Kaveri Pohlman

Kaveri Pohlman asked about any systemic differences or challenges in insurance approval rates for Rezdiffra depending on the prescriber (endocrinologist vs. hepatologist/gastroenterologist), and for any real-world evidence showing Rezdiffra can prevent or delay F4 cirrhosis progression or evidence leading to preference over GLP-1s in F2/F3 MASH patients.

Answer

CEO Bill Sibold stated that real-world evidence is emerging, with some presented at AASLD, and anecdotal feedback from prescribers is 'extremely strong' regarding effects on liver fat, fibrosis, LFTs, and lipids. He noted that insurance approval criteria vary by payer, often requiring prescription by or in consultation with a specialist (hepatologist/gastroenterologist), sometimes including endocrinologists. He emphasized Madrigal's intent for specialists to prescribe Rezdiffra due to the seriousness of MASH.

Kaveri Pohlman inquired about any systemic differences or challenges in insurance approval rates for Rezdiffra based on the prescriber (endocrinologist vs. hepatologist/gastroenterologist). She also asked for real-world evidence, beyond slide 14 data, that Rezdiffra can prevent or delay F4 cirrhosis progression, or evidence supporting a preference for Rezdiffra over GLP-1s in F2/F3 MASH patients.

Answer

Bill Sibold, Chief Executive Officer, stated that real-world evidence is emerging, with strong anecdotal feedback from prescribers on Rezdiffra's effects on liver fat, fibrosis, LFTs, and lipids. Regarding approval rates, he explained that criteria vary by payer, but generally refer to 'specialists' (hepatologists/gastroenterologists), sometimes including endocrinologists. He emphasized Madrigal's intent for specialists to prescribe Rezdiffra due to the seriousness of the disease.

Kaveri Pohlman of Clear Street inquired about the rationale for choosing a GLP-1 over dual/triple agonists, potential overlapping toxicities in a combination, and the clinical development plan for dosing and scheduling.

Answer

CEO Bill Sibold differentiated their strategy from the 'battle for greatest weight loss,' stating their goal is a well-tolerated oral GLP-1 that achieves the ~5% weight loss needed to enhance ResDiffera's effect. CMO David Soergel added that their due diligence on the molecule's preclinical profile was reassuring regarding its compatibility with resmetirom. They noted it was premature to discuss the full development plan.

Kaveri Pohlman of Clear Street asked about plans to manage the placebo effect in longer Phase 3 trials, manufacturing readiness for commercialization, and the company's current perspective on commercial partnerships.

Answer

Chief Development Officer James Cassella expressed confidence in managing the placebo effect due to the drug's rapid onset and large effect size, and confirmed manufacturing is ready for Phase 3. CEO Jennifer Good stated that while partnerships for Europe or Japan are a consideration, the plan is for Trevy to commercialize in the U.S. itself, viewing a U.S. partnership as likely requiring a full company acquisition.

Kaveri Pohlman inquired about the FDA's requirements for long-term patient safety data for a potential Phase III trial and asked about the company's current perspective on potential U.S. or ex-U.S. partnerships.

Answer

Chief Development Officer Dr. James Cassella clarified that the FDA requires 52 weeks of safety data for an NDA, which Trevi plans to collect via a long-term extension study in its Phase III program. Executive Jennifer Good added that while the company is prepared to commercialize in the U.S. itself, it remains in strategic discussions, particularly for potential commercial partners in Europe and Japan.

Speaking on behalf of Kaveri Pohlman from Clear Street, an analyst asked which secondary endpoints across indications would be most crucial for driving prescriptions of Haduvio and minimizing resistance from payers.

Answer

Executive Jennifer Good explained that for regulatory purposes, key secondary endpoints will focus on measures like cough severity that are linked to the primary endpoint of objective cough frequency. For commercial success and payer acceptance, she highlighted that metrics related to patient quality of life will be important, and the commercial team is actively involved in selecting these endpoints for future studies.

Kaveri Pohlman inquired about guidance for Iptrozy's next-quarter sales or patient numbers, the expected rate of patient enrollment, and any available breakdown of first-line versus second-line use. She also asked about upcoming data presentations at the World Lung Cancer Conference and ESMO.

