TAM and potential pricing, implying low penetration. He also asked about the filing strategy for Olzarsen, specifically whether both 50mg and 80mg doses would be filed.

Answer

Brett Monia, CEO, confirmed that both 50mg and 80mg doses of Olzarsen would be filed to provide dosing flexibility. Kyle Jenne, Chief Global Product Strategy Officer, reiterated the greater than $1 billion peak sales estimate, acknowledging ongoing unknowns regarding payer and pricing dynamics, and stated that updated information would be provided as market research progresses.

Luca Issi questioned if the $1 billion+ peak revenue opportunity for olzarsen in sHTG was conservative, given the estimated 1 million high-risk patients and potential pricing, implying low market penetration. He also asked about the latest thinking on filing both 50mg and 80mg doses for olzarsen.

Answer

Brett Monia, CEO, Ionis, confirmed that the company plans to file both 50mg and 80mg doses for olzarsen, believing dosing flexibility will be well-received. Kyle Jenne, Chief Global Product Strategy Officer, Ionis, reiterated the 'greater than $1 billion' peak sales estimate, acknowledging ongoing unknowns regarding payer and pricing dynamics, and stated that updated information would be provided as more market research is completed.

Luca Issi of RBC Capital Markets asked if the physician view that triglyceride lowering is sufficient (without needing AP outcome data) applies globally or just in the U.S., and how uptake outside the U.S. might be affected without strong AP data. He also asked if the upcoming AP data statement would be qualitative or quantitative.

Answer

CEO Brett Monia asserted that U.S. physicians are convinced of the need to lower triglycerides to reduce AP risk. CGO Kyle Jenne added that while triglyceride lowering is sufficient for EU regulatory approval, payer dynamics are more complex. He noted their partner Sobi could leverage existing FCS data and potentially focus on high-risk SHTG subgroups for reimbursement. Monia declined to specify if the AP statement would be qualitative or quantitative.

Luca Issi questioned the rationale for selecting expressive communication as the primary endpoint for the Angelman syndrome study over cognition. He also asked for Ionis's reaction to Eli Lilly discontinuing its APOCIII siRNA program and the potential implications for olezarsen.

Answer

Chief Clinical Development Officer Eugene Schneider explained that expressive communication was chosen as the endpoint because it showed robust results in the HALO study and is what families consistently identify as most important. Regarding Lilly, Chief Development Officer Richard Geary and CEO Brett Monia suggested Lilly may have been deterred by olezarsen's first-mover advantage and noted that Ionis had long ago concluded that the primary unmet need for an APOCIII inhibitor is in sHTG, not cardiovascular outcomes, a conclusion Lilly appears to have recently reached.

Luca Issi asked for Emil Kakkis's reaction to the ReGenxBio CRL, specifically whether the FDA's reservations about using serum biomarkers for ultra-rare diseases indicate a raised bar for all companies in this space. He also asked Howard Horn for the proportion of cash versus non-cash in the $730 million-$760 million 2026 top-line guidance.

Answer

CEO Emil Kakkis stated that while the FDA appears to be pushing back more on biomarkers, Ultragenyx believes its heparan sulfate data for MPS IIIA, supported by the Reagan-Udall meeting, definitively demonstrates a relationship to disease and efficacy. He expressed concern that the FDA's stance might raise the bar for rare disease products, emphasizing the importance of biomarkers for measuring disease and efficacy, and the need for the FDA to align actions with public statements supporting accelerated approval in rare diseases. CFO Howard Horn noted that the question about cash vs. non-cash proportion in 2026 revenue would be followed up offline.

Luca Issi asked for Emil Kakkis's reaction to the REGENXBIO CRL, specifically regarding FDA reservations about using serum biomarkers compared to natural history for ultra-rare diseases, and whether this indicates a raised bar for all companies developing drugs for such conditions. He also asked about the proportion of cash versus non-cash in the 2026 top line guidance.

Answer

Emil Kakkis, Chief Executive Officer and President, stated that while the FDA appears more resistant to biomarkers than agreed upon at the Reagan-Udall meeting, he believes biomarkers are definitive disease cause measurements and accurate for efficacy. He emphasized the need for the FDA to appreciate the science behind biomarkers and support accelerated approval for rare diseases. Howard Horn, Chief Financial Officer, noted he would follow up offline regarding the cash vs. non-cash proportion of the 2026 revenue guidance.

