Prelude Therapeutics Inc (PRLD) 2025 Q3 法說會逐字稿

Good morning everyone and welcome everyone to the Prelude Therapeutics Investor conference call. Today's call is being recorded and is expected to last up to 45 minutes. At this time, I will now turn the call over to Prelude's Chief Financial Officer and Chief Legal Officer Bryant Lim. Please go ahead.

Thank you, operator. During today's call, we will make forward-looking statements based on current expectations, including statements concerning anticipated discovery, pre-clinical and future clinical development activities for our product candidates, the potential safety, efficacy, benefits, and addressable market for our product candidates and clinical trial results for our product candidates. Together with other statements regarding our plans, prospects, and expectations.

Such statements represent our judgments as of today, are not promises or guarantees, and as may involve risks and uncertainties that may cause actual results to differ from the results discussed in the forward-looking statements.

Please refer to our filings with the SEC which are available through the investor relations section of our website for information concerning risk factors that may affect the company.

We undertake no obligation to update forward-looking statements except as required by law.

During this call, we will also be referring to certain slides from our corporate presentation that are available on the investors section of our corporate website under presentations and events.

Also on this call are Kris Vaddi, Prelude's founder and Chief Executive Officer, as well as Peggy Scherle, our Chief Scientific Officer and Sean Brusky, our Chief Business Officer, I will now turn the call over to Kris to Vaddi things off.

Thank you, Bryant, and good morning to everyone joining us today.

Over the past quarter, we've made a series of strategic decisions designed to sharpen our R&D focus optimize our capital allocation and align our business strategy with programs that we believe offer the highest probability of success.

These steps strengthen our ability to deliver on our mission. To discover and develop transformative medicines that can meaningfully improve patient outcomes in cancer.

Importantly, as part of these efforts, we've also enhanced our financial position. Providing us with additional cash runway. To advance our lead programs into clinical development.

Looking ahead, our primary focus will be on rapidly advancing to development candidates. That we believe represent compelling opportunities for our investors with both programs expected to enter the clinic in 2026.

The first is JAK2V617F selective inhibitor for myeloproliferative neoplasms or MPN.

The second is a KAT6A degrader. A selective degrader for positive breast cancer. Both of these programs target clinically validated pathways and have the potential to demonstrate efficacy and safety differentiation in early clinical development.

In addition, we believe that these molecules significantly expand the clinical options over currently available treatments for cancers we are targeting.

Meanwhile, our discovery team made significant progress. In advancing next generation ADCs, call it degraded antibody conjugates or DAC.

Our early stage DAC program targeting mutant calreticulin or MKLR which is a very promising target in MPM shows potential to drive deeper clinical and molecular responses in our preclinical studies.

We look forward to presenting additional data from this program at the at the American Society of Haematology at ASH meeting, annual meeting in December.

I'll begin this morning with an overview of our JAK2V617F selective inhibitor program which will also be featured as an oral presentation at the upcoming Ash.

Given that the content of our oral presentation is embargoed until Ash, I will limit my remark to our approach and the opportunity we see in targeting this mutation as a potential disease modifying approach for a large subset of MPM patients.

Peggy will then review the KAT6A. A selective degrader program with our lead candidate poised to enter the clinic in 2026.

Our Chief Business Officer Sean Rusky will then provide an overview of the exclusive option agreement with Insight for the Jack program that we announced last week.

And future plans for our DAC programs, and I'll return for closing comments.

Before opening up the call for your questions.

Let me draw your attention to the JAK2V617F pathway on slide 7 of our corporate deck.

One of the JAK enzymes called JAK-2, plays a key role in a normal haematopoiesis by mediating growth factor signalling.

These growth factors include erythropoietin for red blood cell production, thrombopoietin for platelet production, and GM-CSF for white blood cell production.

In MPMs, an activating mutation in JAK 2 called JAK2V617F results in an unchecked activation of jack stat signalling and hyperproliferation of myeloid and erythroid cells and platelets which can lead to multiple forms of MP including polycythaemia vera or PV.

Essential thrombocythemia, or ET, And then even a more serious condition known as myelofibrosis or MS. Currently approved JAK2 inhibitors inhibit normal and mutant JAK2 similarly.

