Q1 2020 Earnings Call
2020 at this time all participants are in listen only mode. After the speaker's remarks, there'll be a question and answer session. If you'd like to ask a question. During this time simply press star followed by the number one on your telephone keypad.
If he would like to withdraw your question. Please press the pound key thank you.
As a reminder, this conference call maybe recorded.
I would like to introduce Mr. isn't Cattrall Paulo. Please go ahead.
Thank you Jamie good afternoon, and welcome to the Aptose Biosciences conference call to discuss financial and operational results for the first quarter ended March 31st 2020, I'm, Susan Tetrapod Communications representative for Aptose Biosciences, joining me on the call today are Dr., William G., Rice, Chairman, President and CEO Mr. Greg.
We Chow executive Vice President and Chief Financial Officer, Dr., Yodle, Ronko Senior Vice President Chief Business Officer, and Dr. Rafael They are they Hart Senior Vice President Chief Medical Officer before we proceed I would like to remind everyone that certain statements made during this call will include forward looking statements within the meaning of U.S. and Canadian secured.
These laws forward looking statements reflect aptoses current expectations regarding future events, but are not guarantees or performance and it is possible that actual results and performance could differ materially from these stated expectations. They involve known and unknown risks uncertainties and assumptions that may cause actual results performance and achievements to differ.
Materially from those expressed to learn more about these risks and uncertainties. Please read the risk factors set forth in Aptoses. Most recent annual report on form 10-K, and FCC and SEDAR filings. All forward looking statements made during this call speak only as of the date, they're made aptose undertakes no obligation to revise or update the statements to reflect.
It is after the date of this call except as required by law I will now turn the call over to Dr. Rice, Chairman, President and CEO of Aptose Biosciences Dr. rice.
Thank you Susan blocked and welcome everyone charcoal first quarter ended March 31st 20 Twond.
Although our prior conference calls was not even two months ago much has changed in a world since then.
For our update you on afterwards important potential impact on Cobras 19 could have on our business, depending how lucky express or heartfelt. Thanks to all healthcare workers are comparison to those were infected enter hope to all of you were saying and Hilton.
We are fortunate that aptoses not experiencing the full for some headwinds that many other biotech companies face.
We're certainly have halted propose phone clinical trials and others have experienced significant enrolled issues. The situation is unique to each company into each molecule treatment.
Okay. So as you know is developing CGM six and up from 2.3 to address unmet needs in hematologic cancers.
<unk> patients with hematologic cancers tend to be quite do Friedman of these patients was not elective. Consequently, our phase one clinical trials or can continuing to enroll despite recent events.
An important consideration for clinical investigators and prospective patients is that to date narcolepsy judo six nor at two to five three has been myelosuppressive and importantly during this pandemic. Neither has induced immunosuppression many cancer therapies voter approved and under development can cause immunosuppression.
Potentially elevating risk for patients in general, but even more so during this health care approaches.
Now, let's first thing to consider the potential impact of cobot 19 on C.G. Kum six or just some color.
We have addressed and continue to address challenges that could cause disruption.
We will called these cross winds if you will but thus far we have experienced no material delays in our ongoing b cell malignancy trial.
Our team proactively address these new challenges swiftly and appropriately.
Many safeguards and procedures to ensure the safety of our patients clinicians and employees at the top priority and accommodate the potential challenges due to cope with 19.
With 8.6, we're experiencing more cross winds rather than headwinds and that relates to the properties. If they don't suits. For example, they don't six is orally administered and we can ship bottles of capsules to directly to the patient, thereby reducing the need for paid for visits to clinical sites.
We also had enabled remote monitoring which again produces patient visits patients each received an iPad, which allows them to upload data and observations in real time and also reduces the potential risk of exposure to cope with 19.
This greatly reduces hospital for clinical Psych resources and the sites are appreciative.
We also can reduce the number of site visits by not requiring all of the typical once a week blood draws.
And by relying on local labs for additional safety monitoring.
We're also in constant contact with our drug manufacturers to assess and proactively avoid potential supply chain disruptions. Thus far we have not experienced any such disruptions in our manufacturing of drugs.
And drug product have actually accelerated.
One key adaptation is the fact that we know placing greater focus on enrolling patients from specialty regional cancer centers, rather than focusing on the large hospitals and academic institution.
This is because many of the large academic sites have emergency rooms, and infectious disease units treating cobot 19 patients and faced challenges to say to enroll patients in clinical trials.
In contrast, most of the regional sites are not treated cobot night Cobot 90 patients. They are both the bandwidth to enroll and a lower risk of infection cancer patients coming into their claim it's such an taishan represents a rapid pivot that has served us well and based on our anticipated enrollment rate we continue on.
Right.
Regarding an update on April six development. This is a distinct clinical assets compared to most other therapies that are commercialized are under development.
Many of you've heard this before but for those of you haven't it'll six is much more than a typical split three or BTK inhibitor. As it is not only inhibits wall type and mutant forms of BT K three good potently and simultaneously suppresses multiple oncogenic signaling pathways upon which cancer cells rely for survival.
Drug resistance.
A singular compound targets the primary drivers a b cell malignancies, and acute myeloid leukemia for email, including be Teekay <unk> threed, yet with the precision that avoids known targets that are often associated with toxicities.
It is unparalleled tonic selectivity profile, that's it it'll six apart from other hematology drugs on the market or in development and what is contributing to much the excitement surrounding the compound.
Now, let's focus on our phase one study aveo six the treatment of patients with B cell cancers, including CLL and non Hodgkin's lymphoma or just in nature.
And today ill speak about dose levels, one through four that involve the administration of 150.
304, 50, and 600 milligrams to be I'd, respectively.
Since our last call. We successfully completed the third dose level with 450 milligrams and on March 27th our cohort Safety Review Committee unanimously supported escalation to the fourth dose level was 600 milligrams.
Also we are pleased that the first patient dose on this trial, who began at a dose level. One receiving 150 milligrams has completed 10 cycles that that dose level and now has been dose escalated to dose level, three and receiving 450 milligrams per protocol and that patient is performing well.
Following completion of dose level three we quickly commenced patient treatment on dose level for work with 600 milligrams to date, even at these higher doses.
I do six continues to be well tolerated.
Now, let's discuss a few details of the patients already enrolled in the study cohorts to date.
