Macrogenics Inc Q1 FY2024 Earnings Call

Good afternoon. We will start the MacroGenics 2024 First Quarter Corporate Progress and Financial Results Conference Call shortly. I will now hand the call over to Jim Karrels, Senior Vice President and Chief Financial Officer of MacroGenics.

Thank you, operator. Good afternoon, and welcome to MacroGenics' conference call to discuss our first quarter 2024 financial and operational results. For anyone who has not had the chance to review these results, we issued a press release this afternoon outlining today's announcements. This release is available under the Investors tab on our website at macrogenics.com. You may also listen to this conference call via webcast on our website, where it will be archived for 30 days, beginning approximately 2 hours after the call is completed. I would like to alert listeners that today's discussion will include statements about the company's future expectations, plans and prospects that constitute forward-looking statements for purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our annual, quarterly and current reports filed with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change, except to the extent required by applicable law. And now I'd like to turn the call over to Dr. Scott Koenig, President and Chief Executive Officer of MacroGenics.

Thank you, Jim. I'd like to welcome everyone participating via conference call and webcast today. I will provide key updates on our clinical programs, including an important interim data update on our TAMARACK Phase II study this afternoon. But before I do so, let me first turn the call back to Jim, who will review our financial results.

Thank you, Scott. This afternoon, MacroGenics reported financial results for the quarter ended March 31, 2024, which highlight our financial position. As described in our release this afternoon, MacroGenics total revenue was $9.1 million for the quarter ended March 31, 2024, compared to total revenue of $24.5 million for the quarter ended March 31, 2023. This decrease was primarily due to a decrease in revenue from collaborative and other agreements, including a $15 million milestone received from Incyte in the quarter ended March 31, 2023. Our research and development expenses were $46 million for the quarter ended March 31, 2024, compared to $45.9 million for the quarter ended March 31, 2023. Our selling, general and administrative expenses were $14.7 million for the quarter ended March 31, 2024, compared to $13.5 million for the quarter ended March 31, 2023. The increase was primarily related to increased stock-based compensation expense and consulting fees. Our net loss was $52.2 million for the quarter ended March 31, 2024, compared to a net loss of $38 million for the quarter ended March 31, 2023. Our cash, cash equivalents and marketable securities balance as of March 31, 2024, was $184.2 million compared to $229.8 million as of December 31, 2023. Finally, in terms of our cash runway, consistent with our prior guidance, we anticipate that our cash, cash equivalents and marketable securities balance of $184.2 million as of March 31, 2024, in addition to projected and anticipated future payments from partners and product revenues should provide a cash runway into 2026. Our anticipated funding requirements reflect expected expenditures related to the ongoing Phase II TAMARACK and LORIKEET studies as well as our other ongoing clinical and preclinical studies. And now I'll turn the call back to Scott.

