Q3 2021 Curis Inc Earnings Call
Good afternoon, and welcome to curious as third quarter 2021 earnings call. All participants will be in listen only mode should you need assistance. Please signal a conference specialist by pressing the star key followed by zero.
After the Companys prepared remarks, all participants will have an opportunity to ask questions to ask a question you May Press Star then one on your Touchtone phone.
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I would now like to turn the conference over to curious as Vice President of Investor Relations and corporate communications at least Mcdonald. Please go ahead.
Thank you Gary welcome to cure this third quarter 2021 earnings call.
Before we begin I would encourage everyone to go to the investors section of our website at Www Dot curious dot com to find our third quarter 2021 earnings release and related financial tables.
I would also like to remind everyone that during the call management will be making forward looking statements, which are based on our current expectations and beliefs.
These statements are subject to certain risks and uncertainties and actual results may differ materially.
For additional details please see our SEC filings.
Joining me on today's call are Jim Dentzer, President and Chief Executive Officer.
Bill Steinkrauss, Chief Financial Officer, and Bob Martell head of research and development.
We will also be available for a question and answer period at the end of the call I'd now like to turn the call over to Jim Jim.
Okay.
Thank you Alicia.
Good afternoon, everyone.
It's my pleasure to welcome you to the curious as third quarter earnings call.
As we look back on the year, we have come so far as a company, making important progress with both of our lead clinical programs CA 4948, and Ci 8093.
Every day it curious we strive to develop the next generation of transformative cancer therapies that meaningfully improve and extend patients' lives.
In the third quarter, we made significant progress towards that goal.
To start.
Let me review our lead asset <unk>.
Our novel small molecule Iraq for inhibitor CA 498.
CA 4948 is the most advanced Iraq <unk> inhibitor in clinical development for cancer.
And is currently being evaluated in nine distinct patient populations across AML.
And b cell cancers.
There was a critical unmet need for safe fast acting treatments for patients with AML, the leading cause of leukemia deaths in the United States.
In Mds the need may be even more critical as so many patients are left with only supportive care as their best option for treatment.
We are excited that the original scientific rationale for CA 494, eight and Iraq for inhibition has been followed by consistent and encouraging results in the lab and so far consistent and encouraging results in the clinic.
In both our B cell cancer, and AML and Mds studies.
<unk> hundred 90, <unk> has continually demonstrated a well tolerated safety profile and the ability to demonstrate improved efficacy over multiple cycles of treatment.
These findings were most recently presented at the <unk> meeting in June where we shared data from the monotherapy arm of our phase one two AML Mds study.
Demonstrating clear efficacy with no dose limiting milo suppression potentially key differentiating factor that may allow even extremely sick patients with low thresholds for drug tolerability to be treated with CA 494 eight.
Our second lead program as for our first in class monoclonal anti Vista antibody Ci $89 93.
Our novel immune checkpoint inhibitor that we're developing in collaboration within the next.
Ci 89 to 93 is a clinical stage human <unk> tap a monoclonal antibody designed to antagonize the Vista signaling pathway by increasing T cell mediated immunity.
Reducing myeloid derived suppressor cell or <unk> activity.
This is a key checkpoint for holding T cells in a quite Essent state.
Preventing their transition into effector cells facilitated by <unk>, four and PD one therapies.
In addition.
This is a key driver of Mds.
These are two fundamental and unique roles avista that are not captured by existing immune mediating therapies.
This expression is also believed to be a key resistance mechanism to PD, one and <unk> four therapies as Vista expression is dramatically elevated as patients become resistant to those treatments.
Finally.
This is highly expressed directly uncertain tumor cells themselves. In addition to the surrounding immune cells.
Including mesothelioma and subsets of breast lung and gynecologic malignancies.
Treatment with anti Vista antibody has been shown to suppress the growth of both Transplantable and inducible melanoma in preclinical models.
<unk> 89 to 93 is currently being evaluated in a phase one dose escalation study for the treatment of relapsed or refractory solid tumors.
With that.
Let's dig into some detail on our ongoing programs starting with the Iraq for study in leukemia.
And as I mentioned, we were pleased to present, an ehow earlier. This summer our positive updated data from the monotherapy arm of our AML Mds study, which expanded upon previously observed findings of single agent efficacy across the spectrum of late line AML and Mds patients.
Despite these patients having already experienced several unsuccessful prior lines of therapy.
