Q1 2021 Larimar Therapeutics Inc Earnings Call
[music].
Good morning, and welcome to the <unk> Therapeutics Conference call. All participants are now in listen only mode. There will be a question and answer session. At the end of this call if you'd like to ask a question you May Press Star then one on your telephone keypad.
Should you need assistance during the conference call you May signal, an operator by pressing star and zero. Please be advised that this call is being recorded at the company's request and a replay will be available on the company's website I would now like to turn the call over to Mr. Chase Oswald of lifestyle Advisors. Please go ahead.
Thank you operator, and thank you all for participating in today's conference call before we start I'd like to point out, but there is a slide deck that will accompany today's presentation.
This slide deck can be viewed using the webcast link provided on the investors page of the landmark therapeutics website.
Also posted on this web page of the news release issued earlier today announcing data from landmark phase one doubled.
Double blind placebo controlled multiple ascending dose clinical trial evaluating <unk> 16, O one and free gift ataxia patients.
I'd like to remind all listening, but some of the information contained in the news release and on this conference call contains forward looking statements that are based on the company's beliefs and assumptions and on information currently available to management.
All statements contained in the news release and on this call other than statements of historical fact are forward looking statements, including but not limited to statements regarding the expectations and assumptions regarding the future of the business.
The company's ability to develop and commercialize <unk> 16 O one and other planned product candidates. The Companys planned research and development efforts and other matters regarding the company's business strategies use of capital results of operations and financial position and plans and objectives for future operations.
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These statements involve risks uncertainties and other factors that may cause actual results performance or achievements to be materially different from the information expressed or implied by these forward looking statements.
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The success cost and timing of the company's product development activities non clinical studies and clinical trials, including C. T. I 16 on one clinical milestone.
Clinical trial results may differ from the final clinical trial results that earlier, non clinical and clinical data and testing of <unk> 16 O. One may not be predicted from the results or success of clinical trials and clinical trial data are subject to different interpretations and assessments Bianca.
The ongoing impact from the COVID-19 pandemic on the company's clinical trials manufacturing regulatory and non clinical study timelines ability to raise additional capital in general economic conditions, the company's ability to optimize and scale of <unk> 16 on one's manufacturing process, the company's ability to obtain regulatory approval for <unk>.
Oh, one and future product candidates.
The company's ability to two development sales and marketing capabilities, whether alone or with potential feature clappers.
First we commercialize any approved product candidates.
The company's ability to raise the necessary capital to conduct its been product development activities and other risks described in our filings made by the company with the Securities and Exchange Commission, including but not limited to the company's periodic reports, including the annual report form 10-K quarterly reports on form 10-Q, and current reports on form 8-K.
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With that I'd like to turn the call over to Dr. Carole Ben Maimon, President and CEO of Landmark Therapeutics. Please go ahead Carol.
Thanks Chase.
Morning, everyone and thanks to all of you who are listening in.
In addition to Chase I'm also joined by our Chief Medical Officer, Dr. Nancy relief, and our Chief Financial Officer, Mike Solano, who will be available during the question and answer session. Following my presentation.
For those of you who don't know landmark we are a clinical stage biotechnology company developing a novel protein replacement therapy platform for free trips ataxia and other complex rare diseases.
We were founded by Dr. Mark pain, and Tom Hamilton and at the end of 2016 Deerfield management made the initial investment we went public through a reverse merger and accompanying pipe in may 'twenty 'twenty with the shareholder base made up of high quality institutional investors.
As I previewed above our lead program isn't friedrichs ataxia or S. A a rare and terribly debilitating genetic disorder.
To address the unmet medical needs in S. A we are developing C. T. I 60, you know one a recombinant fusion protein designed to treat the root cause of the disease.
Patients with that they are just fishing in a protein called for taxes.
Protection is a protein that is active in the mitochondria of the sales.
D. T. I 60, you know one is intended to deliver for tax and two the mitochondria in patients suffering from SMA.
We recently completed dosing in two phase one trials.
These trials were a placebo controlled single sending dose trial in a placebo controlled multiple ascending dose trial evaluating C. T. I 16 O one in patients with friedrichs ataxia.
The primary purpose of todays call is to announce the exciting day to these trials have generated which show dose dependent increases in protection levels in all evaluated tissues with daily dosing of C. T. I 16, no one.
The protection levels observed in these tissues actually met or exceeded the levels. We would expect to see encino typically normal heterozygous carriers at that day.
We believe this data demonstrates proof of concept for C. T. I 16 now one in addition, the day to also indicate that C. T. I 16 O. One is generally well tolerated when administered daily for 13 days.
Looking forward, we believe we are well positioned financially to build on these promising results as we ended the first quarter with over $81 million in cash which provides for a projected runway into the first half of 'twenty 'twenty two.
Now before we dive into the details of our data and trial design I wanted to first highlight the key findings from our phase one program.