Thank you, Jim. We continue to believe our proprietary pipeline of product candidates has great promise, and I will walk you through each of our key programs, including the disclosure of new safety and efficacy data from the TAMARACK study of vobramitamab duocarmazine in patients with metastatic castration-resistant prostate cancer. We have lots to cover today, so let's jump in. Vobramitamab duocarmazine, or vobra duo, is our ADC designed to deliver a DNA-alkylating duocarmycin cytotoxic payload to tumors expressing B7-H3. B7-H3 is a member of the B7 family of molecules involved in immune regulation. Vobra duo is designed to take advantage of this antigen's broad expression across multiple solid tumor types. As you know, we believe B7-H3 has the attributes of an ideal cancer target. The TAMARACK study is being conducted in mCRPC patients, who previously received androgen receptor access targeted agents or ARAT and up to 1 prior taxane-containing regimen but no other chemotherapy agents. The study is designed to evaluate vobra duo in patients across 2 experimental arms of either 2 mg per kg or 2.7 mg per kg every 4 weeks with radiographic progression-free survival, or rPFS, as the study's primary endpoint. We recently generated an updated expanded interim data set based on a data cut-off date of April 12, 2024, which is the basis for all of the TAMARACK data we are sharing with you today. Feel free to download the slide set that highlights this data from the Events and Presentations page under the Investor Relations section of our website, or you can find the direct link to the document provided in today's earnings press release. Flip ahead to Slide 4, and you will note we have enrolled a total of 181 patients, although a few patients were on the original control arm and are thus not counted in the safety population of 176 patients who received vobra duo. This is 1 less than the 177 we mentioned in an earlier press release as 1 patient never fully completed the informed consent form process. As you can see on this slide, we've broken out the number of patients with a valuable PSA and baseline target lesions by dosing cohort. Slide 5 provides several baseline characteristics. Both arms are well balanced with the exception of ECOG status as the 2.7 mg per kg arm very slightly favors ECOG 1 over ECOG 0. Keep in mind that this is a fairly subjective measure. I'll point out that despite randomization, fewer patients in the 2.7 mg per kg cohort had measurable disease than not measurable, whereas there was roughly a 50-50 split in the 2 mg per kg cohort. In terms of having a prior taxane versus not, the split was close to 60-40 across both those cohorts. Also recall that mCRPC patients had to have prior androgen receptor access targeted agents for study entry, and as you can see, a few had more than one. Next, let's review biological activity. On Slide 6, we show the PSA50 responses for 153 patients, which represents all subjects who had received at least 1 dose of vobra duo at a baseline PSA greater than 2 nanograms per ml and had at least 1 post-baseline PSA measurement. For the 2 mg per kg dosing cohort, 50% of the 82 evaluable patients experienced a greater than 50% reduction in their PSA while 43.9% of patients had a confirmed greater than 50% PSA reduction. In the 2.7 mg per kg dosing cohort, 50.7% of 71 evaluable patients experienced a greater than 50% reduction in their PSA while 36.6% of patients had a confirmed greater than 50% PSA reduction. Happily, these PSA50 results are generally well aligned with the PSA50 expectations we laid out before the study commenced. Turning to the summary of responses as summarized on Slide 7 and among the 45 patients with baseline target lesion measurements in the 2 mg per kg dosing cohort, 41 or 91.1% achieved disease control as measured by some confirmed complete and partial responses plus stable disease, while the confirmed objective response rate as measured by some complete and partial responses was 17.8%. With the inclusion of unconfirmed CRs and PRs, the unconfirmed ORR was 24.4%. Among the 32 patients with baseline target lesion measurements in the 2.7 mg per kg dosing cohort, the disease control rate was 87.5%. The confirmed ORR was 25%, and with the inclusion of unconfirmed PRs and CRs, the unconfirmed ORR was 43.8%. Let's review the PSA waterfall plot next. Slide 8 shows the PSA waterfall plot for the 2 mg per kg cohort. As you can see, 41 of the 82 patients had a 50% or greater decrease in PSA with 36 or 43.9% of these patients achieving a confirmed PSA50 response. 48 of these patients or 58.5% remained on therapy as of the data cutoff. Also based on the archival biopsy B7-H3 membrane H scores shown on the plot, it does not appear that there are B7-H3 expression thresholds required for reducing PSA. We are still reviewing this interim data. At this point, the implication is that a B7-H3 biomarker diagnostic will likely not be required. Slide 9 shows the PSA waterfall plot for the 2.7 mg per kg cohort. Here, 36 of the 71 patients had a 50% or greater decrease in PSA with 26 or 36.6% of these patients achieving a confirmed PSA50 response. As of the data cutoff, 39 patients or 54.9% of patients remained on therapy. Next, I will review investigator-assessed tumor size waterfall plots. On Slide 10, which shows the 2 mg per kg cohort, of the 45 patients with measurable disease, 1 did not have a post-baseline tumor assessment. As I mentioned earlier, the disease control rate for