We also demonstrated that near total IraQ4 inhibition was achievable at every therapeutic study dose.
With these data.
We saw that 300 milligrams PID struck the optimal balance of durable anticancer activity.
And extended Tolerability.
And accordingly, we selected it as the recommended phase II dose going forward.
This was in line with the findings from our earlier monotherapy study of CA 494, eight in NHL, where we also selected 300 milligrams PID as the primary study dose for further evaluation.
We continue to be pleased with the pace of enrollment in our monotherapy study of CA 4948 in patients with a Youtube <unk>, one or <unk>, one spliceosome mutation.
As we have noted previously our goal is to have 10 to 20 patients with those places so mutation on study by the end of this year.
We believe data from these patients may provide for an opportunity to explore discussions with the FDA on the Registrational path forward in the first half of 2022.
We expect to hit that 10% to 20 patient goal.
And plan to provide a high level update of safety and efficacy data from a subset of these patients in January.
While we obviously don't have data for all 10 to 20 patients just yet.
We do expect in January to have initial efficacy data for eight to 10 spliceosome patients and three slipped three patients or nearly three times. The data we presented at <unk> just five months ago.
This update will include all patients enrolled by mid September.
Which allows the opportunity for at least two disease assessments to determine marrow response.
Not all patients achieve responses this quickly.
But we believe this two assessment view will provide a nice interim snapshot of the clear progress we are achieving in this study.
For these patients we hope to see consistency with the data we shared at Ehealth.
That is.
We hope to see clear anticancer activity and reduction of tumor burden across the population.
That a majority of patients.
Can see their blast counts drop all the way down into the normal range.
<unk> an objective response.
And highlighting <unk> hundred 90, <unk> compelling ability to fight cancer as a monotherapy.
Further we would hope to see additional evidence of hematologic improvement, perhaps even a second patient with complete response to determine whether some patients may be capable of achieving SCR. Despite the effects of damaged tomorrow from both their disease burden and from their prior treatments.
Additionally, we would like to see that the finding of Rhabdomyolysis previously seen at higher doses.
It does not limit treatment at the recommended phase two dose of 300 milligrams B I D.
So this will be an early look at the data.
We expect to have a more comprehensive data update with the full 10 to 20 patients at a medical conference next year.
On the heels of our promising monotherapy data.
We were very excited to be able to announce the recent initiation of our phase one two combination therapy trial of CA 4948 in AML and Mds.
With the positive preclinical data in combination therapy that we presented at <unk>.
Featuring CA 409, freights synergistic antitumor activity when used in combination with Azacitidine and <unk>.
We are optimistic that this combination study will allow us to advance CA 4948.
As a new treatment for patients with AML and Mds across the broader AML and Mds patient population, where there remains a great unmet need with many patients ineligible for intensive chemotherapy.
The combination portion of this study.
Includes two arms.
CA 4948, plus <unk> for patients naive to HMA.
And CA 494, eight plus spinetta clocks for patients naive to venetic locks.
The primary goal of this combination study is to determine the recommended phase two dose for <unk> hundred 90 <unk> in combination.
A nation with <unk> and in combination with genetic locks.
Based on safety Tolerability and biologic activity.
Including pharmacokinetic and Pharmacodynamic findings from the study population.
We expect to have initial data from this combination study in 2022.
I would like to briefly touch on the ongoing phase two Lucas ISG for patients with lower risk Mds.
Led by the co chairman of <unk> scientific working group on Mds, Dr Ebay plus Becker.
We realize theres a lot of interest in this study because.
Because success in this study could lead to a potential breakthrough in the Mds field.
So even though we have a longer time horizon for this study and it is not a company controlled study.
We hope to be able to provide an update on the progress of the Lucas ISG in 2022.
The current standard of care in low risk Mds is supportive care, such as Epo stimulating agents, which can be effective for patients with low serum IPOH or loose Patterson.
Which enhances production of red blood cells.
Unfortunately, these interventions do not alter the underlying disease.
Their effect is often transient.
And they do not prevent progression to AML or further disease complications.
In contrast.
494, eight is disease modifying.
Targeting a key driver of the underlying disease.
Given the direct non Milo suppressive targeting of Iraq for.
And it's demonstrated safety profile.
We believe <unk> hundred 90, <unk> could potentially offer a safe and transformative disease modifying alternative.
For patients in this earlier stage of disease.
In conclusion for AML and Mds.
