MacroGenics Inc (MGNX) 2024 Q1 法說會逐字稿

Good afternoon. We will begin the MacroGenics 2024 first quarter corporate progress and financial results conference call in just a moment. (Operator Instructions) At this point, I will turn the call over to Jim Karrels, Senior Vice President, 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 a 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 two 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 2 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 2 TAMARACK and lowercase 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 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 have previously received an androgen receptor access targeted agent or ARAT and up to one prior taxane-containing regimen, but no other chemotherapy agents.

This study is designed to evaluate vobra duo in patients across two experimental arms of either 2 mgs per kg or 2.7 mgs per kg every four weeks with radiographic progression-free survival or rPFS, as the study's primary endpoint.

We recently generated an updated expanded interim dataset based on a data cutoff 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 a direct link to the document provided in today's earnings press release.

Flip ahead to slide 4, and you'll 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 receive vobra duo. This is one less than the 177 we mentioned in an earlier press release as one 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 evaluable 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/kg on very slightly favors ECOG 1 over ECOG 0. Keep in mind that this is a fairly subjective measure.

I'll point out that despite randomizations, fewer patients in the 2.7 mgs per kg cohort and measurable disease than non-measurable, whereas there was roughly 50-50 split in the 2 mgs 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 a prior androgen receptor access targeted agent 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 one dose of vobra duo had a baseline PSA greater than 2 nanograms per ml and had at least one 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 PSA safety results are generally well aligned with the PSA50 expectations we laid out before the study commenced.

Turning to the summary of two responses as summarized in slide 7, among the 45 patients with baseline target lesion measurements 2 mg per kg dosing cohort, 41 or 91.1% achieved disease control, as measured by some of confirmed, complete, and partial responses for stable disease, while the confirmed objective response rate as measured by some of 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 CR, the unconfirmed ORR was 43.8%.

Let's review the PSA waterfall plots 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 to B7-H3 membrane H scores shown on the plot, it doesn't 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 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 date of 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, one 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 three 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 two 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 plots 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 three unconfirmed responses, the unconfirmed ORR was 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 with 25% had confirmed objective responses with the 6 unconfirmed responses, the unconfirmed ORR is 43.8%, 20 of the 32 patients or 62.5% remained on therapy as of the data of 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. Off the 90 patients who receive vobra duo or 2 mgs 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 TEAE and 10 patients or 11.1% had an adverse events leading to study drug discontinuation.

Of the 86 patients who receive verbo duo at 2.7 mgs per kg, 86 or 100% experienced a TEAE of any grade. 44 or 51.2% of patients had a Grade 3 or greater TEAE and 13 patients or 15.1% at an AE leading to study drug discontinuation.

Also, as noted on slide 14, as of the data cutoff date, a total of five fatal events occurred as follows: one Grade 5 fatal event occurred in 2 mg per kg dosing cohort, an acute myocardial infarction, which was not classified as treatment related; Four Grade 5 events occurred in the 2.7 mg per kg dosing cohort, which included one cardiac arrest not classified as treatment related and two cases of pneumonitis, which are still being investigated initially assessed as possibly treatment related.

In addition, a patient under a 2.7 mgs per kg dosing cohort at a grade three pleural effusion and subsequently died. In terms of specific treatment emergent adverse events, those with incidence greater than or equal to 10%, as shown on slide 13. For the 2 mg per kg dosing cohort, the five most common TEAEs of any grade in this dosing cohort included asthenia, nausea, peripheral oedema, decreased appetite, and fatigue.

Of note, the incidence of pleural effusion in this cohort was Grade 1 of 8.9% and Grade 2 of 0.9%. There were no Grade 3 or greater events. Also the incidence of palmar-plantar erythrodysesthesia syndrome in this cohort was a Grade 1 of 11.1% and Grade 2 of 4.4%. There were no Grade 3 or greater events.

The five most common TEAEs of any grade in the 2.7 mg per kg dosing cohort included asthenia, decreased appetite, peripheral oedema, nausea, and pleural effusion. Of note, the incidence of pleural effusions cohort was Grade 1 of 14.0%, Grade 2 of 14.0%, and Grade 3 of 1.2%. Also the incidence of palmar-plantar erythrodysesthesia syndrome in this cohort was Grade 1 of 12.8%, Grade 2 of 9.3%, and Grade 3 of 1.2%.