this group was 91.1%, with all but 3 patients having either a partial response or stable disease. The confirmed ORR was 17.8%, while the unconfirmed ORR was 24.4%. Slide 11 shows tumor response for the 2.7 mg per kg cohort. Here of the 32 patients with measurable disease, 2 did not have a post-baseline tumor assessment. The disease control rate for this group was 87.5%. The confirmed ORR was 25%, while the unconfirmed ORR was 43.8%. Next, I will review the swimmer plot for the tumor response, which will hopefully convey a sense of durability of vobra duo in the mCRPC setting. Slide 12 shows the interim results for the 2 mg per kg cohort. Here you can see that of the 45 tumor response evaluable patients, 8 or 17.8% had confirmed responses, with the inclusion of the 3 unconfirmed responses, the unconfirmed ORR is 24.4%. 23 of the 45 patients or 51.1% were still on therapy as of the data cutoff. In the 2.7 mg per kg dosing cohort, shown on Slide 13, 8 patients or 25% had confirmed objective responses, and with 6 unconfirmed responses, the unconfirmed ORR is 43.8%. 20 of the 32 patients or 62.5% remained on therapy as of the data cutoff. Next, I will review interim safety in the TAMARACK study as of the data cutoff. Slide 14 shows the overall summary of adverse events in this study to date. I'll point out a few parameters by dosing cohort. Of the 90 patients who receive vobra duo at 2 mg per kg, 89 or 98.9% experienced a study treatment-emergent adverse events of any grade. 49 or 54.4% of the patients had a Grade 3 or greater treatment-emergent adverse event, and 10 patients or 11.1% had adverse events leading to study drug discontinuation. Of the 86 patients who received vobra duo at 2.7 mg per kg, 86 or 100% experienced a treatment-emergent adverse event of any grade. 44 or 51.2% of patients had a Grade 3 or greater treatment-emergent adverse event, and 13 patients or 15.1% had an adverse event leading to study drug discontinuation. Also, as noted on Slide 14, as of the data cut-off date, a total of 5 fatal events occurred as follows: 1 Grade 5 fatal event occurred in the 2 mg per kg dosing cohort, an acute myocardial infarction, which was not classified as treatment-related, and 4 Grade 5 events occurred in the 2.7 mg per kg dosing cohort, which included 1 cardiac arrest, not classified as treatment-related and 2 cases of pneumonitis, which are still being investigated and initially assessed as possibly treatment-related. In addition, a patient on the 2.7 mg per kg dosing cohort had a Grade 3 pleural effusion and subsequently died. In terms of specific treatment-emergent adverse events, those with incidents greater than or equal to 10%, as shown on Slide 15, for the 2 mg per kg dosing cohort, the 5 most common treatment-emergent adverse events of any grade in this dosing cohort included asthenia, nausea, peripheral edema, decreased appetite, and fatigue. Of note, the incidence of pleural effusion in this cohort was Grade 1 at 8.9% and Grade 2 at 9.9%. There were no Grade 3 or greater events. Also, the incidence of palmar-plantar erythrodysesthesia syndrome in this cohort was Grade 1 at 11.1% and Grade 2 at 4.4%. There were no Grade 3 or greater events. The 5 most common treatment-emergent adverse events of any grade in the 2.7 mg per kg dosing cohort included asthenia, decreased appetite, peripheral edema, nausea, and pleural effusion. Of note, the incidence of pleural effusion in this cohort was Grade 1 at 14.0%, Grade 2 at 14.0%, and Grade 3 at 1.2%. Also, the incidence of palmar-plantar erythrodysesthesia syndrome in this cohort was Grade 1 at 12.8%, Grade 2 at 9.3%, and Grade 3 at 1.2%. As visually represented in the butterfly plot on Slide 16, all the treatment-emergent adverse events of greater than or equal to 10% are overwhelmingly limited to either Grade 1 or 2. Overall, we believe these doses are tolerable with side effects that are manageable. Also, we are very pleased with the biological activity observed in the study as of April 12, 2024, data cutoff, with the interim data being well aligned with the parameters of success that we laid out at the onset of the study. We achieved our goal of reducing the incidence and severity of both palmar-plantar erythrodysesthesia and pleural effusion in comparison as of the most recent data cut-off to what we saw in the Phase I dose expansion study. We will continue to evaluate the totality of the data, including future radiographic progression-free survival or rPFS, the study's primary endpoint, as we consider dose selection of either 2 or 2.7 mg per kg. To that end, we are currently undertaking the necessary initial steps to prepare for the potential initiation of a Phase III study in mCRPC in 2025. Looking ahead, we plan to share updated TAMARACK safety, efficacy, and durability data, including rPFS in the second half of 2024 based on a future data cutoff. Also, as mentioned on our prior earnings call, we plan to expand the tumor types being evaluated in the TAMARACK trial and expect to enroll additional patients with non-small cell lung cancer, small cell lung cancer, melanoma, squamous cell carcinoma of the head and neck, and anal cancer. We expect to initiate dosing in these additional cohorts in mid-2024. Recall that we have 2 other clinical molecules that target B7-H3. The first, MGC026, is an investigational ADC incorporating a novel topoisomerase 1 inhibitor-based linker payload, SYNtecan E, which we licensed from Synaffix. Our second additional B7-H3 targeted