Our success earlier this year led us to expand our clinical investment to include both monotherapy and combination therapy and to include patients across the spectrum of disease from low risk Mds to high risk Mds to AML.
We look forward to providing data updates on all of these studies in 2022.
Moving to our B cell cancer program.
We have made steady progress with our CA four nine for a clinical development in B cell cancers.
Data from our monotherapy phase one two study highlighted clear reduction in tumor burden and a strong durability profile, which is particularly notable with a novel monotherapy agent in such extremely sick patients.
Based on these findings as well as our preclinical work.
We believe <unk> hundred 94, eight is the ideal candidate to combine with PTK inhibitors to maximize the downregulation of Nf Kappa B.
Earlier this year, we initiated the combination study evaluating <unk> hundred 94, eight with Ibrutinib.
Which is expected to enroll approximately 18 patients.
Three plus three design with CA 494 eight.
Starting at 200.
And escalating to 300 milligrams PID.
Ibrutinib dosing will be determined based on the appropriate dose for the patients type of cancer.
We are pleased to share today.
<unk> hundred 90, <unk> administered at the 200 milligram twice daily dose has been well tolerated in combination with Ibrutinib with no DLT observed.
We are currently evaluating the 300 milligram twice daily dose of CA 4948 in combination with Ibrutinib. The trial is progressing well and we expect to report initial data from this study at a medical meeting in 2022.
While we are obviously excited about our ongoing studies in AML, Mds and B cell cancers.
We are equally excited by the breadth of its potential application in other cancers and are working with our collaborators at the NCI.
And in the broader KOL community to evaluate additional opportunities for CA 4948.
In October we announced at the Triple meeting conference on molecular targets and cancer Therapeutics.
New preclinical data highlighting the potential benefit of CA 494, eight in multiple new applications.
These data demonstrated that <unk> hundred 94, eight can cross the blood brain barrier and enhanced survival patients with primary central nervous system lymphoma, and incredibly aggressive and rare form of lymphoma, and which malignant cells form in the limpet tissue of the brain and spinal cord.
<unk>.
Additional data at the meeting.
Highlighted CA 4948 is synergistic with small molecules targeting <unk> signaling.
Including both <unk> and Ibrutinib.
These data suggest it may help overcome secondary resistance to these therapies in marginal zone lymphoma.
Last but not least.
Turning to Ci 80 993.
Our first in class monoclonal antibody targeting vista for patients with relapsed or refractory solid tumors.
Enrollment remains on track in this phase one study and we expect to report initial safety data in our January 2022 update.
This is highly differentiated from other existing checkpoint inhibitors because of its primary role in enforcing T cell quite essence.
When unblocked.
<unk> is capable of sequestering, a large proportion of T cells in a quiescent state.
Preventing them from being acted upon by anti <unk>, four or anti PD one antibodies.
This is also a primary driver of Mds fees, which independently promote T cell exhaustion.
And suppress pro inflammatory tumor associated macrophages.
This year, our primary objective is to evaluate safety and tolerability and confirm that using our revised protocol the <unk>.
On target side effects of Ci 8993 can be safely managed enabling dose escalation up to and beyond all doses studied with this anti Vista therapy in prior clinical studies.
Achieving this critical milestone.
Which we hope to report on in January.
Will enable us to begin the exploration for efficacy at higher dose levels in 2022.
I would also note that earlier today, we announced that our preclinical data submission for Ci 89 to 93.
Was accepted for a poster presentation.
At the annual meeting of the society for immunotherapy of cancer or simply.
Being held from November 12, 2014.
We look forward to sharing additional data from this program at that time.
In summary.
This has been an incredibly exciting year for curious and we have even more to look forward to.
Specifically, we expect to report in January.
Both initial safety data from our anti Vista program.
The phase one monotherapy study of Ci 890 93.
And an update of safety and efficacy data from our phase two monotherapy study of CA four 948 in AML Mds patients with certain spliceosome or flit three mutations.
This update will be followed by a more comprehensive update later in 2022.
Also in 2022.
We plan to report initial data at a medical meeting from the ongoing phase <unk> combination study of CA 494, eight plus ibrutinib in patients with B cell cancers.
Before turning the call over to bill to discuss our financials.
I always like to extend my gratitude and appreciation to the entire curious team for their dedication and hard work.
We are eager to build upon our efforts and advance our next generation targeted cancer programs to help patients in need.
