Mitchell Kapoor

Mitchell Kapoor of H.C. Wainwright & Co. asked for an update on the outpatient volume trend for CARVYKTI and inquired about the company's cash runway assumptions and potential need for future capital.

Answer

Alan Bash, President of CARVYKTI, noted that outpatient volume is slightly over half and growing steadily, expecting it to reach a 2/3 outpatient vs. 1/3 inpatient mix over time. Interim CFO Jessie Yeung stated that the current $1 billion in cash is sufficient to reach profitability, which is anticipated in 2026, and there is no present need to raise capital.

Mitchell Kapoor asked for an update on CARVYKTI demand relative to supply, when supply constraints might be fully alleviated, and whether demand growth is primarily from new centers coming online or increased demand at existing centers.

Answer

Executive Alan Bash responded that by the end of the current year, the company expects to be in a situation where supply fully meets demand. He clarified that while they don't break down the specific sources of growth, the predominant growth will come from the existing 104 activated centers and the expanding referral base into them as community outreach continues.

Mitchell Kapoor asked if the use of steroids to manage safety events could be formally incorporated into the label and whether any significant payer hurdles remain for the second-line indication.

Answer

CMO Mythili Koneru confirmed they hope to study steroid use formally in the CARTITUDE-6 protocol, which could potentially lead to a label update. SVP of Commercial Development, Steven Gavel, stated there are no payer barriers for the second-line indication, as insurers value the overall survival benefit and potential for cost savings from outpatient use.

Mitchell Kapoor inquired about the prevalent reasons for dropouts in the Olzarsen SHTG trials, given the impressive 90% rolling into the open-label extension, and whether these reasons should cause caution for the upcoming launch.

Answer

Richard Geary, Chief Development Officer, responded that the dropout rate was about half of what was expected, indicating the medicine was very well tolerated. He clarified that there was no single main reason for discontinuations, with reasons varying across the study, including personal circumstances, and expressed bullishness on the medicine's tolerability and safety.

Mitchell Kapoor asked about the more prevalent dropout reasons in the olzarsen sHTG trials, where 90% rolled into the open-label extension, and if any of these reasons should cause caution for the upcoming launch.

Answer

Richard Geary, Chief Development Officer, Ionis, noted that the dropout rate was about half of what was initially expected, indicating a very well-tolerated medicine. He stated there wasn't one single issue leading to discontinuations, with reasons varying across personal circumstances, and expressed bullishness on the medicine's tolerability and safety.

Mitchell Kapoor asked for relevant regulatory precedents where a strong progression-free survival (PFS) benefit without a statistically significant overall survival (OS) benefit at the time of filing was sufficient for FDA approval, and how these situations were handled by the FDA.

Answer

Urte Gayko, Chief Regulatory Quality and Safety Officer, cited two relevant approvals in EGFR-positive previously treated patients: amivantamab (MARIPOSA-2 study), approved based on statistically significant PFS with a positive OS trend, and Dato-DXd, which received accelerated approval based on ORR with duration of response.

Mitchell Kapoor asked for clarification on the approval pathway for PD-L1 negative patients, given the HARMONi-2 approval was for PD-L1 positive patients. He also inquired if the next HARMONi-2 data update would include a p-value for statistical significance.

Answer

Executive Dave Gancarz and Dr. Jack West clarified that the HARMONi-2 trial was designed for PD-L1 positive patients and did not include the negative population. They explained that a separate trial, such as the all-comer HARMONi-3 (in combination with chemotherapy), would be required to seek approval in the PD-L1 negative setting. Regarding the next data update, Gancarz indicated it would be a planned analysis with more mature data and a larger alpha spend, making a p-value report more likely.

Mitchell Kapoor asked why the NMPA approval for HARMONi-2 didn't include PD-L1 negative patients and whether a p-value would be reported with the next OS update.

Answer

Executive Dave Gancarz clarified that HARMONi-2 was designed for PD-L1 positive patients only. He, along with Dr. H. Jack West and Dr. Allen Yang, explained that approval in the PD-L1 negative setting would require a different trial, like the all-comer HARMONi-3 or HARMONi-6 studies. Regarding the next OS update, he noted it would be a planned analysis with more mature data, making a p-value more likely, though the decision rests with Akeso.