Luca Issa inquired about the loss of exclusivity (LOE) for setrusumab, noting that some initial IP expires in 2028. He asked if this is foundational IP that could allow biosimilar entry soon after, or if additional IP estate exists to extend exclusivity.

Answer

Emil Kakkis, CEO and President, highlighted that orphan drug designation provides protection well past 2030. He also mentioned that biologics rarely face immediate biosimilar competition in the same way as small molecules, and that Ultragenyx is developing additional IP related to discoveries on chronic treatment. He expressed confidence in the combination of orphan drug exclusivity and existing IP to protect the program.

Luca Issi asked if the DSMB would share the p-value with the company if the second interim look for OI is not met, and whether a Priority Review Voucher (PRV) is only achievable if the trial succeeds at this interim due to the 2026 deadline.

Answer

CEO Emil Kakkis confirmed that if the interim analysis is not positive, they will only be told to continue the study and will not receive a p-value. Regarding the PRV, he acknowledged the October 2026 approval deadline makes hitting the interim more favorable, but noted the program's Breakthrough Therapy Designation could help accelerate the review process even if they file later. He also expressed confidence that the PRV program would be reauthorized by Congress.

Luca Issi asked about the expected duration of therapy for OI (chronic vs. capped) and the rationale for using a sham-controlled trial design for Angelman syndrome.

Answer

CEO Emil Kakkis stated that for OI, they believe chronic therapy is necessary, as patients lose ground after stopping treatment, and they are educating the FDA on this. For Angelman syndrome, CEO Emil Kakkis and CMO Eric Crombez explained that a sham control was chosen over placebo due to ethical feedback from regulators (FDA/EMA) regarding placebo injections in this pediatric population.

Luca Issi asked about the Huntington's disease program, specifically regarding the expected initial pharmacodynamic data on mutant huntingtin reduction in CSF later in the year, the preliminary nature of clinical data like CUHDRS, and the go/no-go decision criteria for initiating a pivotal Phase 3 trial based on target engagement versus functional signals.

Answer

Chief Research and Development Officer Pushkal Garg highlighted the unique exon-one targeting approach and the unmet need in Huntington's. He stated that in the ongoing Phase 1 program, they are seeking convincing evidence of Huntington's protein lowering (aiming for over 50%) and safety, noting challenges faced by prior efforts. While Phase 1 data is expected by year-end, clinical data will be preliminary. If safety and knockdown are favorable, they aim to accelerate to Phase 3 responsibly.

Luca Issi asked about the Huntington's disease program (ALN-HTT02), specifically regarding the expected initial pharmacodynamic data on mutant huntingtin reduction in CSF, the preliminary nature of clinical data like CUHDRS, and the go/no-go decision criteria for initiating a pivotal Phase 3 trial.

Answer

Pushkal Garg, Chief Research and Development Officer, highlighted the high conviction in the Huntington's program and its unique exon-one targeting approach. He stated that the Phase 1 program is seeking convincing evidence of Huntington's protein lowering (aiming for over 50% knockdown) and safety. While preliminary clinical data is expected by year-end, the focus for a go/no-go decision for Phase 3 will be on achieving good knockdown levels durably and safely, given the significant unmet need.

Luca Issi at RBC Capital Markets asked for the company's reaction to CMS's proposed 57% cut in PYP scintigraphy reimbursement, questioning if this would remain insulated to diagnostics or extend to therapeutics. He also sought comment on the subpoena from the U.S. Attorney General.

Answer

Yvonne Greenstreet, CEO, stated the company's intention to cooperate with the U.S. Attorney's office regarding the subpoena, declining further comment on legal matters. Tolga Tanguler, Chief Commercial Officer, acknowledged the importance of PB scan reimbursement for category growth but noted no current anxiety in health systems, expecting to manage the situation as policy clarifies, without directly addressing the insulation question.

Luca Issi asked about the company's reaction to CMS's proposed 57% cut in PYP scintigraphy reimbursement, whether this could extend to therapeutics, and requested an update on the subpoena from the U.S. Attorney General.

Answer

Yvonne Greenstreet, Chief Executive Officer, stated the company intends to cooperate with the U.S. Attorney's office regarding the subpoena and address any concerns about government price reporting. Tolga Tanguler, Chief Commercial Officer, acknowledged PYP scans as an important growth driver but noted no anxiety in health systems, and the company is monitoring policy clarification.