With regards to safety, we saw that repeated subcutaneous injections with C. T. I 60, you know one appear to have been generally well tolerated at doses up to 100 milligrams administered daily for up to 13 doses.
When looking at Pharmacodynamic data, we saw dose dependent increases in pretax and levels from baseline can player compared to placebo controls in all evaluated tissues with daily dosing of C. T F 16 on one.
And finally, our pharmacokinetic analysis together with the P. D day that I, just mentioned support evaluating a once daily dosing regimen for C. T. I 16 O one.
Before I leave this slide I'd like to highlight one of the most important findings from the study, notably protection levels and buckle cells cause the two highest dose groups were equal to or in excess of those we would expect to see in heterozygous carriers, who show no signs of the disease.
Yes.
Given that insufficient protects the levels are the root cause of friedrichs ataxia. We believe that these exciting findings demonstrate proof of concept for C. T. I 16 O one.
So now that I've introduced the main takeaways of today's presentation I want to take a moment to provide some context for the detailed data I'll be presenting by giving some background on free to let's say tax year and C. T. I 16 on one.
We just say taxi is a rare terribly debilitating disease caused by a genetic defect that results in insufficient levels of pretax and a key mitochondrial protein.
It is important to note that the vast majority of patients with that they have some normal for taxes. They just don't have enough for tax.
Cash studies have shown that patients with that they produce only about 20 to 40 per cent of normal protection levels, depending on the tissue sampling technique and assay utilized.
That's a is a terrible disease. This deficiency of pretax and causes patients who are born appearing to be healthy to develop heart disease and progressive neurological symptoms that will eventually force them into a wheelchair seven to 10 years after diagnosis.
The life expectancy for these patients is between 30 to 50 years of age with the primary cause of death being cardiomyopathy.
It's S. A is truly a systemic disease every cell in the body that has mitochondria has for tax and.
In addition to the neurologic dysfunction and cardiac disease patients with that they dealt developed diabetes. They can go blind and deaf and they lose the ability to speak there.
There is a substantial unmet medical need NFA as there are no approved therapies available and current treatment options are limited to symptom management.
In response to this unmet medical need we are developing C. T. I 16 O one a recombinant fusion protein.
Through the administration of C. T. I 16 O. One we are aiming to address the root cause of friedrichs ataxia by delivering mature for tax and protein to the mitochondria.
Understand how C. T. I 60, no. One does is it's first important to understand the structure of endogenous for taxes.
If you look on the left side of the slide you can see that for toxin, which is coded in the nucleus produced in the cytoplasm and then transported into the mitochondria is originally coded as what I like to call appropriate team.
This pro protein includes mitochondrial targeting sequence or M. T S that carries the protein across the mitochondrial membrane.
Once in the mitochondria. The MTS is cleaved off by the mitochondrial processing peptidase enzyme, allowing mature for tax then to accumulate within New York and L to function.
Now if you look to the right side of the slide you can see what's significant about C. T I 16 O on.
This recombinant protein has been designed to allow exogenous administered for tax and it's across the cell membrane and the mitochondrial membrane.
This is accomplished by attaching a cell penetrating peptide or C. P. P. A small amino acid sequence, so the mitochondrial targeting sequence and not to the pretax and molecule itself.
This maintains the cleavage like between the M T S and the protection molecule.
By maintaining this cleavage site one C. T. I 16 O. One enters the mitochondria the mitochondrial processing peptidase can now cleaved off the cell penetrating peptide and D. M. T S, leaving the active for cats in molecule in the mitochondria.
We believe that attaching the C. P P to the MTS and preserving that cleavage side is what constitutes the secret sauce of C. T. I 16 O one.
So now that I've set the stage by describing how C. T. I 60, no one's mechanism of action directly addresses the root cause of that day I'd like to introduce the design of our phase one program and talk in depth about the exciting data I previewed earlier in the call.
As you can see on this slide our phase one program includes two double blind placebo controlled trials in patients with SMA.
The first of these trials is a sad study that evaluated the safety of single subcutaneous injections of C. T. I 16 O one.
This trial has been completed with data from the studies showing that single subcutaneous injections of C. T. I 16 O. One appeared to be generally well tolerated at doses up to 100 milligrams.
Eligible patients from this side trials had the opportunity to screen for a mad trial, which is the primary focus of today's call.
Patients in this trial were randomized to receive multiple increasing doses of C. T I 61, or placebo administered subcutaneously over 13 days.
The primary endpoints of the trial, where safety and Tolerability with secondary endpoints, including protection levels, and buckle cells skin and platelets as well as Pharmacopeia net kinetic analyses.
Hosting and the trial was completed in the first quarter of the year.
Here on this slide you'll notice that 16 of the 28 patients who participated in the Sad study went on to enroll in our Mad trial.
This is important as the Mad study was conducted during the pandemic throughout the winter and required patients and their caregivers to travel from across the country to the single clinical research unit, where the study was conducted.
