Shattuck Labs, Inc. Q4 FY2022 earnings call

• Taylor Schreiber highlighted that 2022 was operationally focused with progress on SL-172154 (154), including completion of Phase 1a monotherapy trial in platinum-resistant ovarian cancer and selection of 3 mg/kg dose for Phase 1b combination cohorts. Also, progress in AML and high-risk MDS trials. The SL-279252 program was discontinued as it didn't meet response rate targets.
• Lini Pandite provided details on 154's Phase 1a/1b trials, including combination with liposomal doxorubicin and mirvetuximab soravtansine, and progress in AML/MDS trial enrollment and expected data milestones.
• Andrew Neill discussed financials: as of Dec 31, 2022, cash, cash equivalents, and investments were ~$161.3M; Q4 2022 R&D expenses were $21.9M vs $16.2M in Q4 2021; full-year 2022 R&D expenses were $82.9M vs $56.6M in 2021; net loss for Q4 2022 was $25.4M; full-year 2022 net loss was $101.9M. Financial guidance for 2023 and beyond stated existing cash expected to fund operations into second half of 2024.
• Taylor Schreiber mentioned preclinical progress with GADLEN platform, promotion of scientists, and strong financial position with exploration of monetization opportunities.

No specific product segments with revenue contribution percentages were discussed as the focus was on clinical programs rather than traditional product revenue segments.

• Existing cash, cash equivalents, and investments are expected to fund planned operations into the second half of 2024.
• Key clinical data from 154 trials are expected in 2023, including complete data from Phase 1a monotherapy trial in platinum-resistant ovarian cancer, initial data from combination with liposomal doxorubicin in ovarian cancer, and initial data from AML and high-risk MDS trial.
• Financial discipline is maintained in ongoing clinical programs.

• Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those expressed. Risks and uncertainties are detailed in the most recent Annual Report on Form 10-K and other SEC filings.

Q: Hi, guys. Thanks so much for taking the question. I’d love to start with the 154 program. I know you were seeing some liver tox at higher doses. I’m wondering how that seems to be filling out as you move forward. Have you seen any Grade 3 or any of high grade, I should say, liver tox in the 3 mg combo cohort? And just to build off of that, how many patients in combo do you expect to be available in the initial release, especially in AML and MDS, is it enough that we should expect to be getting a good ORR comp relative to other CD47’s in these releases this half?

A: Hey, Jon, thanks for the question. So I’ll – Lini can provide you guidance on patient numbers coming up in all the cohorts. With regard to tox, the profile that we’re seeing in all of the combination studies is similar to what we’ve seen in the monotherapy dose escalation. So with regard to the specific liver toxicity question, we’re not seeing any evidence of any cumulative tox between the molecules and 3 mg/kg was well tolerated as monotherapy in that monotherapy dose escalation study as well. So looking good so far from that perspective, also consistent profile from what we saw in the monotherapy dose escalation with regard to no evidence of cytokine release syndrome or destructive anemias. Then on the combination, Jon, with the AML, MDS cohort, the patients that we’re enrolling in the dose escalation are patients who have relapsed refractory disease. We expect in excess of 20 patients a custom monotherapy and the pump cohorts by the middle of the year. The – just to put this in context, the CD47 targeted agents, they have a benchmark in the frontline setting in treatment-naive patients. These patients are relapsed/refractory patients. We will be starting those expansion cohorts in the frontline setting as soon as we complete the dose escalation.

Q: Thanks for taking my questions. Maybe I’ll ask similar questions and but we will go to the Doxil combo because that’s the prep test. May be Lini, if you can give an update on kind of the scope of that presentation or likely to see. And then related to that, as we get towards the mirve dataset, just in your prepared remarks, Taylor, you mentioned the kind of approved response rate that mirvetuximab has in the bio micro selected population, but of course, the trial is going to enroll a broader population. So, how should we think about kind of interpreting that data as we get it given that you will include patients who aren’t approved for monotherapy plus some of your proposed benefit is really on durability not so not as much on the response rate.