This lack of selectivity results in inhibiting normal and abnormal bone marrow function equally and to a very narrow therapeutic window.

Ruxalitinib or JAAI is the first approved JAK-2 inhibitor for MDM. As the first targeted therapy to be approved for MS and the only JAK-2 inhibitor approved for PV, Ruxalitinib has been absolutely transformative for many patients.

It should be noted that several members of our team played significant roles in its discovery and development in our previous roles at insight.

It was tremendously gratifying to see the Ruxalitinib become the gold standard in the treatment of MPM. Especially in the spleen and symptom benefits it delivers to MPM patients with a debilitating disease.

However, despite the clinical benefits it offers, flexib treatment is associated with high rates of anaemia and thrombocytopenia.

That requires dose modifications and often limit the use in patients that are anaemic and or thrombocytopenic at baseline, along with the limitation of dosing for maximal efficacy.

And because Rux does not specifically target V617F mutated progenitor cells. Molecular responses occur at very low rates and take years to achieve.

Ever since the discovery of JAK2V617F mutation in 2004, what we really wanted is an inhibitor that is selective for the mutant cells.

And one that does not interfere with normal bone marrow function. Such a molecule could provide the same transformative treatment for MPMs.

That BCR-ABL inhibitors like Gleevec delivered for CML. We are excited about the possibility of finally achieving that goal by the breakthroughs in designing molecules that can directly target JAK2V617F.

As shown on slide 9, the challenge had been that the mutation occurs in the part of the enzyme called the JH2 domain. That is distinct from the catalytic kinase domain called the JH1 domain.

Where the current JAK-2 inhibitors bind. Our scientists were able to design potent inhibitors of JAK2. That bind an allosteric JH2 binding site where the V617F mutation resides.

We further achieve selectivity over normal JAK 2 by directly targeting what we refer to as deep pocket which contains 3 phenylalanine residues that include the 3rd phenylalanine coming from the V617F mutation.

By utilizing extra structure-based approaches, our chemists identified a novel series of compounds. That can access the deep pocket to selectively target mutant JAK 2.

Over wild type of normal JAK2 that is present in normal cells. Digging a bit more into the specifics of our lead development candidate, the Peka Mauler JAK 2 JH2 binder, with significant selectivity for mutton JAK 2 over normal JAK 2.

In addition to the biochemical and cellular potency and selectivity, our lead candidate has demonstrated that acquired physicochemical and pharmacokinetic properties.

That enable achieving high levels of mutton 2 inhibition.

In pre-clinical efficacy and toxicology studies, this molecule achieved better efficacy compared to dexalutinib without impacting with JA-2 and normal bone marrow function.

We look forward to providing additional preclinical data once it's presented at ASH in December, but I can inform you that we're well along with that IND enabling activities, and we're planning to file an IND in the first quarter of 2026.

And expect to initiate the phase 1 in the first half of 2026. In terms of prevalence. Market size and opportunity. The target patient population include greater than 95% of TB patients.

50% to 60% of patients with MS and ET that are B617F positive. Collectively, more than 200,000 MPM patients in the US alone could ultimately benefit from a JAK2B617F selective inhibitor with a disease modifying potential.

We did announce last week, and Shaan will provide more detail that we entered into an exclusive option agreement with Insight.

That provides them an opportunity to acquire the program during a defined time period. As we aggressively drive forward the clinical development of our lead candidate and pre-clinical development of potential backup candidates during that option period.

We look forward to sharing more details at ASH.

I'll now turn the call over to Peggy to provide an overview of our selective KAT6A degraded program, Peggy.

Thanks, Kris, and good morning, everyone.

Today I wanted to summarize our efforts that led to the successful discovery of our first in class oral KAT6A selective degrader and highlight how this is a differentiated approach to maximize the benefits of a clinically validated target in positive breast cancer.

Although multiple agents, including CDK 46 inhibitors and oral SEDs, have been developed for patients with positive breast cancer, resistance to these agents continues to occur.

Thus, there remains an important need for additional treatment options that can complement the current therapies in the management of the breast cancer.

Recent data that Pfizer presented on their KAT6A dual inhibitor suggests that targeting the KAT6A protein may provide a new avenue to address this important unmet need.

