Q2 2023 Kymera Therapeutics Inc Earnings Call
Okay.
Hello, and welcome to the marathon.
For 2023 quarterly results call I'd now like to turn the call over to Bruce Jacobs Mr. Jacobs. Please go ahead.
Good morning, everyone and welcome to the <unk> Therapeutics Quarterly conference call I Bridge, Jacobs, Chief Financial Officer, Eric Hi, Meera and I'll be joined today by now and then I'll pass.
President and CEO , Jared Garber, our Chief Medical Officer, and I'm also excited to welcome Justine Koenigsberg Chimeras, New head of Investor Relations to her first quarterly call. After our prepared remarks, we'll open the call to your questions as we always do before we get started I'd like to remind everyone that some of the comments that management may make on this call include forward looking.
As outlined in the press release actual events and results could differ materially from those expressed or implied by any forward looking statements. As a result of various risks uncertainties and other factors, including those set forth in <unk>. Most recent filings with the SEC and any other future filings that the company may make with the SEC you are cautioned not to place any.
Due reliance on those forward looking statements and <unk> disclaims any obligations to update such statements, except as required by law, but that said I will now hand, the call over to Noel.
Thanks, Bruce and thank you everyone for joining US today, we're excited to review the progress we've made over the last quarter and discuss how it contributes to achieving our mission of building a best in class fully integrated global the greater magazines company over.
Over the past few months, we've shared updates on our clinical oncology pipeline and preclinical work, including multiple presentations at scientific meetings across the world relating to <unk> two phase III <unk> III <unk> III I will provide an overview of this progress and Gerald will share more details during his remarks.
Data, we presented at <unk> June showed that two phase III has the potential to overcome the inherent limitations of small molecule <unk> two inhibitors against these well validated target.
In preclinical models of ALLL and AML is single dose of <unk> II <unk> III drove durable tumor regression and demonstrated differentiated pharmacology compared to a small molecule inhibitor.
In June 2003 was also granted orphan drug designation by the FDA for the treatment of AML. This program exemplifies our unique approach of selecting targets with strong genetic validation and pathways, where we believe targeted protein degradation offers the best the only auction for an <unk>.
Effective treatment and we look forward to investigating <unk> in a variety of cancers and sharing more on this program, including clinical proof of mechanism in patients later this year.
With respect to <unk>, which targets <unk>, four and the EBIT substrates, <unk> and <unk> III, which targets that three both are continuing in the dose escalation stages of their phase one studies.
As a reminder, our focus this year for these programs is to evaluate the degradation in the safety profile of this first in class mechanism and their biological and clinical impact in the appropriate patient populations. We recently shared encouraging data from the trials showing fidelity of PK PD translation from preclinical models.
Patients.
At the <unk> meeting in June we shared data demonstrating that both molecules, we're approaching or we're already at the target degradation levels. We believe based on preclinical models are sufficient to achieve anti tumor activity without any dose limiting toxicities observed.
Later this year, we intend to provide additional data evaluating antitumor activity in the target patient populations for these two programs.
Our first in class Eric for the Greater <unk> 47, four is in development with our partners signed a fee for the treatment of DLR IL, one hour driven immune inflammatory diseases with high unmet medical need such as hydrogen as a separate Eva atopic dermatitis and potentially others. We're very excited about the potential of <unk>.
For <unk> for patients with inflammatory diseases currently lack an effective oral medicines with a good safety profile and we expect the phase II studies in both <unk> and <unk> to initiate in the fourth quarter of 2023.
It is the greater is designed to block <unk> mediated inflammation more broadly compared to monoclonal antibodies targeting single cytokines and to enable pathway inhibition that is superior to Erik for kinase inhibitors by eliminating both the kinases scaffolding functions of Iraq for.
Jared recently presented the phase one data from this program at the <unk> symposium in <unk>, which demonstrated that 47% for administered to Hs in HD patients at Tolerability, PK and PD similar to healthy volunteers achieved a robust Eric full degradation in blood and skin associated with it.
Semicon inflammatory effect and showed promising clinical activity in both Hs.
In parallel to our clinical programs, we continue to drive the signs of targeted protein degradation and identify first and best in class opportunities to transform the treatment of disease. We had several exciting programs in our preclinical pipeline. There are designed to address well validated pathways in areas of significant.
Patient need with multibillion dollar revenue potential we look forward to sharing more details on these programs. Later this year early next in an R&D day.
Along with our clinical and scientific progress we've worked to ensure that we have the people and resources to build a sustainable fully integrated company to that end, we recently appointed Dr. Jeremy <unk> as Chief operating officer, who will serve as a key member of our leadership team as guys a divestment of our first in class.
<unk> programs and scale our capabilities to support our growth Jeremy joins us from Takeda, where he held leadership roles in global regulatory Affairs drug safety global clinical supply chain and development operation.
As Bruce mentioned, we're also very happy to welcome Justine Koenigsberg, Vice President and head of Investor Relations Justine its been more than 25 years in the industry and she'll be engaging with many of you on the call in the upcoming weeks, let me pause here and turn the call over to Jared who will now cover in more details.
