Vanza Triple Market Impact
Q: How will vanzacaftor triple therapy capture market share from TRIKAFTA?
A: Management anticipates rapid adoption of vanzacaftor triple therapy due to its superior efficacy and once-daily dosing, making it attractive to both current TRIKAFTA patients seeking better control and those who previously discontinued CFTR modulators. They expect enthusiasm from the cystic fibrosis community and believe payers will be receptive, as vanzacaftor targets a similar patient population without significant budget impact.

Royalty Implications of Vanza Triple
Q: How will the lower royalty rate of vanzacaftor triple affect financials?
A: The blended royalty rate on the current CF portfolio is just under 10%. With vanzacaftor triple therapy, the royalty burden will be meaningfully lower, in the single digits, improving the company's leverage.

CASGEVY Launch Expectations
Q: What are the expectations for the CASGEVY launch and its market potential?
A: Management expects the CASGEVY launch to be a foundational year, with patient journeys taking several months due to multiple phases. They anticipate CASGEVY to be used in thousands of patients, representing a multibillion-dollar opportunity. Progress is being made in activating treatment centers, and payers have responded positively.

Switching from TRIKAFTA to Vanza Triple
Q: How will physicians motivate stable TRIKAFTA patients to switch to vanzacaftor triple?
A: The company expects rapid transitions based on past experience, as patients and physicians are motivated by the better benefit-risk profile, higher efficacy, and the convenience of once-daily dosing with vanzacaftor triple therapy. Educated patients seek the most effective treatments available.

Clinical Differentiation: Vanza Triple vs. TRIKAFTA
Q: How does vanzacaftor triple therapy clinically differ from TRIKAFTA?
A: Vanzacaftor triple therapy achieves higher levels of CFTR protein function and greater reductions in sweat chloride than TRIKAFTA. Management believes this will translate into long-term benefits, such as reduced pulmonary exacerbations, as suggested by fewer exacerbations observed in trials.

Pain Program Consistency and Strategy
Q: Was there underperformance in the bunionectomy Phase 3 trial for VX-548, and what's the strategy for follow-on pain assets?
A: Management finds VX-548 data remarkably consistent across studies, with similar reductions in pain scores in both bunionectomy and abdominoplasty trials. They are pursuing a portfolio approach with follow-on assets like VX-993, aiming for formulations suitable for both oral and IV dosing, potentially allowing intraoperative use and seamless transition to oral therapy.

Sweat Chloride Measurement in Practice
Q: Do doctors routinely check sweat chloride levels for prescribing?
A: Sweat chloride is primarily used for diagnosis and is not routinely measured for treatment decisions. However, physicians understand that CFTR dysfunction is the underlying cause of cystic fibrosis, and sweat chloride is a direct readout of CFTR function. The concepts are well understood, so extensive education may not be necessary.

Cost of Goods Sold Impact from CASGEVY
Q: Will the shift of costs from R&D to COGS due to CASGEVY continue?
A: With CASGEVY's U.S. approval in Q4 2023, manufacturing costs previously recorded in R&D were moved to cost of goods sold. These costs will remain in COGS going forward.

Transplant Center Capacity for CASGEVY
Q: Are transplant center capacities a concern for CASGEVY adoption?
A: Management has not encountered capacity issues at treatment centers. They are making progress in activating authorized treatment centers, which are fully intending to treat patients with CASGEVY, and have received positive feedback from payers.

First Commercial CASGEVY Patients
Q: Can you provide details on the first patients starting CASGEVY?
A: Management will not comment in detail but expects the first patient to start shortly.