As visually represented in the butterfly plot on slide 16, all the TEAEs have 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 this study as of April 12, 2024, data cutoff with 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 1 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 to be the 2 or 2.7 mgs per kg, To that end, we are currently undertaking the necessary initial steps to prepare for the potential initiation of a Phase 3 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 two other clinical molecules that target B7-H3. The first MGCO26 is an investigational ADC incorporating a novel topoisomerase 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.

MGCO26 incorporates a linker payload based on SYNtecan, a clinically validated and potent camptothecin that readily combined Synaffix's hydro space technology. MGCO26 preclinical data was presented recently at the American Association for Cancer Research annual meeting.

In preclinical studies MGCO26 was shown to have greater potency than B7-H3 directed antibodies conjugated to deruxtecan or DXD, a topoisomerase as payload utilized in other ADCs. In addition, the MGCO26 payload has been shown to be less susceptible to multidrug resistant mechanisms than DXD and SN-38. Also, our toxicology study conducted in cynomolgus monkeys showed that MGCO26 was well tolerated at all dose levels tested.

Finally, MGCO26 displayed approximate dose-proportional pharmacokinetics in the animal models tested indicating predictable behavior conducive to further clinical development. We recently initiated a Phase 1 dose escalation study of MGCO26.

The variable domain of the molecule targeting B7-H3 for MGCO26 is the same sequence contained in vobra duo. We view MGCO26 as a complementary approach to vobra duo for targeting B7-H3. More specifically, we believe that having distinct mechanisms of action vobra duo and MGCO26 may address different cancers, tumor stages, will be used in combination with alternate 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 2 investigator-sponsored study of this molecule in up to 219 patients with prostate cancer. The HEAT study is evaluating the activity of neoadjuvant and enoblituzumab given prior to radical prostatectomy in men with high risk localized prostate cancer.

Eligible patients will undergo a pretreatment, prostate biopsy and conventional immunigib, including CT and bone scan, 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 by CTLA-4 DART molecule.

We design 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 LORIKEET study, a randomized Phase 2 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 1/2 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 one additional indication in 2024.

Next up MGDO24 is our next-generation bispecific CD123 by CD3 DART molecule that incorporates a CD3 component designed to minimize cytokine release syndrome while maintaining antitumor cytolytic activity and permitting intermittent dosing through a longer half-life.

Our Phase 1 dose escalation study of MGDO24 is ongoing in patients with CD123 positive relapsed or refractory hematologic malignancies, including acute myeloid leukemia and myelodysplastic syndrome. Recall that Gilead has the option to license MGDO24 at pre-defined decision points during the Phase 1 study.

In terms of preclinical projects, MGCO28 is our second topoisomerase-1 inhibitor based ADC incorporating Synaffix' novel linker payload and an ADAM9 targeting antibody. ADAM9 is a member of the ADAM's family a multifunctional Type 1 transmembrane proteins that play a role in tumor genesis and cancer progression and is overexpressed in multiple cancers, making it an attractive target for cancer treatments.

We recently presented MGCO28 pre-clinical data at the AACR Annual Meeting in April. In preclinical studies, MGCO28 demonstrated specific anti-tumor activity in vivo models representing gastric, lung, pancreatic, colorectal, small cell carcinoma of the head, neck, and cholangiocarcinoma.

In addition, in a nonhuman primate study, MGCO28 was well tolerated at high dose levels with mild reversible side effects and no ocular toxicity, which is often a concern with tubulin inhibitor base ADC. These promising preclinical results support the continued investigation of MGCO28 as a therapeutic option for treating ADAM9 expressing solid tumors.

We are currently anticipating submitting an investigational new drug or IND application for MGCO28 by the end of this year. Beyond MGCO28, we're 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. Operator?

(Operator Instructions) Tara Bancroft, TD Cowen.

Hi. Good afternoon. So, lots of questions here, I'm sure, but so looking at the safety, it does look somewhat similar to the Phase 1 now with these two extra cycles versus the abstract. So could you elaborate more on what it is that you're seeing as improved in terms of safety with these doses? Or is it what you're referring to more on the efficacy side and how this looks like quite different from the abstract with these just two more median cycles? So could you describe more what happened there?

Well, actually, Tara, let me sort of go through the safety. First of all, safety data cut was in January and now we're in April greater than three months since the January cutoffs. We are -- first of all on compared to the Phase 1 data we are now exceeding the mean number of doses that were achieved in the Phase 1 study.