With that I'll turn the call over to Bill to review our financial results for the quarter Bill.
Thank you Jim.
The third quarter 2021, we reported a net loss of $11 1 million or <unk> 12 per.
Our share on both the basic and diluted basis.
As compared to a net loss of $6 million or <unk> 11 per share on both a basic and diluted basis for the same period in 2020.
For the nine months ended September 32021, we reported a net loss of $31 8 million or <unk> 35 per share.
As compared to a net loss of $22 $4 million.
<unk> 52 per share for the same period 2020.
Revenues for the third quarter 2021 2023.
$3 million and $2 7 million respectively.
Revenues for the nine months ended September 32021 were $7 $5 million.
As compared to $7 8 million for the same period in 2020.
Revenues for both periods comprised primarily of royalty revenues recorded on Genentech and Roche's net sales of <unk>.
Operating expenses for the third quarter of 2021 were $13 1 million.
As compared to seven 5 million for the same period of 2020.
Operating expenses for the nine months ended September 32021, or.
With $37 million as.
Compared to $26 4 million for the same period 2020 and were comprised of the following.
Cost of royalty revenues.
Primarily amounts due to third party University patent license stores in connection with Genentech and motions <unk> net sales.
Were $2 million for the third quarter of 2021.
As compared to $1 million for the same period in 2020.
Cost of royalty revenues were $4 million.
For the nine months ended September 32021, and 2020.
Research and development expenses were $8 6 million for the third quarter of 2021 as compared to $4 7 million for the same period in 2020.
The increase in direct research and development expenses for the quarter is primarily attributable to increased clinical and manufacturing costs for our clinical programs.
Additionally, employee related R&D cost increased by $2 3 million.
Merrily attributable to increased stock based compensation and personnel costs as a result of additional head count.
Research and development expenses were $24 1 million for the nine months ended September 32021.
As compared to $17 $5 million.
Same period in 2020.
General and administrative expenses were $4 3 million for the third quarter of 2021.
As compared to $2 6 million for the same period 2020.
The increase in general administrative expense was driven primarily by higher costs for.
Stock based compensation personnel professional and consulting services.
General and administrative expenses were $12 5 million for the nine months ended September 32021.
As compared to $8 $6 million for the same period in 2020.
For the third quarter of 2021, and 2020 net other expense was $1 million and $1 $3 million respectively.
Net other expense primarily consisted of imputed interest expense related to future royalty payments.
Net other expense was $2 3 million for.
For the nine months ended September 32021.
Compared with $3 8 million.
For the same period 2020.
As of September 32021, curious with cash cash equivalents and investments totaled $149 $8 million and there were approximately 91 6 million shares of common stock outstanding.
We expect that our existing cash cash equivalents and investments should enable us to maintain our planned operations into 2024.
With that I'd like to open the call for questions operator.
We will now begin the question and answer session.
To ask a question you May Press Star then one on your Touchtone phone.
If you are using a speakerphone. Please pick up your handset before pressing the keys to withdraw your question. Please press Star then two at this time, we will pause momentarily to assemble our roster.
Our first question is from Alethia young with Cantor. Please go ahead.
They are black counts all the way back down in the normal range. That's what we Wanna see we've already seen one C. R. We'd love to see another one.
We want to get that updated in January we don't have all those day to get but of course, if you ask for what we were hoping for that was sort of our guidance in terms of the F. D. A meeting.
We have always planned and we've been very clear about this oh here we.
We have always been planning to get the concentration focused on spliceosome patients and put three patients. When we saw that the data we had any hardware. So compelling we really ramped up our efforts to get patients on drug.
Our regulatory consultants have given us guidance that in order to meet with the FDA, we probably need 10 to 20 patients and that's our goal to get 20 patients tend to 20 patients on drug by December 31st whether or not the F. D. A of grease with those consultants and takes our meeting and has this discussion we hope for of course, we don't have any <unk>.
Roll over but the general consensus seems to be that if we can get 10 to 20 patients and the data look consistent.
Then we should have a good shot at having a successful discussion with the FDA. The reason for the new update that we're offering in January is of course, we're very pleased with where we said we don't have all the data yet, but the data that we have we think do look compelling and consistent with what we have been and we think that if we can make that cut.
A off to have eight to 10 patients at year end with slices of mutations and another three <unk> three that's.
Let's go a long way to giving everybody.