The very first page not us it.
On a study at 150 milligrams. This patient has CLL with an L.L. phenotype.
At that dose level, we achieved steady state exposure level in the platinum of approximately 0.1 marketable.
Steady state represent the minimum level observed in the plasma overtime.
Importantly, we collected plasma from Asian, and tested in a plasma inhibitory activity or P.A. assay.
With that.
Yes.
We first click the plasma from the patient returning to our lives and placed on reporter sales.
After a few hours, we use western blotting to determine if there is sufficient drug in the plasma to inhibit the phosphorylation of key Baltimore.
Including BTK ERC, PDGF, our alpha and sick and that is spelled as why do we.
We observed that wants to patient achieved steady state plasma levels. They go six the platinum inhibited all of these pharmacodynamic markers in the <unk> assay.
And that's with dose level one.
At the second dose level, we placed one CLL patients on study with that CLL patients, we observed a rapid and dramatic lymphocytosis indicated that a pharmacologically active exposure. They don't six had been achieved.
The second or effect its classically described as a response to the inhibition of BT Kate.
Concurrently we observed 100% inhibition of phosphorylation Ob decay in the Pbmcs from depletion patients bloodstream.
Moreover, steady state levels Aveo six approach the one macro moeller range.
And the P. I say revealed that levels, if they don't six in the plasma we're capable of fully inhibiting the phosphorylation of BTK sick, Kirk and PDGF for Alpha and the report ourselves.
After evaluating the data from dose level to 300 milligrams, we moved to dose level three with 450 milligrams.
Which we enrolled and completed the 28 day cycle with two Follicular lymphoma patients and one at they'll they'll patient.
As a result, we completed that dose level and collected the necessary data quickly and safely.
Although we will now discuss the data quantitatively at those data are now embargoed perk up for presentation at the conference in June we can say that the drug was well tolerated the steady state PKD levels were well behaved and in the circa one marker mower range and that the levels of Ito six in the plasma inhibited the expected piece.
Markers in the P eight assays.
After a successful completion of the 28 day cycle with those three patients at the third dose level with 450 milligrams, we didn't escalating dose level for on which the patients would receive 600 milligrams. At this time, we continue to dose in this cohort and 8.6 continues to be well tolerated.
Well, we're quite pleased with the findings thus far dose levels three and four.
We once again more remind you that we were unable to share and Bargoed findings from these dose levels until the hawk offerings.
Provided we successfully complete 20 dosing of three patients at the 600 milligram dose level, we plan to dose escalate with three patients at 750 milligrams and 900 milligrams to ultimately determine the recommended phase two dose for patients with B cell malignancies, depending on the clinical activity in specific sub groups.
And this dose escalation phase, we may enroll up to 100 patients across four expansion studies.
Our Chief Medical Officer, Dr. Raphael base.
Recently presented a summary of data from patients on the first two dose levels during that you see our virtual for.
Note that the press release in corresponding slides are available on our website.
The conference format was a bit amended from life to virtual and we were unable to deliver the the de life oral presentation that reads. We originally had been granted so we utilized the five minute virtual opportunity to summarize data from the first two cohorts for medical professionals and to indicate that we continue to dose.
Lastly success.
As I noted earlier, we look forward to presenting a more complete picture of the pharmacokinetic and Pharmacodynamic profile of the higher dose levels at the European Hematology Association also known as U haul meeting in June.
Which will also be a virtual meeting and at Ash later in the year as of today, we have 21 U.S. sites open for screening and enrolling patients for the study with additional sites scheduled to come onboard.
For more specific information on the B cell malignancy trial, and the clinical sites enrolling patients. Please visit clinical trials dot Gov.
Now, let's move onto the application of six to patients with a mill, we spoken before about our rationale for the email study and the K will support behind it. So I'll update you briefly on the status of this plan study.
They don't six is the only BTK inhibitor that also person possess a strong three inhibitory activity, giving a broad therapeutic potential across the hematology spectrum, including both lymphoid and model would malignancies.
Based on our extensive preclinical work it has always been our intent to treat ammo patients would take those six in addition to the B cell malignancies.
As you May recall back in 2017, we had applied for and were granted orphan drug designation for Eagle six by the FDA for the treatment of patients with email.
At first glance emails appears to be a competitive market with recently approved drugs and others on the ROI horizon. However, none of these approved Asians agents offers cures in in among themselves.
Paul current targeted therapies may initially show some clinical benefit eventually most responders relapse and become refractory to such treatments.
We along with a growing number of investigators and industry experts continue to believe that you'll see it is clearly distinct from other agents on the market and in development and it has the potential to serve as a transformational agent for multiple hematologic cancers, including ml CLL and others.
So far the big question has been what dose level will we recommend for the starting dose with a male patients.
To answer this we must consider the data in their totality that we have glean from our clinical study in patients with B cell malignancies, we must choose a dose that first it's safe and well tolerated in humans that has achieved plasma exposure levels that we believe can inhibit fossil fleet threed and other key Connor.
She's operative in a mill.
That can kill AML cells, and that correlates with potent efficacy and animal models of email.
As I mentioned earlier, all dose levels, thus far up to 600 milligrams had been safe and well tolerated. So that takes care of the safety consideration.
Also already we have observed what I'll call circa one mark from older steady state plasma levels at the 300 and 450 milligram dose levels.
Plasma exposure level inhibits fossil fleet.
And other relevant target in the <unk> assay and that plasma exposure level is in the same steady state steady state exposure range that led to a mill cures in mice and without ins or toxicities.
Overall based on safety pharmacokinetic and Pharmacodynamic data from patients in the ongoing phase one a b study in patients with B cell malignancies. We now have identified what we believe can serve as a therapeutic starting dose for the treatment of AML patients.
We're in the final stages of preparing to new I, Indeed for submission to the FDA sequel, and wants to initiate the clinical study aveo, six and relapsed and refractory AML patients I want to point out that is not the same as submitting an R&D for a new agent that has never been in humans.
New R&D for April six will consolidate all preclinical data as well as the safety Tolerability PK PD and pharmacologic activity findings gathered to date in patients with B cell malignancies. Thus this requires more time to prepare than the first in human I'd, but we are her heartened by the data and we.
Look forward to submission of the findings to the FDA and we hope to move into AML patients as soon as possible.
