Michael DiFiore

Michael DiFiore inquired about Madrigal's future competitive positioning and market access in light of recent M&A in the MASH space, particularly if large pharma bundles their assets. He also asked about Madrigal's stance on Sagimet's plans to test denifanstat with Rezdiffra.

Answer

Bill Sibold, Chief Executive Officer, stated Madrigal has no knowledge of Sagimet's plans. Regarding M&A, he viewed it as validation of the MASH market, which will accelerate innovation and ultimately favor Rezdiffra due to its differentiated profile. He highlighted Madrigal's long-term market access strategy, designed with Rezdiffra's 2045 IP and future pipeline in mind, to ensure durable leadership in MASH.

Michael Difiore of Evercore ISI inquired about potential differentiation from AstraZeneca's upcoming Vax HTN data, particularly concerning hyperkalemia rates, and asked for an update on partnership discussions.

Answer

CEO Jon Congleton expressed confidence in lorunderstat's well-characterized efficacy and safety profile from four completed trials, noting a low 0.6% rate of significant hyperkalemia. He stated it was premature to compare data before AstraZeneca's release. Regarding partnerships, Congleton confirmed ongoing interest in ex-U.S. and U.S. collaborations to maximize the drug's reach and value.

Michael DiFiore of HC Wainwright & Co. inquired about the acceptable level of hyperkalemia in the Explore-CKD trial and whether lorundrostat's efficacy and safety would be similar to competitor cadrostat's Phase II CKD trial results.

Answer

Executive Jon Congleton explained that the company has not defined a specific acceptable level of hyperkalemia, noting that specialists are comfortable managing it to achieve blood pressure and kidney function benefits. He stated it was too early to compare efficacy directly with competitors but anticipates a clinically meaningful blood pressure reduction for lorundrostat consistent with its established profile.

Michael DiFiore of Leerink Partners questioned the confidence in extrapolating Phase II Target-HTN results from a small patient group to the larger pivotal studies, and asked about the mechanisms of action in the OSA and CKD trials.

Answer

Executive Jon Congleton expressed confidence in the 50mg dose for the pivotal program, citing the totality of evidence and exposure-response data from the Phase II trial. Chief Medical Officer Dr. David Rodman explained that in the OSA trial, improvement is likely driven by reduced fluid shifts and inflammation, not fibrosis. For the CKD trial, he noted the study design, including a run-in period and crossover structure, is built to assess and account for any potential confounding effects from SGLT2 inhibitors.

Michael DiFiore of Evercore ISI inquired about the Target-HTN trial's nighttime blood pressure data, specifically the lack of nocturnal dipping in the 50mg group, and asked for clarification on two early-stage safety signals: a case of sinus tachycardia and a case of dysgeusia.

Answer

Dr. David Rodman, Chief Medical Officer, explained that the 100mg cohort showed a normal nighttime response, suggesting the 50mg data was skewed by a high number of 'white coat hypertension' subjects, which reduced the sample size in sensitivity analysis. He attributed the sinus tachycardia to a predictable pharmacodynamic effect of volume depletion at a very high, non-therapeutic dose (360mg) and noted the single case of dysgeusia has not been a recurring issue in subsequent trials.

Michael Difiore questioned the potential for payers to enforce step-edits with non-approved therapies for PBH and sought clarity on the PSP trial's interim analysis, particularly the impact of varied treatment durations.

Answer

Co-CEO & Co-Founder Josh Cohen stated that payer step-edits are not anticipated due to the lack of clinical evidence and low satisfaction with existing off-label therapies. Chief Medical Officer Dr. Camille Bedrosian clarified that the PSP analysis will be based on all patients completing 24 weeks, but all available longer-term data will also be considered.

Michael DiFiore of Leerink Partners questioned the need for a large patient education campaign for Avexitide in post-bariatric hypoglycemia (PBH), asking if it targets undiagnosed patients or aims to expand into less symptomatic groups. He also inquired about the efficacy benchmark for the upcoming interim data in the Progressive Supranuclear Palsy (PSP) trial, specifically regarding the expected placebo decline and what would constitute a clinically meaningful improvement on the PSP rating scale.