As summarized in slide 14 in the corporate deck, the data Pfizer presented at ASCO earlier this year demonstrated that their KAT6A dual inhibitor in combination with silvestrant.

Had impressive activity in a heavily pretreated population of positive metastatic breast cancer patients showing high response rates of greater than 30%.

And significant improvement in progression-free survival. Based on this, the program is now advancing into pivotal studies.

Despite the promising efficacy, the safety and tolerability profile has left room for improvement, as investigators noted rates of grade 34 neutropenia and also dyscusia in most patients.

This has resulted in the majority of patients requiring dose reductions or modifications to address the neutropenia issues.

These findings likely suggest that there will be challenges combining with standard of care CDK46 inhibitors and as such may initially be limited to second or third line therapy.

We believe that these safety and tolerability issues are the result of dual inhibition of KAT6A and KAT6B, and that selective degradation of KAT6A provides a real opportunity for differentiation in the clinic.

Slide 15 of our corporate deck schematically shows the rationale for selective degradation of KAT6A.

KAT6A amplification and overexpression in cancer leads to its increased activity. And because KATR6A regulates the expression of the estrogen receptor, MCC and other cell cycle genes.

It's increased activity drives positive breast cancer growth.

Although KAT6A overexpression drives cancer growth, both KAT6A and its related family member KAT6B.

Are important in driving normal haematopoiesis.

And preclinical data demonstrate that loss of both KAT6A and KAT6B results in bone marrow toxicity.

Based on this, our approach of selectively degrading KAT6A has the potential to deliver differentiated safety and efficacy over non-selective KAT6AB inhibitors.

As shown in slide 16, our lead compound is a highly potent degrader of KAT 6A with selectivity for KAT 6A over KAT6B of greater than 1,000 fold as shown in the middle panel of the slide.

We've seen excellent oral PK across all species, and compelling in vivo efficacy is monotherapy, as shown in the graph on the right with complete regressions observed at well tolerated low once daily oral doses in a model of KAT6A amplified positive breast cancer.

As shown on slide 17, we also explored the in vivo activity of our KAT 6A selective degraders in additional models that are more resistant to KAT 6AB inhibitors.

In the more resistant T47D model, we still have significant efficacy with complete regressions observed at well tolerated doses.

Importantly, as shown on the right panel, when we benchmarked against a dual inhibitor, we seemed to demonstrate much better efficacy as a monotherapy, even when compared to a KAT 6AB dual inhibitor in combination with fulvestrant.

Our preclinical data clearly demonstrates that selective KAT 6A nation shows robust efficacy in positive breast cancer models.

We next asked if selective KAT6A degradation could mitigate the neutropenia observed with dual KAT6AB inhibitors.

As shown in slide 18 on the left, ex vivo experiments with human bone marrow cells demonstrated a reduction in these cells that give rise to neutrophils, whereas we see a very limited effect in this assay with our selective KAT 6A to greater.

On the right, we ran an in vivo experiment to confirm these results, and after 10 days of treatment, we see there is transient neutropenia in the mice treated with a dual KAT6AB inhibitor.

But we have not observed significant neutropenia with our selective compounds.

In summary, Prelude has discovered and developed multiple first in class, highly selective KAT6A degraders which in preclinical models show the potential to achieve best in class efficacy and to differentiate on safety and combinability early in clinical development.

Our lead development candidate has completed dosing in non-GLP studies in rats and dogs and has a favorable tolerability profile, and importantly, no dose-dependent hematologic toxicities were observed.

With that as background, we're excited to note that we're on track for an I&D filing in mid-2026, with a phase 1 start expected in the second half of 2026.

And with that, I'll now turn the call over to Sean to provide an update on our recent business development activities.

Thank you and good morning everyone. Today I want to provide an overview of the exclusive option agreement we entered into last week with Insight and also discuss our plans as it relates to degrader antibody conjugates.

The agreement with Insight is a time-bound exclusive option agreement for the potential future purchase of our JAK2V617F program assets.

The option period commenced upon executing the deal and is structured so that Insight has up to 15 months with potential for a 3 month extension as needed to exercise its option, no more than 18 months in total.