Once their patients and their caregivers hutch remain in the unit for more than three weeks.
The fact that 16 out of 28 patients were willing to endure this is really a tribute to the patient commitment and tenacity and we want to thank them for their participation and perseverance.
The Mad trial had three cohorts with cohort one enrolling six patients into the active arm and cohorts two and three each enrolling seven patients into the active on collectively the three cohorts enrolled seven patients into the placebo group.
Moving on to slide nine you can see that as we moved from cohort one to cohort three and the Mad trial, we increased both the dose of C. T. I 16 O one as well as the frequency of administration.
Patients in cohort one we're just with 25 milligrams daily for four days and then every third day after that until day 13th.
In cohort two we doubled the Joseph C. T. I 60, you know one to 50 milligrams and administered the protein daily for seven days before moving to a once every other day dosing schedule until day 13th.
Finally patients in cohort three we're giving 100 milligram dose daily for 13 consecutive days.
Looking now at the bottom half of the slide I'll briefly explain how we will be presenting the data for each cohort.
You'll notice from the tables that for cohort one we will be selling protection levels at baseline day, four and day 13, and both buckle sells in place.
Well on cohorts two and three the data presented for these tissues will be from baseline day, seven and day 13th.
Looking at the day that in this way allows us to capture the final day of the daily dosing period for both cohorts, one and two which will be informative for the design of subsequent studies.
For the study protocol skin biopsies were collected only at baseline and day 13th.
That's those are the two time points, we will be looking at for the tissue and all three cohorts. In addition, skin biopsies were optional so patients could elect not to have them performed.
Here on slides 10, and 11, you can see the demographics and disease characteristics of patients who participated in the Mad trial.
I won't go through the day that in detail now as the slides are posted on our website for those interested in taking a deeper dive.
We will however point out that the patient demographics and the Mad trial were similar to those in the sad trial, which is obviously not surprising given that there were 16 patients who participated in both studies.
Additionally, approximately half of the patients enrolled in our trials you used a wheelchair to move around and thus are considered non ambulatory.
This is different than many of the phase two three trials to date, and that's where patients who participated were required to be ambulatory.
Having these patients in our phase one trials as well as our open label extension. The Jive study will provide important data on the long term safety and Tolerability of C. T. I 60, no one as well as potentially allow detection of the signal of efficacy in this population.
On slide 12, you'll see the day that I previewed at the beginning of the call which shows the daily subcutaneous injections of C. T. I 16 O. One resulted in dose dependent increases in pretax and levels from baseline compared to placebo.
The day that you are looking at now is from buckle cells, but as you'll see in a moment. These data are consistent with what we saw in all evaluated tissues.
Looking in more detail now we can start with the graph on the left which shows absolute for tax and concentrations and collected buckle cells normalized total protein the.
The points on the graph represent the median from each groups, while the Arab bars represent the 25th and 75th Percentiles.
You'll also notice that as we move from baseline to the next measurement, which again was day four for the 25 milligram dose group and day seven for the 50 and 100 milligram dose groups, we see an increase in pretax and levels in the second to the highest dose groups with the highest median protect some level being in a.
100 milligram dose group, the highest dose dosing groups.
That said in the 100 milligram dose group, we saw an approximately two and a half fold increase in pretax and levels from baseline.
Importantly, we see little to no change in for tax on levels in the placebo group or in the 25 milligram dose group, which received the lowest dose of C. T. I 16 on one.
I'd like to draw your attention now to what was seen between day, seven and day 13 measurements.
As this shows something that it's a bit subtle, but quite informative you can see from the graph that between day seven and day 13 protests on levels in the 100 milligram dose group remain relatively constant while the protests and levels in the 50 milligram dose group decrease the.
The important thing to remember here is the patience and the 50 milligram dose groups were receiving C. T. I 60, no one daily for the first seven days, but then they were switched to receiving the protein every other day between day seven and day 13.
Conversely patients in the 100 milligram dose groups received both a higher dose with C. T. O. Six you know one and remained on the daily administration schedule throughout the 13 day. This is important because it suggests that a once daily dosing schedule may be appropriate for subsequent studies.
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Turning our attention now to the graph on the right. We see the same day that are presented as a change from baseline. So this represents the additional for tax and that is being supplied by administration of C. T. O. Six you know one.
Once again, we see little to no change from baseline in bulk will sell for tax and levels from patients in the placebo group or the 25 milligram dose group.
On day seven when both the the 50 and 100 milligram dose groups were on daily dosing schedules, we see increases in protection levels with the greatest increase coming from patients in the 100 milligram dose group.
As I will show you in a moment. These protests on levels are at or above what we would see in heterozygous, who show no signs of the disease.
On slide 13, you can see the protests in levels measured in skin biopsies, which were collected both at baseline and on day 13th.