<unk> progress from our clinical oncology programs before turning the call over to Bruce for a financial update.
Thanks Noah.
I'll provide a brief recap of where we stand with our clinical programs and what to expect in the coming months.
As Noel mentioned, we have begun dosing patients in the phase I Multicenter open label dose escalation clinical trial evaluating our investigational MGM two to greater <unk>, three and recruitment and the trial is going well.
MDM too is the crucial regulator of the most common tumor suppressor P 53.
P 53 remains intact or wild type and close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth.
We believe <unk> has the potential to be a highly potent integrator that unlike small molecule inhibitor has been shown pre clinically to have the ability to overcome the <unk> feedback loop and rapidly induce apoptotic cells, even with <unk> exposures.
So 53 has the potential to be effective in a wide range of hematological malignancies, and solid tumors with functioning <unk> 53.
We've shown pre clinically that 253 has superior activity compared to MDM to small molecule inhibitors and demonstrated greater than 200 fold improvements in both in vitro cell growth inhibition at a pop ptosis.
And Additionally, we presented data at <unk> in June demonstrating that a single high dose of 250 III administered intravenously in preclinical models of AML and <unk> that is greater than 90% MDM to degradation in tumors within one hour of dosing strong PSE three upregulation and induction of <unk> within the first $8 20.
For hours and sustained tumor regressions.
And contract lower doses of 250, III administered more frequently or repeat dosing with an orally <unk> small molecule inhibitor, let only to relatively weak P 33 activation and APAC ptosis induction and modest tumor growth inhibition.
These preclinical results suggest that a pulse IV dosing regimen of <unk> III has the potential for an improved efficacy and safety profile over MDM to small molecule inhibitors currently in the clinic.
The phase one trial is evaluating the safety Tolerability, PK PD and clinical activity in patients with relapsed or refractory high grade myeloid malignancies.
<unk> lymphomas and solid tumors.
Patients in the phase one dose escalation study are receiving IV doses of <unk> administered once every three weeks.
The open label study is intended to identify the recommended phase II dose and is comprised of two arms with <unk> doses of 253 in each arm.
RMA consists of patients with lymphomas in advanced solid tumors and RMB consists of patients with high grade myeloid malignancies in AML.
Dosing in RMB will start once a pharmacologically active dose has been reached and RMA at which time dose escalation will proceed in parallel across both arms and continue until the maximum tolerated dose is established for each arm.
We plan to share initial safety and proof of mechanism data from the phase one clinical trial later this year.
Now turning to our other two ongoing oncology trials.
So that three is a transcriptional regulator that has been linked to numerous cancers as well as to inflammatory and autoimmune diseases.
<unk> hundred <unk> three is being developed for the treatment of stat, three dependent hematological malignancies and solid tumors.
The phase one clinical trial of 333 is designed to evaluate the safety Tolerability PK PD and clinical activity of <unk> hundred three dose weekly and adult patients with relapsed <unk> refractory lymphoma leukemia and solid tumors.
In June at <unk> with the data cutoff date of May one 2023 primary share. The 13 patients received a mean of five doses across the first four dose levels of the trial, including patients with solid tumors as well as <unk> and <unk>.
While the fourth dose level, we're still open for accrual at that time data reported from day, one through three found plasma exposure increased with dose reaching levels close to those predicted to be efficacious and demonstrated dose dependent stat, three degradation with up to 88% mean maximum reduction in peripheral blood mononuclear cells.
With evidence of statutory pathway inhibition and downregulation of inflammatory biomarkers in peripheral blood.
Degradation profile the deal three were near levels of knockdown that lead to anti tumor activity in preclinical models.
We shared an ICM out that there were no dose limiting toxicities observed in the study.
The phase one dose escalation stage is ongoing recruiting broadly across solid and liquid tumors.
<unk> three is a novel.
And Robert functional the greater that target degradation of both Iraq for in the <unk> substrates Nicholas <unk>.
<unk> hundred three was designed to address both the <unk> and the type one interferon pathway synergistically to.
To broaden activity against <unk> B cell malignancies.
The phase one clinical trial is designed to evaluate the safety Tolerability PK PD and clinical activity of <unk> hundred three administered as an IV infusion. Once every three weeks two adult patients with relapsed <unk> refractory b cell non Hodgkin's lymphomas.
In conjunction with the ICM all meeting we shared that as of June 1st the first three dose levels have been completed and the fourth was accruing patients at that 0.5 patients were treated across deal one through four and received a need at $2 two doses, including patients with transformed activated visa like diffuse large b cell lymphoma.
Lymphoma marginal zone lymphoma, and Plasmablast like lymphoma, all of whom were at <unk> 88, Wild type, except for one who had a <unk> gain of function mutation.
Data reported across deal one through four showed plasma exposure increase with dose reaching levels close to those predicted to be efficacious.