Mitchell Kapoor of H.C. Wainwright & Co. inquired about the strategy behind the Pfizer deal, whether it precludes other business development, and if future deals would be similar. He also asked about potential patient enrollment competition between the HARMONi-3 and HARMONi-7 trials.

Answer

An executive highlighted that Summit's independence allows it to combine ivonescimab with the best available therapies. Manmeet Soni, COO & CFO, explicitly stated the Pfizer deal does not preclude other partnerships. Regarding trial enrollment, Mr. Soni acknowledged a patient overlap but does not expect significant competition due to HARMONi-3's head start and the use of different clinical sites for HARMONi-7.

Mitchell Kapoor of H.C. Wainwright & Co. inquired about the patient recruitment strategy for the expanded HARMONi-3 trial, specifically for first-line non-squamous patients, and asked about the potential for accelerated approval for the HARMONi trial based on Progression-Free Survival (PFS) data.

Answer

Executive Dave Gancarz clarified the HARMONi-3 expansion targets a similar population to the KEYNOTE-189 study. CFO Manmeet Soni noted that a specific enrollment split between squamous and non-squamous has not been disclosed. Regarding the HARMONi trial, Soni reiterated it is their "fast-to-market" strategy with data expected mid-2025, and CMO Dr. Allen Yang added that approvals in this setting have historically been based on PFS.

Mitchell Kapoor questioned whether data from the HARMONi-2 trial could be leveraged for a U.S. regulatory filing and asked if there is a specific PD-L1 TPS score threshold where ivonescimab's effectiveness becomes more pronounced.

Answer

Chairman and CEO Robert Duggan stated that while they are in discussions with the FDA, it is unlikely they can file for approval in all regions based solely on HARMONi-2 data, though it can be leveraged in future studies. Chief Medical Officer Dr. Allen Yang explained that while response rates increase with higher PD-L1 expression, ivonescimab shows strong activity across the entire spectrum, with a notable relative benefit in the low PD-L1 population compared to other PD-1 agents.

Asked about the go/no-go criteria for moving CX-2051 into a Phase 2 monotherapy trial and about plans for advancing multiple combinations in earlier lines of CRC, including any FDA discussions.

Answer

The company saw a 28% ORR in the first 18 patients, which is a very strong signal for a go-forward decision. While no specific numerical bar was given, they feel they have room to maneuver. For earlier lines, multiple combinations are possible, but they must be mindful of resources. The most likely starting point is a combination with bevacizumab. No significant discussions with the FDA on combination strategy have occurred yet.

Mitchell Kapoor of H.C. Wainwright & Co., LLC inquired about the specific data triggers for a go/no-go decision to move CX-2051 into a Phase 2 trial and whether multiple combination studies are planned for earlier lines.

Answer

Sean A. McCarthy, Chairman & CEO, noted that the previously reported 28% confirmed ORR is very exciting and that the go-forward bar doesn't necessarily need to be that high, given the unmet need. Regarding combinations, he stated that multiple options are on the table, but the most likely starting point would be with bevacizumab (Bev), while being mindful of company resources.

Speaking for Mitchell Kapoor, an analyst asked why the PROBODY masking technology worked so well with the EpCAM strategy compared to past efforts, if the platform is being enhanced for future candidates, and about the strategy for the planned pan-tumor study, including whether it would be a basket trial and if it would select for high EpCAM expression.

Answer

CEO Sean McCarthy attributed the success to getting the combination of tumor type (CRC), target (EpCAM), and effector mechanism (TOPO I payload) right, rather than a fundamental change in the masking technology, which he stated has always worked. Regarding the pan-tumor study, McCarthy said the specific design is under discussion. While patient selection isn't needed for CRC, the company's IHC assay could be helpful in other tumors, though the exact target level needed for response is not yet known.

Asked about the rationale for CX-2051's bystander effect in specific tumor types and for clarification on the timing and reason for the CX-904 program update.

Answer

The design of CX-2051, including its payload and linker, is optimized for a bystander effect in tumors with high EpCAM expression like CRC. The CX-904 update was provided on the current call, with a more detailed data release planned for next year as dose escalation is ongoing to find the optimal dose.

An analyst on behalf of Mitchell Kapoor asked about the biological rationale for CX-2051's bystander effect in specific tumor types and inquired about the status of the previously expected year-end update for CX-904, asking if it was delayed.