These results are consistent with what we saw it in buckle cells, but with a more from pronounced approximate three three fold increase in pretax and levels compared to baseline in patients in the 100 milligram dose groups.
The increases in pretax on levels were observed on.
The increases in pretax on levels observed where once again dose dependent with daily dosing with little to no change from baseline seen in the placebo group or the 25 milligram dose groups.
On Slide 14, you can see the results we obtained from platelets, which was the last tissue. We evaluated well results here were generally consistent with what was seen in other tissues. We did see a good deal of variability in the baseline measurements of all groups. However.
When when looking at change from baseline in the 100 milligram dose group in the graph on the right. It becomes clear that we are once again seeing increases in pretax and levels at the highest dose when compared to placebo.
Now if we look here on slide 15, we can see a different representation of the day with a bit more detail on how increases in pretax on levels from baseline correlated with C. T. I 60, no one does.
The three graphs represents a change from baseline on day 13, with each bar representing an individual patient.
As you can see from the color coding as you move from left to right. The largest increases from baseline tended to come from higher dosing cohorts with more frequent dosing collectively these patient level data further support the dose dependent effects of C. T. I 60, you know one that.
Were observed with daily dosing and all tissue studied.
So once we establish that we could increase protection levels in peripheral tissues. We then asked ourselves two questions. The first being our peripheral for taxes on levels clinically relevant.
And the second thing how do the pretax on levels, we achieved with C. T. I six you know one administration in our clinical trial compared to pretax on levels from healthy controls and heterozygous carriers, who show no signs of the disease.
To answer the first question, we were able to look at the literature, which is shown that protection levels and buckle sales in blood are predictive of disease severity.
Has been shown that the low with a pretax on level in these tissues the longer the G. A a repeat and the earlier the onset of the disease.
Further while published data varies on the level of protection in patients. We have referenced a study that shows that patients with S. A produce approximately 20% to 40% of normal for tax from levels in buckle cells and blood, while heterozygous carriers, who show no disease.
Symptoms display for tax and levels that are about 50% of those seen in healthy controls collectively. These findings suggest the peripheral for tax on levels are clinically relevant highlighting the significance of the results we have presented here today.
Now to answer your second question, we can look at data from a non interventional study we began conducting prior to the coronavirus pandemic.
This study.
Which included healthy controls measured for Tacksman levels, and buckle cells using the same sampling technique and assay employed in our phase one mad trial.
Well, we ended up terminating this non interventional study due to the COVID-19 related restrictions, we have data from the first eight healthy control subjects.
If you look at the graph on the right you'll notice the dashed Green line, which represents a 60 per cent of the median for tax and levels measured in these eight healthy controls.
You can see from this graph the patients in the 1500 milligram dose groups. Both achieved median for tax on levels at or above this line, which notably exceeds the pretax from levels. We would expect to see in Buffalo sells a pheno typically normal heterozygous carriers.
Although others have reported toxicity with very high levels of pretax and the levels. We are reporting here do not approach the levels reported in those studies as we advance the development program for C. T. I sits you know one we will continue to monitor for tax from levels in these tissues and optimize.
Dosing regimen.
Given what is known about the predictive nature of buckle for tax and levels on neurological function in <unk> patients. We believe the favorable parison speaks to the significance of our phase one results and the extent to which they demonstrate proof of concept for our clinical program.
Looking forward, we are planning to collect additional data from healthy controls and a separate non interventional study utilizing the same sampling techniques and our proprietary assay in order to better inform C. T I 16th on one's continued clinical development.
Shifting gears a bit now I'd like to talk about some of the safety findings from our Mad trial based on these findings C. T. I 60, you know one appears to be generally well tolerated when administered daily for 13 days.
Of the 27 patients who enrolled in the Mad trial 26 completed the study with one patient in the 50 milligram dose group withdrawing after experiencing mild to moderate nausea and vomiting.
Notably we observed no serious adverse events important medical events or treatment related severe adverse events in the trial. The most common adverse events were mild and moderate injection site reactions.
At least one sub in at least one injection site reaction was noted in 43 per cent of placebo patients and then 100 per cent of C. T. I 16 O one patients.
Should also note that the number and severity of adverse events did not increase with increasing exposure to C. T. I 16 on one.
Shifting our focus now to our pharmacokinetic analyses, we found that C. T. I 16 O. One was quickly absorbed following subcutaneous administration.
Notably we saw a dose proportional increases in exposure with increasing doses of C. T. I 60, no one and a mean half life of approximately 11 hours.
Although we have flexibility and can increase the Joseph necessary. These analyses support evaluating a once daily dosing regimen for C. T. R 16 O one.
So to summarize our topline phase one findings repeated subcutaneous injections of C. T. I 16 O. One appeared to be generally well tolerated at doses up to 100 milligrams administered daily for 13 days with no serious adverse events reported in either of the sad.
