Summit Therapeutics Inc.

Good morning and welcome to Summit Therapeutics third quarter 2024 earnings and update call. All participants will be in a listen only mode until the question and answer portion of the call. We do not expect any technical difficulties today. However, in the event that we lose the webcast connection and are unable to provide any updates, please wait up to 10 minutes for resolution. Please refer to the company's website for updates. Please note that today's call is being recorded. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, again, press star one. Thank you. At this time, I would like to turn the call over to Dave Gankars, Summit Therapeutics Chief Business and Strategy Officer. You may proceed.

Good morning, and thank you for joining us. Our press release was issued earlier this morning and is available on the homepage of our website. Our Form 10-Q was also filed earlier this morning and is available on our website. Today's call is being simultaneously webcast and an archived replay will also be made available later today on our website, www.smmttx.com. Joining me on the call today is Bob Duggan, our Chairman of the Board and Chief Executive Officer. Dr. Marquis Zongede, our Chief Executive Officer and President, Manmeet Soni, our Chief Operating Officer and Chief Financial Officer, and Dr. Alan Yang, our Chief Medical Officer. Before we get started with the rest of the call, I would like to note that some of the statements made by our management team today and some responses to questions that we will make may be considered forward-looking statements based on our current expectations. Summit cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information about these risks and uncertainties. Summit undertakes no obligation to update these forward-looking statements, except as required by law. Following comments from Bob, Mechie, and Monmouth, we will take questions. And with that, I'd like to turn the call over to Bob.

Thank you, Dave. Good morning, everyone. Thank you for joining us today. I'm very proud of the recent accomplishment of Team Summit and the continuing positive information to be shared surrounding Ivanissimab, our lead investigational asset. There have been several meaningful achievements around the progress of Ivanissimab since our last earnings call, both with our partners in China, as well as here in the US and Western markets. We continue to progress towards our mission of building an organization making a significant positive difference in serious unmet medical needs. Specifically, we intend to amend the protocol for our multi-regional phase three trial Harmony 3 to now evaluate patients with first-line treatment for metastatic non-small cell lung cancer with both squamous and non-squamous histologies. The prior trial design previously included only tumors of squamous histology. This is a significant immediate expansion of total addressable market of our current phase three clinical trial portfolio. We will provide additional context in a few moments around Harmony 3's expanded patient population. We have completed enrollment of our global Phase III Harmony trial in patients with EGFR-mutated advanced non-small cell lung cancer who have progressed after treatment with the third-generation EGFR tyrosine kinase inhibitor, or TKI. As previously announced, we expect Harmony top-line data in mid-2025. In addition, we received fast-track designation from the FDA for this setting in the United States. Following the positive results of HARMONY-2, we announced our intentions for launching a third global phase three trial, HARMONY-7, studying Ivernissimab monotherapy in patients with first-line metastatic non-small cell lung cancer whose tumors have high PD-L1 expression. Additionally, encouraging phase two data featuring Ivernissimab from China was featured at World Lung and the 2024 European Society for Medical Oncology, or ESMO. annual meeting in prairie operative non-small cell lung cancer, as well as indications outside of non-small cell lung cancer, including advanced triple negative breast cancer, recurrent metastatic head and neck cancer, and microsatellite stable metastatic colorectal cancer. Each of these phase two studies were sponsored by Oceso, with data generated and analyzed by Oceso. These encouraging data reflect why we are continuing to explore the expansion of our clinical development of ibanizumab outside of metastatic non-small cell lung cancer. In addition, we raised $235 million from leading biotech investors and individuals, including insiders, extending our cash runway and increasing our resources to execute upon expansive goals. Manmeet will provide more details about our financial position in a few minutes. These accomplishments have been foundational to our 2024 goals of successfully executing on our registrational phase three trials while expanding our clinical development plan. McKee will further discuss these accomplishments, including additional strides taken to drive our continued belief and conviction in Team Summit and the potential of venesumab in non-small cell lung cancer and indications beyond lung. We are a mission-driven organization with the collective goal to improve quality of life, increase potential duration of life, and resolve serious medical needs. We believe we have the right team and the right molecule in Ibenizumab to help us realize this goal. With that, I will turn the call over to my key for additional context and recent highlights for consideration.