Answer

Co-CEO Justin Klee clarified that PBH is well-known among endocrinologists and patients due to its severity, but education is crucial as it's a rare disease with no prior treatments. Regarding PSP, Co-CEO Joshua Cohen stated the ORION trial is 80% powered to detect a 30% effect on the PSP rating scale. He noted that the decision to advance will be based on all data, not just the primary endpoint, and that KOLs have suggested even a single-point difference could be meaningful in this severe, progressive disease.

Michael DiFiore of Leerink Partners inquired about the clinical trial design for two of Amylyx's key programs. He asked why the Phase III LUCIDITY trial for post-bariatric hypoglycemia (PBH) was limited to Roux-en-Y gastric bypass patients, and how efficacy would be interpreted in the PSP ORION study given the use of different rating scales in the U.S. and ex-U.S.

Answer

Chief Medical Officer Dr. Camille Bedrosian explained the LUCIDITY trial's focus on Roux-en-Y patients is to minimize heterogeneity, as this is where Amylyx has the most data, though they believe the drug will be applicable to all PBH patients. Co-CEO Justin Klee added that the Roux-en-Y market is substantial. Regarding the PSP trial, Co-CEO Joshua Cohen stated that the 10-item and 28-item PSP rating scales are highly consistent, and they expect similar results from both endpoints.

Michael DiFiore of Evercore ISI asked about the risk of hyperglycemia with avexitide, a GLP-1 antagonist. He also requested color on the FDA's clinical hold on AMX0114 and its potential impact on U.S. commercialization.

Answer

Dr. Camille Bedrosian, Chief Medical Officer, stated that avexitide restores homeostasis and has not caused hyperglycemia in prior studies. Co-CEO Justin Klee added it is well-tolerated. Regarding AMX0114, Dr. Bedrosian expressed confidence in its safety profile, noting a >10x safety margin and clearance from Health Canada. Mr. Klee mentioned a trend of first-in-human trials for RNA therapeutics occurring ex-U.S.

Michael DiFior of Evercore ISI inquired about the Merck litigation, asking if the increasing number of instituted PGRs strengthens Merck's position or affects settlement timing. He also asked if potential partner deal conversations have slowed in anticipation of the final CMS Part B guidance.

Answer

President and CEO Dr. Helen Torley stated that settlement timing is in Merck's hands and that the ultimate arbiter of infringement is the district court, where Halozyme has patents not subject to the PTAB process. She also confirmed that deal conversations have not slowed down, as the IRA is not a major factor, especially since many partners are considering subcutaneous formulations from the early stages of development.

Michael DiFiore of Evercore ISI asked if AstraZeneca's deal with Alteogen suggests large pharma is now willing to risk patent litigation rather than partner with Halozyme. He also questioned if any existing or potential ENHANZE partners have paused negotiations while awaiting the outcome of the Merck litigation.

Answer

Dr. Helen Torley, President and CEO, stated that no current or potential partners have paused discussions due to the litigation, emphasizing ENHANZE's position as the derisked market leader. She asserted that companies signing with Alteogen, including AstraZeneca, had previously approached Halozyme for targets that were already exclusively licensed to other partners.

Michael DiFiore asked if 2025 could be the year VYVGART subcutaneous sales exceed IV sales and whether the three undisclosed pipeline products represent new deals or expansions of current partnerships.

Answer

President and CEO Dr. Helen Torley expressed excitement for VYVGART's growth but stated it would be inappropriate to comment on the subcu vs. IV sales timeline, as partner Argenx has not provided that guidance. She clarified that the three undisclosed products are from current partners, and any new deals would be incremental to those.

Michael DiFiore of Evercore ISI asked for an update on expectations for new collaboration deals before year-end. He also questioned how licensees of the new MDASE platform would manage development and regulatory challenges without Halozyme's traditional support services.