And then second -- third is, if you look at the butterfly plot of the AEs, the side effects are overwhelmingly Grade 1 or 2 manageable with a smattering of Grade 3s, no, concerning new type of side effects has cropped up, as you see on the figure or in the listings in this interim dataset. And as you note on both the PSA figures as well as the figures we included on the targeted lesion figures, the majority of these individuals are still on studying.

We are clearly in the Phase 1, they were coming off study. We did a head-to-head analysis at 16 weeks of all patients that are on TAMARACK and compared it to the prostate patients on the Phase 1 study also at 16 weeks and the results in TAMARACK are dramatically improved.

For example, specifically, we had half the amount of Grade 3 in TAMARACK as compared to the Phase 1 prostate group. One-half to one-third of the total of discontinuations and about half of the reductions in TAMARACK as compared to the Phase 1 and only one-third to one-half of drug interruptions.

So as we have laid out in terms of achieving this, these are the Phase 1 study we are -- we have accomplished what we wanted to achieve. Furthermore, we did some key comparisons to other prostate studies.

For example, in our discontinuation rates at the 11% at the 2 mgs or the 15% of the 2.7 mgs, this compares well to a number of other studies. For example, in the card study, capacity taxol, there was a discontinuation rate of 19.8% in keynote 921, the docetaxel arm was 22.4%. And similarly, the combo arm with pembro was 29.2% and then in TRITON3, for the dosing arm, there was 32.4%. So as you see, we're doing quite well there with regard to discontinuations, vis-a vis the others.

And similarly for Grade 3, we can compare what we're seeing here, for instance, in the docetaxel arm and TRITON3 61%, KEYNOTE-921, 36%. And then if you even look at experimental Phase 1 studies in prostate, some new targets, if you look at Amgen's STEAP1 by CD3 was 55%. And in Daiichi 7,300, it was 47% in the prostate.

So overall, again, as I've pointed out, while the safety data has accumulated more safety side effects, we believe that these are extremely manageable, in discussions with investigators and they are very comfortable with managing these patients and are very encouraged by both the safety and obviously the activity data they've seen to date.

Okay. Thank you. That's super helpful. Thanks.

Jonathan Chang, Leerink Partners.

Hi, guys. Thanks for taking my questions. I guess I'm also just trying to better understand the evolution in the tolerability profile versus the previously submitted abstract. Is there time dependency to the AE's? Or does this evolution reflects something else?

And then second question, can you provide any additional color on the patient deaths and whether or not they were treatment related? Thank you.

Yeah, thanks very much for the point. So again, as I started off with the question from Tara, the cut off from safety was as of January -- beginning of January. And as we did a comparison between the original Phase 1 prostate data and that of the data that we had as of the January cutoff, we looked at 95 patients that had reached the 12 weeks. So that was a head-to-head comparison of where the safety was at that point versus that of the Phase 1 study.

And so as I said before, this data will continue to accumulate. We now have a data -- safety data on the entire population of now greater than three more months of data that's accumulated. But again, as I reiterate, look at the butterfly part where we have a very safety data that's limited to Phase 1, 2 quite manageable going forward, and as I was pointing out earlier, this is not that different from what has been seen with other ADCs as well as other agents that have been approved in prostate cancer.

So that's a summary there. With regard to the patient deaths, as pointed out, cardiac death and a cardiac arrest were not deemed to be associated with a drug unrelated. The additional cases of -- two cases of pneumonitis are being investigated. These are sort of real-time observations in the 2.7 mg per kg cohort.

What we can say is that, particularly one of these cases was very complicated with other confounding the medical matters with this patient but we're -- it's being further investigated right now, so I don't have a further decision with regards to cause that effect, with regards to drug. And similarly, the patient that was dealing with a pleural effusion, the occurrence of that death occurred more than three months later. And again, it's being investigated at this time.

Got it. Thanks for taking my questions.

Yigal Nochomovitz, Citi.

Hi guys. This is Ashiq Mubarack on for Yigal. Thanks for taking my questions. 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 B7-H3 expression in the lungs and are you considering maybe integrating some type of steroid prophylaxis to help prevent pneumonitis moving forward?

Well, again, as I was indicating, these are still being investigated. So the cause and effect with regard to the drug is still under investigation and we are not -- and in fact, we have not seen in a large number of patients here any association with the pneumonitis in that patient. So that again, raises questions of what is the ultimate cause of these patients associated with the pneumonitis.

Okay. Got it. And then --

I will just finish. I'm sorry, I didn't finish your second question, which was expression of B7-H3 in the lung, normally seen in a lung, we had no lung findings in the cynomolgus monkey toxicology studies. Clearly with certain activation, you can have certain cells that may have expression of B7-H3, but it's not a normal occurrence.