Thank you, Bob, and good morning, everyone. As Bob said, I remain incredibly enthusiastic about the accomplishments of Team Summit and our partnership with ECESO. Before providing on some of the highlights as Bob mentioned, I would like to discuss the clinical work that has been conducted with Avonisimab. There are more than 25 clinical trials around the globe evaluating Avonisimab across 17 tumor settings, including nine phase three trials planned, ongoing, or completed either in China or globally. While six of the phase three programs across Summit and ECASO are currently focused in non-small cell lung cancer, three additional phase three clinical trials have been announced by ECASO, evaluating our lead candidate in solid tumor settings beyond non-small cell lung cancer. These include BTC, head and neck cancer, and pancreatic cancer. At Summit, we are sponsoring two ongoing Phase III clinical trials, Harmony and Harmony III. We are planning to initiate Harmony VII in early 2025. Based on the data Bob mentioned that was released at ESMO that I will speak more to it in a moment, we are excited to and are actively exploring expanding our Summit-led clinical development plan beyond metastatic non-small cell lung cancer. As a reminder, Ivonecimab is the only PD-1 VEGF bispecific antibody in Phase III in our licensed territories. Ivonecimab brings these two highly validated mechanisms of action together into one novel molecule targeting simultaneously both PD-1 and VEGF. Next, I would like to review the many achievements completed as well as discuss some upcoming catalysts for the remainder of this year. The third quarter of 2024 was a landmark moment for Ibonissima and its development, with significant catalyst events in the form of data releases in September at the World Long and ESMO conferences. Last month at the World Long Conference, Harmony II results were featured as part of the presidential symposium and received a tremendous response from leading KOLs. In this head-to-head trial comparing Ibonissima versus Pembroke, Both as monotherapy, Harmony II met its primary endpoint of progression-free survival, with Ivonecimab achieving a 49% reduction in the risk of disease progression or death compared to Pembroke. Ivonecimab showed consistent, clinically meaningful benefit across key subgroups, including patients with either PD-L1 low or PD-L1 high-expressing tumors and in squamous and non-squamous histologies. Consistent with previous studies, Ibanesimab demonstrated an acceptable and manageable safety profile. With the additional Phase II data released in the third quarter at both Ward-Long and ESMO, we continue to expand the meaningful data that has been generated with Ibanesimab in various solid tumor settings beyond non-small cell lung cancer. We are fortunate to have created such a strong partnership in our ongoing collaboration with as we leverage data from multiple solid tumor studies, supporting and informing Summit's own late-stage clinical development strategy in our licensed territories. In addition to touching on our current clinical development plans, we initiated our strategic alliances with the University of Texas MD Anderson Cancer Center this quarter, providing additional opportunities to evaluate abonissimab in tumor types and settings in which we have not yet tested its potential Patients are expected to soon begin treatment and clinical development effort will soon begin via this collaboration. After the Harmony 2 data was announced, we have received inbound interest from physicians regarding approximately 75 proposed investigator-sponsored trials or ISDs in a wide range of cancer types. With meaningful updates this past quarter from AKSO's Harmony 2 study and several Phase 2 studies, we wanted to take the opportunity to review the respective study designs and further highlight key results. We will start with HARMONY-2. HARMONY-2 is a randomized, double-blind clinical trial evaluating frontline monotherapy ivanesimab as compared to monotherapy PEMBRO in patients with locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression. This is a single-region, multi-center phase III clinical trial conducted and sponsored by AKSO in China. Our partners at AKSO generated and analyzed the data in Harmony 2. Here is the primary endpoint of progression-free survival by blinded independent radiologic review committee for the entire study at the time of the first planned interim analysis, with a median follow-up of 8.67 months demonstrating a significant improvement for Ivonizumab with a hazard ratio of 0.51, corresponding to a 49% improvement over the control arm. The median PFS was 11.1 months versus 5.8 months in the Ibanissimab and PEMBRO arms, respectively. Of note, the curves begin to separate at the first point of radiographic assessment and maintain separation over the entire duration of follow-up thus far. The analysis of PFS subgroups reveals that the PFS benefit with ibanesimab was observed across nearly all subgroups. Specifically, the benefit is quite comparable across the spectrum of PD-L1 expression with a hazard ratio of 0.54 for patients with PD-L1 low-expressing tumors and 0.46 for patients with tumors of high PD-L1 expression. As previously discussed, and this is particularly true in the United States and Europe, Monotherapy checkpoint inhibitor usage is a standard of care for patients with high PD-L1 expression. With regard to non-small cell lung cancer histology, the benefit was also similar for patients with squamous non-small cell lung cancer, who showed a hazard ratio of 0.48, favoring ibanesimab, and those patients with tumors of non-squamous histology with