Answer

President and CEO Dr. Helen Torley pointed to the updated collaboration revenue guidance of $130M-$150M as the current outlook but affirmed that efforts to sign new deals continue. She explained that MDASE licensees would be responsible for their own development and regulatory processes, as Halozyme would only license the IP, unlike the full support provided with ENHANZE partnerships.

Michael Difiore asked for a breakdown of the intravenous (IV) anti-CD20 market, specifically how the 60% of patients not choosing a subcutaneous option are split between BRIUMVI and its IV competitors. He also questioned if a payer push toward at-home therapies could accelerate a market shift to subcutaneous options.

Answer

Chief Commercial Officer Adam Waldman stated that within the physician-administered IV segment, BRIUMVI is capturing approximately one out of every three new patients. Regarding payer dynamics, Waldman noted that while a significant push for at-home therapies is not currently observed, it is a possibility, which strategically validates the company's development of a subcutaneous BRIUMVI formulation.

Michael DiFiore asked for an update on gross-to-net trends, the impact of the Part D redesign, and when the company expects to fully deplete its pre-launch inventory reserves affecting gross margin.

Answer

Chief Commercialization Officer Adam Waldman clarified there was no material change in gross-to-net and that the Part D redesign is not relevant for Briumvi, a Part B drug. Chief Financial Officer Sean Power confirmed that the pre-commercial inventory has been fully depleted, meaning the gross margin reported this quarter is the 'fully baked number' expected going forward.

Michael DiFiore asked for an update on the pivotal trial design for the subcutaneous formulation of BRIUMVI and inquired about the gross-to-net expectations for the remainder of the year.

Answer

Chief Commercialization Officer Adam Waldman stated that gross-to-net is expected to be in the 70% to 75% range, with some quarterly fluctuations. CEO Michael Weiss added that the subcutaneous trial design is not yet finalized as they are still gathering data, and it remains to be determined whether the dosing regimen will be every two or three months.

Michael DiFiore from Evercore ISI inquired about any inventory channel dynamics in Q3 and asked for the TRx script count and new patient hub enrollments, noting their absence from the press release.

Answer

Chief Commercialization Officer Adam Waldman confirmed there were no changes to inventory levels, which remain normal. He explained that the company is moving away from reporting hub enrollment numbers because they are becoming a less accurate measure of growth as the hospital business, which uses the hub less, now accounts for 55% of their business. The focus will be on revenue guidance going forward.

Michael DiFiore of Evercore ISI questioned if recent FDA shakeups could slow regulatory processes, asked about remaining gating factors for the Rejuva CTA submission, and inquired about developments for Rejuva's obesity construct.

Answer

CEO Harith Rajagopalan expressed no concern about FDA changes impacting Revita and noted Rejuva's OUS-first strategy mitigates any CBER impact. He confirmed the Rejuva CTA submission is on track, with no gating factors beyond standard documentation preparation. He mentioned exciting but not-yet-public developments for the obesity construct.

Michael DiFiore of Evercore ISI asked for an update on the first patient treated in the REVEAL-1 study, specifically regarding their continued weight maintenance and any new biomarker analysis. He also inquired about the company's plans for seeking strategic partnerships, contingent on positive clinical data.

Answer

CEO Harith Rajagopalan stated that while he had no new specific information on the first patient, the company will continue to follow the cohort and report longer-term data at 3 and 6-month intervals. On the topic of partnerships, he confirmed that Fractyl is actively engaged in discussions with major players in the obesity space who are interested in the opportunity.

Michael DiFiore from Evercore ISI posed technical questions about the Rejuva platform, asking why a different dose was used in a recent 12-week analysis, the reason for wide error bars in the data, and whether the company could share details on the Rejuva-002 candidate's receptor affinities.

Answer

Executive Harith Rajagopalan clarified that the dose in the 12-week study was selected by their collaborator at the University of Michigan. He attributed the wide error bars in the data to the natural weight variability of DIO mice on a high-fat diet over an extended period. He stated that it was too early to comment on the specific receptor affinities for the Rejuva-002 candidate.