Answer

CEO Sean McCarthy clarified that the design of CX-2051, including its Topo-1 inhibitor payload and linker, was deliberately optimized for bystander effect in high-target tumors like CRC. Regarding CX-904, he stated that the current call served as the update and that the timeline shifted because dose escalation is continuing, with the next data release planned for 2025.

Mitchell Kapoor from H.C. Wainwright & Co. asked about the characteristics of patients choosing permanent gene editing therapies, the implications for commercial positioning, and the potential market split for permanent versus non-permanent options.

Answer

President and CEO John Leonard explained that trial participants are "high quality" patients who are not out of options; many are coming off effective standard-of-care drugs. He interprets the robust enrollment across all Phase 3 programs as strong evidence that both patients and physicians are motivated by and embracing the concept of a permanent, one-time treatment for their diseases.

Mitchell Kapoor asked about the payer perception of potentially covering both tafamidis and Nex-z, and how this dynamic might influence the interpretation of data from the ATTR studies.

Answer

CEO John Leonard anticipates that tafamidis will be a generic drug by the time Nex-z launches, which should minimize payer concerns about covering both. He stressed that the MAGNITUDE trial is designed with sufficient patients on baseline tafamidis to demonstrate a clinical benefit on top of the stabilizer, ensuring strong clinical evidence to support its use, regardless of payer views.

Mitchell Kapoor from H.C. Wainwright & Co., LLC asked about the conservatism of the current 2025 financial guidance, noting it has been raised multiple times. He also questioned Merck's potential motivation for filing additional PGRs sequentially.

Answer

CFO Nicole LaBrosse explained that guidance is updated based on the latest trend data, with recent outperformance from key products supporting the raise. President and CEO Dr. Helen Torley added that the dynamic nature of multiple growth catalysts has led to partner overperformance. Regarding Merck, Dr. Torley speculated they are challenging new patents as they are issued but reiterated that the key focus remains the district court infringement case.

Mitchell Kapoor of H.C. Wainwright & Co. inquired about the future mix of royalty revenues and the timeline for newer products to become more significant contributors alongside the current blockbusters. He also asked for more detail on the M&A strategy, including target profiles, how it differs from past strategies, and the desired timing and size of potential deals.

Answer

Dr. Helen Torley, President and CEO, and Nicole LaBrosse, CFO, explained that while DARZALEX remains a key contributor, products like VYVGART Hytrulo and OCREVUS are expected to become very important. LaBrosse noted that the next wave of products represents a $35 billion market opportunity by 2028, compared to $20 billion for DARZALEX and Phesgo, indicating a future shift in the royalty mix. On M&A, Torley stated the focus is on drug delivery platform technologies with licensing models that generate durable royalties. She emphasized they are not in a hurry and it was premature to comment on deal size or specific timing.

Mitchell Kapoor of H.C. Wainwright & Co. requested more context on the potential size of the MDASE platform opportunity, questioning how significant it might be compared to the well-established ENHANZE platform.

Answer

President and CEO Dr. Helen Torley positioned ENHANZE as the "gold standard" and primary focus for partnerships. She described the MDASE opportunity as an emerging field for companies that may be unable or unwilling to use ENHANZE but are developing a modified hyaluronidase. While not quantifying the opportunity, she framed it as an additional, distinct growth driver for Halozyme's IP portfolio.

Daniel Smith, on behalf of Mitchell Kapoor, asked how recent FDA leadership changes might alter Sarepta's approach to clinical trial design and impact development timelines.

Answer

President and CEO Douglas Ingram stated that based on recent interactions with the FDA's OTP, he has seen no changes in their innovative approach. He expressed confidence that the FDA will remain a science-based organization focused on modernizing drug development, noting recent public statements from new leadership supporting the use of biomarkers in rare disease, which aligns with Sarepta's strategy.

Mitchell Kapoor asked about the clinical implications of the higher peak drug concentration (Cmax) observed with RT-114 compared to its subcutaneous version. He also requested an update on business development interest and the company's strategic priorities between platform expansion and specific product development.

Answer

Executive Talat Imran acknowledged the potential for higher peak concentrations to affect tolerability but noted it wasn't an issue in canine studies and can be managed in the clinic via titration or dose splitting. On business development, he confirmed partnering remains a primary focus, citing the ProGen deal and a research collaboration with a large pharma, with strong interest across obesity, immunology, and rare diseases.