molecule is enoblituzumab, an investigational Fc-optimized monoclonal antibody. I'll walk you through both of these molecules next. MGC026 incorporates the linker payload based on exatecan, a clinically validated and potent cancer agent that readily combines with Synaffix' hydrospace technology. MGC026 preclinical data was presented recently at the American Association for Cancer Research Annual Meeting. In preclinical studies, MGC026 was shown to have greater potency than B7-H3-directed antibodies conjugated to deruxitecan or DXd, a topoisomerase-based payload utilized in other ADCs. In addition, the MGC026 payload has been shown to be less susceptible to multidrug-resistant mechanisms than DXd and SN-38. Also, our toxicology study conducted in cynomologous monkeys showed that MGC026 was well tolerated at all dose levels tested. Finally, MGC026 displayed approximate dose proportional pharmacokinetics in the animal models tested, indicating predictable behavior conducive to further clinical development. We recently initiated a Phase I dose escalation study of MGC026. The variable domain of the molecule targeting B7-H3 for MGC026 is the same sequence contained in vobra duo. We view MGC026 as a complementary approach to vobra duo for targeting B7-H3. More specifically, we believe that having distinct mechanisms of action for vobra duo and MGC026 may address different cancers, tumor stages, or be used in combination with other agents or potentially with one another to enhance their clinical utility. We remain confident in the potential of targeting the B7-H3 pathway, viewing our Topo 1 inhibitor strategy as an additional valuable tool in our therapeutic repertoire. Regarding enoblituzumab, our academic collaborators are enrolling an investigator-sponsored, randomized translationally intense Phase II investigator-sponsored study of this molecule in up to 219 patients with prostate cancer. The HEAT study is evaluating the activity of neoadjuvant enoblituzumab given prior to radical prostatectomy in men with high-risk localized prostate cancer. Eligible patients will undergo a pretreatment prostate biopsy and conventional imaging, including CT and bone scans, as well as PSMA PET and optional prostate MRI as per institutional preferences. Next, I'll update you on lorigerlimab, our bispecific tetravalent PD-1 x CTLA-4 DART molecule. We designed lorigerlimab to have preferential blockade on dual PD-1 CTLA-4 expressing cells, such as tumor-infiltrating lymphocytes, which are most abundant in the tumor microenvironment. We are enrolling the LORIKEET study, a randomized Phase II clinical trial of lorigerlimab in combination with docetaxel versus docetaxel alone in second-line chemotherapy-naive mCRPC patients. A total of 150 patients are planned to be treated in the 2:1 randomized study. The current study design includes the primary study endpoint of rPFS. We anticipate completing enrollment of the study this year and expect to provide a LORIKEET clinical data update in the first half of 2025. In addition, we continue to enroll patients in the Phase I/II dose escalation study of vobra duo in combination with lorigerlimab in patients with advanced solid tumors. We anticipate commencing a dose expansion study of this combination in mCRPC and at least 1 additional indication in 2024. Next up, MGD024 is our next-generation bispecific CD123 x CD3 DART molecule that incorporates the CD3 component designed to minimize cytokine release syndrome while maintaining antitumor cytolytic activity and permitting intermittent dosing through a longer half-life. Our Phase I dose escalation study of MGD024 is ongoing in patients with CD123 positive relapsed or refractory hematologic malignancies, including acute myeloid leukemia and myelodysplastic syndromes. Recall that Gilead has the option to license MGD024 at predefined decision points during the Phase I study. In terms of preclinical projects, MGC028 is our second topoisomerase 1 inhibitor-based ADC incorporating Synaffix's novel linker payload and an ADAM9 targeting antibody. ADAM9 is a member of the Adams family, a multifunctional type 1 transmembrane protein that plays a role in tumor genesis and cancer progression and is overexpressed in multiple cancers, making it an attractive target for cancer treatment. We recently presented MGC028 preclinical data at the AACR Annual Meeting in April. In preclinical studies, MGC028 demonstrated specific antitumor activity in vivo models representing gastric, lung, pancreatic, colorectal, small cell carcinoma of the head and neck, and cholangiocarcinoma. In addition, in a nonhuman primate study, MGC028 was well tolerated at high dose levels with mild reversible side effects and no ocular toxicity, which is often a concern with tubulin inhibitor-based ADCs. These promising preclinical results support the continued investigation of MGC028 as a therapeutic option for treating ADAM9 solid tumors. We are currently anticipating submitting an investigational new drug or IND application for MGC028 by the end of this year. Beyond MGC028, we are exploring additional molecules for potential future IND submission. I look forward to telling you more about these additional molecules on future calls. To conclude, we believe MacroGenics has the technical development and clinical expertise as well as financial resources to support our vision of developing and delivering life-changing medicines to cancer patients. We would now be happy to open the call for questions.