Okay. Got it. And then maybe another a question. I mean, how are you thinking about choosing the dose move forward into Phase 3? And also, it seems a little confounding. It seems like efficacy is balanced on PSA 50 but ORR 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. And so 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 mid-year. 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.

Got it. Thanks very much.

Kaveri Pohlman, BTIG.

Hi, good evening. Thanks for taking my questions. Can you comment on how the efficacy and safety look like in chemo pre-treated 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 experience populations are under consideration for development as we go forward into the Phase 3 study and 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 rates, the reduced level of doses that were used and their potential to impact durability?

Well, again, as I -- we've shown very nicely, and we wanted to illustrate that on the swimmer's plot, that these patients had sustained responses and continue to even under the circumstances when doses had been modified and reduced. As you looked on some of the longer treated patients, we had -- as you saw patient with 2.7 mg per kg, patient on 2 mg per kg, that were over 30 weeks of treatment. There was some dose reductions there and again, patients are doing quite well.

So they are very comfortable and with the experiences in using other chemotherapies, for example, on doing dose modification. And we have seen that this is has not led to any mitigation or reduction in the responses so far as of this interim data.

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

Well, that was something we pointed out on the Phase 1 study, we did not see that either. We were observing responses even in patients that have lower age scores. Although this may be a situation that is a threshold of effect where if you have a modest number of expression B7-H3, that's sufficient to provide entry of the linker toxin into the cell.

So we see that as actually a positive result here. The caveat is, of course, these are archival specimens and there may be some differences if you do fresh biopsies.

Helpful. Thanks for taking my questions.

Stephen Willey, Stifel.

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

I don't believe that there is a screening protocol for this because, A, as I pointed out earlier, there was no observed increase rate of pneumonitis in the population. With regard to patient has dyspnea they would normally get as part of their treatment. All I Canoe comment on the specific patients here is obviously a full workup and clearly, there are a lot of different causes of dyspnea, although again, the percentages are quite low.

So again, I'd just reiterate the cases of pneumonitis are under investigation and clearly there are at least the data to date other complicating factors of one of the patients with pneumonitis of other medical issues, and we still need to get the additional information on the other patient. So still too early to draw any conclusions.

Okay. 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?

It was -- there was -- the time, we don't have included here and I don't know what's at the top of my head. But what we do is obviously you saw on the swimmers plot the time and large number of these -- significant numbers of these patients have exceeded the 16 to 20 week’s time interval. There the number of doses -- the mean number of doses is now five, so which is on the cumulative basis.

And then just lastly, I know this trial allowed for patients who had not been on, I guess, quote-unquote, stable ARPI for 12 months. Do you know how those patients attribute out between two treatment arms with respect to patient baseline?

With regard to that population, if I without -- I don't have the specific percentages in front of me. But as I recall, I believe it was about a 40% to 60% split in terms of less than 12 months, greater than 12 months of historical ARAT exposure in that regard.

Thanks for taking my questions.

Jon Miller, Evercore.

Hi, guys. Thanks for taking my questions. Very interesting update here. Scott, I would love to get a little bit more confirmation. I know you said in response to an earlier question that you saw interruptions and discontinuations looking better than Phase 1, but that I wanted to confirm that you said that and what exactly number you're pulling from when I look at the Phase 1 poster, I see 50% discontinuations, 59% interruptions.

That looks right in line with what we're seeing with today's update at 15% and 56% of a 2.7 mg per kg arm there and for hand-foot syndrome, well, obviously, the grading appears to be lower in this update. You're seeing 31% in the Phase 1 results going to 23% in the 2.7 mg arm today.

So when you look at the tox signals versus Phase 1, you'd characterize them as being much better than they were, but I would love to see like is there a place -- this particular number you can point to they say, look, this is where it got better, this is where docs are going to be comfortable dosing this, this is the linchpin number that is going to let people stay on therapy longer than they did in Phase 1?

Yeah, so we again, I wanted to compare apples to apples here. And so I'm comparing as we did in the previous safety data or reveal from the abstract, it was the comparison to the prostate cohort, I believe, what you were pulling out is all different populations. So I'm just looking and I have -- I know the specific data and what I said before is absolutely correct that in patients in the Phase 1 study, whether do you look at severity of Grade 3, whether you look at drug discontinuations, whether you look at drug dose reductions, whether you look at drug interruptions, the percentage of those patients in the Phase 1 study was anywhere from greater than two times what we're seeing at the same six -- at same time interval around 16 weeks on trying to as best do an apples-to-apples comparison from a time exposure to drug.