403 achieved dose dependent degradation of up to 70%, Iraq, four and 96% to 100% a growth of <unk> and peripheral blood mononuclear cells. After a single dose.
Degradation profiles at deal three to four were consistent with knockdown levels associated with anti tumor activity in preclinical models of <unk> 88 lymphomas.
We showed at <unk>, but there were no dose limiting toxicities or drug related neutropenia observed in this study.
The phase one dose escalation portion of the trial is ongoing recruiting a broad population of b cell lymphoma patients.
We look forward to sharing data evaluating the anti tumor activity of <unk> III and Katie for one three and their respective target patient populations later this year.
And finally, the KC 40, 74 phase II studies in both <unk> and <unk>.
Which are being advanced by Sanofi are expected to commence in <unk> 'twenty three first NHS and follow shortly thereafter.
We will share more details around the trials as we approach the dosing of the first patients.
I will now hand, the call to Bruce who will share some brief comments on our financial results for the second quarter.
Thanks, Jared I will quickly cover the financials before turning the call back to <unk> for some concluding remarks for the quarter, we recognized $16 5 million of collaboration revenue and at the end of the quarter. Our deferred revenue total on the balance sheet was approximately $45 million that reflects partnership revenue, we expect to recognize over the next several years, excluding the receipt of any.
Potential future milestones with respect to operating expenses R&D for the quarter was $45 8 million of that approximately $5 7 million represented noncash stock based compensation. The adjusted cash R&D spend of $40 1 million, which excludes that stock based comp reflects a 7% increase from the comparable amount.
In the first quarter of 2023 on the G&A side, our spending for the quarter was $14 1 million of which $5 5 billion represented noncash stock based comp the adjusted cash G&A spend of $8 6 million again, excluding stock based compensation reflects a 9% increase from the comparable amount in the first quarter of 2023.
We exited the first quarter with a cash and equivalents balance of approximately $472 million as we shared earlier in the year, we believe that our cash runway extends into the second half of 2025 projection that includes milestones only related to the start of the first two phase II trials for <unk> 474, both of which we sell.
Today are expected to occur in 2023, I'll now turn the call back to narrow.
Bruce has said we're very excited to be soon in phase two with Kt 474 in two indications as well as by the progress we've made on our oncology clinical programs.
Our rapid progress in building, our pipeline generating clinical momentum and advancing the science of TBD gives us confidence that <unk> will be able to capitalize on the untapped potential of this powerful modality to enhance the treatment of disease and improving patients' lives. We look forward to sharing the exciting updates on our clinical.
Programs platform company in the second half of the year I will now hand, the microphone to the operator, so we can take your questions.
Thank you.
At this point, we will open the call for questions. As a reminder to ask a question. Please press star one on your telephone keypad.
If any time you would like to withdraw from the queue. Please press star. One. Please also be reminded that you can only ask one question and one follow up question that being said, we will now take a moment to <unk>.
Okay.
Okay.
Thank you for waiting your first question comes from the line of Marc Frahm from TD Cowen.
Sir your line is open.
Okay. Thanks for taking my questions.
Maybe start off with.
<unk> 333, monotherapy clinical responses or can we expect it to be only relevant for maybe a fraction of the opportunity in that segment is a bit of a different hypothesis and the rest of the population.
Can you walk through kind of how you plan to approach dose selection as you get this larger data set later this year.
Thanks, Mark So maybe I'll just take the first part of the question and then I'll pass it to Jerry So just to remind everybody. So.
<unk> III program, which encompasses legally.
Liquid tumor opportunity.
Solid tumor opportunity in opportunities outside of oncology.
Yes.
<unk> with that first clinical endeavor with <unk> III. So obviously, it's a brother.
Two the across several potential indications and we have clear hypothesis that were.
We're pursuing into cleaning the first one which is in our mind. The the earliest one that could lead to proof of concept is single agent activity in a subset of T cell lymphoma, and leukemia that we've discussed in the past.
<unk> Leukemias, which obviously also have subset. The reason why we are focused on those indications as a single agent opportunities is because we've seen pre clinically that when we those are degrader KC 333, once a week or even once every two weeks, we're able to achieve.
Profound anti tumor effects as single agent and we can rationalize the translation Lee.
The fact that.
Many patients in those particular subsets have.
Either start three mutations or pathway activation. So we added biomarker activity as well as biomarker sensitivity in those in those opportunities.
The phase one dose escalation includes those particular subtypes as well as solid tumors.
As I've said in the past we've said in the past in solid tumors the opportunity based on our preclinical data in combination we've talked about combination with immune therapy. We've mentioned in combination with targeted agents that we havent discussed externally yet and so now circling back to your question.
Just so clear so in terms of single agent activity in terms of responses antitumor activity that we expect to being able to talk about later in the year will come from a subset of patients from the phase one dose escalation and we've said in the past the handful of patients that might include <unk>.
Joe.
With regards to how we think about selecting I assume you meant the phase two the phase two dose maybe I'll, let Jerry comment on that.
Sure.