Our first question comes from Tara Bancroft with TD Cowen.

There are certainly many questions here. Regarding safety, it appears to be somewhat comparable to Phase I with the addition of these two extra cycles compared to the abstract. Could you provide more details on what improvements in safety you are observing with these doses? Or are you referring more to the efficacy? I'm curious about how these two additional median cycles lead to a significantly different outcome from the abstract. Could you please clarify what transpired?

Certainly, Tara. Let me discuss the safety data. First, the safety data cut-off was in January, and now, more than three months have passed since then. Compared to the Phase I data, we are now surpassing the mean number of doses that were given in that study. Furthermore, the adverse events primarily consist of Grade 1 or 2 side effects, which are manageable, with only a few instances of Grade 3; no new concerning side effects have emerged in this interim data set. The majority of the participants are still on the study, unlike in Phase I, where patients were exiting. We conducted a head-to-head analysis after 16 weeks of all patients on TAMARACK versus those on the Phase I prostate study. The results from TAMARACK are significantly better. For instance, we observed half the number of Grade 3 events in TAMARACK compared to the Phase I prostate group, a reduction in discontinuations, and fewer drug interruptions. We also compared our discontinuation rates, which are 11% at 2 mg and 15% at 2.7 mg, with other studies, such as 19.8% in the CARD study and 22.4% in KEYNOTE-921. Similarly, Grade 3 events are lower in our study compared to others, showing we are performing well regarding safety. Overall, the safety data have shown manageable side effects, and our discussions with investigators indicate they feel comfortable and encouraged by the safety and activity data we have seen thus far.

Our next question comes from the line of Jonathan Chang with Leerink Partners.

I guess I'm also just trying to better understand the evolution and the tolerability profile versus the previously submitted abstract. Is there a time dependency to the AEs, or does this evolution reflect something else? And then second question, can you provide any additional color on the patient deaths and whether or not they were treatment-related?

Yes, thank you. To address Tara's question, the cutoff for safety data was at the beginning of January. We compared the original Phase I prostate data with data collected as of that January cutoff, focusing on the 95 patients who had reached the 12-week mark. This allowed for a direct comparison of safety at that moment against the Phase I study. The data will keep accumulating, and we now have safety data for the entire population, which includes more than three additional months of information. It's important to note the butterfly plot, which shows that safety data is quite manageable with Phase I/II data being low. This is consistent with observations from other antibody-drug conjugates and agents approved for prostate cancer. Regarding patient deaths, the cardiac death and cardiac arrest were found to be unrelated to the drug. We are investigating two cases of pneumonitis in the 2.7 mg per kg cohort, with one case being particularly complex due to the patient's other medical issues. We don't have a determination on cause and effect related to the drug yet. Similarly, the patient with pleural effusion passed away more than three months later, and that incident is also under investigation.

Our next question comes from the line of Yigal Nochomovitz with Citi.

This is Ashiq Mubarack on for Yigal. A few from me. I guess on the Grade 5 pneumonitis events, were you surprised that these occurred? I can't quite recall if pneumonitis had been observed as a signal previously. And to that end, is there a B7-H3 expression in the lungs? And are you considering maybe integrating some type of steroid prophylaxis to help prevent pneumonitis moving forward?

These matters are still under investigation. The relationship between the drug and the observed effects is not yet clear. We have not observed any association with pneumonitis in a large patient population, which raises further questions about the underlying causes of pneumonitis in these patients. Regarding your second question about B7-H3 expression in the lungs, it is not typically found there, and our toxicology studies in cynomolgus monkeys did not show any lung findings. It is possible that certain cellular activations could lead to B7-H3 expression, but it is not a common occurrence.

Okay. Okay. Got it. And then maybe another question. I mean, how are you thinking about choosing the dose moving forward into Phase III? I know it seems a little confounding. It seems like efficacy is balanced on PSA50, but ORR is a little bit higher at the higher dose, but maybe the safety is a little better at the lower dose. So how are you thinking about that?

Well, I think that's exactly the point here, is that we're seeing a nice gradation. We believe that we have picked the correct dosing range to evaluate what will be the optimal dose. This will be determined when we achieve the rPFS values and the disease control rate values, which we expect to happen towards later in the midyear. So stay tuned for that, but as we view the data right now, both doses are potentially usable and further developable going forward with this interim data.