a hazard ratio of 0.54, favoring ibanesimab. This slide is a strong indicator that the benefit was seen across clinical subgroups and underscores that the success of the trial overall was not driven by an especially strong performance of a subgroup. For safety, we see that there was a numerically higher rate of serious treatment-related adverse event with ibanesimab, 20.8% compared to 16.1%. This did not translate to greater treatment discontinuation or treatment-related advanced events leading to death, both of which were numerically higher in the PEMBRO arm. This pattern held true in patients with squamous non-small cell lung cancer as well, a place where anti-VEGAS therapy has historically demonstrated safety risk, where there were comparable rates of serious treatment-related advanced events. discontinuation, and death in the Ibonizumab ARB compared with the PEMBRO ARB. This is the first randomized Phase III clinical trial evaluating the safety profile of Ibonizumab in the squamous population, especially confirming its tolerability in this group. In more detail, we see that nearly all of the higher rates of treatment-related adverse events were lab-related abnormalities, hypertension, and proteinuria, but generally did not lead to discontinuation of dosing. These are conditions that are often seen by oncologists who, in general, are experienced managing these AEs. Finally, looking at the immune-related and possibly VEGF-related advanced events, in the table to the left, we see comparable immune-related AEs with Ivonisimab compared to Pembroke. On the right, we see that, as expected, Avonisimab was associated with more possibly VGEF-related AEs, both in all graders and Grade 3 or higher. Importantly, however, all Grade 3 or higher AEs were all classified as Grade 3. There were no Grade 4 or Grade 5 AEs that were possibly VGEF-related in either arm of the study. The table in the bottom right shows that most of the possible VGEF-related advanced events represented proteinuria and hypertension. There is no evidence of life-threatening or fatal bleeding complications, including among patients with advanced squamous non-small cell lung cancer and in patients with central tumors, cavitary lesions, and or tumor-encasing large blood vessels in this Phase III study. As a result of the successful Harmony 2 study and our analysis of the underlying data, we announced our plan to initiate Harmony 7, a randomized global phase 3 study evaluating ibanesimab versus PEMBRO, both monotherapy in frontline non-small cell lung cancer in the PD-L1 high expressor population. Harmony 7 is planned with the two primary endpoints, progression-free survival and overall survival. We are planning for an estimated 780 patients in this registration-enabling study. Turning to Harmony 3, as Bob mentioned, we intend to amend this randomized global phase 3 clinical trial to include patients with tumors of non-squamous histology in addition to continuing to enroll squamous patients. As part of the trial amendment, the primary endpoint is intended to be updated to include two primary endpoints of progression-free survival, and overall survival. The total sample size for this randomized multi-regional phase III clinical trial has been adjusted to include an estimated 1,080 patients. Expanding Harmony III is the most efficient way to cover all metastasic non-small cell lung cancer patients without driver mutation. Harmony III will now cover metastasic non-small cell lung cancer, both squamous and non-squamous tumors, In combination with chemotherapy and Harmony 7 intent to cover PD-L1 high-expressing tumors via monotherapy, Ivonecimab now providing the opportunity to capture a significantly broadened addressable market as quickly as possible. Supporting this proposed amendment, in part, is both the result of Harmony 2 showing benefit to patients with both squamous and non-squamous tumors, as well as the Phase 2 data that has been previously presented. As a reminder, updated phase two data for this setting was announced at the 2024 European lung cancer conference in March from the AK112201 clinical trial centered around the cohort of patients in which ibanesimab is combined with chemotherapy for first-line treatment of squamous and non-squamous advanced or metastasic non-small cell lung cancer in patients without actionable genomic alterations. This data was generated and analyzed by ECASO. First-line patients with advanced or metastatic non-squamous tumors experienced a median progression-free survival of 13.3 months. In addition, first-line advanced or metastatic squamous patients experienced a median progression-free survival of 11.1 months. Both metrics are encouraging considering the expectation for the current standard of care in this patient population largely driven by PD-1 inhibitors plus chemotherapy. Median overall survival was not reached in either subset of patients after a median follow-up time of approximately 22.1 months. The frequency of treatment emergent events leading to the discontinuation of Ibonissima was 11.1% and 2.8% respectively in patients with squamous and non-squamous tumors. We are highly encouraged by the opportunity of Ibonissimab to demonstrate its potential across non-small cell lung cancer in multiple clinical settings. Finally, as we have stated, we are evaluating opportunity to expand our clinical development beyond metastatic non-small cell lung cancer. We will review the encouraging Phase II data announced this past quarter at Ward, Long, and ESMO, starting with an overview of the respective study designs. At the World Long Perioperative Non-Small Cell Lung Cancer Phase 2 data was featured