Importantly, Insight has the ability to exercise its option at any point during the option period. If at the end of the option period Insight elects to not exercise its option, Prelude retains full ownership and global rights to the JAK program.

At the outset of the option agreement, Insight paid an upfront fee of $35 million and also purchased $25 million of Prelude non-voting common stock at a price of $4 per share, $60 million in total.

If Insight elects to exercise its option, an additional upfront payment of $100 million will be paid to Prelude upon closing of the asset purchase agreement plus additional downstream milestones and royalties.

In fact, the deal includes up to $775 million in additional payments if certain clinical development and regulatory milestones are met, plus single-digit royalties on global sales as our JAK 2 development candidates advance. In total, the deal can deliver up to $910 million in cash payments and future milestones to Prelude.

Next, I'd like to mention our business development work on degrader antibody conjugates. We've recently amended and expanded the scope of our existing collaboration with AbCellera.

This agreement enables AbCellera to use Prelude's proprietary degrader payloads on additional undisclosed antibody targets of interest and importantly also enables Prelude to license our payloads to other potential partners.

The DAC field is really taking off, and the greater payload licensing arrangements have the potential to further expand the impact of this new technology while bringing in non-ilutive capital to support our ongoing R&D efforts as the field advances.

With that, I want to hand it back over to Kris.

Thanks, Sean. So before opening up the line for questions, I'd like to offer a few additional remarks related to our progress to date and where we expect to go moving forward.

As I mentioned at the outset, today marks a transformative day for Prelude. We are a company that is rooted in science and discovery excellence.

With a mission to develop precision oncology medicines to transform the treatment landscape for patients with cancer.

We are energized to be entering 2026 with two lead programs with highly differentiated development candidates. Well understood and clinically validated mechanisms and clear development paths.

A strong and experienced team and the financial means to provide a runway for execution into 2027. We look forward to keeping you apprised of our progress and additional updates in the coming months.

With that, I'll take some time to answer your questions.

Thank you. (Operator Instructions)

Our first question comes from the line of Reni Benjamin from Citizens.

Hey, good morning, guys. Thanks for taking the questions and congratulations on this deal with Insight and for kind of reorganizing the company to go after, what are extremely well validated targets. I have a couple of questions for you. I guess starting off, can you talk a little bit about how you're thinking about the clinical development of both the mute Kear and the KAT6 programs, especially given that you have, competitors that are, call it a couple of years ahead of you in development.

How are you thinking about the clinical development of these assets? Do you want to be a fast follower into the same indications? Do you want to explore, different indications? How should we be thinking about the path forward? And I, then I have a couple of follow-ups.

Thanks. This is Kris Vaddi.

So, as we discussed in the call, our molecule is a very potent and selective inhibitor of JAK2V617F, right? So, as a result, B617F positive MPMs that include myelofibrosis, polycythemia vera, and essential thrombocythemia are the three indications that we could look at.

As for in person human study, myelofibrosis, which is the most serious of the conditions, would be certainly, the most, one of the most appropriate, initial person and man studies that we can start with. High risk, Polycythemia vera or high risk essential thrombocyttemia are additional indications that could be added either from the beginning as part of the dose escalation or once we demonstrate that we have a biologically or pharmacologically active dose. Those are the things that we're currently, in the process of finalizing. And so, hopefully, we will be underway shortly, so we'll be able to talk about it in more detail.

So, you actually answered, oh sorry, go ahead.

No, I was also going to comment on the KAT6 program, and then, of course, happy to take any further follow-up questions. On the KAT6 program, again, our intent in developing a highly selective KAT6A is to fundamentally ask the question, in positive breast cancer where we see a clear proof of concept and clinical validation from Pfizer's molecule and the hypothesis we have based on genetic data, preclinical data that if you can selectively hit, that you can reduce and avoid, the haematological toxicity.

So, we're going to be focused in the phase one development to initially, obviously as a monotherapy, but rapidly, advances to all combinations. And really asking the question, do we see the differentiated profile that we're seeing in the preclinical studies in the clinic, and if so, rapidly move into the combinations with, the backbone therapy in positive breast cancer. So, we're really going to be focused on positive breast cancer for our KAT6A program.