Our next question comes from the line of Kaveri Pohlman with BTIG.

Can you comment on how the efficacy and safety look like in chemo-pretreated versus chemo-naive patients, if you saw any notable differences there?

Thank you, Kaveri, for that question. And I'm not going to comment on that, but what I would say at this point is that both populations, both the chemo-naive and the chemo-experienced populations are under consideration for development as we go forward into the Phase III study. Nothing unexpected was observed with regard to either populations in terms of overall responses.

Got it. And then is there any feedback you received from physicians regarding dose reduction, interruption grade, the reduced level of doses that were used, and their potential to impact durability?

We want to emphasize that the swimmers' plot clearly illustrates that these patients have maintained their responses, even when doses were modified or reduced. In the case of longer-treated patients, we observed positive outcomes with individuals receiving 2.7 mg per kg and another on 2 mg per kg after over 30 weeks of treatment, despite some dose reductions. Overall, patients are doing well and are accustomed to using other chemotherapies, including dose modifications, with no evidence so far, based on interim data, that this has affected their responses.

Got it. That's helpful. And maybe a last one. Any thoughts on why there is no correlation between efficacy and B7-H3 expression?

We noted this in the Phase I study as well. We didn't observe a correlation there either. We saw responses even in patients with lower H scores, which might indicate a threshold effect. If there is a modest expression of B7-H3, it could be enough to allow the linker toxin to enter the cells. We view this as a positive outcome. However, it's important to point out that these are our primal specimens, and results could vary with fresh biopsies.

Our next question comes from the line of Stephen Willey with Stifel.

Just with respect to the pneumonitis, I know that this is typically something that needs to be proactively looked for, whether it's via chest x-ray or CT. And just I'm curious if that was kind of a routine screening procedure for some of these patients, and could some of the higher rates of dyspnea that are observed in the 2.7 arm, including some of the Grade 3 plus events, could those be miscategorized as pneumonitis in the context of perhaps not proactively screening for it?

I don't believe there is a screening protocol for this because, as I mentioned earlier, there was no observed increase in the rate of pneumonitis in the population. For a patient experiencing dyspnea, that would typically be addressed as part of their treatment. While I can't discuss specific patients, it's important to note that a thorough investigation is standard and there are many potential causes of dyspnea, even though the percentages are quite low. I want to emphasize that the cases of pneumonitis are still being studied. The data we have so far indicates that there are complicating factors for at least one patient with pneumonitis who has other medical issues, and we still need further information on the other patients. Therefore, it is too early to reach any conclusions.

And I'm not sure if it's in the presentation, but can you also provide us with what the median duration of follow-up is in both of these arms at this point?

We don't have the specific timeline available right now, but as shown in the swimmers plot, many of these patients have surpassed the 16- to 20-week interval. The average number of doses is currently 5, which is on a weekly basis.

And then just lastly, I know this trial allowed for patients who had not been on, I guess, 'stable ARPI' for 12 months. Do you know how those patients distribute between the 2 treatment arms with respect to patient baseline?

Regarding that population, I don't have the specific percentages in front of me, but I believe it was about a 40% to 60% split in terms of less than 12 months and greater than 12 months of historical ARAT exposure.

Our next question comes from the line of Jon Miller with Evercore.

Very interesting update here. Scott, I would appreciate some more confirmation. I remember you mentioned earlier that interruptions and discontinuations looked better than in Phase I, and I want to confirm what you said and the specific numbers you're referencing. When I refer to the Phase I poster, I see 15% discontinuations and 59% interruptions, which aligns with today's update showing 15% and 56% in the 2.7 mg per kg arm. Regarding hand-foot syndrome, while the grading seems lower in this update, we're observing a decrease from 31% in the Phase I results to 23% in the 2.7 mg arm today. So when analyzing the toxicity signals compared to Phase I, would you say they have significantly improved? I would like to know if there is a specific number you can highlight that indicates improvement and suggests that doctors will feel comfortable maintaining this therapy for a longer duration than they did in Phase I.