from AK112205, a single-region, multi-center, open-label study of patients with stage 2 or 3 resectable non-small cell lung cancer with data generated analyzed by ECESO. The study was designed to assess patients receiving either Ibonizumab monotherapy or Ibonizumab plus chemotherapy prior to surgical resection and then Ivonisimab monotherapy after surgery. Due to the maturity of the data and the timing of the data cutoff, the results were mature for the no adjuvant portion of the clinical trial. In September 2024, promising anti-tumor activity and safety data for Ivonisimab were presented at ESMO, featuring updated data in advanced triple negative breast cancer, recurrent metastatic head and neck squamous cell cancer, carcinoma, and metastasic microsatellite-stable colorectal cancer. The head and neck study assessed patients who receive Ibonizumab with or without ligofalimab with PD-L1 positive, locally advanced or metastasic recurrent head and neck squamous cell carcinoma. Note that ligofalimab, or AK117, is a case-host property investigational product that is not approved by any regulatory authority and to which Summit does not have any license or ownership rights. The colorectal study was designed to assess patients who were randomly assigned to receive Ibonizumab plus Folfaxillary with or without Ligofalimab, an investigational anti-CD47 monoclonal antibody. The triple negative breast cancer study assessed patients who receive Ibonizumab plus chemotherapy, either Paclitaxel or Nab Paclitaxel, with locally advanced or metastatic TNBC. Turning now to anti-tumor activity and safety data from these Phase II studies. In preoperative non-small cell lung cancer, at the time of data cutoff, 49 patients had been enrolled into the Evonissima plus chemotherapy arm in the neoadjuvant setting. Of these 49 patients, 39 went on to complete surgery. Of the 39 patients who received Avonissima-plugged chemotherapy in the neoadjuvant stage and completed surgery, 71.8% of patients experienced a major pathological response and 43.6% of patients experienced a pathological complete response. In the 49 patients enrolled in this cohort, median event-free survival was not yet reached after 8.9 months of the median follow-up time. The 12-month event-free survival rate was 80.3%. These results are encouraging compared to the historical data that has been observed in global pivotal studies in a similar setting. The safety profile in this Phase II study was acceptable and manageable. No surgeries were delayed or canceled due to the treatment-related advanced events. In colorectal cancer, at the time of data cutoff, 22 patients received abonissima plus falvoxiliary with a median follow-up time of nine months. 18 patients received ibanesimab plus ligofalimab plus falvoxiril with a median follow-up time of 9.6 months. All patients in both groups experienced a reduction in their tumor burden compared to their baseline tumor assessment. The overall response rate and DCR for the 39 patients combined from both groups who had at least one post-baseline tumor assessment was 84.6% and 100% respectively. Median progression-free survival was not reached in either group at the time of this analysis. The safety profile in this Phase II study was acceptable and manageable. This response rate are very encouraging considering historical benchmarks in this setting. In addition, these patients have tumors that are considered microsatellite stable, a setting where PD-1 therapy has not been historically successful. This is another indicator of Ivonecima potential beyond the current PD-1 landscape. In triple-negative breast cancer, at the time of data cutoff, 30 patients received Ivonecima plus chemotherapy with median follow-up time of 10.2 months. 60% of patients had previously received taxon-based chemotherapy in either the neoadjuvant or adjuvant settings in this Phase II dataset. All patients experienced a reduction in their tumor burden compared to their baseline tumor assessment. The overall response rate and DCR for the 29 patients who had at least one post-baseline tumor assessment were 72.4% and 100% respectively. Median progression-free survival was 9.3 months at the time of this analysis. The safety profile in this Phase II study was acceptable and manageable. The PD-L1 low or negative TNBC is yet another clinical setting without PD-1 therapy as a standard of care. Moving to head and neck, at the time of data cutoff, 10 patients received Ibonizumab with median follow-up of 3.3 months, and 20 patients received Ibonizumab plus Ligothalimab with median follow-up 4.1 months. All patients had tumors with PD-L1 expression The overall response rate and VCR for the 30 patients combined was 50% and 86.7% respectively. The safety profile in this Phase 2 study was acceptable and manageable. The third quarter of 2024 was a pivotal moment in cementing the growing confidence of Urbanissima. Before I turn it over to Manmeet to provide a financial update, I would like to take a moment to thank our incredible team at Summit. As Bob and I have described all of the accomplishments we have achieved over the past seven quarters with Advanisimab, this team has done a remarkable job across every team in making our goals a reality and condensing time where and when possible to accelerate our timeline in bringing additional therapeutic options to patients with cancer. It is a tremendous honor and privilege to work with each member of Team Summit and I would like to express my heartfelt thanks to everyone of our phenomenal team members. With that update, I would now ask Manmeet to provide details on our financial position and operational updates.