So mark we've always sort of stated that our dose selection will be based on a combination of.
PD and safety, we've looked at our preclinical data, especially in these factory dependent T cell malignancies, when we found that 90% or greater notch analysts that three 448 72 hours associated with anti tumor activity. So our aim is to be able to get to a dose that gives us at least that sort of a profile.
80% or greater knocked out.
In peripheral blood <unk> and tumor where we can get tumor biopsies, that's lasting 48 to 72 hours and that associated with a favorable safety profile, that's the sort of.
Our PD profile that we want to be able to then take into the phase one expansion. So a recommended phase II dose will likely be a combination of being able to see that level of PD along with safety if possible.
<unk> mentioned it in a handful of patients in the target patient population with the stats <unk> dependent T cell malignancies, we can see a few responses at those doses that are giving us that's where the PD and safety that would give us even more confidence in bringing that.
Dose into the next phase, but are these things won't be expansion, which right now are slated to be in these T cell malignancies like CTC LPT seal of lgs as well as in solid tumors.
Yes.
Okay. That's very helpful and maybe a similar type of question, but for <unk> II.
You kind of walked through the depth of.
Thirdly, we want to get in with that pulsatile dosing, but how long do you think you need to be at 90, 90% kind of what's the minimum there.
I mean so.
I'll start this and then if needed Jud Ken can add.
So the.
The nice thing about the <unk> program and how we're developing it is really trying to replicate.
What we've seen in cancer genetics, which is ablation of the gene in this case MDM to lead to a rapid and complete.
Anita from stifle.
Sir your line is open.
Good morning for <unk> now that Youre getting a handle on the clinical PK PD should we expect you to open a healthy volunteer study to dial in the stat III degradation to green kinetics that you need based on your ini models.
In order to prepare for a potential phase <unk> study or is this going to be pursued by a separate asset altogether.
Hey, Brad Thanks, Great question.
Net.
I'm going to answer high level now and then hopefully when we meet in an R&D day and as I said.
Most likely late this year, but most likely early next.
I think we will cover hopefully with more details that question, but I can see right now that.
We're evaluating opportunities both.
For a potential <unk> III transition into.
Into immunology as well as other probe or other particular.
The assets <unk> and <unk>.
Either formulation, so maybe I'll leave it at that this is where we're investigating but I think what we take from this phase one study which is.
Not to be underestimated ease.
The really good translation that we've seen not only in PK and PD, which to be honest with this company as being in constant now for multiple programs.
More importantly on safety. So we feel now we're in a pleased where.
We can come more much more comfortably plan.
Outside of oncology clinical study for a first in class target that has.
Obviously very broad biology biological application.
So sorry, if I can answer with details, but hopefully this gives you an idea about what we're thinking about that.
Alright, I look forward to that update let me also ask an MDM too when you think about the safety data from the prior small molecule inhibitors, particularly knowing that your target population as AML, where the blood count recovery is going to be important for those patients. What are you looking in terms of platelet impact thrombocytopenia rates.
In this first look to gain confidence in the profile for continued development. Thank you.
Yeah, Thanks, Brian I'll actually let Jed comment specifically on your question, but I do want to take the opportunity to add something to your question.
Which is so.
Clinical development team has designed I think.
I would say elegant and people's Unlike this word but it still use it and elegant plans to evaluate the.
PK PD safety and activity in both solid tumors liquid tumors and these myeloid malignancies and the idea was to split the.
<unk> type of dose escalation from the other indications because as you know and as you mentioned the context is quite different and.
And so the plan is right now were escalating in solid tumor and other liquid tumors until we feel we've reached a clinically active dose and then enter the AML space only when were clinically active already saw that.
The safety.
Does not.
Unnecessarily.
Sometimes the more challenging safety assessment doesn't influence the readout on the clinical activity.
One other thing that I would say is.
That the way that this molecule works, which is.
Said that rapid degradation with the recovery.
Within the first three weeks should allow us to build a therapeutic index that should allow us to evaluate the clinical activity of MDM to degradation in MDM to PCT III sensitive.
Tumor types.
And as with all the other programs in <unk> pipeline. We believe we can answer. This question in early safety in early clinical development, meaning in in phase one or late phase one clinical investigation, our ability to build the therapeutic index is really the goal of our phase one study and <unk>.
Able to show that and demonstrate that to ourselves.
I think that will hugely derisked this program and will allow us to be confident in investing a lot of money to develop this program and if not we obviously will be willing to make decisions and that's what the philosophies around all of our programs, but John maybe you can comment specifically on.
How we're looking at thrombocytopenia and other possibly related events that one might expect from P 53 upregulation.
Sure well I think as you just alluded to with this hit and run approach of dosing. Once every three weeks and based on our GOP Tox data our expectation is that our sort of depths of myeloid suppression Android the duration of mindless depression will be less.
Then what is seen with the small molecule <unk> two inhibitors, which as Neville just said should give us a superior therapeutic index.
That being said in AML of course.
The tolerability of myeloid suppression.