Luca Issi of RBC Capital Markets suggested the updated TTR guidance appeared conservative given the strong Q2 results and upcoming international launches, asking for management's perspective.

Answer

CFO Jeff Poulton reiterated the context for the guidance, which implies approximately $1 billion in year-over-year TTR growth. While expressing high confidence, he emphasized that it is only one quarter into the launch and they will reassess in Q3, stopping short of labeling the guidance as conservative.

Luca Issi asked about the likelihood of step-edits for AMVUTTRA, suggesting they are less likely for Medicare fee-for-service but more likely for commercial plans, and questioned where Medicare Advantage plans would fall on that spectrum.

Answer

Chief Commercial Officer Tolga Tanguler reported a "very nice broad uptake on all payer mix" with no significant restrictions. He confirmed no step-edits for fee-for-service and stated that they are "not seeing any step edits so far" for commercial or Medicare Advantage plans. He credited their value-based agreements for providing an advantage in securing access.

Luca Issi asked about the forward-looking trajectory for gross margin, given the significant royalty burden on AMVUTTRA sales.

Answer

Chief Financial Officer Jeff Poulton confirmed that gross margin on product sales, which was 81% in 2024, is expected to decrease. This is driven by AMVUTTRA being the fastest-growing product and having the highest royalty burden, with the average rate expected to rise from 21% into the mid-to-high 20s. He noted this could be offset in the future by high-margin collaboration revenue and the potential success of royalty-free Nucresiran.

Luca Issi asked about Ascendis Pharma's 2030 goal of remaining an independent and profitable biotech company, inquiring how this vision aligns with potentially operating under a larger pharmaceutical company's umbrella and the company's strategic path A versus path B. He also asked about the implications for formulary access and reimbursement given BioMarin's filing for full approval of VOXZOGO versus Ascendis Pharma's anticipated initial accelerated approval for TransCon CNP.

Answer

Jan Møller Mikkelsen, President and Chief Executive Officer, clarified that 'independent' refers to financial independence, signifying the company's ability to operate without needing external investment, transitioning to an 'adult life.' He stated that BioMarin's filing for full approval has no impact on Ascendis Pharma's regulatory pathway or approval for TransCon CNP, as they are entirely independent.

Luca Issi asked about Ascendis Pharma's strategic vision for 2030, specifically regarding remaining an independent and profitable biotech company versus potentially operating under a larger pharmaceutical company. He also asked about the implications of BioMarin filing VOXZOGO for full approval versus Ascendis Pharma's anticipated accelerated approval for TransCon CNP on formulary access and reimbursement.

Answer

Jan Møller Mikkelsen, President and Chief Executive Officer, defined independence as financial independence, signifying Ascendis Pharma's transition from a 'teenager' to an 'adult' company that no longer requires investor funding. He stated that BioMarin's filing for full approval has no impact on Ascendis Pharma's regulatory pathway or approval for TransCon CNP, and does not create any barriers.

Luca Issi of RBC Capital Markets asked about SG&A expense trends, the timeline for achieving quarterly profitability, and the company's potential exposure to U.S. tariffs or Most Favored Nation (MFN) pricing policies.

Answer

EVP & CFO Scott Smith suggested that quarterly operating expenses of around €190 million is a reasonable run rate and confirmed the company expects to reach quarterly cash flow positivity this year, noting Q2 was near breakeven excluding currency impacts. Regarding tariffs/MFN, he stated they are well-positioned to mitigate impacts. CEO Jan Møller Mikkelsen added that since they do not import finished product into the U.S., the material impact should be limited.

Luca Issi asked for Ascendis's latest perspective on the competitive threat from molecules in development at BridgeBio and MBX Biosciences. He also inquired about the SG&A expense outlook for the rest of the year.

Answer

President and CEO Jan Mikkelsen expressed skepticism about both potential competitors. He characterized BridgeBio's drug as targeting a very small ADH1 patient niche and questioned its scientific rationale in the broader hypoparathyroidism population. Regarding MBX's once-weekly PTH, he questioned the clinical need for a weekly formulation given patient titration needs and also expressed doubts about its scientific mechanism of action. The question on SG&A was not addressed.

Luca Issi inquired about competition from BridgeBio and NBX, and SG&A expenses for the remainder of the year.

Answer

CEO Jan Mikkelsen discussed the science behind the competing molecules. No SG&A guidance was provided.