Thank you, Miki, and good morning, everyone. We issued this morning our earnest release for the third quarter of 2024. Today, in addition to providing you with an update on our cash position, recent financing, and third quarter operating expenses, I will also be providing an update on our clinical operations. On the clinical operations front, I'm really proud of the team summit for completing the enrollment ahead of schedule for our first registrational global trial, Harmony, in patients with EGFR mutations post-targeted therapy. We expect to have the top-line data from our Harmony trial, including patients from U.S. and Europe, in mid-2025. Also, since the release of Avanosimab data during September 2024 at World Conference on Lung Cancer and ESMO Annual Meeting, we have seen an increase in the screening and enrollment activity for the squamous patients at our existing sites in our Harmony trial. Additionally, we have seen lots of excitement and outreach from both academic and community physicians to participate in the development of Avanosimab. We believe this interest will help us in accelerating activation of additional sites and ultimately enrolling patients faster for the two planned trials. Harmony 3 for addition of non-scrimmage arm and also for recently announced Harmony 7 trial which we had in 2025. On the financials front, let me start with our cash position. We ended the third quarter of 2024 with a cash position of approximately $487 million. This cash position was strengthened at the end of third quarter with the closing of a $235 million private placement in September 2024 for multiple leading biotech institutional investors and insiders. Turning to operating expenses, I'll provide details to both GAAP and non-GAAP numbers. You can refer to our press release issued this morning for a reconciliation of GAAP to non-GAAP financial measures. To remind, non-GAAP expenses exclude stock-based compensation and one-time charges related to acquired in-process R&D expenses. Our GAAP R&D expenses during the third quarter were $37.7 million compared to $30.8 million for the second quarter of 2024. and non-GAAP R&D expenses were $31.9 million in the second quarter of 2024 compared to $27.3 million for the second quarter of 2024. Turning to G&A, our GAAP G&A expenses during the third quarter 2024 totaled $20.4 million compared to $14 million for the second quarter of 2024. and non-GAAP G&A expenses were $6.8 million during the third quarter of 2024 compared to $6.4 million for the second quarter of 2024. The increase in GAAP operating expenses was primarily related to the increase in stock-based compensation expense during the quarter related to charges from the achievement of certain market conditions on performance stock option awards, and an increase in R&D expenses due to expansion of clinical study and development costs related to AvanisMAP and increase in people cost as we continue to build our R&D team. On a non-GAAP basis, which excludes stock-based compensation, our non-GAAP operating expenses during the third quarter 2024 were $38.7 million compared to $33.7 million for the second quarter of 2024. We have been executing efficiently on our two registration studies, Harmony and Harmony 3, with quarterly cash burn in our operating activities keeping it below $35 million. Finally, to conclude, we believe our current cash balance at quarter end aggregating to $487 million provides us enough cash to continue to invest in the Avanisweb trials planned to be expanded and initiated in 2025. And with that, I'll hand it back over to Dave.