Finally, our clinical team has identified and is working closely with top tier institutional side Pan regional cancer treatment sites to initiate the new any mill trial.
All of the features that are mentioned about 806 before that it is oral that is well tolerated and that we can remotely monitor patients make us all parts and optimistic that the FDA will allow our I'd. So that we may begin dosing elmo patients.
What we believe may be a therapeutic dose.
To wrap up on April six with some additional precautionary measures because of cope with 19 arena, we have already made significant progress in 2020.
We look forward to reporting on our progress on the ongoing phase one it'd be study in CLL b cell malignancies, as well as to perspective email trial throughout the remainder of this year.
And now on to Upto, two five htthree or just to fight through our second clinical candidate and it first in class Mic inhibitor currently in the phase one of the trial for patients with email and Mds as many of you know the Myc oncogene is a major driver of cancer, So flip operation.
It's express is estimated to be elevated up to 70% of human cancers, including a AML and Mds as well as solvent.
Per our phase one clinical protocol to five three is being administered once weekly over 20 big cycle at ascending doses in patients with relapsed or refractory mill or high risk Mds until a maximum tolerated dose has reached the study is designed to then transition as appropriate to single agent expansion cohorts in Hmm.
In Mds.
We have completed the 28 dosing in the 28 day dosing in the first three cohorts, but less being three patients on 66 mics per meter squared dose.
Well as one patient thus far in the fourth dosing cohort of 100 mics per meter squared two fivethree continues to be well tolerated with no models friction and we continue to observe mic inhibition that all dose levels to date in this phase one trial, we continue to learn a great deal about the molecule. We're encouraged that we continue to observe.
Nick inhibition.
Toric Lee difficult target modified clinical.
The trial to continues to be open for enrollment and we continue to learn what to expect clinically about two fivethree and are making decisions on how best to move forward with the molecule. We may consider dosing more than once a week. We're also pursuing preclinical studies and other cancer indications, including solid tumors. In addition, we.
Working on an oral formulation of the draw.
Because to par three is administered to patients intravenously, which requires the need for hospital or clinical site resources to assist and monitor patients during each infusion. The cobot 19 environment may have an impact on future enrollment of patients.
Because of the activity and safety. We've noted thus far with 2.3, it remains a viable candidate and our pipeline and we look forward to keeping you apprised of its progress I'll now called turn the call over to our executive Vice President and Chief Financial Officer, Mr., Greg, Joe who will review the results at the quarter Greg.
Thank you Bill and good afternoon, everyone. We ended the quarter with approximately $90 million in cash and cash equivalence and investments compared to 97 million at December 31st 2019.
During the quarter, we utilized approximately $8.1 million, the cash and operating activities compared with 4.9 million for the same quarter last year. The increase is attributable to increased activity surrounding to slide three and 86 in general and administrative purposes moving onto the income statement. We have no revenues for the quarter research and development expenses were $5.9 million for the quarter compared to three.
Three for the same quarter last year. This increase was primarily again due to CDN six.
Activity, particularly the clinical trial, which did not begin until Q2 of last year.
Operating expenses for the quarter were 5.9 million compared to $2.3 million for the same quarter. This variance is primarily due to an increase in stock based compensation finally, our net loss for the quarter. It was $11.5 million or 15 cents per share.
Before I turn the call back to Dr. ISO one dimension that we entered into it and you at the market ATM agreement for $75 million with Piper sender and Canaccord Genuity as co agents. This ATM replaces the previous one we had with than last year, which we terminated in conjunction with the $74 million public offering in December.
Although we have sufficient cash to fund our planned operations and 19 to 20.2, and we don't plan to utilize the ATM anytime in near future, having an ATM does provide a strategic indexing flexibility and extending that runway.
I'll now turn the call over that conduct race.
Thank you Greg.
I'll remind everyone on the line that we also have with US Dr. Jody Morongo, our chief business Officer, and Dr. off LP Hart, our Chief Medical Officer.
We open the call for questions feel free to pose questions to any of US operator, if you could please introduce the first question.
Thank you.
First question comes from Tyler Van Buren Hyper Sandler Your line is now open.
Hey, guys good afternoon, and congrats and all the progress in such a short period of time.
I guess the first question is of course on Ido, six and 12 malignancies with respect to dose level three can you just clarify.
You stated that it was.
One.
Microliter.
Exposure levels and so.
Specifically, how consistent was that among the three patients and then a dose level for.
Anything you could say with respect to initial.
Alright, Hi, Todd Thanks for coming on.
With regard to dose level three it was we had achieved.
The I'll call it the circa one my promoter microcontroller plasma exposure levels.
Some you know you have a little bit of chatter around.
Around the the patients over time somewhere a little bit below one mark from older somewhere a little bit above.
Yes, we.
It was the pharmacokinetics, we're very well behaved they were all in that one macro moeller arranged and we were thrilled to see that and it was very consistent among the three patients in terms of dose level for again, we have to be careful study.
In terms of the patients that are on there as I mentioned, the it's been very well tolerated, we're very happy with what we're seeing in the patients that are on the study but the.
Any pharmacodynamic in farm logic parameters at this point.
I have to wait for.
And perhaps understood documents.
Dr Bay harm may want to head of it today.
No I think you did a great job characterizing that behavior. This patient index level three.
I have nothing to add there.
Thank you.
I guess since you can't state the levels I guess could you just say you know if you expect the increase in our plasma exposure to be linear throughout the dose cohorts or or potentially.
To be more exponential as we get into higher doses.
I really can't say at this point, we do not have the PK or BD.
Steady state levels from dose level for at this time, so it's very difficult to making your judgment on that.
Several one and dose level two were only one patients and so the one where we have the greatest confident the dose level three where we have three patients and they were all within the expected range.
So we'll be able to provide a bit more data on that we get into it.
But again, we just don't have the PK PD data yet from dose of before.
Understood and.
And now you identified initial dose but.
Didnt state, which goes.
Would be weather.
Level three or four.
Or even potentially too as you referred to with the 300 450 milligram, So I guess.
It's possible, but maybe you dropdown of use dose level to as a starting dose and when could we learn of what the starting doses, but you guys used to their miller for wafer I'd be approval.
What I will say is we are recommending a dose that is derived from a cohort that had been completed.