Our investigators the K O L community and investors are very good sense of where the data trending we've only seen three patients so far where the data trending so that we have a good sense of how that discussion with the F. D. A might go that's the point of that update so we're very happy with where we sit but of course, we've got more data internally.
And we'd like to make it public so that January plan is to make all of that public.
And then just maybe it's the phone on the safety with the <unk> in Britain of combination that you mentioned you haven't seen anything like related to Rhabdo or anything I say I think he said there was no dlt's. So I just wanted to confirm that.
Yeah actually Bob would you mind talking about that.
[noise] yeah. So we've obviously continued to those.
Those patients with our 300 dose level in the mono therapy study uhm, that's going along well and as Jim said will update the safety on that.
We probably won't be giving an update on the combination study at that point, but yeah. There were no no dose limiting issues yep at that initial dose level. So it was quite well tolerated, which which is really exciting because.
No no we're able to dose escalate up to the full dose of both both drugs.
Great. Thank you.
The next question.
Question is from daily one with Raymond James. Please go ahead.
Alright, Thank you for taking the questions and and congratulations on the progress.
I guess in.
In in light of the announcement that you're going to host an update call. In January now you know maybe given this isn't gonna be the fold date at that of what you hope to have an spices put three could.
Could you maybe just clarify.
How does that expectations.
You know I got the worry is if you're giving this update in January you know everyone tried to interpret it in in terms of a data set that you'd actually walk into the F. D a with.
Maybe something that can <unk> inhibitor class, but it seems like from your commentary you're you're trying to get more of an anecdotal update.
Uhm. So maybe you can just provide some caveat to what this data analysis is actually going to look like and you know the contacts that you're trying to hope to pull out of updating people publicly without maybe the fall datasets here for the spices one group.
Sure what what are they making the initial comment on that and I'll ask Bob to expand as well. So I think the thought processes of course, we gave.
A terrific update of three patients, but it was only three patient.
At <unk> with a slices on mutation and in fact, one for three patients flipped three patients did exactly what we hoped exactly what the literature would suggest.
Patients that did not respond to other flip three inhibitors.
Coming onto our study and within two cycles not only getting a response between complete eradication of mutation I mean, both datasets the first three and the one look terrific.
And we've been moved fast and furious have the discussion with the F. D. A and I think what we were just trying to respond to is.
It's a long time between <unk> and that discussion with the F. D. A we have a lot of confidence and we're seeing terrific progress in that study and we wanted to give everybody else a chance to see what we're seeing.
So it's it's not the full update that will have an you know six months from now, but we think the data that we have now and the data. We're gonna have by year end is a nice update and it gives a significant upgrade just five months. After he we're gonna triple the dataset, we think that's gonna be.
I think a very robust discussion it's not anecdotal.
And it's not it's not the complete total of all patients that will ever be on the drug, but it's a significant increase of the data size and really should give everyone a chance to share our enthusiasm for the progress of the study.
Would you like to add to that.
I think he was just schedule well Jim.
<unk> you said, we we've been so excited about the the disease modifying aspect of this drug really <unk>.
Mostly in this population seems to have a really potent effect on you know limiting blast grows in reducing blast and <unk>.
We think that this is a therapy that that the F. D. A will be very interested in in a population where no. Other drugs are approved and so based on <unk> data, we thought to really build our case around that I'm really focused on the F. D. A with our goal being <unk>.
We would like to update that community publicly along the way with this data when we have relevant update and so that's the goal here in January this isn't gonna be the exact data set that we take to the F. D. A uhm, but it'll be as Jim said, a tripling of the number of patients that we presented.
<unk> so far do we think it it should give the community a lot more confidence about the drug and the anti cancer activity of the drug going into that.
Hope for the potential discussion with the FDA.
Great sorry, just to clarify one thing what at what.
Point, a follow up for for the cohort of spices. All mutations are you calling to to go to the F. D. A are you looking to have that fully enrolled with with clinical.
Follow up for all those patients to properly evaluate efficacy before having that discussion with that day or you're doing that before.
You have a more mature data set back cohort.
Well, they're obviously when when we do go there will be you know a range of patients in terms of duration on study, we'd obviously like to have you know a minimum duration for all the patients that we present to them uhm, it's an ongoing process and even the data that we present to them will be interim data to some extent.
But we think you know by the first half and so we've committed to.