Thank you, Bob, Maki, and Manmeet. Now we'd like to see if there are any questions that our team can help answer. Operator, would you please open the line for questions?

Thank you. As a reminder, to ask a question, please press star followed by the number one on your telephone keypad. Once again, that is star followed by the number one. We'll pause for just a moment to compile the Q&A roster. Our first question comes from the line of Mitchell Kapoor with H.C. Wainwright. Your line is opened.

Hey, everyone. Thanks for taking the questions. Just wanted to know on the expansion of the Harmony III trial, who are the likely first-line non-squamous patients that you could likely enroll? And specifically, how do you think about recruiting patients who would otherwise be good candidates for Keytruda? How do you think about getting those patients to participate in this study?

Yeah. Thanks, Mitchell, for the question. The expansion is basically similar to the population that was treated in the Keynote 189 study. So these are going to be non-squamous patients, probably adeno patients. And I think McKee reviewed the trial. I think the key here will be the chemo will be slightly different. It'll be platinum pametrexate for these patients. However, we have extensive experience with that from the Harmony studies, Harmony A and Harmony.

Okay, great. And do you have a

target enrollment for the split between non-squamous and squamous for this trial uh we've not disclosed that we're just in the planning phase right now as we said we did the we gave the combined number 1080 patients which we plan to enroll in both squamous and non-squamous we have not given further splits yet okay great and then the last one for me is just on harmony can you talk about the potential for accelerated approval could you file on pfs and

How does that differ in terms of the unmet need from the strategy with Harmony 3 and Harmony 7?

Harmony has always been our fast-to-market strategy, and as you know, we announced that we completed the enrollment earlier this month, and now we expect the data in mid-2025. Obviously, based on the data, obviously, we'll be assessing our regulatory strategy and then providing further updates.

Great.

Yeah. Thank you all. Just to clarify, there's two parts to that question in terms of the PFS, right? So there's could you file only on PFS data and then the timing of which could you file with the PFS data before you have the OS readout? And so, you know, just for the precedent in this EGFR second line space, you know, the approval has been on PFS, right? And unfortunately, it is second line. It's a large unmet need. So the time between PFS and OS readouts may not be significantly different, right?