We are still in dosing cohort for so that nerves it down to the other cohorts.
What I also would say is based on the exposure levels and the Pharmacodynamic and from pharmacologic activity that we we saw in those two dose levels either dose level to four dose level three could represent starting doses I would feel comfortable with either of those and so we are making the recommendation up to the FDA based.
On all the the totality of the data and.
Thats, all being written up and we're trying to get it in within a matter weeks and submitted to the FDA.
Okay very helpful. Thanks for taking the questions.
Thank you.
Thank you and our next question comes from John Newman with Kim Accord. Your line is now open.
Hey, guys. Thanks for taking the question and.
Congrats.
Chris.
So bill just wondered if you could give us a sense as to.
[music].
Type of data and the.
Cohorts that we might see it he ha I don't I know that's you obviously, you can't talk too much but it but just generally speaking I wondered if you could.
Maybe describe.
Fit for us to.
Just the type of.
Issues might see there.
All right John Thanks for coming on so we've been very consistent about this and we want to make sure everyone understands our guidance.
Our guidance is that we plan to present safety PK and PD data Pharmacodynamic data from cohorts one three cohorts.
Yes.
I believe the required submission date.
Four abstracts to to be uploaded 2027 of the model of me.
So we're trying to collect as much data as we can at this time, especially as far as we came through cool work get those data clean valuate them and then get them integrated into a into the posters if additional data come through after that.
May 27 days between that and the time that we presented a hot then we would likely have to include that.
Such data there in a in a press release, but those are the types of data were telling people don't expect to see response data. We're just now getting into the higher dose levels, we're getting into the right patient types that we want to see and possibly get responses, but it does take time, we're seeing everything that we're hoping to see at this.
But it can take a couple of months, where you start seeing or spot in chronic.
B cell malignancy patients once you achieve these hard.
Perhaps gray.
Okay.
John Sorry, and just one additional question, which is could you just.
Remind us.
The way that the CHF six study was designed could you just remind us of the time that the patients.
We're on a specific dose before the next cohort and role I'm, what I'm trying to get at Harris.
Just that the amount of follow up time between the dose escalation I think is relatively short and I just wonder if you could.
Explain that to people. Thank you.
Yes. So for instance, cohort three we had to place three patients on that study all of them had to complete the safely and successfully complete a full cycle, which is 28 days now if you could enroll all three patients on day, one than it would only be effectively a month of dosing and then it takes weeks to collect all the.
From the clinical sites monitored the data ensure the data or accurate that PK PD safety data.
Present, those data into the CSRC clinical safety review committee. It can be several weeks. After you complete the dosing of retained a stock.
When you have the data presented to the CSRC than they have to vote move up to the next dose level. So that gives you a sense and if you could get all three patients on day one.
Clearly would.
Accelerate the timelines, but that's just not the way it happened in lease.
Escalation Charles you May get one immediately it may be a week or two before the next from the week before the next week, we actually look at many patients, but they have to 50 inch of entry criteria.
And not be excluded because of the other data there are often patients that we see that we'd like to bring on but they have to be excluded because of their disease status.
So that just gives you a sense of what it takes and the other thing I'm sure you're trying to get us how many scan for we have on some of these patients and.
And try to provide a little bit more guidance on that as we get closer towards E off.
Some of these patients that had been on for a long time patient one as I said completed 10 cohort excuse me 10 cycles at the first dose level, they've now moved up to dose level, three and it's going to be squeaking to try to get to scan in there we will try but there's no guarantee we can get to scan in considering the coven environment before.
Eat all we will try the same is true from dose level, three and dose level for hopefully we can sweep couple in before that.
But there's no guarantee considering the coven environment that will actually be able to get all those scan.
And Bouchie, we will do everything possible to do so and to to then be able to represent those data at.
Let me see if any of the other.
He may want to add anything to that Greg Jody.
Yes, I guess not.
Alright, Thank you John.
Thank you.
Yes.
Thank you and our next question comes on Gregory brands Love with RBC capital markets. Your line is now open.
Hey, guys. Thanks for taking my question and congratulations.
On the progress and gone glad to hear then all as well the team even team I'm in this environment.
Yes, Bill and team just stay connected to the two environment and I appreciate the color on.
He met expectations coming into land to eat into June and I'm. Just curious if you would have the ability to land.
At least touch on or anticipate some of those expectations at the six trial progressive toward the back half of the year and as you want to talk about getting to sales levels, where we would.
Perhaps see responses and looking at what has been a disciplined disclosure plan. How you think about that this environment affecting or maybe even greater rate and getting the color you provided on on and how you're sort of cross when thinking about the impact pure about them how disclosures could look at the back half working here with respect to trial.
Thanks.
Alright, Thanks, Greg will do.
Yes first of all it reminds me so I can see all you got sitting in New York City roll thinking about your hope everybody is safe there.
Regarding the expectations as I've just described for you all we've been consistent all along with what we expect to be able to presented email and that's in June it's coming up very soon.
But as we get into the second half the year, we expect to be able to present additional data, especially at ash at the ended the year. We hope by then that we will that had the correct types of patients on the higher doses doses long enough to see responses.
Again, we're seeing everything that we hope for.
At this point, except that we need to have the patients on longer to start seeing those responses and again, we hope to be able to present true responses.
At the Ash later this year and you've seen this with other Kobe <unk> non covalent BTK inhibitors. It just takes time, especially for these deeply relapsed refractory patients takes time for them to to show responses. Even if you were to get lymphocytosis earlier on it still takes time for that scans to show.
So when you only scanned the patients every two cycles. So thats two months apart and only then are you able to tell whether or not they truly have a response.
So that speaks to the B cell malignancy trial for the ml as I mentioned, we want to get that trial up and running as soon as possible, but we've been able to collect all the data that we need from the ongoing b cell malignancy thrall all of those data are being now cleaned and put into into the new R&D for the ml study the perspective.
Mel study, we want to get that get it submitted to the FDA as soon as we can again, we have the 30 day turnaround because we have orphan drug designation, we hope that in today's environment that the FDA will be able to turn to ground in 30 days I commend the FDA. They have a lot on your plate, but they've actually done a tremendous job.
We've been in contact with among other activities.
Bob.
Progress reports annual reports and so we've been.