It was much higher in fact, one does expect to see a certain degree of miles compression as you are clearing blast and having an effect on the bone marrow that usually would then lead to clinical responses hopefully complete responses and so that's why we've separated out these two arms of the high grade myeloid malignancies in AML.
From the arm looking at solid tumors and lymphoma, because there is.
Different.
Level of Tolerability in terms of how clinicians view myeloid suppression. So we may see mild depression in AML patients, which would be a good thing because that.
That would be telling us that we're seeing in response to <unk> inhibition, but again, we do expect the depth and duration of that myeloma depression to be less as it gives us a better therapeutic index and likewise in solid tumors, we do expect to see less Milo suppression in that particular population, which could allow us having a more attraction in developing the drug in patients with lymphomas.
Solid tumors compared to the small molecule inhibitors that had been limited in their dosing by the dose limiting toxicity, the Gi tox as well as viral suppression.
Okay.
Okay.
Thank you.
Question comes from the line of Chris <unk> from Goldman Sachs.
Sir your line is open.
Great. Thank you very much good morning too.
Two questions. So on <unk> hundred 74, it certainly is sounding reassuring that sounds he has.
Formally committed if I understand the conversation that we've had in June the device. It seemed as if <unk> was a trial that was going to start in 'twenty, three perhaps a little bit less clarity and possibly to following in.
In Hs, perhaps I've gotten that mixed but to be clear I think the update today is that both trials will commence by the end of this year is that the case and then Bruce what kind of additional sort of timeline should we think about in terms of milestone payments as the program progresses and are you guys advancing 400.
For any of the other tool compounds through phase one type work potentially to look at additional indications I know you've highlighted mechanistically biological rationale to go into other broader categories are a glucose et cetera. Thank you.
Yeah. Thanks, Chris So I'll answer some of these and I think you had like three four questions. In there there was very elegant and then I'll, let Bruce answer the milestone question.
So first one just to clarify further so what we've said for the past nine months since December seven months.
We've said that.
Sanofi was it was going to take over clinical development of <unk>, four seven and four and that there was a commitment to initiate at least one phase II study in 2023 that was named to be DHS phase II study.
These can be also to initiate a phase two study, but we were not as our collaborators that collaborations we did not.
0.2, the exact time of face to start it was not clear they would have been.
Excuse me in 2023, so we're updating today with finally that also the fees to start with a D will happen in 2023, So Hs would be <unk> and <unk> will be second both of them will start in fourth quarter of 2023, and so we want to thank Sanofi for.
Allowing us to share more details then.
Also too.
With regards to.
Other indications before alleged.
Comment on the milestones.
Collaborators continues to discuss.
There are opportunities.
I think we both feel I can probably speak put speak for both we both feel that there are.
Other opportunities there are both mechanistically and clinically.
They fit the profile of Antarctic four degree there.
We're just not at this moment able to share more details.
Rest assure that as things progress we will be updating.
On those strategies yeah. Thanks, Chris This is Bruce just to clarify on the milestones. So what we've said in the past is that the.
The first phase III patient dose generate milestones by indication up to a certain number and we said at least two and hadn't commented before that.
Beyond that I should say the first two milestones for <unk> are included in our runway guidance, but no other milestones and then I think I heard you.
Ask about.
The additional program or the additional molecules that we might generate targeting Iraq for.
That was contemplated in the initial <unk>.
Hibernation agreement and so the work that is ongoing there has the potential to generate milestones as well. We just haven't said specifically what those critical events are and the timing, but I think that's something you'll you'll hear updates from us on over time as well.
Okay and you said initial collaboration agreement there was an update to that collaboration agreement in November of 2022, So thats still contemplated in the most recent active agreement correct.
Compounds molecules that may be generated as well so the aggregate total remains unchanged.
Thanks confirmation reassuring progress I appreciate it.
Okay.
Thank you.
Your next question comes from the line of Michael Schmidt from Guggenheim.
Hey, guys. Good morning, Thanks for taking my questions I had one on K T 413.
We've seen the updated phase one data at <unk> recently, where it looks like youre achieving target degradation already at.
Dose level three or four.
Can you talk a bit about.
How the neutrophil recovery and neutropenia has tracked with your expectations based on a cyclic dosing and also perhaps talk about the scope of the clinical update later this year and expectations for that thank you so much.
Thanks, Michael So maybe I'll start with the second part of your question and then I'll, let I'll, let Jeff address the first part of your question with regards to expectations for both programs as we said the goal is really to continue.
Continue and.
PK PD safety.
And potentially complete the dose escalation.
And as you know the goal of dose escalation with established.
Safety.
In this case also PK PD, but as you know in clinical development, especially in oncology. It is important to assess early signs of antitumor activity too.
Solidify the policies of these.
These oncology programs, providing benefits to patients so as part of the dose escalation for both program. We expect that we will have a handful of patients with <unk> mutant and out of the old B cell lymphoma, the recruiting and for 333 <unk>.
We'll leave it in solid tumor cohort.