Luca Issi with RBC Capital Markets inquired about Arrowhead's strategy to demonstrate acute pancreatitis (AP) benefit for Plozasiran, specifically asking if the SHASTA III and IV trials, powered for triglyceride reduction, are sufficient or if the event-driven SHASTA V trial is the primary vehicle, noting recent design changes to SHASTA V.

Answer

Bruce Given, Chief Medical Officer for Arrowhead Pharmaceuticals, explained that SHASTA III and IV were powered for triglyceride reduction, not AP, but are designed to allow pooling for AP evaluation. He clarified that SHASTA V is specifically designed with AP as the primary endpoint and its design was recently broadened to include a more generalizable high-risk SHTG population, serving as a "belt and suspenders" approach.

Luca Issi asked about Arrowhead's plan to demonstrate acute pancreatitis benefit for Plozasiran, specifically the confidence in SHASTA III and IV hitting this endpoint versus the need for SHASTA V, and the recent increase in SHASTA V's patient enrollment.

Answer

Bruce Given, Chief Medical Officer, explained that SHASTA III and IV were powered for triglyceride reduction, not specifically pancreatitis, but are designed to allow pooling of data for pancreatitis evaluation. He clarified that SHASTA V is specifically designed with acute pancreatitis as the primary endpoint and its design was recently broadened to include a more generalizable population with persistent chylomicronemia and a history of pancreatitis, rather than solely increasing power. He described this as a 'belt and suspenders' approach.

Luca Issy's representative inquired about the initial presentation of plozasiran, asking if it will be a prefilled syringe and what the timeline is for developing an auto-injector.

Answer

SVP Andy Davis confirmed the initial launch for FCS will use a prefilled syringe. Interim Chief Medical Scientist Bruce Given added that an auto-injector is being developed for the SHTG indication and is expected to be available at or soon after that launch.

Luca Issi of RBC Capital Markets asked for details on the SHASTA-5 study design, including patient enrollment criteria and powering assumptions, and questioned the company's ex-U.S. commercialization strategy for plozasiran.

Answer

Interim Chief Medical Scientist, Dr. Bruce Given, stated that the SHASTA-5 trial enrolls patients with a recent history of pancreatitis but did not provide specific enrollment numbers. An executive clarified the ex-U.S. strategy, noting the company is preparing to commercialize independently in major European markets and Canada for the rare FCS indication.

Luca Issi asked about the clinical strategy for the obesity candidate ARO-INHBE, questioning if it's viewed as a monotherapy or an add-on, and inquired about the data expectations for the upcoming readout. He also asked for the company's reaction to Novartis delaying its Lp(a) data.

Answer

James Hamilton, Chief of Discovery and Translational Medicine, explained that ARO-INHBE is being studied as both a monotherapy and in combination, with the final development path pending data. President and CEO Dr. Christopher Anzalone added that the obesity market requires a suite of options. Regarding Lp(a), an executive expressed more excitement for Amgen's olpasiran due to its efficacy and convenience but noted a lack of inside information on competitor programs.

Luca Issi questioned the rationale behind describing the Sixth Street debt deal as having 'favorable economics,' asking for context on the interest rate. He also asked how payers might differentiate between genetically and clinically confirmed FCS patients.

Answer

President and CEO Dr. Christopher Anzalone described the deal's favorability due to its long 7-year term, non-dilutive nature, and attractive risk-sharing structure with no regular coupon payments. CFO Ken Myszkowski added its cost was reasonable compared to equity. Dr. Bruce Given, Interim Chief Medical Scientist, opined that payers will likely follow the package insert, and since the patients are clinically identical, coverage for both groups is expected if approved.

Luca Issi questioned Moderna's confidence in reiterating the 2028 cash break-even guidance, given the need for significant top-line reinflection and recent pipeline developments. He also asked Stéphane Bancel about media reports concerning potential large deals with pharma and the company's latest thinking on business development.

Answer

Jamey Mock, Chief Financial Officer, reiterated commitment to the 2028 cash break-even, emphasizing it's a mix of revenue growth (geographic expansion, strategic partnerships, new products) and continued cost reduction, with more details to be provided at Analyst Day. Stéphane Bancel, Chief Executive Officer, confirmed ongoing discussions with pharma companies and financial sponsors for products like latent vaccines (e.g., EBV) where Moderna does not intend to fund Phase 3 trials independently, citing the Blackstone partnership for flu as an example.