A protocol amendments so we've been very pleased with the turnaround time, but there's just no guarantee going forward.
We will get that study up and running as soon as possible and you have to remember the AML patients. That's that's an acute disease. If you have truly a therapeutic dose that hits split three we would expect to start seeing some effects within the first month of dosing and hopefully by the second month you start to see some once you can consider.
To be responses in the bone marrow as well as to peripheral blood.
So that speaks to the second half of the year, what would be able to hope to be able to present.
In multiple patients with email toward the ended the year at ash.
Keep your fingers crossed that we'll be able to get everything through the FDA, we're working with a variety of clinical sites major institutions as well as we said the regional sites, we want to get those patients on and again as soon as we started dosing. We believe it will be a therapeutically active dose and they should be three patients at the dose level.
One other thing that I would add I forgot to mention earlier.
We do however protocol amendment for our B cell malignancy trial that will allow us to.
Backfill patients into earlier dose levels, if we choose to do so.
Good case, where you might want to do that is when you've completed one dose level to three patients you're waiting to click the data and get the CSRC to move up to the next dose level. So before you can move patients next dose level, we might consider backfilling. Some on the prior levels and also we will try to keep moving patients up.
To the highest dose level, we can so for instance, we moved up patient one up to dose level three when we complete dose level for assuming we complete it and it's safe we'd want to move up all patients on dose level, one and dose level three to dose level for so those are the types of activities throughout the rest of year.
Thanks for being that force Greg.
All of it.
Thanks, and one more question if I may.
Just as far as I've covered 90 potential impacts and I'm. Just curious if you could remind US you had mentioned in the past healthy volunteer trial may be to characterize frame PK PD more fully I'm. Just curious if there is how that fits and if theres any impacts we should be thinking there and what you clean from that how important that is.
And cut to the overall program. Thank you very much.
That's actually an interesting question. So we described is these as cross winds rather than headwinds I think is Greg child that came up with the analogy and with the scope of 19 out there what it means that theres. So many additional challenges we have to address so we're still able to fly the plane. It may be just in little few different.
Changes in direction to get where we need to go but we're still maintaining on our original timeline plan.
And as opposed to a headwind that really pushes you and hold you back.
So at this point, we don't see the the cobot 19 necessarily.
Uplift leased at this point dramatically influencing any of our timelines we're still on plan in terms of the healthy Volunteer study. We were originally considering doing that study so that we could get additional PK data, but as we were putting that together we realized we were getting plenty of the PK data both from the B cell malignancy try.
Well as well as the upcoming email trial, we should be able to get all the PK PD data that we need and so there is not the need to perform an additional healthy volunteer trial. It doesn't really added anything Additionally to us at this time, we believe we can get all the data that we need from the current drops.
Does that answer your questions adequately.
It's shared a super helpful. Thanks, Phil and congrats again on the progress.
Thanks, Chris.
Thank you and our next question comes from mapping clear with Oppenheimer. Your line is now open.
Hey, guys. Thanks for taking my question.
My Congrats is on the progress Phil for that you had dataset.
What are some of the other important biomarkers in addition to possibly T.K. and evidence of lymphocytosis that you think we should be paying attention to.
Well the lymphocytosis is you would only expect to see that in some CLL patients. So for instance, if you haven't seal opaque comes in with a reasonable.
Load of malignant cells in the bloodstream, then when you start treating with an active BTK inhibitor you could expect to see lymphocytosis. So that is something that we definitely are watching for you should watch for that around the timeframe.
As for the responses again to get a response you have to look at the scan and the timing of that is very close we're going to do all we can we hope to be able to see responses, but again don't expect entity off.
What else would look for is in.
But let me back up so we talked about lymphocytosis, you don't expect to see those and the other types of patients. So flicker lymphoma patients deal Bcl Asian, maybe even richters. So you don't necessarily expect to see them up toasters and those or even the L.L. patients because the low load in the peripheral blood.
But we would hope to see it from the CLL patients. That's why it was important for us to get us CLL patient on very early that was dose level too and then also.
In these current dose levels and going forward, it's important for us to get those types of patients going forward. So that we can show you. These types of activity. We also want to be able in particular to collect pbmcs again from CLL patients.
Why because if you're trying to click nor pbmcs from patients that applicant or foam on some of these other lymphomas you don't necessarily get a picture of what's going on in the malignant cells, but if you have CLL patients that have reasonable load of CLL sales any dose patients you very often can pick up enough.
Of the signal you can see inhibition of Bostco BTK.
Using analyze the assay and that is in the Pbmcs and we actually showed that in dose of for demonstrating its pharmacologically active. We also have been able to demonstrate that we inhibit these other.
We talk about our drug inhibiting multiple key kind exists in these key oncogenic pathway. So of course, we talk about sick syp and BTK and down in downstream of BTK you want to look at ERC, we've been able to show we inhibit those fully in the dose level so far.
Hey, Jeff our Alpha is another one that we want to see if a cell surface receptor, we want to make sure that we see that we're turning it off as well as some of the interest rate or kind of in that P. C and we've been able to show that as I mentioned in dose levels, one two and three.
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One of the other thing that you should look for but we haven't spoken about it yet that much is possible flipped three.
In order for us to move into ml, we have to confidently say that we believe in this peiyi assay that we can inhibit also flip three so that gives you a since we've seen that and I'll just say we've seen inhibition of also fit.
In our assay that gives us confidence that we can inhibit not only is it possible flip three it's also a wild type also flip through that we're able to turn off and that even more difficult than the flip three ITD. So that gives you a sense of what we're having to look for not only the safety.
PK levels, but the PK levels will show those data.
What we know is that the locals we are already achieving.
Above the levels that required to get complete cures in animal models of the mill. So all of this in its totality gives us confidence to move forward does the TBSA data will be able to present.
And thanks, great that coming off.
You Tour in New York and Hope you Tursi, thanks for joining.
Absolutely. Thanks, Thanks for taking my questions.
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Thank you. Our next question comes on the Jason Mccarthy with Maxim Group. Your line is now open.
Hi, This is actually marine on for Jason Thanks for taking my questions.
So I guess I have a sort of a devils advocate type of question regarding your PIH airfreight.
Hi, initiate our fixed study in CLL is there any concern that the degree of.
BP inhibition that you're seeing that it shows a 100% inhibition say.