Considering that as a possibility in the first half of 2022, and we believe that we'll have enough data that's mature enough at that point to speak with them at least will request to speak with them.
Okay. So just to be clear you you won't actually have feedback from the F. D. A when you give that update in January correct.
That's right.
Okay I understand.
Yeah, Yeah, we used to be really clear day, we haven't already spoke with the F. D. A the the plan has that right. We are having a meeting with the F. D. A and first half of 2022. This is just a chance to give everybody a snapshot to see all of the data that we are now seeing uhm triple the size of the data they've seen so far to give them a greater confidence that we really do have some.
The the the skepticism that you get in developing a new drug in this space should be high.
In mono therapy. There is nothing approved for these patients because nothing works the data that we've seen so far a remarkable but it's small and a three and then have one so I think being able to provide people a greater sense of confidence that this really is something that nobody has seen before that we really do have a drug in monitor.
Therapy that can address cancer in these patients I think is tremendously exciting and so we're very interested in providing that update.
Okay. Thank you.
The next question is from Justin Walsh would be Riley secure excuse me be Riley Securities. Please go ahead.
Hi, Thanks for taking my question, maybe could you give us some color on what we should be looking for in the B cell cancer combo data I believe that you have a time in two states designed to help explore signals and the expansion portion, but maybe you can remind us what response rates do you think would be meaningful and the various lymphoma indications you're looking at.
At.
Yeah, that's probably a better question for Bob Bob.
Yeah. So obviously started that that's a combination with ibrutinib and just to to recount uhm, a brute nib hits. The other primary pathway that activates enough capital B, So and another B T. K inhibitors inhibit that pathway 4948 is really the old.
The drug that targeting the other primary pathway activating and how can it be any malignancies, and that's T. O R signaling through the medicine and that drives the you know the.
[noise] combination that we're we're putting in here you know.
Right now clinically we've seen activity with our drug has a mono therapy targeting this pathway, obviously burnt now than other B T. K as have mono therapy activity. There what we would like to do is in hand that activity is part of as part of this combination and the and the study that you mentioned.
And really has four different cohorts each each of which is a what we consider a low hanging fruit for targeting Iraq for either indications, where you know there is a high incidence of mid 88 mutation, which is a key.
Part of the medicine.
And a strong signaling through in a capital B via that pathway is also indications, where we think there is a straightforward registrational path as well and so we'll be expanding in each of these will be looking to gain estimates of the efficacy of these combinations.
Is one example, the the fourth cohort is a cohort were were looking at adaptive resistance.
That's where a patient has experienced progression unapproved nib.
In this case, we add 4948 and so to to address your question any efficacy that we see there suggest sort of proof of concept of adding 49482 Boutonniere that's part of that combination.
Ultimately once we get those estimates of efficacy will discuss with the F. D. A you know what what we think is a relative relevant target or a pivotal study going forward from that.
But we haven't we haven't put a stake in the ground specifically for a target response rate, we would obviously hope too.
You can get a reasonable percentage of patients, having durable responses and hopefully deep responsive and in many cases deeper than what we would expect with a D. T K inhibitor by itself.
Got it and do you do you have a sense of roughly how many patients. We can expect that that that read out and if those include patients from those for a specific cohorts of interest.
Yeah. So just to reiterate the four cohorts I already mentioned, one which is the adaptive resistance and that can be any patient across any indication who's had a root <unk>. The other three include primary CNS lymphoma. This is a very deadly and difficult to treat.
Disease that actually has a very high incidence of mid aviate mutation.
Marginal zone lymphoma is another one that has a high activation and I've kept a b.
Through this pathway.
And so you know with those we you know we hope that we'll see you know.
Strong efficacy there.
Got it alright, thanks for taking my question.
Again, if you have a question. Please press Star then one.
The next question is from summit Roy with junk trading. Please go ahead.
Hello, everyone. Thank you for taking the question [noise].
If you could remind us a little bit on the natural history of progression of the.
The M D as from Loras too high risk do we see an increase accumulation of these places a mutation.
And what what would the standard of care response rates looked like some kind of benchmark look at.
Yeah, Hi, Thanks for your call. It Bob would you mind, commenting on that I know this is more your area of expertise.
Yeah. So the natural history, you know it's interesting uhm these slices cell mutation.
Occur extremely early in the natural history of the disease.
As you May know they've been known for quite a while and correlating oftentimes with one of the first mutations found in the disease and it wasn't until about a year and a half or two years ago that it was even known what the slices. So mutations did in terms of their oncogenic wrong and it was it was some work by.