Luca Issi (RBC Capital Markets) asked about Moderna's confidence in reiterating the 2028 cash break-even guidance, given the need for significant top-line reinflection and recent pipeline developments. He also inquired about potential large deals with pharma and Moderna's latest thinking on M&A/business development.

Answer

CFO Jamey Mock reiterated commitment to the 2028 cash break-even, attributing it to a mix of revenue growth (geographic expansion, strategic partnerships, new products) and continued cost reduction, with further updates expected at Analyst Day. CEO Stéphane Bancel confirmed ongoing discussions with pharma companies and financial sponsors for products like latent vaccines (e.g., EBV) where Moderna seeks external funding for Phase 3, similar to the Blackstone partnership for mRNA 1010.

Luca Issi asked a broader question about Moderna's business development strategy, particularly regarding in-licensing, and inquired about the likely filing sequence for the COVID-plus-flu combination vaccine with the FDA.

Answer

CEO Stéphane Bancel explained that the company's focus is on finding partners for its own abundant pipeline assets, like EBV, rather than in-licensing, though it remains open to partnerships for non-mRNA technology. President Stephen Hoge stated that for the combo vaccine, a sequential filing (flu monotherapy first) is the most pragmatic and likely path with the U.S. FDA.

Luca Issi asked a big-picture question about whether Moderna's management has engaged with the Trump administration or other political candidates this election cycle, and also inquired about the timing of the GBS case in the Norovirus trial relative to vaccination.

Answer

CEO Stéphane Bancel stated that Moderna worked productively with the previous Trump administration and looks forward to working with the new team. President Stephen Hoge described the GBS case as 'relatively proximal' to vaccination due to the rapid trial enrollment but noted that determining causation is very difficult for such rare events.

Luca Issi asked if it's fair to assume Moderna could capture one-third of the RSV market next year and requested color on U.S. COVID market share dynamics, noting a potential loss of share this year.

Answer

CEO Stéphane Bancel declined to provide market share guidance for RSV but noted that a full contracting season in 2025 will be a key difference. For COVID, he acknowledged a loss of share in the U.S. retail market amid a competitive environment but stated that the full picture, including IDN and government channels, is not yet clear.

Luca Issi from RBC Capital Markets asked for a comparison of the enrollment pace for the TTR cardiomyopathy trial against competitors like AstraZeneca, questioning if it reflects patient preference, and also asked about the impact of existing commercial options on enrollment.

Answer

EVP & Chief Medical Officer David Lebwohl described Intellia's enrollment pace as "astounding" and noted their trial has different inclusion criteria than the competitor's depleter study. He emphasized that enrollment has actually accelerated despite new commercial therapies becoming available, which he interprets as strong interest from both patients and physicians in Intellia's approach.

Luca Issi asked for the company's reaction to Alnylam maintaining its price upon label expansion to TTR cardiomyopathy and how this influences Intellia's pricing strategy for its one-and-done therapies.

Answer

CEO John Leonard stated that Intellia is closely monitoring the entire, rapidly growing TTR market. He views the competitor pricing and market dynamics as indicative of a very significant opportunity for Intellia's differentiated product profile. He expressed confidence that Intellia will perform very well in this market upon entry.

An analyst on behalf of Luca Issi asked if Alnylam's decision to run a larger pivotal trial for its next-generation TTR silencer has prompted Intellia to reconsider the design of its MAGNITUDE study, such as increasing its size.

Answer

CFO Edward Dulac stated that while Intellia monitors competitor activity, they see important differences and are pleased with their current trial design. CMO David Lebwohl added that Alnylam's recent commentary reinforces Intellia's hypothesis about the importance of achieving very low TTR levels for better patient outcomes.

A representative for Luca Issi asked why the MAGNITUDE-2 study has an 18-month primary endpoint, unlike a competitor who filed on 9 months of data, and whether this longer duration was a regulatory requirement.

Answer

CMO David Lebwohl clarified that the 18-month endpoint was the company's own decision, not a regulatory requirement. He stated that Intellia believes 18 months is the optimal time to demonstrate the full clinical benefit of the drug.

Luca Issi asked about Amgen's interest in adding an oral small molecule to its obesity pipeline and for its view on the eventual market split between oral and injectable treatments.