Isn't exactly indicative of clinical activity in the body that it may not capture levels of BTK inhibition throughout the body.
I guess I'm actually asking because if you look at one competing BTK drug that's a bit more advance which showed complete inhibition that early doses and yet up to now they haven't quite it hasn't quite translate into clinical activity. So.
I guess I guess my question congressional yes, how confident are you in the clinical applicability of this asset.
Oh, Great question, because you are preaching to the quarter I have I've addressed this on many occasions.
Inhibition of fossil BTK indicates that you are hitting farm Bart your drug as pharmacologically active and you are hitting a key component.
But inhibition of the T.K. does not kill the CLL sells it just changes the the homing device so be teekays responsible for maintaining those sales in the limply tissues, the the lymph nodes to spleen.
And it keeps them there when you inhibit BTK that changes the home so that the cells now leave those important issues going into the peripheral blood for they have a tendency to die and if you maintain that activity over long term then the patients tend to respond but the BTK inhibitor itself is not killing the sells directly.
So other companies you've seen this lower dose levels, they will see inhibition of fossil BTK.
And it may take two or three or even for dose levels above that until they start seeing responses.
Particularly in these relapsed refractory patients. These deep failure patients why is that most because BDK is not enough just inhibiting BTK and those patients is not enough. They have other pathways. Other kinds pathways that are activated additional mutations so one of our competitors, yes, I think a dose.
So before they have complete inhibition and BTK, but it was dose level seven or so before they actually showed responses. They had to continue increasing their dose levels to begin hitting those other kind a says before they started seeing responses. So you're skepticism is very it's founded in reality and I agree with you.
The difference here is we can already tell you we're not just hitting BT Kate we're also inhibiting those other kind exists. So some of the other molecules were more potent against BTK and less potent against the other counties. So they really had dose escalate to inhibit the other ones.
Hours has much more of a a similar activity profile in the peak I'm older load animal range against these these key kind of cases that were inhibiting I mentioned three BTK PDGF, our alpha ERC sick all of these.
We're inhibiting all of these at these dose levels, so that should give us more confidence as we show that we inhibit these multiple kind of exit that should translate into efficacy.
It's more difficult to predict that in B cell malignancies, but based on the science and the medical observations to date, we should be able to see responses overtime and we do know that in a mill. If you have an active inhibitor split three that is known it is sufficient to give responses. It is not sufficient.
Over time to maintain responses you need other tiny exists and also the different forms of three but if you have an active flip three inhibitor. It is confirmed that you can get responses in these patients, perhaps dr. be harder ore dr. morongo want to add to that.
Yes, Thank you Bill and thinking arrangement. The question Bill captured very well the the application and the coverage of these targets they PIH hi names.
Activity at the one thing I was going to add is.
Perhaps just highlight again some of the differences between the indications when you apply this assay and CLL question and now.
Specifically in AML direction now that we have ahead of us and later this year.
In addition to roughly three in this assay is a surrogate for clinical activity, we've actually seen this and.
Previous drug trials, and P. acetate publish from storing and get to written it back from the phase one appeal to read.
Leaner all that seem to be required in the same patient was just about 85% or more in addition, actually three activity and those were the patient Denmark response.
Johnson Rice said, it's efficient harder response that slipped three in addition, and that is in contracts entered BTK in CLL wont be teekay necessary, but not entirely sufficient or need to hit the cytokine Heath is which coincidentally we do.
And I know, we also have at one of the Myanma late disease experts on the call it sounds to be horsetail outflow.
The pass it to him if he has an extra cost.
Look the other important get an important point to make is that when we're doing these assays were using a reporter cell line in the laboratory cell line doesn't mimic the tissue architecture in the supporting hovered around it so you're right. It is actually easier to inhibit does markers in these artificial cell line reporters and it isn't the patient.
But we also have the ability to take sales from the patient whether they be normal peripheral blood mononuclear cells and look to see if the activity. These athletes inhibited by the level of drug that's in there plasma. So we that's additional data that we're collecting on the steady that hopefully will give us a better insight about what these drugs are actually doing mechanistically inpatient and I agree with talked Mancos point.
About and now that AML seems to be more straightforward in terms of its susceptibility or rich addiction to that activated oncogene and when you inhibit.
Three activity you see a rapid child that which is why we see more rapid response is in this patient population.
As Decorates mentioned, that's not sufficient that there are mechanisms of escape and either new or immunogenic or have to do with gene expression regulation that can quickly come into play. So you need to have a little broader activity against other potential salvage pathways in order to have a lasting result patient population.
That's really helpful from all of you. Thank you so much I just have one more follow up question.
You mentioned that there is.
One patient dose level, one that was.
At the point that Weve been moved up to that their dose level.
I guess first yes, so my own sake, how would you count this patient now as part of only the first cohort or would you count this patient as part of both you know the first and third and perhaps can you talk about the rationale for moving from him or her up to that they're down. Thank you.
The answer is yes, there would be considered part of one and part of three.
So I'm going to ask Dr. Bay hard to address why you would want to have moved them up to the higher dose.
Sure so getting back to the same point the decorations, making with your prior question. We think that it's important to hit not just BTK, but the other enzymes that are essentially compensatory short lots at the Teekay activity and we know that we're going to have different sensitivity to be different enzymes to different about the drug to patients thats on a dose of one.
50 milligrams twice a day for example, where we show inhibition of UK.
May need higher doses in order to achieve the addition of other compensatory pathways. So if the drug is being safe.
At that higher dose level I think we improved the likelihood of patient might have a beneficial outcome. If we're able to dose escalate come to that level. So that motivation to do that is to help increase their chances is having a good outcome. It does also give us an opportunity to learn more about PK and PD activity in that patient and ultimately.
This is something that the patient also is interested in doing.
In the hooks in achieving a better response.
Yes, so I think the a good example of that is one of our competitor companies that purchased by another large company this past year.
They they moved up patients from the lower dose levels up to at least 65 milligrams and the 75 milligram patients down to 65.
So they selected a dose level at which they felt was was efficacious and non non toxic and at that point up leave no maybe not fully correct, but I do believe that is the only dose level at which they they demonstrated to yours. The responses in the b cell malignancy patients. So again.