Yeah, the only thing I would add to that, Mitchell, just to round it out, I think you asked the question in terms of, you know, the difference between the Harmony and the Harmony 3 perspective. So just to reiterate, so Harmony 3 is, with our intention to expand that population, that is Patients already with squamous, so we'll keep that cohort, we'll add patients who are non-squamous, but they'll be without actionable genomic alterations, right? So, without driver mutations. Our Harmony trial is focused on those with EGFR mutant, the driver mutation of EGFR mutations, right? That is, they are separate. They're not overlapping populations, Harmony and Harmony 3. I just want to make sure that that's clear.

And just to further clarify, I just want to clarify for the Harmony 3, as McKee mentioned, now the endpoint is PFS and OS. And the question around PFS filing versus OS timing of the filing is relevant for that study.

Great. Thank you all very much.

You're welcome. Our next question comes from the line of Brad Canino with Stifle. Your line is open.

Good morning, and thanks for all the updates. Like, on the addition of PFS to the primary endpoint of Harmony 3, can you talk about what types of regulatory feedback and clinical investigator feedback that went into that decision? And then related, and sorry to push with a question like this, but we all know that investors are keenly aware and awaiting for an OS answer from your partner or KESO And a change like this before we get that naturally makes one wonder what the confidence of management is to achieve a clinically meaningful OS benefit in the front line among settings. So can you talk about both of those elements?

Yeah, Brad, thanks for the question. So let me answer the last one first. There's no change in our confidence for the Harmony 2 data around the OS, right? I think the opportunity was, you know, and it was unrelated, but the magnitude of the PFS benefit in Harmony 2 was so striking. You know, you don't want to have a therapy that provides such a significant benefit and not make that benefit available to patients, right, just based on that number. Granted, there's a lot of issues that we won't get into about payer reimbursement and the value of OS versus PFS, but we think that this is a positive thing, the addition of the PFS endpoint. as a primary endpoint for the Harmony III study, in both timing and availability, and benefit to patients.

Yeah, and just to answer the other part of your question there, Brad, you asked about regulatory feedback. So, as we've promised from the beginning of this relationship, you know, with ACASO and our licensing of ibanesimab, we would be speaking in particular with the FDA prior to these changes so that we have had communications with the FDA here. Especially for such an important change.

Great. And now that Harmony 3 does have both histologies, do you plan to wait for them both to have data to do the top line, or can they be reported separately? You know, right now, the NCT, before you've updated, says the primary completion estimate is September 27. Now that the trial has changed, how should we think about data flow, both histologies together, etc.? ?

Yeah, so at the highest level, what I would say there, Brad, is this is a single trial. So it's a single, you know, analysis set. So we wouldn't necessarily look to break out timing there. Now, we did say in the slides that we presented this morning that, you know, like and as would be expected from a stratification perspective, we would stratify by histology. But it wouldn't be from a timing perspective broken out. You know, I would say, without going too far into the details, you know, just given that we're intending to amend this shortly, there's a significantly broader population of non-squamous patients as well. And so, from a timing perspective, you know, there's more availability of those patients, and there's a broader availability to enroll patients with non-squamous tumors.

Okay. And then last for me, I think as we see multiple PD-1 and L1 by VEGF bispecifics advance across multiple companies. I mean, every day there seems to be a press release. It would be great to hear your thoughts on whether other designs and constructs, be they those that leverage PD-L1 or maybe broader VEGF isoform inhibition, are viewed internally as close replications of ivanesumab and its incredible profile to date, or viewed as potentially different. Thank you.