Now there could be some modest variations of what the ultimate drug exposure was. But I'm clearly seeing at least two to three times more of the side effect profiles and severity of grades in the Phase 1 prostate on versus what we're seeing here in TAMARACK. And so again, I will reiterate the feedback we're getting from the investigators has been manageable tolerability, not concerning.

And in addition, as I pointed out earlier, we are now past the where the mean number of doses in this TAMARACK is vis-a vis where we were in the Phase 1 study. And so I'm feeling very encouraged and that we are on the right pathway here for delivering this drug. And as I showed in the various swimmers plots, the majority of the patients are still on treatment, despite some of the dose modifications and interruptions.

All right. I guess I understand that. Maybe on the efficacy side, I would love to -- I don't see in the deck how many prior lines of therapy, what's the median prior line of therapy in these cohorts? And then what are you looking at for the comps for ORR and DCR in that population?

So here as I pointed out, the entry criteria was no more than three lines of therapy. I don't know where it ended up from on with regard to the median for this study, whether it was two or three, but we'll have to get back to you on that.

Again, in terms of the ORR I mean, if you listened as you have to some of the continuous guidance I had which I started back in November, we were seeing approximately a 25% confirmed unconfirmed rate of objective responses and what was observed in the Daiichi 7,300 in the ESMO presentation was a solid 25% as well.

The point I made was that we should certainly achieve the 25% by this end of the study. And as we see here, not only are we achieving it is likely we're going to exceed this, and when this final data comes out, given that, as I pointed out, many of these patients are still on study. But we have a confirmed and unconfirmed ORR in the 2.7 mg per kg of 43.8% and in the 2.0 Q4 in a confirmed, unconfirmed 24.4%.

So I think we're doing quite well with regard to what the expectations were and what the data is as of this cut. But again, continue to expect further maturation of this data and continuing improvement.

Alright, makes sense. Can you talk about a potential use of vobra duo in combinations given the safety profile here? It's obviously not an innocuous molecule and some of the taxes are overlapping with other agents that you might expect to see in the prostate space. So I'm thinking about pneumonitis and pleural fusion.

So are you looking -- what does this mean for potential use in combination and thereby uses in earlier lines of therapy compared to other programs that are enthusiastically pursuing larger combinations in early line therapy?

Well, again, we are very much interested in looking at combinations of vobra duo, all with different agents. And as you know, we have initiated dose finding studies with lorigerlimab PD-1, CTLA-4, DART bispecific molecule. And as I commented earlier, we expect to be able to define the go-forward doses from these dose-finding studies very shortly where we would not only look at this combination in prostate cancer, but in other tumors as well.

And given then mechanistically, we believe these are very orthogonal mechanism for controlling tumor. And as we have already shown, in addition to the vobra duo data that we've described today, activity independently simulations of lorigerlimab late-stage patients. I think this will be a very good combinations to explore and we are looking at the potential of others as well.

All right. Thanks very much.

Etzer Darout, BMO Capital Markets.

Great. Thanks. Just wanted to know if you could provide a little bit more color around sort of the combination with specifically with lorigerlimab, given that you had sort of indicated that you could move into sort of dose expansion studies with vobra duo and lorigerlimab in the first half. I believe maybe you could comment on where you are with that program and is that still sort of a viable plan moving forward given the profile that we've seen today? Thanks.

Yeah, 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 one when put together to maximize both the safety and activity to explore. So I think we will be in pretty good shape in the second half of the year to initiate enrollment in prostate and potentially in other tumor indications. So stay tuned for that.

Thank you.

Mayank Mamtani, B. Riley Securities.

Good afternoon. Thanks for taking my question. So maybe on the look-forward basis, Scott, if you could comment on your expectations for the rPFS data and how you may look to present that in the next few months based on what you're seeing on durability, median cycles? And I think importantly, how you see based on all that, you see the split in the paradigm relative to PSMA STEAP-1 when you think about sequencing, you think about designing your Phase 3 next year?

Yeah. Thanks very much Mayank. Right now, as I again laid out the parameters here as baseline, what we had indicated was in rPFS of baseline of 6 but greater and obviously looking for 7, 8, 9, 10 or higher.

I think that the data that we showed today and the fact that these patients are still on therapy, I think we will ultimately see the results, but there's no reason we can't meet some of the longer lived rPFS values here. So we'll have to wait to be seeing the results. The expectation is that this would be presented at a scientific conference in the second half of this year.