Order for us to again establish early signs of antitumor activity. So again in terms of expectation, we hope to being able to report on a complete.
<unk> complete dataset on the PK PD and safety as part of the dose escalation study and then hope to have let's say a handful of patients from each of the studies that fit the sensitive patient population, where we would be able to evaluate the anti tumor activity of this first in class mechanisms.
We're now going to be able to discuss these obviously extend.
Response rates and metrics just because we believe that those are more scientifically sound better.
Better design study to evaluate the clinical activity, which we believe is expansion cohorts and beyond.
But again antitumor activity validation of these mechanisms.
Ability to correlate degradation to impacts on tumors.
We hope to being able to share later in the year. So maybe you can talk about the neutropenia question.
Sure Mike So in terms of your question about neutropenia.
We provided our update back in June around the ICL meeting, we indicated that we had not seen any dose toxicity or any drug related.
Which was very encouraging to us as you as you mentioned because of the we're seeing strong <unk> activity with.
Greater than 90% back down as they close in <unk>, but we're not seeing the Japan yen.
Yes, we're expecting to see some decrease in neutrophil count we have seen some decrease of neutrophils, followed by recovery, but it hasn't risen to the level of being neutropenia, which is in line with our preclinical data our GOP tox data.
See some decline and you can build that we saw a recovery prior to the next dose three weeks later so the use of this every three week dosing schedule at least so far in the clinic has been successful from a safety standpoint in helping us to mitigate.
Any sort of dose limiting neutropenia.
We think it is important because we do have this.
Emmett activity as part of <unk> of course, along with the strong Iraq for lowering activity that our ability to dose escalate without being limited by Milo suppression, especially neutropenia or buy stock.
Which we see as being very encouraging so far.
Thank you. The next question comes from the line of Colby <unk> from B Riley Securities.
Sir your line is open.
Yeah, Hey, good morning, and thanks for taking the question.
The planned phase II phase.
Phase II study in H at can you give us any.
Color on the expected trial design and maybe what types of patients you.
Planning to include in that trial.
Would you allow the use of prior use of Humira in that study.
And then I have a follow up.
Yes.
Thanks for the question. It's a great question. Unfortunately, we're not in the position to comment on it but I think.
Soon enough I believe.
Be updates on clinical trials Gov at that point, we might be able to add some color around what's been disclosed that's what we've agreed with our partner at this point.
Okay got it and.
What are you looking in terms of.
Expectations for that trial in Hs.
Are you looking to be or match, what Humira has performed historically or do you think there is a slight <unk>.
Room here that you don't need.
As much efficacy because you have an oral option.
Another great question I'm glad we're starting now setting expectations.
What we've seen so far we've seen some really encouraging TVD I havent seen both HSA.
Obviously your question was focused on Hs, which is okay, but I would say on both indications.
In both indications locked at this point.
A well tolerated potent oral option that can help patients manage these really difficult diseases, especially obviously the moderate to severe cases.
And our goal is to add.
Oral option that is well tolerated and that works and help patients.
And we believe.
Can be competitive with other agents that have been approved in those patient populations.
I think once we complete the study and we have a data set that is placebo control and solid I mean, we can then start to discuss if that type of data set is repeated in the phase III study where is the <unk>.
Commercial strategic placement of this particular drug, but I think right now it's premature to discuss.
The commercial option all I can say in terms of clinical and patient impact.
We are planning to develop this drug and to be honest, others that youll hear about in the future to fill a need which is an oral option for patients that don't have one that is both well tolerated enacted and our limited experience I would say a limited again.
<unk> are looking for well tolerated easy.
Z to peak oral drugs and Thats, what <unk> is going to be focused on in the next few years.
Thank you. Your next question comes from the line of Vikram.
From Morgan Stanley Sir Your line is open.
Hi, good morning, Thanks for taking our questions. So one follow up and I apologize. If this was discussed and we missed it but on.
On the topic of additional potential indications for <unk> hundred 74 beyond HSN.
What is.
Your incentive fees kind of cadence of decision, making there is that going to be dependent on data from the planned phase II studies in these two indications or is that a separate decision, making process that youre going through with Santa Fe at this time.
And then secondly, I'm not sure to the extent you can talk about this network just given your recent remarks on the question around Hs, but has your incentive you're thinking around the design for the Hs study in the patients you might grow up and impacted at all by.
Recent competitive developments in that indication.
Yes. Thanks, Vikram are both great questions and I think I can address both so the first one.
I can't speak for incentive fee. Unfortunately.
What I can say, though that we are.
And as any responsible drug development organization and in this case partnership are discussing.
Obviously, we don't have to reinvent the wheel that many times, but the conversations are around.
What are the other potential opportunities beyond their chest.
I can't speak to the decision, making process that maybe from my perspective, what I can say is that obviously generating.
Exciting data in Hs and indeed.
Influence.
Some other indications that are very close mechanistically and biologically to HSN.
But it will not in my mind again influent indications that are biologically.