Yes. I want to ensure we are making a fair comparison. I'm comparing the current results to the previous safety data from the abstract, which looked at the prostate cohort. It seems you are highlighting various populations. My focus is specifically on the data, which confirms that in the patients from the Phase I study, whether considering the severity of Grade 3, drug discontinuations, dose reductions, or interruptions, the percentages in the Phase I study were more than double what we see here at the same 16-week interval. I aim to provide a fair comparison regarding time exposed to the drug, although there may be minor variations in overall drug exposure. I am clearly observing that the side effect profiles and severity in the Phase I prostate cohort are 2 to 3 times higher than what we are observing in the TAMARACK study. The feedback from investigators has indicated manageable tolerability, which is not concerning. Additionally, we have surpassed the average number of doses in TAMARACK compared to the Phase I study. I'm feeling very positive that we are progressing well with this drug. As demonstrated in the swimmers plot, most patients are still receiving treatment despite some dose adjustments and interruptions.

I understand your point. Regarding efficacy, I would like to know the median number of prior therapies in these groups and what comparisons you are considering for overall response rate and disease control rate in that population.

So here, as I mentioned, the entry criteria was no more than three lines of therapy. I'm not sure what the median is for this study, whether it's two or three, but we'll need to follow up on that. Regarding the objective response rate, as I have been indicating since November, we were seeing about a 25% confirmed and unconfirmed rate of objective responses, which was also reflected in the Daiichi 7300 presentation at ESMO, showing a solid 25%. My point was that we should certainly reach 25% by the end of the study. As we can see now, not only are we achieving that, but it looks likely we'll exceed it when the final data is released, considering that many of these patients are still in the study. We have a confirmed and unconfirmed objective response rate of 43.8% at the 2.7 mg per kg dose and 24.4% at the 2 mg dose. Overall, I believe we are performing well compared to the expectations and the data available at this point. However, we still anticipate further maturation of this data and ongoing improvement.

Can you discuss the potential use of vobra duo in combination, considering its safety profile? It's not a completely harmless molecule, and some of its toxins overlap with other agents typically found in the prostate area, such as pneumonitis and pleural effusion. What implications does this have for its potential use in combination therapies and its application in earlier treatment lines compared to other programs that are actively pursuing larger combinations in early treatment stages?

We are very interested in exploring combinations of vobra duo with various agents. We have started dose-finding studies with lorigerlimab, our PD-1, CTLA-4 DART bispecific molecule. As I mentioned earlier, we expect to define the appropriate doses from these studies very soon. We plan to investigate this combination not only in prostate cancer but also in other tumors, as we believe these mechanisms work very well together for tumor control. Additionally, we have shown activity from lorigerlimab as a single agent in late-stage patients, which suggests that this combination is worth examining further, and we are considering other potential combinations as well.

Our next question comes from the line of Etzer Darout with BMO Capital Markets.

Could you provide more information about the combination with lorigerlimab, considering you mentioned the possibility of moving into dose expansion studies with vobra duo and lorigerlimab in the first half? Can you update us on the progress of that program? Is this still a feasible plan moving forward based on the data we've seen today?

Yes, we are on track for moving forward with that. I think we're at the final evaluation of the dose-finding cohort of finding what the ideal doses of each 1, when put together, to maximize both the safety and activity to explore. I think we will be in pretty good shape in the second half of the year to initiate enrollment in the prostate and potentially another tumor indication. So stay tuned for that.

Our next question comes from Mayank Mamtani with B. Riley Securities.

So maybe looking ahead, Scott, could you share your expectations for the rPFS data? Also, how might you present that in the coming months based on what you’re observing regarding durability and median cycles? Importantly, how do you perceive the difference in the treatment landscape compared to PSMA STEAP1? When considering sequencing, how do you plan to design your Phase III study for next year?

Yes. Thanks very much, Mayank. Right now, as I again laid out the parameters here as baseline, what we had indicated was an rPFS baseline of 6, but greater and obviously, looking for 7, 8, 9, 10 or higher. I think that the data that we show today and the fact that these patients are still on therapy. I think we will ultimately see the results, but there is no reason we can't meet some of the longer-lived rPFS values here. We'll have to wait to see the results. The expectation is that this would be presented at a scientific conference in the second half of this year.

Got it. And maybe just one quick clarification. There weren't too many RLT or Pluvicto exposed patients in the study. Is that right to do any kind of analysis if you could answer that?

That's true. As you observed in the geographic distribution of patients, there was a very small number of patients from the U.S. who could have either previously received Pluvicto or progressed on it, given the timing of its marketing in the U.S. compared to Europe, where most of the patients were located. Therefore, we anticipate only a few of those patients will be involved in this study.

Our next question comes from the line of Silvan Tuerkcan with Citizens JMP Securities.