From that trial.
Pharmacodynamic assessment showed the daily subcutaneous administrations of C. T. I 60, you know one resulted in dose dependent increases in protests on levels from baseline compared to placebo in all evaluated tissues, which included buckle cells skin and platelets.
Finding was particularly notable given the pretax on levels and buckle cells have been shown to correlate with neurological function in patients with SMA.
Moreover, we were able to achieve pretax on levels that exceed that protects the levels, we would expect to see and pheno typically normal carriers of the S. A gene based on data and eight healthy controls obtained from a non interventional trial, using our collection techniques and proprietary assay.
Finally, our pharmacokinetic assessments.
So that's C. T. I 16 O. One was quickly absorbed with dose proportional exposure supporting the evaluation of once daily dosing in future clinical studies.
Collectively we believe these results demonstrate proof of concept for C. T. I 16 O one as they establish its ability to deliver the critical protein to peripheral tissues that patients with SMA are missing.
Let me switch gears for a moment, we have several events coming up this year in particular, we are planning to discuss these data and our future clinical development plans with both the FDA and the European Medicines Agency. As you May also have seen in our 10-Q filed last night.
We have an ongoing 180 day non human Primate study and which mortality were observed in the highest dose groups. FDA is aware of these findings and does the dosing in this study is ongoing we continue to collect relevant data and we'll share it with the agency prior to the initiation of future clinical trials.
While the cause of these findings has not yet been determined what I can say now is that based on all of the information we have from our clinical and non clinical programs to date plus extensive input from toxicologists and other relevant experts we do not expect these non clinical findings to <unk>.
In fact, our previously disclosed timelines with regards to our Jive open label extension and pediatric Mad trials, both of which we expect to initiate in the second half of the year.
Looking a bit further down the road, we are planning for a global pivotal study as early as the second half of 2022. In addition, we will also be engaging in conversations with the regulatory regulatory authorities. So that we are pursuing the most expeditious development path in an attempt to provide.
Axis the C T I 16 O one as soon as its feasible.
Let's now refocus on the clinical program Slide 21 provides an overview of our drive trial, which is a multicenter open label extension trial that we expect to initiate in the second half of the year.
Patients from both our sad and Mad trials will be eligible to screen for Jive asthma patients from a pediatric Mad trial, which is also expected to begin in the second half.
While the exact dosing levels evaluated and Jive will be determined based on additional analysis from our phase one program, we expect to treat patients and drive for up to 24 months with any necessary extensions, we expect to enroll up to 50 patients who will likely be given once daily.
Doses of C. T. I 60, you know one administered subcutaneously.
While there will be no placebo group for the Jive trial, we will utilize an external control arm derived from the critical path Institute data.
The primary endpoint of Jive will be safety and Tolerability, while key secondary endpoints include long term measurements of protection levels and efficacy assessments, but long term data we gain from this study will be very useful as we work to advance the C. T. I six you know one development program.
Now before we move to Q&A I just wanted to once again some of the key findings and conclusions from our phase one data.
First we saw that repeated subcutaneous injections of C. T. I 16 O. One appear to have been generally well tolerated at doses up to 100 milligrams administered daily for 13 days.
Second we saw a dose dependent increases in pretax and levels from baseline compared to placebo controls and all evaluated tissues with daily dosing.
And third our pharmacokinetic and Pharmacodynamic analyses support evaluating a once daily dosing regimen for C. T. I 16 on one.
As I mentioned several times throughout the call, but for taxes on levels achieved in buckle cells with C. T. I 16 O. One administration were equal to or in excess of those we would expect to see in heterozygous carriers, who show no signs of disease.
Given that insufficient for tax and levels are the root cause of friedrichs ataxia. We believe that these exciting findings demonstrate proof of concept for C. T. I 16 O one.
It is also important to note that to the best of our knowledge C. T. I 16 O. One is the only drug candidates in clinical development that is designed to supplement for tax in levels in patients with SMA, thus addressing the root cause of the disease.
Finally, I would like to take a minute to acknowledge that none of the progress. We've discussed here today would have been possible without the commitment of our patients.
The great work being done by the Friedrichs Ataxia research alliance or the talent of our employees partners and investigators.
I am extremely grateful to all of these individuals for the important roles. They have played in advancing C. T. I 60, no one's clinical development.
With that I'd like to extend one last thank you to all of those listening to our call today, we will now open the call to questions operator.
Thank you we will now begin the question and answer session to join the question queue. You May plus press Star then one on your telephone keypad, you'll hear a tone acknowledging your request. If you are using a speakerphone. Please pick up your handset before pressing any keys to withdraw your question. Please press Star then two.
<unk> once again to join the question queue. Please press Star then one now.
Our first question comes from Myles been car of William Blair. Please go ahead.
Oh, hi, thanks for taking the questions and congrats on the data it's real and also say this protection expression in United True.
The outcome for patients really.