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

I'm sorry, did you say radiotherapy?

Yeah, R&D or radiotherapy-exposed spaces.

That's true. As you saw on the geographic distribution of the patients, there were a very modest number of patients from the US where they would have the ability to when we initiated the study and when the enrollment occurred, to either have seen [pavicto] or have progressed on that given the timing of the marketing of that drug in the US versus Europe, where the majority of the patients came from Western Europe. So we expect small numbers of those patients in this study.

Got it. Thanks for taking my question.

Silvan Tuerkcan, Citizens JMP Securities.

Yeah, good afternoon and thanks for taking my question. 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 presume so. Obviously, we're giving you ongoing results as they come in. I mean, we're here in early May and as we just did this data cut in April. So the expectation is the teams are working very hard in finding out the details on the patient study and evaluating co-morbidities and other things that may have contributed to this specific deaths.

Great. But the DSMB is looking at these right, presumably between -- (multiple speaker)

Absolutely, absolutely.

Great. And then maybe talk to me -- maybe if you can walk me either through the waterfall plot or basically I'm trying to understand or reconcile the unconfirmed responses there's a fair amount in the especially high -- in the high dose arm where your confirmed response rate of 25%, but it could be with the uncontrolled as high as 43%. Are those responses, the majority why they are comparable that is still ongoing? Do the patients are not scanned yet? Or could you please characterize that?

Well, yes. I mean, it's very -- if you look at the plots there of the swimmers plot, say, for the 2.7 mgs, the timing frequency with regard to the scans is every eight weeks. And so again, if you look at the majority of these patients, if they were still on therapy as of 16 weeks would have had two scans those that had achieved 24 weeks would have had three scans, and there's at least one patient that probably had four scans.

So for instance, if you look at the patient with 2.7 mgs per kg Q4, the one on the top of that curve, they had initial evaluation for a PR that he achieved at eight week the first scan, but it wasn't until the probably the fourth scan that it was confirmed -- as a confirmed PR. So the bottom line is that it will take longer time. I mean, there are a number of patients I see here that have one positive value and have not gotten the second scan yet to confirm it.

Great. Thanks for taking my questions.

Kelsey Goodwin, Guggenheim Partners.

Well, hey, thanks for taking my question. I guess given the early looks at durability with the swimmer plots 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 follow-up there? Just any additional color you could provide there? Thank you.

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

Got it. Thank you. And for the non-RECIST patients, I guess, did the swimmer plots kind of, are they representative for the non-RECIST evaluable patients as well as this (multiple speakers) to it?

Yeah, 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 with regard to RECIST evaluable with measurable disease at baseline. But I would say that our general view is that this can be extended to patients with bony disease as well, et cetera.

So we're just -- we have this balance that we want to provide investors a look at the data as we have promised. But in the same time, is having additional data that we can then present at scientific conferences. But nothing here is more selective in that regard.

Got it. Okay. Thank you so much.

Peter Lawson, Barclays.

Great. Thank you. Thanks, Scott for the update. Just wondering if you could possibly characterize what the spider plots look like and if there's these patients are staying on the PSA50 reduction or PSA reductions improving over time or kind of the best way you could potentially characterize that?

Yeah. Again, what we started to do is give you a capsule so, but I would say that the spider plots are exceptionally encouraging. As we had shown in the Phase 1 data, you will see initial reductions in PSAs and they seem to be sustained for long periods of time and the time interval, at least at this interim data going forward.

Clearly there are individual patients that we'll not have the continued PSA50 responses. But I would say, as we characterize the Phase 1, they do very well similarly over a long period of time.

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

I think this is just idiosyncratic. I would not over-interpret this even though these are nice size populations, I don't think there is anything of particular I would more look at the -- I mean, the 50-50 with regard to the patients that have at least one PSA50 reduction, I think, says that both populations are seeing a similar even though the confirmed ones seem a little low on a 2.7 mgs.

I think it is just spurious in that regard and as I pointed out, is expecting that those numbers to potentially increase over time. So I don't look at that as an estimate or parameter of the difference at this point,

Thank you. And then 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 it's going to be rPFS and disease control rate. As I pointed out previously, avoiding new growth of lesions is the most important thing here. And so that obviously if a patient has 30% or greater percentage would call it as a PR, but if a patient has 20% reduction will be recorded as a 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.

Okay. Thank you so much.

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 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.