Answer

CEO Dr. David Hung stated that while it's too early for formal guidance, the new patient start rate has already increased from approximately two per day to three per day in early August. He noted that a breakdown of patient use by line of therapy is not yet available due to limited visibility from specialty distributors. Dr. Hung confirmed that updated TRUST-1 and TRUST-2 data will be presented at World Lung, and data on Iptrozy use following entrectinib will be presented at ESMO.

Kaveri Pohlman inquired about guidance for future Iptrozy sales or patient numbers, the expected rate of patient enrollment, and any available breakdown of first-line versus second-line use. She also asked about upcoming data presentations at the World Lung Cancer Conference and ESMO, specifically if updated PFS and DOR data would be included.

Answer

David Hung, Founder, President & CEO, stated that while it's early, the patient enrollment rate has slightly increased from two to three new patients per day in early August. He explained that a breakdown of first-line versus second-line use is not yet available due to limited visibility from specialty distributors. Hung confirmed that World Lung will feature an update on the TRUST-1 and TRUST-2 NDA submission data, and ESMO will include new data on Iptrozy use following entrectinib treatment.

Inquired about efficacy and safety differences between chemo-pretreated and chemo-naive patients, physician feedback on the impact of dose modifications on durability, and the reason for the lack of correlation between efficacy and B7-H3 expression.

Answer

The executive stated that both chemo-naive and pretreated populations are being considered for Phase III with no unexpected observations. He noted that physicians are comfortable with dose modifications, which have not negatively impacted durability. The lack of B7-H3 correlation is viewed as a positive, potentially indicating a biomarker won't be needed, possibly due to a threshold effect.

Kaveri Pohlman of BTIG, LLC asked about efficacy differences in chemo-pretreated versus chemo-naive patients, physician feedback on dose modifications, and the lack of correlation between efficacy and B7-H3 expression.

Answer

Dr. Scott Koenig, President and CEO, stated that both chemo-naive and pretreated populations are being considered for Phase III. He noted that physicians are comfortable with dose modifications, which have not appeared to reduce response durability. On B7-H3 expression, he suggested a threshold effect may be at play, where only a modest level of expression is needed for efficacy, viewing this as a positive.

Kaveri Pohlman of Guggenheim Securities inquired about the HIF-2 alpha pathway's relationship with VEGF, asking about potential overlapping toxicities between casdatifan and cabozantinib. She also asked about the STAR-121 trial's dual primary endpoints (PFS/OS) and the acceptable variation for the zimberelimab monotherapy arm (Arm C).

Answer

CEO Terry Rosen stated that while HIF-2 alpha and VEGF are in the same pathway, overlapping toxicities are not expected, noting that casdatifan's AE profile is well-defined and manageable, primarily involving anemia. CMO Dimitry Nuyten clarified that for the STAR-121 trial, a statistically significant result in either PFS or OS would make the trial positive, but OS is the key registrational endpoint. He added that the contribution of components from Arm C is a review issue but expressed confidence in the study's design to meet regulatory expectations.

Asked about vudalimab's safety profile versus Ipi/Nivo, the go-forward dose, patient numbers for go/no-go decisions, and response rates in patients with bone disease.

Answer

The safety profile is typical for checkpoint inhibitors, with a Q3 week flat dose being used going forward. Go/no-go decisions will be based on ~20-30 patients per cohort. Responses were observed in patients who also had bone disease.

An analyst on behalf of Kaveri Pohlman asked what would be considered a meaningful response rate in the mirvetuximab combo trial, whether prior bevacizumab use would be a requirement, and if biomarker analysis would be used in the PLD trial to differentiate responders.

Answer

The company did not provide a specific number for a meaningful response rate but is working with ImmunoGen on benchmarks. They confirmed that prior bevacizumab use is a requirement for the mirvetuximab combo trial, mirroring the SORAYA trial's criteria. They are also collecting extensive biomarker data from the PLD trial to analyze responders vs. non-responders, which may inform future patient selection.