I'm in Burma, and dance I was gonna ask <unk>, who determined that it's actually this alternate splicing of Iraq for L.
And so well you know as I mentioned it to find out what <unk>, what some people call a founder mutation. Despite the so mutations and they tend to persist throughout the disease. So normally patient may start out with low risk M. D. S.
With one of these places have mutations in overtime their disease starts to accumulate other changes and ultimately becomes more aggressive.
Unfortunately, some patients die along the way because of the complications of the disease, such as neutropenia, and Ah low platelet count Cytopenia Uhm.
Uhm, but in general these spices limitations persist if the patient does evolve their disease and ultimately can transform into leukemia M. L and again during that transformation most of the patients still retain the Iraq, where they spices how rotation.
Testing that this is a really critical components, that's important for the survival of the disease itself.
Yeah.
And that's why we you know we think that this drug has a very important role for all stages and exactly why we're going after the low risk disease as part of the movie plots Becker collaboration as well as he's later line with.
The high risk M D S and ultimately the M L.
Just the you know the response rate and information that you look for in terms of airplanes.
Across the spectrum, ranging from low risk to high risk M. D. S. All the way to M. L differs depending on the specific disease heading that you're looking at so for example in low risk M. D. S.
Inappropriate endpoint, there might E transfusions number of transfusions required or frequency or maybe even achieving transfusion independence.
Uhm as you get to higher risk disease, you're you know you're looking for.
Robert E. Martell: You know, you're looking for, you know, disease control, reduction in blast coats, as well as, you know, reduction in transfusions and hematologic improvement. And same with it with AML. Again, you're looking for a variety of different impacts.
Disease control reduction and blast cold as well as.
Reduction in transfusions, and hematologic improvement and same with it with a M. L. Again, you are looking for a variety of different endpoints.
Robert E. Martell: When we think about, you know, this population that we're looking at with the splice of phones, it's important to remember the very potent inflammatory microenvironment that develops because of these splices and because of IREC-4L. And that creates a damaging effect on the marrow, including the healthy marrow. You know, I often liken it to hepatitis, where hepatitis C causes liver cirrhosis. You can even get rid of hepatitis C, but the cirrhosis of the liver remains.
When we think about.
This population that we're looking at with a slice of phones, it's important to remember the the very.
Totally inflammatory microenvironment that develops because of these slices for mutations going because of Iraq for L and that creates Ah Ah Ah damaging effect to the marrow, including the healthy marrow.
I often like in it too.
Hepatitis where in hepatitis C causes liver cirrhosis uhm, you can even get rid of the hepatitis C. But the cirrhosis of the liver let me names.
Robert E. Martell: This can be the case as well in the bone marrow. As a result, healthy marrow may be damaged. It makes it difficult for these spliceosum mutations to recover. And so that's important to think about when we're thinking about potential efficacy, the hurdle. There was a nice publication a few years ago that looked at intensive induction chemotherapy in AML. In the broader population, 80% of patients achieve full hematologic recovery. But when you break out those patients with lysosome mutations, you know, only about 22%, almost three or fourfold fewer patients, were able to achieve a full CIO if they had an SF3B1 mutation. It's a splice cell mutation.
This can be the case as well in the bone marrow. So healthy marrow may be damaged it makes it difficult to me slices so mutations to recover.
And so that's important to think about when we're thinking about potential efficacy hurdles.
There was a nice publication in a few years ago that looked at inductive intensive induction chemotherapy in M. L actually in the broader population, 80% of patients achieved before hematologic recovery.
But when you break out those pieces with places so mutations.
Only about 22% almost three or four fold less of the patients we're able to achieve a whole C. R. If they had an S. F. Three D. One mutation spices cell mutation, so dramatically reduced ability to achieve.
Robert E. Martell: So dramatically reduced ability to achieve, you know, hematologic recovery in this population. So that's what we want to think about. And when we're thinking about precedents for response rates, it's important to take that into consideration. So that'll be a really big goal of ours when we actually speak to the FDA. We've seen really striking anti-cancer efficacy with this drug so far, and we've also seen, you know, good, strong evidence of other potential endpoints.
Hematologic recovery in this population. So that's what we want to think about and when we're thinking about precedents for a response rate it's important to take that into consideration, but that'll be a really big goal of ours may actually speak to the F. D. A we've seen really striking.