And pathologically differentiated from Hs and India, and if you look at the list of potential indications that even we have on our website you can imagine that there are.
Which was around or have other studies impacted our clinical trial design and the short answer is no.
Obviously safety as you know.
Safety and the clinical activity of in an Arctic full degree the NHS.
And we believe that our design is going to be able to answer that question.
Question is whether the drug is superior inferior clinically to other drugs thats not the goal of our phase II study.
I'll put it out there already so.
As you can imagine again and this goes back to we believe there is a clear need in Hs.
I would.
Arguing asthma and COPD in IBD, a well tolerated at these again these are my words.
<unk> oral well tolerated active drugs and Thats what were trying to develop here.
Thank you.
Your next question comes from the line of Eric Joseph from Jpmorgan.
Your line is open.
Thanks, Thanks for taking the question.
Just a couple from us on 253.
Point of differentiation, where you.
Expect to be bypassing the feedback regulation of MTM to <unk> can you just remind us the kinetics.
Back in.
Is looking at.
Sure.
Degradation after cycle one.
Enough to.
Support having a differentiated degradation profile would you.
Okay.
Perhaps need to look at.
Degradation with subsequent cycle to get to.
A better understanding of the Max degradation profile.
And use that to optimize that.
Natural selection.
Yes, another great question.
We're very fortunate here.
Great great questions today, so the $2 three.
Is the kinetics of the feedback loop and where does the overcoming of the feedback loop impacted biology of P 53, I might add.
A follow up point to your first point.
We have we have experimentally.
Demonstrated.
That the the feedback loop needs to overcome one needs to be overcome.
Which means we need to retain high level of MDM to degradation only for the first few hours actually beyond the first few hours it doesn't matter anymore, whether you're you're degrading MDM to or not.
Because once you the grade for the first few hours sales.
Irreversible commitment to them.
And so thats the hypothesis here.
Small molecules you actually doesn't really depend on the dues.
I had a really hard time overcoming that just because it's.
It's limited by how much compound you can given the pace of that re synthesis of P. 53% of MDM too, we being a cuddle easy it doesn't really matter exactly what the doses, we're able to degrade a large amount of MTM to every minute.
The compound is onboard.
We should be able to evaluate mechanistically.
Our ability to suppress MTM too and to lead to sell that.
On cycle one now.
Multiple cycles might be needed to have maximal anti tumor effect, but as you know, it's just standard oncology drug development and importantly.
For us the hypothesis is MDM to degradation leads to a book doses leads to cancer said that leads to antitumor activity before we hit dose limiting toxicity, which does not happen with small molecule inhibitors and Thats why I said earlier, we should be able to show that in a phase one study again, we're not going to be able to talk.
About what is the response rate in population X Y and Z with big numbers, just because its a dose escalation studies, but we should be able to demonstrate that in patients and tumor types that are sensitive to this mechanism.
Right those we should be able to see anti tumor activity before we hit dose limiting toxicity and that will be the definition of success at least early success for this program that other MDM two inhibitor programs haven't been able to demonstrate convincingly.
Rice.
One is open.
Hey, guys. This is Jonathan on for Elliot. Thanks, So much for taking our question.
Lisa.
In June .
Jeremy Joseph Alright with Macquarie.
Okay.
So how should that like in former expectation or.
Any potential anti tumor effect.
You expect that proportion to change at this moment.
And then I have a follow up.
I didn't hear it very well, but I think you asked.
I think I'm going to answer anyway, and you tell me if I understood. Your question. So it's true that as of.
As of the CML update, which I want to remind everybody. The cutoff date I believe was June <unk>.
All the patients, but one where.
<unk> Wi Fi and actually the only patient that was <unk> was the first patients in dose level, four which in a way I think it was a bit of coincidence, but it was unfortunate coincidence, meaning the only or the first patient with <unk>.
Mutant or mutation was at a cohort that we believe.
It should be or could be clinically active.
We do expect to see activity only <unk> mutant patients Thats based on our preclinical data were really strong activity. We've seen only in my view the amusing patient so.
Our ability to demonstrate antitumor activity as I said earlier in this program will be will.
We will be driven by our ability.
To have multiple <unk> mutant patients as I said, a handful as part of the dose escalation to evaluate the clinical activity, while the rest of the patients I assume will be mostly generating PK PD and safety data, which is again really.
<unk>.
Official goal of the phase one study but.
Hopefully that answered your question.
Yeah. Thank you and then on that ratio is great program, how should we think about the continuing.
Going forward and then of course.
Great. Thank you for you that you showed an ICM a poster.
Related to the mechanism do you expect to see any of that going forward.
As suggested.
I'll answer this one Jared hopefully you heard that well.
A little bit of it was wasn't entirely clear.
So maybe to summarize.
Potentially.
Discontinuation rates in 333 and then.
The what.
Did we see in terms of re lateness of adverse events in the 333 study up to the CMO.
Disclosure that for My addition, yeah, Yeah, I mean, we really haven't seen much in the way of discontinuation due to due to adverse events, but we have had people.