Answer

Robert Bradway, Chairman & CEO, confirmed openness to BD. James Bradner, EVP of R&D, mentioned earlier-stage research into potential oral candidates. Murdo Gordon, EVP of Global Commercial Operations, acknowledged orals will be a significant market segment but emphasized the differentiation of their injectable, Meritide, for chronic management.

Luca Issi of RBC Capital Markets inquired about any interactions with senior CBER leadership, whether the current data could support full approval versus accelerated approval, and the potential timing of a confirmatory trial.

Answer

CEO Matt Kapusta shared that he had met CBER's Dr. Vinay Prasad and is confident in his openness to external control data. He clarified that accelerated approval is the base case, but the FDA has indicated the Phase I/II study results could be leveraged to support a full approval, potentially requiring incremental data for confirmation.

Luca Issi asked about the potential impact of the new CBER head, Dr. Prasad, on uniQure's regulatory path for AMT-130, questioning if productive conversations with the FDA could be reversed.

Answer

CEO Matthew Kapusta stated he looks forward to working with Dr. Prasad and expressed strong confidence in uniQure's data. He emphasized that uniQure's accelerated approval strategy for AMT-130 is based on clinical outcomes (cUHDRS), not surrogate biomarkers, which he believes is a key differentiator and strengthens their path forward.

Luca Issi from RBC Capital Markets asked about the STAC-BBB capsid platform, drawing a comparison to a competitor's technology. The questions focused on whether STAC-BBB would show a dual impact both systemically and in the CNS, and if it would require preconditioning with prophylactic steroids.

Answer

CEO Alexander Macrae stated that a decision on using steroid pre-treatment has not yet been made. He highlighted the platform's effectiveness in non-human primates and its selection by major partners like Lilly, Astellas, and Genentech. Chief Development Officer Nathalie Dubois-Stringfellow added that an upcoming ASGCT presentation will show profound survival benefits and sustained protein suppression in both mouse and NHP models, demonstrating its potential as a one-time therapy.

Luca Issi asked about the evolution of Sangamo's discussions with the FDA, contrasting the favorable single-arm pathway for its Fabry program with the more stringent requirements previously imposed on competitors. He also questioned Pfizer's commitment to the hemophilia A program, given recent commercial challenges in the space.

Answer

CEO Sandy Macrae attributed the FDA's evolving stance to the passage of time, a changing competitive landscape, and CBER's initiative to support genomic medicines for rare diseases. Chief Development Officer Nathalie Dubois-Stringfellow detailed the regulatory interactions that led to the agreement. Regarding Pfizer, Macrae expressed confidence, noting that Pfizer is actively in discussions with regulatory authorities and will present detailed Phase 3 data at ASH, which he views as signs of their continued enthusiasm.

Shelby Tucker on for Luca Issi asked about the administration setting for the ALPHA3 trial, inquiring if the choice between inpatient and outpatient treatment is left to the investigator and what the expected mix might be.

Answer

EVP of R&D and CMO Dr. Zachary Roberts and President and CEO Dr. David Chang both responded. Dr. Roberts confirmed the decision is entirely up to the investigator and a significant number of patients are already being treated as outpatients. Dr. Chang added that not requiring hospitalization provides flexibility, making the trial operate like standard cancer care.

Luca Issi asked if Allogene has tumor biopsy data for ALLO-316 that demonstrates CAR-T cells are successfully infiltrating the solid tumor microenvironment in RCC. He also sought clarification on whether all responses to date have been partial responses (PRs) rather than complete responses (CRs).

Answer

Dr. Zachary Roberts, EVP of R&D and CMO, confirmed they have collected numerous tumor biopsies and will present data showing robust tumor infiltration, with CAR transgene levels in the tumor equivalent to those in peripheral blood. Regarding responses, he clarified that they observed one complete metabolic remission in a patient who unfortunately later died from a COVID-19 infection.

Luca Issi from RBC Capital Markets asked if Wave is considering running the pivotal Huntington's disease trial for WVE-003 solo or if a partner is a gating item, and questioned the trade-off between subcutaneous delivery and editing efficiency for WVE-006 compared to potentially more efficient IV methods.

Answer

CEO Paul Bolno addressed the partnership question by stating that while they are actively engaged in discussions to optimize the program, the immediate focus is on advancing it, leveraging the new regulatory clarity. On the delivery method, he argued that direct comparisons of preclinical models can be misleading and that the most relevant metric is M-protein levels in the clinic. He asserted that their clinical data demonstrates high efficiency for subcutaneous delivery, with significant potential for improvement from the current low starting dose.