Sure. Thanks, Brad. So what I would say, when we entered into the deal with Acceso, we naturally expected to see a few more assets emerge with a similar construct in general, as you mentioned, given the data that had been produced to date and our willingness to enter into a deal of that size and magnitude that we did. Of course, once the data from Harmony 2 emerged, we expected to continue to see a rapid emergence of products looking to capitalize on the potential that Ivanessa MAP had created at that point. And so most of these assets I would point out it very early, a majority, a vast majority of preclinical with no inhuman data. However, we do review the construct of each of these compounds individually. And while we're not going to comment on any individual asset particularly, what I would say is that ibanesimab was specifically engineered to improve antitumor activity and reduce toxicities associated with these two targets. And this specific engineering was not accidental. It was not serendipitous. And we're very happy with IVAN-SMAB and its construct in particular in that IVAN-SMAB is our asset. And we've yet to find one that we would rather have versus IVAN-SMAB. Two successful randomized phase three clinical studies involving IVAN-SMAB will only kind of bolster that perspective. All right. Thanks for the call. Thanks, Brett.

Our next question comes from the line of Yigal Notomovich with Citi. Your line is open.

Hi, guys. Thank you so much for taking the question. So just thinking a little bit more about the Harmony 3 amendment, which you announced, I'm just curious, did you consider just simply starting a new study in non-squamous so you could preserve the timelines for Harmony 3? Or is the argument that because you're amending to PFS, you're going to win back time? on the time to primary endpoint since you're no longer looking at OS.

Hey, Gal. This is Anit. Yeah. No, we totally understand and we valid it. But as you know, right, in order to capitalize on our existing sites, which we already have on Scrumus, and this timeline to amend was much faster to add the non-Scrumus arm. Dave just mentioned, right, non-squamous is almost double the population and it increases our total market size, right, and the potential. And there are long lead times. If we have to start another trial with new sites and new clinical trial agreements, the lead time is much longer. So this would allow us to enroll patients on both arms quicker and expand our market almost like tripling our market opportunity. Yes, we had not provided you timelines because we were still enrolling and activating sites for squamous, so we had not provided you earlier. So we don't see this as a material change in delaying squamous, but it adds non-squamous opportunity and get non-squamous much faster and earlier into the market.

Yeah, if I can give some physician feedback that we've been receiving, they're very excited about this change. They see the logic in this change. This is a type of patient that they see more commonly in their practices. So it just increased sort of participation and excitement around the study.

Okay. Well, yeah, no, I mean, clearly it makes sense given you fill the gap in terms of the spectrum of all the non-small cell patients that are addressable. The other question I had was regarding, you know, we've gotten a lot of questions on Harmony 2 hitting on OS, as you know. it's been a significant debate. I'm just wondering if you could kind of walk through the logic as far as the confidence you have that Harmony 2 will eventually hit on OS. Obviously, people have been making comparisons, perhaps inappropriate comparisons, to Harmony A and the strong PFS there, and then the OS, which is trending well, but obviously not hitting stat sig yet. So just wondering if you could frame that and talk about you know, how you see the path to confidence on hitting OS in Harmony 2, which would obviously be a very big win and translate positively to everything you're doing over in the United States.

Yeah, again, I think our confidence hasn't changed. I think if you look back at data from multiple frontline non-small cell lung cancer studies, remember the Harmony A study was a second line study. in patients with refractory dose imertinib or other TKIs. You know, probably the classic study, if you look at the criticism around bevacizumab, the ECOG study that led to the approval of bevacizumab had a strong hazard ratio, I think, but it was well above 0.6, and it still hit its OSN point. The ATESO BEV studies as well, the EMPOWER studies as well. With this strong of a hazard ratio in PFS, it's unlikely that the OS won't be there, the OS benefit won't be there. But I just want to remind everybody, for Harmony 2, the primary endpoint was PFS, and this study was designed for PFS. And, you know, the question around statistical significance, you know, that's a numeric value that the people are after. And the question is, is how long will it take to show that given the sample size?

Got it. Thank you very much.

There are no further questions at this time. I would like to hand things back over to Dave Kankars for some closing remarks.

Thank you, Ian. I just want to take the time to thank everybody for attending today's earnings call. An archived version of this webcast will be available on our website, www.smmttx.com. Thank you for taking the time to join us and enjoy the rest of your day. Thank you.