First of all, when could we find out about the adjudication of the death, if they are treatment-related or not? Would that be available by the time we get that presentation at a medical conference in the second half?

I would assume so. Clearly, we're providing you with ongoing results as they become available. We're currently in early May, having just completed this data cut in April. Therefore, the expectation is that the teams are diligently working to uncover the details of the patient study and assess comorbidities and other factors that might have played a role in the specific deaths.

But the DSMB is reviewing these, correct? Presumably between the recent data cut.

Absolutely.

Can you walk me through the waterfall plot? I'm trying to understand the unconfirmed responses, especially in the high-dose arm, where the confirmed response rate is 25%, but the unconfirmed rate could be as high as 43%. Why are most of these responses not confirmed, even though they are ongoing? Have the patients in that group been scanned yet? Could you please provide more details on that?

Yes, if I examine the swimmer plot for the 2.7 mg dose, the scans occur every 8 weeks. Most patients who remained on therapy for 16 weeks would have had 2 scans, while those who reached 24 weeks would have had 3 scans, and at least one patient may have had 4 scans. For example, consider the patient receiving 2.7 mg per kg in Q4, who is at the top of that curve. They were initially evaluated for a partial response at 8 weeks, but it wasn't until possibly the fourth scan that this was confirmed as a verified partial response. The key takeaway is that confirmation may take more time. There are several patients here with one positive result who have not yet received a second scan to confirm it.

Our next question comes from the line of Kelsey Goodwin with Guggenheim Partners.

I guess, given the early looks at durability with the swimmer plot for the RECIST evaluable patients, at least, I guess, do you have any update on how you're thinking about where durability may land for the fall update? Or just any additional color you could provide there?

Yes. I think it's just too early to say, given that, again, the majority of patients are still on, for example, the 2.7 mg per kg, in the patients with measurable disease. We have, as noted here on the slide, 62.5% that are still ongoing treatment. So again, we feel very encouraged that given even at this point, that we should be able to have an opportunity to treat a large number of these patients with mCRPC.

Got it. And for the non-RECIST evaluable patients, are the swimmer plots representative for those patients as well?

Yes. Again, what we wanted to do is give you a representative feel for the various durability, and we felt that this was a good representation regarding RECIST evaluable with measurable disease at baseline. Our general view is that this can be extended to patients with bony disease as well, etc. We have this balance that we want to provide investors a look at the data as we had promised, but at the same time, having additional data that we can then present at scientific conferences. But nothing here is more selective in that regard.

Our next question comes from the line of Peter Lawson with Barclays.

Could you describe what the spider plots look like? Are the patients maintaining their PSA50 reduction, or is there an improvement in PSA reductions over time? What would be the best way to characterize that?

Yes. Again, what we started to do is give you a representation, but I would say that the spider plots are exceptionally encouraging. As we had shown in the Phase I data, you will see initial reductions in PSAs, and they seem to be sustained for long periods of time at the time interval at least at this interim data going forward. Clearly, there are individual patients that will not have the continued PSA50 responses but I would say as we characterize the Phase I, they do very well similarly over a long period.

Got you. And the PSA50 reduction was higher in that lower dose. Was that driven by a lower discontinuation rate? Or is there something else going on?

I think this situation is quite unique and shouldn't be overanalyzed, despite the sizeable populations involved. There's nothing specific I would focus on regarding the patients who experienced at least one PSA50 reduction. It suggests that both groups are showing comparable results, although the confirmed numbers appear slightly lower at 2.7, which I believe is just incidental. As I mentioned, we anticipate that these figures may improve over time. Therefore, I don't consider this a conclusive indicator of a difference at this stage.

Final question, whether the PSA reductions, or if it's ORR or disease control rate, what correlates best in your mind for this agent and PFS?

My sense is it's going to be our PFS and disease control rate. As I pointed out previously, avoiding new growth of lesions is the most important thing here. So that, obviously, if a patient has 30% or greater, it's recorded as a PR, but if a patient has a 20% reduction, it will be recorded as stable disease. As long as there are no new lesions, I think that is fine. But again, we'll have to see as the data continues to mature.

That concludes today's question-and-answer session. I'd like to turn the call back to Dr. Koenig for closing remarks.

Well, thank you, everybody, for your questions today, and we look forward to following up on the completion of the TAMARACK study and further updates on our other programs soon. Have a good evening.

This concludes today's conference call. Thank you for participating. You may now disconnect.