Even if they're on the lower dose levels doing well hitting certain timings and move them up to those higher dose levels because the burden is upon us to make sure that were given the chance. These patients the best chance to respond and to do so safely and you need to give them as much drug as you can as long as its safe and well talk.
I'll into that.
Thank you. Thank you for the color that's all for me.
Okay.
Thank you. Our next question comes from Matthew Cross with Jones trading your line is now open.
Hey, guys. Good to hear from you and appreciate you addressing some of the key questions out there, but beyond that the Cgeight hundred six ml program with this call I'm just a few questions for me I guess first of all being I am glad that you were very clear here about kind of the expectations for Nash.
And just wanted drilling a little bit about.
Related to that comment you made in your introductory remarks about kind of expectation of a reduction in blood draws as a result of the cobot situation.
I was curious to get kind of a little bit more insight into how that reduction in blood draws that may have already have have started and going forward may impact the the PK evaluations.
And at Ash.
Given that Youve stressed it, particularly the hot PK PK PD and safety will kind of you. The most important things to look at I'm, just how that may impact the data flow for that for those amounts.
Alright, Thanks, Mike.
Bill again so.
What we wanted to make certain is that we're collecting all of the blood samples that really tell us the picture of what's going on.
Good example is we've shown previously that by day eight all the patients achieved steady state. So we would make you want to make certain that we get all the dose.
All the blood samples throughout day one.
The beginning of day, two and then day eight.
So that we understand the initial pharmacokinetics on day, one as well as Dan hitting the steady state we didn't have been collecting it day eight.
15, 22, and then at the end of the cycle cycle two day, one which is think of it the 29.
So that gives us all of the steady state, but what we've decided is well we can miss maybe a couple of those in between presence. They 15, we can live without that proven day 22, if we had too. So we're trying to minimize the burden on the patients and then coming back into the sites. We're trying to make it so that if possible. We can go out and have someone draw the blood.
Remotely or they can go to other sites to have them drawn if they can't get into a clinical trial, but we're we're we're certain that we can have.
An understanding of the steady state pharmacokinetics of these patients which is what we really want to know it's that minimum dose minimal exposure level, that's critical to achieve and maintain to to continue pressure on the so on these counties in the patients.
So those are the main point, so we're still collecting the the samples for the Pbmcs on day, one we're going to actually try to come to collect those that also it later times. So we can get a better read on what's going on in also be decay in the pbmcs. So we may we believe we're going to be able to provide all the needed data.
Correlate PK PD relationships.
Adequately answer your question.
Yes, it did thanks, but thats great insight.
And but it sounds small vehicle to me as far as the handling of it prior to this is a clean read outs I.
I guess had kind of a two part question then as a follow up on on a male and that program beginning I know we're early days and this is still a discussion with the FDA, but just trying to get a little bit of.
More color around your expectations of what you're putting forward to the agency.
I guess, it's kind of two parts like I said here.
One wondering if you're going to intend to focus on patients or from an accretion standpoint, or maybe just from a certification standpoint.
Enrolling patients based on what three mutation particular flipped through mutations there and I know you've shown evidence across and across the board within put three.
But is there is there and intend to focus on AML patients broadly in the dose escalation portion or to focus on these put through mutants.
Whichever forms those may be.
The second part was free and in particular, you've been very prudent I think to not begin testing and patients.
But dose you would expect to be to some degree efficacious, but because of that I'm sure. You're also eager to begin testing.
In combination with another clocks, where I know you separate preclinical synergies maybe other agents. So just curious what you hope to kind of see from the Cgeight hundred six monotherapy in initial dose dose escalation at prior to moving it to into combination testing to really drive it at best outcomes as we're going to beginning to speculate about what we may see from from the initial dose escalation.
All right, let's if I can get through all of those happy to repeat cutting if any do you know thats uptake.
So for the first part you want to know what types of female patients we want to bring on this trial. So in effect. We are mutation agnostic. So we're not going to differentiate among the patients based on the genetic background of patients we effectively want to have all comers, having said that we'd love to be able to get some fleet three ITD patients on.
Early because those likely would be by far the most responsive very quickly. So thats something that we would hope to get on at the early dose levels or early cohorts. Among the first three patients we would try.
But we're also eager to show that this drug should be active against those patients as well as patients.
That have wall type split three various other mutations in Flint three patients a P 53 mutations rast mutations all of these types of patients in particular ones that are now resistant to other fleet three inhibitors, we'd like to get those on now it may be that we try to push some of those to the higher dose levels, where we think maybe of so we'll be more effect.
But we just have to see how effective it is at the the entry dose level here.
But yes.
To answer your question, we want to put value on the molecule soon as we can get it in this what we believe or some of the most since the patients, but we are going to go after all these patient populations within that study.
In terms of.
We've spoken that we want to test this drug in patients with a mill with Mds single agent and in combination.
Order to try to get this study going as quickly as we can we're going to focus immediately on AML patients and single agent. Once we get that lined up then we would likely come back and expand to Mds patients because we believe our drug the active there and then also to then began also the the combination studies.
So what I'm going to do is I'm going to ask dr. be hard to address those and give some of his thoughts on that because he is also the expert on Mds.
Yes, Thanks, Phil Hi, as usual Youve already answered the question that lead me to follow up so.
Exactly right.
We do have an intense to look at the activity Cdsixteen Mylan malignancies beyond AML and Mds in particular given that the.
Relationship, it's biology to AML in general and in the short term, we wants to get the ammo study up and running did the dose escalation understand how they started performing in a patient population and then go and expand to other indications including mdx.
And consider combinations with drugs like the networks for example, where we have certain preclinical data and shared for.
I think it certainly is that population that has need and as far as tyrosine kinase inhibition in Mds because this would be a novel.
Yes. This is not something that is currently considered part of the standard of care to really expand that treatment options for that patient population as well.
Perhaps you can talk about the.
The titration of phonetic flex into AML patients versus CLL patients and why we'd like to go into AML patients first for the combo.
Right and unlike in CLL, where we never quite has very potent single agent activity.
And can become a little bit more.
Difficulty combined with other active agents due to the risk.
Tumor lysis syndrome, and things of that nature, yet the little bit more cautious in that patient population in AML then adequate Acs has very modest are marginal single agent activity really has only shown significant benefit when combined with other agents like hypomethylating agent and in that patient population. We don't see the same risks it tends to be much safer and easier to.