A: Great. Thanks, Marc. Lini can handle it for us. Yes, with the Doxil we are expecting something in the order of 10 to 20 patients by the middle of the year. So based – we would be sharing data both on the safety, as well as the efficacy. It will be a mixture of that data, depending on the enrollment. And we expect that we would provide some guidance closer to the time as to what to expect by the middle of the year. But to answer your question in the Doxil it will be in the order of 10 to 20 patients. With the mirve, looking at the mirve data, so yes, I mean, with mirve approved in the high expresser group, 75% of weight and here we are enrolling patients with 25% or greater. So we will be looking at the response by subgroup in those subset. But at this stage, what we are doing with ImmunoGen is that we are partnering with ImmunoGen to see what would be an interesting response rate and durability of response based on their database, we will definitely be working with them to benchmark the data that we see against the datasets that they have. And by the end of the year, we would hope to have or expect to have about 40 patients of worth of data.

Q: Hi, thanks. I’m just trying to get a feeling for expectations for the combo study with 154 in aza both in the relapsed/refractory setting, as well as in the frontline setting. What do you generally believe is the efficacy bar for aza by itself and with the addition of 154 in both relapsed/refractory AML and MDS as well as in the frontline setting in TP53 mutant, what might you expect to see with the combo above aza?

A: Thanks, Yigal. As Lini said in the initial portion of the trial, we’re enrolling primarily venetoclax to an HMA experienced subject. So any activity in that relapsed/refractory setting, I think would be helpful and perhaps provide some guidance toward what you might expect in the frontline setting. The first two cohorts that we expect to have data from in the second half of this year in the frontline setting are number one in the TP53 mutant AML patients. There we believe that the expected effect in terms of complete responses for azacitidine alone, are in the range of 22%. And so we’re looking for a combination complete response rate in the neighborhood of 40% or so. And in the high-risk MDS cohort, this is where there continues to be a bit of blurriness, honestly, in the field as to what the expected effect size of azacitidine alone is. Some of the older studies place that complete response rate in the high teens, the more recent Takeda study with Pevonedistat suggest that it could be as high as the low 30s. And so we think it’s best to cite the higher response rate as the benchmark. And so we’re looking for a combination response rate somewhere in the neighborhood of 50% for complete responses.

Q: Good afternoon. Thanks for taking the questions. My question is related to your 252 program. Obviously, it’s not surprising to see the discontinuation there, but I was wondering if you can talk about the learnings from this program, particularly around the PK/PD aspect to 154, what the PK/PD from 252 is consistent with what you are observing in 154? Thanks very much.

A: Sure, thank you. Zhi. So the trial cross comparisons here are, I think, quite valuable. And with the 252 program, we completed dose escalation through that 24 mg/kg dose compound continued to be extremely well tolerated. And across that dose escalation, we saw dose dependent binding to CD4 cells expressing OX40 and migration of those cells out of the peripheral blood post dose. And so again, from a TNF receptor agonist perspective, the tolerability and lack of any evidence of a bell-shaped dose response curve and the pharmacodynamic effects with both 252 and 154 are helpful in terms of validating one of the central hypotheses of the ARC platform that if you engage TNF receptors with a hexameric drug, you will not observe some of the toxicities and pharmacodynamic – abnormal pharmacodynamic effects that prior antibody-based regimens have seen. So that’s an important finding from a platform expansion standpoint, again both from the safety and the pharmacodynamic side. And we’re also learning some important lessons I think in terms of what OX40 and what CD40 stimulation achieve in human cancer patients. And when you look at the 252 data and you note that there really are – there were no appreciable serum cytokine changes. The only cells that were migrating were the specific CD4 positive, OX40 positive cells. It was a much more immunologically quiet molecule, so to speak, in this patient population, whereas the CD40 agonist clearly all across the dose escalation led to very clear escalations in a number of cytokines, infusion-related reactions have been much more common with that agent. And so the differentiation in biology between the two constructs paints a very clear picture that this is target-mediated activity that we’re seeing here. So always hard to close down a program like this, but I think we’ve learned what we needed to learn from this molecule and those learnings will benefit other compounds moving forward.