Luca Issi of RBC Capital Markets asked for a reaction to Pfizer's recent Duchenne data, where expression didn't translate to functional benefit, and whether this could change FDA standards. He also asked new CFO Mitchell Chan about his motivation for joining REGENXBIO.

Answer

Dr. Steve Pakola, CMO, attributed the difference to construct design, emphasizing that RGX-202's second-generation construct more closely mimics native dystrophin, preserving the 'reasonably likely to predict' standard. CEO Curran Simpson added that the FDA already considers functional data supportive. CFO Mitchell Chan cited the company's scientific excellence, the potential for multiple BLAs in the next 18-24 months, and the opportunity to help build a commercial-stage company.

Luca Issi from RBC Capital Markets asked about Beam's commitment to commercializing BEAM-101 on its own if the ESCAPE program does not prove to be a game-changer, and whether they would consider partnering the asset.

Answer

CEO John Evans affirmed Beam's long-term commitment to its hematology franchise and its readiness to commercialize BEAM-101 independently. He stated that the company does not need to partner for financial reasons and would only do so strategically if a partner could accelerate patient access more effectively than Beam could alone. He noted this strategic calculus would remain the same even in a hypothetical scenario where ESCAPE did not advance.

Luca Issi of RBC Capital Markets asked about Beam's commitment to commercializing BEAM-101 independently if the ESCAPE platform does not prove to be a game-changer, and whether the company would be open to a partnership.

Answer

CEO John Evans affirmed Beam's long-term commitment to its hematology franchise, starting with BEAM-101 as a potential best-in-class therapy. He stated that the company is well-financed to proceed alone but would consider a strategic partnership if a partner could help reach more patients faster, regardless of ESCAPE's outcome. The decision would be strategic, not financial.

Luca Issi from RBC Capital Markets asked if Beam would remain committed to commercializing BEAM-101 alone if ESCAPE proves not to be game-changing, or if they would consider a partnership.

Answer

CEO John Evans affirmed Beam's commitment to its long-term hematology strategy and stated the company is well-financed and would only partner strategically to accelerate patient access, not for financial reasons. He clarified that even if ESCAPE's outlook changed, the significant value of BEAM-101 for its target population would remain, and the strategic calculus for partnering would not fundamentally change.

Luca Issi asked for Editas' take on the HHS decision not to cover fertility preservation for sickle cell gene therapy patients and whether the company might partner reni-cel entirely to focus on its in vivo strategy.

Answer

Chief Commercial and Strategy Officer Caren Deardorf called the HHS decision 'deeply disappointing' but noted their launch timing may allow the issue to be resolved. CFO Erick Lucera addressed partnering, stating that while the plan is to partner ex-U.S., they will ultimately do what is best for patients and shareholder returns.

Asked about the BLA filing strategy for Reni-cel, specifically whether adult and adolescent populations would be filed concurrently or sequentially, and inquired about the company's strategy for the sickle cell disease market in the Middle East.

Answer

The company has not disclosed specific details of its BLA filing strategy but noted that strong enrollment in both adult and adolescent cohorts provides a great position. For the Middle East and other ex-U.S. markets, the company's focus on execution in the U.S. supports future partnership opportunities at the appropriate time.

Luca Issi from RBC Capital Markets asked for an update on the partial clinical hold, questioning if it was related to dose or manufacturing, and also inquired about the lower number of prior anti-VEGF injections in Cohort 4 patients compared to other cohorts.

Answer

Chief Medical Officer Aaron Osborne explained that the lower injection history in Cohort 4 was due to enrolling some patients earlier in their disease, reflecting growing investigator confidence. President Leone Patterson addressed the clinical hold, confirming it is related to the 6E12 dose, which is not being pursued, and to CMC issues. She stated the company is on track to resolve the CMC issues before the pivotal program begins in 2021.

Luca Issi asked about the kinetics of ocular inflammation observed in the OPTIC trial, specifically if it occurs within a predictable time window. He also requested color on the recent termination of the collaboration with Regeneron.

Answer

Chief Medical Officer Aaron Osborne explained that inflammation typically peaks 4-6 weeks post-injection, which is why a longer course of steroid eye drops is now used, and noted it appears manageable and declines over time. President & CEO Leone Patterson clarified that the Regeneron collaboration expired, which she views as a positive development as it frees up several targets for Adverum to pursue internally.