The dosing combination.
Especially if you're combining it with the drugs that doesn't have overlapping toxicities. So as you know than other KLAX has the potential week lower blood counts, particularly neutrophils. So far we have not seen any evidence of that with Cts fixing our b cell patient population. So we're hopeful that that kind of combination would allow us to marry safely and quickly understand how to put the two drugs together.
Ill patients.
Thank you and then we could apply that to what we've learned in AML patients to be some malignancies for the combinations I would I also ask Dr. morongo. If he has any additional input in terms of the selection of patients for the emails from.
Yes. Thank you Bill Thank you Matt the question.
As you heard about at this 0.2 or three months ago, We held symposium around E Mail in New York City, we discussed in light of the she is.
In this relapse refractory population.
Activity that we've seen pretty uniquely.
From this drug and and how we are thinking about this but also how some of the experts in field our thinking about.
And if it's exactly.
Like that and feedback like that which is.
Also driving.
Our positioning and our strategy until as Dr. I can be higher mentioned.
There are some lower hanging fruit population out there.
On the trend sort of clinical.
Needs, we didn't see it suite patient CCT to their just before.
Last nicks resistance intolerance.
Patients with Denny problematic mutations fit into three RASK, although these should be able to be captions in this phase one study and then pragmatically crudes densities too.
Occasions.
As you know that most traditional password agent like this.
Is typically a staged approach right.
In hematology things started as a monotherapy in relapsed refractory disease.
South sense that could be resistant or intolerant to understand currencies. These present, all fast development path to accelerated approval next call that stage one and.
And then following closely not quite in parallel potentially assistance behind you can have stage, two we should be expansions towards combinations and an expansion towards the frontline and in many hematology indications, including CLL and help these to actually go hand in hand, right companies and move towards the frontline and this path would apply.
I'll now be sell tumors as wellness and now and that is that is something that likely see here.
Thank you.
Great. That's super helpful. And appreciate you guys all chime in there with some input I think it's very cogent to describe the differences that you may see with somebody with a new clecs. These two different indications and the path forward and even kind of looking very much ahead, maybe but to put the frontline usage. So really appreciate all the insight and stay safe guys.
Thank you too.
Thanks Bye.
Thank you and the next question comes from Joe Pack, and that's where they <unk> Wainwright. Your line is now open.
Hi, guys. This is pasquale hunger vinyl Joel.
Good question, who on the two key.
Trial, so basically I know, it's no secret smoothing the plasma station.
I'm sorry. It was difficulty are we looking at specific genes in the patients is that what you're saying.
Are you looking at Pacific mid associated you, who seem to plant location.
In the.
I'm not sure I fully understand your question. So we are collecting.
Pbmcs from these patients we're measuring.
The expression levels of mix as well as a variety of other.
Jeans fill the gene expression by joint based at the yes, we are doing that in these patients we haven't reported out all the other genes that we're looking at primarily mix because it does that mix, but yes, we're looking at a number of genes in the pbmcs expression levels.
And these sientra asphyxiated, we look at pathway is that correct.
But some are some are not yes. So some of these you expect might be altered if you inhibit Mick but they're also other genes that we're interested.
Yes.
So my second question, you said a specific mix signature associated we did fine and Mount genetic entity. So basically in other words, what would be up low to correct.
Two quick to treat they now fairmount target population.
Actually I think.
Mic is known to be Overexpressed in many different.
Subgroups of.
Ill patients.
I think what we would look for hopefully as patients who were over expressing mix. So as we've looked in cell lines that are overexpressing mic both in a mill as well as other he malignancy and even in solid tumors. Those that are overexpressing, Nick tend to be more sensitive to the drug.
It's one of the reason, we've talked about possibly expanding out into other malignancies right now with cobot, it's difficult to expand we're trying to maintain the ml trough, but we've made what to expand into Burqas lymphoma that is one that is known to be driven by mix.
There are also other indications that are heavily mix driven so thats most likely were ultimately we might look to to focus in patients.
Respond to this hope that answered your question.
You are basically.
Yeah, Oh go ahead.
I didn't know if dr. bahar, one said anything to that email in India.
We just say that we're collecting samples to be able to answer. This question, we havent predefine to make signature that we're looking for in this patient population in order to decide who might be responsive, but we definitely want to capture that.
In the patients that we do treat so that if there is such a signal that we'll be able to understand and characterize.
Yes, that's correct so another yet.
Well, we don't know what's going to happen when you just not young mix. So all the other drugs that in the past that had been designed to inhibit Mick have been quite toxic. So it's not known yet at least clinically what will happen. If you can selectively knockdown Mick and safely to do so.
So we're looking we're eager to find that.
Okay, Yes, the sale you sort of wait to select patients we make all the expression.
With what expression I'm sorry.
With me call the expression.
I was wondering if you know full what youre looking at the way all like to like five month, because 50 patients.
So we feel that.
The best one to look out there is literally mic expression itself, we're able to do that very quickly in the pdmcs.
So one of those as I said earlier was Bearkat lymphoma now that we know this is the mic inhibitor, we'd want to look at those types of patients and hopefully slick those with ml, let us clicks and data in patients, let us see if the mic inhibition correlates with with sensitivity and with clinical activity overtime as we get into the higher dose.
Levels I I'd like to think that would be that's true, but I do not yet have data to support that so we'll have to collect the data.
Yes.
Thank you so much.
Thank you.
Thank you and I'm showing no further questions in the queue at this time.
I'd like to turn the call back to Dr. rice for closing remarks.
Alright, well I want to thank everyone for joining us in this afternoon.
Typically want to say thank you for all the insightful thoughtful questions that came to us.
Although we have much work ahead of us we're gratified by the progress of our two clinical programs, both two part three and six.
And that we've been able to recruit new patients and escalate the dosing and our clinical trials even in these difficult times.
Well I, particularly want to thank our clinical team our investigators are patients for their help in this important work. We appreciate the support of our shareholders and analysts that are on this call. We look forward to keep you updated our progress we hope to see with all although it's going to be virtual.
Want to thank everyone have a great evening NBC. Thank you very much.
Thank you ladies and gentlemen that concludes today's conference call. You may now disconnect and have a wonderful day.
Thank you.
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