My first question is on cargo true it seems as if there's been a slight decline in expression from day to day change across the tissues.
Just trying to clarify whether that's just true to the reduction in the dosing frequency.
And wait to wait one or is that variability of knee share.
Jackson expression of the patient so it might be it from the outside.
And is it safe to say that when you switch those patient sorry, but a job that will all be pushing up to the 100 <unk>. That's the first one.
Hi, Michael Good to hear your voice. So we believe that the decrease in cohort two between day seven and 13 is because those patients were switched to every other day dosing.
So we do believe that it's probably going to at least initially be a daily doses of <unk> 16 on one that's required and we think that's borne out by the 100 milligram dose group, where you really don't see that decrease and so yeah. We do think it's a true it's because of the change in regimen, which was part of the reason why we designed.
The trial the way we did.
With regard to Jive being 100 milligrams.
We really cant answer that question yet were still looking at a whole bunch of other pieces of data on this is really top line data and Theres still a lot of number crunching that needs to go on you know looking at the Pharmacodynamic data by patient you know looking at it by weight things like that so.
So I don't think we really know at this point what dose will be in Jive, but I do think it's fair to say that it will is likely to be daily dosing at least initially.
Hmm mm.
That makes sense and then on the injection site reaction frequency.
I'm wondering whether it'd be incidents rates changed with the true waste treatment period did I care more frequently or with greater severity upfront as opposed to dosing throughout that second wake any any indications there.
Not that we can tell right now if it was pretty random some patients you know like we said that all of the patients on the active had at least one but not every time they injected do they have an injection site reaction and.
And I don't think they necessarily changed with frequency we have not looked at yet at site. We use we actually administered the drug at four sites, both size and either side of the abdomen and those sites were rotated which is pretty traditional with the with the subcutaneous injections and so which we still have to look at things like.
Site of administration, but these injection site reactions were really very transient and were real.
Like we said mild or moderate.
Okay.
So on before I jump back in the queue on.
Just on the Monkey talks are on are you.
Can't really comment too much on it but.
When you notified the S. T I S. T. A C was there any back and forth commentary with the agency that we should be aware about and then sort of when you're going to update the IGT and.
Can you give us a sense for the darice ranges.
The mortality as occurred in the monkey.
Relative to that that youre using in the clinic excited 100 baked arsenic patients.
Yeah. So we don't really like to give a lot of detail with our conversations with FDA, but I can tell you that they have been notified.
And you know, they're they're okay with us submitting the data when when we need to.
And when we're ready to the trial is still ongoing so until it is complete and we can get all our data and.
I think it's premature to continue to have a lot of conversation with the agency because we have to obviously determine what we think is the cause and make sure that we have all of the data with regard to dose I wouldn't focus on dose I would focus on exposure because that's what's really relevant and what most of the.
Tori authorities, we'll we'll look at and from the standpoint of exposure, we don't have the exposure yet in the 180 day, because they're still being dose it's still ongoing but.
But we did complete as you well know a 90 day study and based on the exposure seen in that study, we do have significant safety margins.
And so on and it's the same species of monkey. Its the same size monkeys. So I would anticipate that what we saw on the 90 day is relevant and like I said, we have significant safety margins.
Okay.
Okay. Thanks for the questions I'll jump back in the queue.
Our next question comes from Jonathan Goldman of G. N P Securities. Please go ahead.
Hey, good morning, and thanks for taking the question from congrats on the data.
Just a few from me when we take a look at the baseline for tax from levels. I'm wondering if this is consistent with what you would expect based on.
On some of the other characteristics like you mentioned, 50% of patients being on non ambulatory.
Yeah, I think it is it's really hard to compare protection levels across trials.
Because they use different sampling techniques and there's different assays and I think what's really consistent is it patient usually have somewhere around 20%. We've said 20 to 40, but I think if you talk to the patient community. They actually think its closer to 20 or maybe even a little bit less but I do think it.
Consistent and as you saw it's consistent between patients I mean, the baseline numbers all look pretty similar in all the different tissues with the exception on platelets, which seem to have more variability.
Was there anything besides dose when you look across demographics are crucial characteristics for those who seem to have a more for tax and observed and then when you think about the time course, obviously, we're it's.
Very short right now really have two time points, but.
Do you think there's a leveling off you're already or do you expect to see them.
Kind of more increases overtime.
Dose.
Yeah. Its a hard question to answer Jonathan on a good one and an important one I think we really need to get into the Jive study and could go out further to know whether we're actually at steady state or not you know there is a theory that for tax and it has a longer half life and then probably see T. F 16 on one.
Does and even then you know iron sulfur cluster enzymes may even have a longer half life. So I think until we actually get into a chronic dosing like we will in the Jive study its really hard to know whether we couldn't even at some point switched to every other day.
Or whether we see you know, we're really at steady state and we need to to dose daily.