Got it. Okay, and just as a follow-up, just to help us understand the prelude platform and the kind of pre-clinical work that you do, is the chemistry so differentiated that the preclinical models predict, for any of these molecules, by the way, does it predict a better efficacy, safety, or both? And as part of your pre-clinical testing, and I didn't get a chance to see the slides, but. What tests do you run to give you the confidence that you have a best in class drug on your hands versus let's say a competitor like Pfizer, that's already in the clinic.

So, just set a very high level start and just say that, there are really good free clinical models for that your question pertains to both programs, for myeloproliferative neoplasms, and, also you have positive breast cancers that we can profile head to head against already, approved agents are the ones that are moving, in the clinical development.

But for details, I will, just turn the question over to Peggy to answer.

Sure, so, in terms of the pre-clinical models that are both in vitro and in vivo, we really established a robust number of those, models to characterize the compounds, but it's more than just the in vivo and in vitro assays. We also spend a lot of time building in, the PK properties. And really optimize those so that we know we have a molecule that will be optimal in the clinic in terms of covering the target and giving us the selectivity and the potency that we'll need to really to really target the pathway.

So, with KAT6AC, specifically, I think we have a number of differentiating features. We have KAT6A selectivity over the other, family members, and we also took a degrader approach as opposed to an inhibitor approach. We thought that that would, be a differentiating feature. We can eliminate the protein, as through degradation, and it also helps us build in that selectivity that we think is really critical, the selectivity and the potency. So, in that, setting, we have a very differentiated approach for KAT6Afor over the 5.

Terrific.

Thank you very much. I'll, jump back in the queue.

Thank you. One moment for our next question.

Our next question comes from the line of Roger Song from Jefferies.

Okay, great. Thanks for taking my question. Thanks for sharing additional information around those two new the clinical program, interclinical program. So, on JAK2, can you just remind us of how the current mutation testing for this mutation, currently performing the clinical and then, how likely you need to do the companion diagnosis as you, continue the clinical develop.

And I have a question around the classics as well.

Absolutely. So, B617F itself, now that we have multiple therapies and MPMs that are approved, even prior to that, has, really become a sort of a standard of care diagnostic test for MPM.

For, in the case of PV, where greater than 95% of the patients are positive, so B617F, it, there is not a huge need. For the test, however, in myelofibrosis, that do not progress from PG to MS, there are, primary myelofibrosis patients for whom, it is, somewhat critical currently approved Therapies really are not specific to B617F positive, so they don't really require the testing, but in our case, we were going to be relying on, routinely used, QPCR type testing, that is performed as standard of care for MS.

Got it. Okay, and then regarding the KAT6, given this is also a degrader approach, how do you differentiate this degrader approach versus your previous mark 2, and then what are the learning you have applied from the previous degrader to KAT6 and maybe just lastly. In you're moving those two programs into the clinical in 2026 with current cash runway, how much, clinical data release we should expect, in 2026, and then, what will be the, value press, inflection point, for those data results.

Thank you.

let Peggy answer the first part of your question, and I'll come back to answer the second part.

Sure, so, we've learned a lot from our Mart K2, program in terms of building in potency and selectivity. And also building and as I mentioned, all those really important PK properties like oral bioavailability into the KAT program. So we really learned a lot from the SparA program in terms of building and all those features that you need to optimize the compound to take it forward in the clinic.

Especially selectivity for the KAT6A over KAT6B, protein, we utilized a lot of the, knowledge and experience that we gained through the SACA program, to generate what we believe are really optimized, to greater compounds, to take into the clinic.

With regard to your question on how far the cash takes us, as we said, we are currently, on track to file IND for the JAK program, in the early part of 26, and, initiate the trials and perhaps the second quarter. So, for that program we will be in dose escalation. And until we get into the clinic, we have certain projections in terms of how many dose cohorts that it might take to get to the levels, that we would expect the pharmacological activity but, I can't provide exact guidance until we actually start to enroll patients. So, we think we'll be, well under way in the phase one program, and we'll be keeping the street, obviously, updated with any progress we make.