<unk> modest.
So far we've seen relatively little of that as we've been dose escalating.
And.
We have had adverse events, many of which have been related to disease as opposed to being related to the drug itself.
But as we continue to dose escalate, we will be watching carefully for any adverse events that are thought to be related to treatment and see how the lineup with what we saw pre clinically, but I think that's the whole point of phase one is that as we.
It is difficult sometimes in these early phase one studies, we can have very heavily pretreated patients to be able to sort out.
Youre seeing that are related to the disease itself versus those that are related to the drug and the investigators at the sites ultimately have to make the call there, but so far.
Your profile has been encouraging.
And we'll just continue to watch as we continue to enroll patients onto the trial.
Operator in the interest of time can we ask the question is just to keep to one question. So we can try to get through the rest of the queue.
Understood. Thank you.
Your next question comes from the line of Clipper Varun.
Nevada Conder from <unk> Securities.
Line is open.
Good morning. Thank you so much for taking my question I know a lot of them have been answered with respect to <unk> initiating programs and HSN.
But given southeast footprint in that space and also the evolution of the competitive landscape in Hs as well as in <unk> would be great to get your thoughts on potential for Commvault that could be just for instance, with an antibody targeting the downstream cytokines and the pathway potential.
Pardon me thank you.
Yes, great question. So I mean, I would start with again, saying, what I said earlier, which is in.
In both indications and others Ah patients.
Still need.
And so I think there is still a need for effective therapy that are.
Simple to use and there are well tolerated.
I want to indulge your question on scientists on the scientific merits, yes sure there are.
<unk> to synergize across these multiple immune mechanisms and I can't speak to those plans because to be honest I have not been discussed, but one would say, let's say an observer of how deep understanding of immune inflammatory diseases is evolving with.
Time that yes, there could be potential synergies across more than one mechanism, but that's just.
Scientific observation at this point.
From my from my standpoint.
Your line is open.
Hey, good morning, Thanks for taking my questions just a follow up to an earlier question on <unk> 333, 4%.
Another staff III integrator, you might develop for.
<unk> indications.
This is something that you would explore yourself or is this purely for something that you would look to partner.
Casey for seven four thanks.
No.
Our strategy is not to partner immunology programs, we did partner <unk> I should say <unk> four in 2020.
This is to partner these programs before they reach key inflection point in general.
Thank you.
Your next question comes from the line of Kelly <unk> from Jefferies.
Hi, This is <unk> on for Kelly. Thanks for taking our question. So one of your three objectives to deliver two new <unk> can.
Can you provide more colors in terms of the indication and targets and how the learnings on the current clinical programs.
You started your plan. Thank you.
Yes, it's a great question.
<unk>.
I'm not going to go into the specifics of the numbers there, but just generally what I said earlier is that we've learned a lot from the first seven years of this company.
I think it's fair to say, we're pioneering protein degradation and for sure. We're pioneering a protein degradation in immune inflammatory diseases.
Lots of learnings on how to develop at least early to discover and early development of immune inflammatory degraders that have the potential to be best in class oral auctions and so I think the expectation.
To have is that there'll be a lot of focus on those particular type of programs.
Large larger opportunities unmet needs at Oro immune inflammatory drugs and other indications.
I would say that the expectation is a lot of focus in that particular area.
Thank you.
Your next question comes from the line of Rich law from Credit Suisse.
Your line is open.
Okay.
Good morning, this is Greg.
Thank you.
Sure.
I'm wondering for the fourth.
Alright.
Just wondering for the program.
How are you thinking about positioning that and lines of therapy in the phase two study.
Rather we're in there to a more specific patient population in this study.
Yes.
So thanks, I kind of addressed this earlier.
At this point, we're developing a drug that we believe will be has the potential to be safe active and access.
A broader population of patients right now are not served by existing therapies again, when we talk about labels and commercial positioning that will that will happen further in clinical development right. Now we don't have any reason to believe that we will be limited by any factors at this point.
Thank you. The last question on queue comes from the line of Jos <unk> from Bank of America.
Your line is open.
Good morning. This is <unk>, calling it like estimate you and thank you for the question.
Other than in the analogy.
Looking for <unk> and for <unk>.
Especially with the BD.
Did you say BD business development.
Yes, like Katie said seven four type of <unk>.
Collaboration.
Yes, yes, so I mean, we've commented on this particular topic at length in the past.
And keep this short.
The company with a broad pipeline.
Enabling platform that can deliver.
<unk> innovation.
We'll continue to entertain potential synergistic partnerships.
I would say that's a broad concept.
Indications area programs, but I think that statement apply and probably will apply always for a company like camera that.
Has this <unk>.
Thank you good afternoon, and thank you everyone for participating on today's call I am very excited to join the <unk> team and look forward to working with many of you going forward.
In the meantime, please don't hesitate to reach out to me and Bruce If you have any follow up questions. Thank you and this concludes today's call.
Okay.
Okay.
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Yes.