But I think we need more data.
I guess last one from me to that point do you have any sense based on literature natural history. When seeing these increases on levels might translate to some kind of a clinical benefit right.
Yeah, I don't [laughter], because nobody else's replace for taxing them.
So we've really at least you know historically I mean in the animals you'd actually see it relatively quickly we do as you may recall have some clinical data. We did timed 25 foot walk for those patients who could walk we did the nine hole peg repeatedly. We've also looked at speech and the modified Fars that data is not yet.
And annualized it's in the process and we'll be releasing that data later later in the year and so I think that'll give us some hint like we've said I've said many times. After 13 days I really don't anticipate to see a clinical outcome, but obviously, we are going to look and evaluate that data and then once we get into the Jive study.
We'll be able to be able to compare some of that clinical data to our natural history to the natural history database into our control arm.
Looking forward to it congrats again on the data today.
Thanks, Jonathan Thanks for the questions.
Our next question comes from yet so nature of Guggenheim Partners. Please go ahead.
Hey, guys. Thank you for taking my question on on the excellent presentation.
Just a couple from me. So it seems like you are emphasizing that are only in buckled sales you are achieving protection level that are similar or exceeds the the heterozygous carrier, what about skin and or pay for it.
Yeah. So a.
Nice to hear your voice again on the reason we talk about buckle cells is because that's the only data we have it in your in the literature first from the literature. Its really just buckle sales, but as importantly, it's the fact that we did on this non interventional study and we didn't do skin biopsies or platelets, we just didnt vocal sales.
And so that's where we have that control.
We are going to be doing a non interventional study I'm looking at healthy volunteers, where we will be collecting skin and platelet and buckle cells, but it's not because we're so much emphasizing the buckle cells. It's because that's the data we have at this point I think actually skin is highly relevant.
You you may on I'm.
I'm sure you know the buckle cells are mucosal membranes. So they sales turnover very quickly.
And skin is a much more stable tissue as well as the sampling techniques. When you do buccal swabs you know how hard you Hugh you swab, how long your swap obviously, we tried to control that and we were at a single unit. So it was a bit more easier to control it and in our study.
Skin biopsies are routine youre using a specific device. So you always get the same amount of tissue in the same depth of tissue.
And so I actually think the skin biopsies are are really interesting and obviously in those tissues. We saw a threefold increase between day baseline on day, 13th So I I actually really like the skin.
Platelets I think are a little less indicative and I think I've said this before to you because they are intravascular right and we know the drug gets into the Intravascular space and we know it's absorbed quickly and the half life is about 11 11 hours. So.
I think platelets are variable for a whole host of reasons and I think probably not as relevant because they're not really a peripheral tissue.
Buccal swabs and skin or peripheral tissues, and we show the that the process protein is in those tissues.
Got it got it and then with regard to the dosing I mean, it seems like the 100 milligram given that it was daily seemed to go very consistent and robust increase in for tax on level across all measure tissues right do you intend to go higher or do you think you have a pretty good handle on it.
So either if 50 milligram on a daily basis on 100 milligram are on a daily basis is sort of is the go forward dose or do you think you need to go higher because you are achieving the threshold that you need to achieve.
Yeah, I think that's right I don't think we need to go higher whether we do 50 or 100, I think is yet to be seen like I said, we wanted to do some more detailed analysis looking at some of the detailed demographics and characteristics of the individual patients.
But I do think daily dosing is likely at least initially until we see you know what happens out 30 days and 60 days kind of thing.
And we're still looking at those but I do think that we I don't believe that we need to go higher I think we've we've achieved where we want to go and also given the fact that granted at multiples high multiples people have described especially the viral gene therapy folks are described on some toxicity.
You know, we don't want to be you know a two or three times, what a normal person is walking around with we want to be somewhere between you know that 60, and 80% of normal would be what I think and that's exactly where we are.
Just one final question do we know the protein concentration or ethics and in healthy and heterozygous in all of these three evaluated our measures.
So there is data out there on and it's highly variable depending upon the assay.
And the sampling techniques as I said earlier, we are going and I in my script that we are going to be doing a non interventional study using our assay techniques and our assets are proprietary assay. So that we have that data going forward and as we go into drive will be able to compare it to.
Similar pieces of information, but they're the best data is really in buckle sales and was published out of I think out of chop and that's really where the best day that comes from but like I said, it usually on a different assets.
Got it very helpful. One more question. If I may you also looked at the gene expression in the buckle fell one where you might be able to see that at all or anything you could share on that.
Yeah, we don't have that day to back yet worst and it's going to be some time those assets are not a simple and straightforward as you might think plus also analyzing them because we looked at a whole host of different genes. So probably not that day that probably won't be available till second half of the year.
Got it very good thank you so much.
Our next question comes from.
Our next question comes from Patrick Dolezal of lifestyle capital. Please go ahead.