Mitchell Kapoor of H.C. Wainwright sought more details on the company's business development strategy, including what a 'technology platform' might entail and a potential timeline, and also asked for expense guidance for upcoming quarters.

Answer

CEO Avanish Vellanki declined to provide specifics on the business development strategy at this time. On the financial question, Acting SVP, Finance Nelson Cabatuan confirmed that cash burn and expenses will be significantly lower from Q3 2023 onwards compared to the first half of the year, but did not give specific R&D or SG&A figures.

Mitchell Kapoor from H.C. Wainwright asked if combination strategies would still be pursued for MDM2 amplified patients even with positive monotherapy data from MANTRA-2. He also inquired about the planned U.S. launch strategy for liposarcoma, including sales force size.

Answer

CEO Avanish Vellanki explained the MANTRA-2 strategy depends on the totality of data to determine the best regulatory path. CMO Richard Bryce added that combination studies are of high interest and could be explored. For the launch, CEO Vellanki reiterated prior guidance of a 25-35 person domestic sales force and partnering ex-U.S.

Mitchell Kapoor from H.C. Wainwright asked about the clinical profile of patients currently enrolling in MANTRA-2 compared to the initial cohort and if MDM2 copy number correlates with disease severity. He also sought more rationale for the delay of the MANTRA-4 trial.

Answer

CSO Robert Doebele stated that the patient profile is expected to be similar as inclusion criteria have not changed, and while MDM2 amplification indicates a worse prognosis, the specific copy number level is not thought to affect clinical status. CMO Richard Bryce explained the MANTRA-4 delay was to incorporate helpful, non-contentious FDA suggestions regarding inclusion criteria and stopping rules.

Mitchell Kapoor from H.C. Wainwright asked for details on what to expect from the top-line Phase 3 MANTRA data in liposarcoma, including potential regulatory filing timelines. He also inquired about the benchmarks for success, specifically regarding progression-free survival (PFS) and objective response rate (ORR).

Answer

CEO Avanish Vellanki declined to provide specific details on the top-line data release or filing timelines beyond stating they would follow conventional timeframes. He emphasized that the primary endpoint is PFS, with a goal of doubling it versus the standard of care, and that ORR is not an adequate measure of efficacy in liposarcoma, which has historically shown very low response rates.

Mitchell Kapoor of H.C. Wainwright & Co. asked for details on how the data collection for the PKU Phase III trial will differ from the more intensive, 'data-rich' Phase II study.

Answer

CEO Aoife Brennan explained that the Phase III trial will be less burdensome for patients. It will focus on simpler primary endpoints like the proportion of responders and the magnitude of plasma Phe lowering, eliminating the need for the intensive meal tests and frequent biomarker sampling used in Phase II. She also noted that Phase III will incorporate learnings on tolerability, allowing for dose titration to manage GI side effects.

Mitchell Kapoor of HC Wainwright inquired about the potential performance difference between SYNB1934 and SYNB1618 in reducing blood Phe levels and asked about the regulatory feedback from the FDA regarding the newer strain.

Answer

CEO Aoife Brennan explained that while SYNB1618 results were strong, data from healthy volunteers showed SYNB1934 has 2x greater activity, suggesting it will be superior. She clarified that the company has not yet had its End-of-Phase II meeting with the FDA but has worked collaboratively with them. Due to the high similarity between the strains, extensive new preclinical work was not required for SYNB1934, and the company feels it is in a strong position pending the formal meeting.

Mitchell Kapoor of H.C. Wainwright & Co. inquired about the timing and nature of the initial data readout for the INM-755 Phase 2 trial in Epidermolysis Bullosa (EB), asking what would constitute positive data and if it could be benchmarked against competitors like Amryt.

Answer

Alexandra Mancini, SVP of Clinical and Regulatory Affairs, clarified that there will be no interim analysis, with full results announced upon trial completion, which is estimated to be about one year after enrollment began. She explained that positive data will be determined by within-patient comparisons of the active cream versus a vehicle control, assessing individual patient benefits. Mancini explicitly advised against benchmarking to Amryt's Phase 3 data, as InMed's Phase 2 study is smaller and has broader endpoints beyond just wound healing, such as anti-itch effects.