Michael DiFiore asked if the Zenrelia label change request was progressing faster than expected and for color on vets' willingness to use it as a first-line treatment. He also asked about the discrepancy between lower cattle-on-feed numbers and strong Experior performance.

Answer

CEO Jeff Simmons clarified there are two workstreams for the Zenrelia label: a shorter-term language change with an expected H2 2025 answer, and a longer-term trial for a full label change. He noted a nice ramp in vets moving Zenrelia to first-line treatment. CFO Todd Young explained Experior's strong performance is due to expanded market access from the heifer clearance.

Representing Umer Raffat, Michael DiFiore asked about specific omnichannel strategies to mitigate cannibalization from the Credelio Quattro launch and the expected impact of potential tariffs on input costs and the supply chain.

Answer

President and CEO Jeff Simmons explained that Elanco is less concerned about cannibalization with Quattro due to its smaller notional share in the U.S. parasiticide market and early tracking that shows less cannibalization than with other recent launches. The focus is on activating pet owners to drive new interest. CFO Todd Young stated that the only current tariff impact is from China, costing $3-4 million in 2025, which is factored into guidance. He noted that potential tariffs on Mexico and Canada would have less impact due to a smaller manufacturing footprint there.

Michael DiFiore, on behalf of Umer Raffat from Evercore ISI, asked about the Zenrelia vaccination booster study results and if it was a concern for veterinarians. He also asked about market enthusiasm for Credelio Quattro in regions where tapeworm is not endemic, and for the driver behind the increased 2024 innovation sales guidance.

Answer

CEO Jeff Simmons responded that the Zenrelia booster study was well-received by veterinarians and has been helpful in technical conversations. On Credelio Quattro, he emphasized that its appeal is driven by the major trend towards broad-spectrum coverage, its tick efficacy, and heartworm prevention, not just tapeworm coverage. CFO Todd Young explained that the increased 2024 innovation guidance was driven by stronger-than-expected performance from Experior, AdTab, and Credelio Plus.

Michael DiFiore, on for Umer Raffat, noted that a competitor's drug launch was tracking ahead of LEQEMBI's and asked if Biogen had paved the way and about current competitive dynamics.

Answer

CEO Christopher Viehbacher acknowledged that Biogen and Eisai's early work to establish treatment pathways likely did pave the way for competitors. He stated that the current dynamic is focused on which drug a patient is initiated on, as switching is not expected. He reiterated that the primary goal is to collectively grow the overall market for Alzheimer's treatments, which remains vastly underserved.

Michael DiFiore asked for an outline of the expected timeline for Nictimbo's U.S. market penetration and ramp to peak sales, as well as management's thoughts on its probability of success in the Idiopathic Pulmonary Fibrosis (IPF) indication.

Answer

Marshall Urist, EVP, Head of Research and Investments, stated that due to significant unmet patient need and partner Incyte's strong market presence, they are hopeful for material demand upon launch. He clarified that the base investment case is focused on the current chronic GVHD approval, which is expected to generate attractive returns, while potential success in IPF or earlier lines of GVHD represents exciting upside.

Asked for an update on the anxious distress indication strategy and for more details on the scale and geographic focus of the planned 2025 sales force expansion.

Answer

For anxious distress, they have seen robust results and will present more data at upcoming conferences before providing further program updates. Regarding the 2025 sales force expansion, they confirmed it will be a further expansion beyond the current 530 reps to optimize the MDD launch but will share more specific details at a later time.

Inquired about the dose to be used in the Phase III DAYBREAK trial, the difference in the new KSI-501 formulation, and the rationale for including tarcocimab as a comparator in that trial.

Answer

The dose for both tarcocimab and KSI-501 will be 5 milligrams in their 'go-to-market' formulations, which are adjusted from previous versions. Including tarcocimab in the DAYBREAK study is a strategic, cash-efficient decision by Kodiak to strengthen the wet AMD data package, not an FDA requirement.