Hi, Thanks for taking the questions on congrats on a great data.
Can you just help us think about the relationship the relationship between buccal skin cells on platelets presence after tax and on some of the other important tissues such.
Such as CNS heart in skeletal muscle on.
To the extent that it's possible I know its really tricky, but how much do you each of those tissues ultimately contribute to some of the the various clinical endpoints from FX.
Hi, Patrick.
So.
The better the best day that the buckle cells have been there are some really good publications out there I think we reference it in our in our deck.
There's some really good publications that look at buckle cells pretax and levels and compare them to the G. A repeat which many of you know is the longer the G. A repeat.
On the day.
On more severe the low earlier, the onset of the disease and the more severe diseases.
So buckle pretax on levels do correlate with the G. A repeat as well as severity of disease as measured by modified Fars.
And so there is a correlation there it is really hard to know what to then transition that obviously into cardiac and skeletal muscle and CNS.
But we believe that C. T F 16 O one.
Will be taken up based on the amount of mitochondria in a given tissue so more mitochondrial rich.
Tissues will take up more C. T. R 16 on one simply because they process more of the protein.
And we do know from our basic science data and our ex his two cytochemistry plus all the animal data that <unk> 16 on one does really go everywhere in the cell so as long as it's getting into the mitochondria it shouldn't be process there.
Got it thanks.
I guess, if you could provide a bit more detail on the endpoints on the timing of those assessments in the Jive study.
Any granularity as to when you could potentially provide an update from from that data set would be helpful and I guess on a more general sense I'm just trying to get at what is the time and we're quite for initial clinical assessments.
<unk> 16 net one.
Yeah. So good question. So that study is still being designed although we'll look at all of the things that you know routinely people look at modified Fars 25 foot walk in those patients who can performed the twenty-five book work nine hole Peg, we will be looking at speech as we did.
Here and how we design that will be interesting because it'll be based on some of the data that we collected in the Mad study.
And then we're also you know obviously safety is a huge en pointe and enjoyed from the standpoint of timing and.
And obviously also protection levels. So we'll also be you know looking at maintaining for tax and levels over time and as some of the others have alluded to making at seeing whether we can whether we should change the relative regimen, whether we add a daily dosing are at steady state or whether we you know may be increasing over time, if you dose.
For longer than 13 days, so you might be able to actually decrease the frequency of dosing. So all of that it'll be data coming out of the Jive I can't really tell you exactly when youll when we'll be able to provide data because this trial is still being designed but more importantly, we have to initiate the site.
It's not you know patients it won't be a cohort driven study like this is patients will come in over time, so it'll really depend on our site initiation.
And and patient enrollment, which we did.
I have said, we will start the second half of this year. Once we once we see how long it takes us to get the sites initiated I think we can give you a better read on how long when the day that will come.
Got it that's super helpful. Thank you.
Thanks for your questions.
Our next question is a follow up from miles main Carr of William Blair. Please go ahead.
Yeah, Thanks for the follow up.
Just following on from Jon's question I think he was trying to get at the baseline protection levels in an ambulatory versus non ambulatory patients did you actually say a difference in the protection level increase.
And that was true patient populations with <unk> six day narwhal.
We haven't actually I don't think we've looked at that day to yet we will I mean, that's an important question, but we had there I mean, you know it's somewhat definitional, who is ambulatory and who is non ambulatory. When you go on get a chance to go into the demographics youre going to see that half the population was wheel.
Our balance sheet, clearly non ambulatory, but the other half of the population I. If I recall I think only two patients didn't use an assisted device.
So most of those patients were walking with walkers and suddenly had a cane, but very few and these patients were pretty far along it's it's really hard to this population, it's not like a spinal cord injury, right, where you're walking one day and not walking. The next we will be looking I think what we'll probably.
We also be looking at is.
Pretax on levels based on modified Fars, which is a more maybe a more continuous scale to be looking at but we haven't we haven't analyzed from data to that detail yet we will be but we haven't.
Okay Cool and then I'm on technical question was the book.
Patients who have the healthy control for tax on levels with that diet or run on the same.
You know as I as the <unk> six that I wasn't traded patient biopsies, though what I true different assets and then you superimpose that's either ASO.
They were identical assays. It was the same assay at the same site.
Identical assay as well as the sampling technique it was a different site, but the sampling technique was identical as well.
Okay beautiful congrats on the diet or again a question on the questions. Thanks. Thanks, Thanks for your questions.
This concludes the question and answer session I would like to turn the conference back over to Carole Ben Maimon on for any closing remarks.
Just I just like to thank everybody for coming on for listening.
Listening to the call on participating and thanks to everybody for the questions. We're obviously very excited about the data and we look forward to continuing to progress the clinical development program again, thanks to everybody for coming and thanks to the patients who participated in the trial.
This concludes today's conference call you may disconnect. Your lines. Thank you for participating and have a pleasant day.
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