With regard to the KAT6 program, again, the major milestone is really, successfully completing the IND enabling studies and, opening up the IND and starting enrolling patients. So, in terms of actual clinical update, we probably have to wait until 2027 to be providing them. But in terms of progress into the Clinic, obviously we will, update, as we advance to 26.

Got it, thank you for taking the question.

Thank you. One moment for our next question.

Our next question comes on the line of Robert Burns from HC Wainwright.

Hey guys, thanks for taking my questions and congrats on the deal with Insight. Just a few from me if I may. So obviously the KAT6, competitive landscape, when we look at that, there's obviously numerous players in the space, not just 5, they obviously got B1 as well, and I see the differentiation with the selective KAT6A degradation. So, I was curious for those more selective inhibitors or degraders that are in the landscape, how are you looking at them from a competitive landscape threat perspective?

And then my second one would be, obviously we're also seeing a lot of companies go straight from phase one when they see encouraging efficacy straight into phase 3. Is that something that you would also consider? And are there ways that you could expedite the development time of that compound?

Thank you.

So I can start with that in terms of the selectivity, the selective inhibitors that have been profiled, at least the ones that, we've seen to date, they do show, the selectivity mitigates. Some of the bone marrow toxicity that we also see. I'd say with the degrader approach, it really allowed us to have, more robust efficacy compared to even the selective inhibitors, as we think that there's, a different biology associated with degrading the protein because it is part of a complex than just inhibiting it, and we think that's really beneficial for the efficacy point of view. So, there will be differentiation from the selective inhibitors, but they also provide additional, abilities to mitigate some of the bone marrow tests.

I can just follow-up on that, again, fundamentally the whole concept of degraders right that are currently being developed across, multiple targets is the idea that, you just get much more deeper target engagement and given the potency of a KAT6A molecule and the PKA properties that the team has built into should allow us to very rapidly get to the levels of thyroid inhibition, that would differentiate our molecule versus others.

That is a really important aspect of it, because the sooner you get there in the clinic, the faster we can move. And then, the, this is the second part of this question. Would we advance rapidly and quickly, so good question. So there's a lot of learning from the data that's out there in terms of, PK as well as combinations. We would be looking to actually do more combinations early. In the development because ultimately, we want to get to, earlier lines of therapy which currently not being at least pursued by the existing, clinical stage inhibitors, we would be looking to generate that data. And to answer your question, yes, we would be looking for ways to advance rapidly, to, registrational, stage programs once we confirm, some of the preclinical hypothesis we had in the clinic.

Thank you. One moment for our next question.

Our next question comes from the line of Reni Benjamin from Citizens.

Hey guys, thanks for taking the follow-up. Can you just talk a little bit about the genesis of kind of why and how the deal with Insight took place given that they have their own inhibitor already in the clinic, is it, something that was ongoing for a while? Is this something once the new CEO took over discussion started anything that would, give us a clue as to how this came up, this nice deal came about? Thanks.

Yes, thanks, man. So, as we were thinking throughout 2025 and even late 2024 in terms of capitalizing the company and funding the programs that we had ongoing, right, so both JAK 2 and KAT6 programs made significant advances, and we were really anticipating that that they would be moving into the IND enabling phase in this calirier, as well as marketing program that was moving forward in the clinic. Obviously companies of our size would always be looking at business development as, one of the options to basically fund this really important programs.

So you know we've been in discussions with a number of companies for both for KAT6 and for all the programs and you know obviously Insight is a leader in NM space and there were several other companies that were very interested in the program as well so at the end of the day, when we look at, all the options that the company had the option agreement with Insight actually was we believed was the best option to not only, bring the capital that we need to the company, but also put the program in the hands of a company for whom it is fundamentally a core strategic area.

And, not only they would move aggressively through the clinical development, but also, commercialize the product, if we're fortunate to get to that point. So we're excited to be working with Insight, in moving this program and with regard to, your other question about their own program, and we really don't have any visibility into the program, but, we hope that our novel chemical space that our scientists discovered to create our molecules, would find a place, ultimately in the patient's hands and in the market.

Perfect, thanks very much.

Thank you. At this time, I would now like to turn the conference back over to Kris Vaddi for closing remarks.

Right.

Thank you everyone for your time and, have a great day.

This concludes today's conference call.

Thank you for participating. You may now disconnect.