Anti cancer advocacy with this drug so far and we've also seen you know good strong evidence other potential endpoint.
Robert E. Martell: And, you know, we'll put all those data together, and the additional patients that we will now be able to take to the FDA, I think will help us in that discussion with them and ultimately come to an agreement in a population, for example, with splicephom mutations where, you know, the endpoints that we need to shoot for are likely to be different than what you might see in typical de novo AML, for example. Is that going to answer your question? It's kind of a long way. Thank you, Bob, for the really detailed color; we really have a lot to look forward to in January and beyond.
And we'll put all those data together and the additional patient that we will now be able to take to the F. D. A I think will help US you know in that discussion with them and ultimately came to an agreement and a population for example, this licensing mutations where.
The the endpoints that we need to shoot for are likely to be different than what you might see in a typical dinovo AML for example.
That answer your question, it's kind of a long prison yeah [laughter]. Thank you about for the really detailed kind of really a lot to look forward to in January.
And beyond [laughter] last question is can you remind us if you're.
Robert E. Martell: Last question is, can you remind us if your Phlyt 3 mutant patient can be Flit 3 inhibitor experienced, or do they have to be naive? They can be a split-3 inhibitor experienced. In fact, you know, the patient we actually presented at EHA had flip-3 inhibitor experience. So that patient had been treated with Gilteritinib and had absolutely no response to Gilteritinib, which is, you know, one of the primary split-3 inhibitors that are approved by the FDA.
She mutant patient can be be flipped three inhibitory experienced or do they have to be knife.
They can be put three inhibitor experienced in fact, he know the patient we actually presented at E was <unk> three inhibitor experience. So that patient had been treated with guilt written up and had absolutely no response to guilt written it which is one of the primary.
Three inhibitors that are approved by the F. D. A and then they came onto this study and had a dramatic reduction in the bone marrow blast achieved a P. R and you know done quite well so.
Robert E. Martell: And then they came on to this study and had a dramatic reduction in the bone marrow blast, achieved the PR, and you know, did quite well. You know, I think the important point to note here is that for patients who are on flip three inhibitors, it's been demonstrated that one of the primary mechanisms of resistance to those inhibitors is, in fact, signaling through TLR pathways and specifically through IREC 4. So, you know, the suggestion in the literature is to combine an IRA4 inhibitor with a flip 3 inhibitor. Well, fortunately, 4948 is the perfect drug in this case because we hit both IREC 4 and, click three.
You know I think I think the important point to note here is that.
For patients who are on slippery inhibitors, it's been demonstrated that one.
One of the primary mechanisms are resistant to those inhibitors is in fact signalling to T. L. R pathways and specifically through Iraq. Four so you know the suggestion in the literature is combine in Iraq for inhibitor with a put three inhibitor well Fortunately.
4948 is the perfect drug in this case, because we hit both Iraq for and put three so yes, we'll we'll definitely be open to both of those possibilities.
Unnamed: So, yes, we'll definitely be open to both of those possibilities. Got it. See?
Unnamed: Got it, so you'll continue to enroll for three experiences. Thank you so much for taking the questions and congratulations on the progress.
Got it so you'll continue to enroll for three experienced okay. Thank you so much for taking the questions and.
Congrats on the progress.
Thank you very much.
Unnamed: This concludes our question and answer session. I would like to turn the conference back over to the company's president and chief executive officer, James Denser, for any closing remarks.
This concludes our question and answer session I would like to turn the conference back over to the company's President and Chief Executive Officer, James dancer for any closing remarks.
James E. Dentzer: Thank you, Gary. And thank you everyone for participating in today's call. As always, thank you to the patients and families participating in our clinical trials, to our team that cures us for their hard work and commitment, and to our partners at Origen, Indianex, and the NCI for their ongoing help and support. We look forward to updating you again. Operator? The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
Thank you Gary and thank you everyone for participating in today's call.
<unk> always thank you to the patients and families participating in our clinical trials.
To our team make sure it's for their hard work and commitment.
And do our partners at origin any next in the NCI for their ongoing help and support.
We look forward to offer to [noise] excuse me, we look forward to updating your against them.
The operator.
The conference has now concluded. Thank you for attending today's presentation you may now disconnect.
[music].
Unnamed: and the I'm going to be the I'm going to I'm going to I'm going to I'm going to I'm I'm