Q1 2021 Regulus Therapeutics Inc Earnings Call
Okay.
Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Regulus Therapeutics 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press Starmon on your telephone. Please be advised that today's conference is being recorded. If you require further assistance, please press Star Zero. I would like to hand the conference over to Chris Carl Sada. Thank you. Please go ahead.
Ladies and gentlemen, thank you for standing by and welcome to the regular Therapeutics 2021 financial results conference call.
This time, all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session.
And that's great question during the session you will need to press star one on your telephone please be advised the today's conference is being recorded.
The car for this instance, please press star zero.
And I'd like to hand, the conference over to Christopher outside the.
Thank you. Please go ahead.
Good afternoon, everyone and thank you for joining us to discuss Regulus Therapeutics first quarter 2021 financial results and corporate highlights Joy.
Unknown Executive: Good afternoon, everyone, and thank you for joining us to discuss Regulus Therapeutics' first quarter 2021 financial results and corporate highlights. Joining me on today's call is Jay Hagan, President and Chief Executive Officer, and Dennis Drygen, the Chief Scientific Officer.
Joining me on today's call and Jay Hagan, President and Chief Executive Officer, and Dennis <unk>, Chief Scientific Officer.
Unknown Executive: Jay will provide opening remarks and share progress on our 80 PKD program, and I will review the financial results before we open the line for questions. Before we begin, I would like to remind you that this call will contain forward-looking statements concerning regular therapeutics, future expectations, plans, prospects, corporate strategy, and performance, which constitute forward-looking statements for the purpose of the Safe Harbor provision under the Private Security Litigation Reform Act of 1995.
Jay will provide opening remarks and share progress on our E. P. J D program and I will review the financial results before we open the line for questions.
Before we begin I would like to remind you that this call will contain forward looking statements concerning regulus therapeutics future expectations plans prospects and corporate strategy and performance.
Which constitute forward looking statements for the purpose of the Safe Harbor provision under the private Securities Litigation Reform Act of 90 to 95.
Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in our filings with the SEC.
Unknown Executive: Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our filings with the SEC. In addition, any forward-looking statements represent our views only as of the date of the webcast and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. I'll now turn the call over to Jay. Thanks, Chris.
In addition, any forward looking statements represent our views only as of the date of the webcast and should not be relied upon as representing our views as of any subsequent date.
We specifically disclaim any obligations to update such statements.
I'll now turn the call over to Jay.
Joseph P. Hagan: Thanks, Chris, and welcome everyone to our Q1 earnings call and business update. Last week, we were very pleased to announce top-line data from the first cohort of patients who completed dosing and follow-up in our ongoing Phase 1B Mechanism of Action Study of RGLS 4326 in patients with ADPKD. We were successful in showing that measured levels of polycystin 1 and 2 increased greater than 50% and 20%, respectively, by the end of the study compared to baseline levels in this short treatment duration study.
Thanks, Chris and welcome everyone to our Q1 earnings call and business update last week, we're very pleased to announce topline data from the first cohort of patients who completed dosing and follow up and our ongoing phase one the mechanism of action study of RG <unk> for three to six in patients with ADP J D.
We were successful and showing that measured levels of poly system, one and two increased greater than 50% and 20% respectively. By the end of study compared to baseline levels in this short treatment duration study.
Joseph P. Hagan: We shared those preliminary results from the available data set because we believe these initial data demonstrate human proof of mechanism that the drug hits the target MIR 17 in the kidney as designed. You may recall that we indicated in the press release that eight of the nine patients had completed the study follow-up, with the remaining ninth patient anticipated in the next couple of weeks. That ninth patient's trends through day 44, or the end of dosing, were very encouraging. And as we complete the overall data analysis and have any material updates, we'll be sure to share them with you.
We share those preliminary results from the available dataset because we believe these initial data demonstrate human proof of mechanism that the drug hits, the target and Mira <unk> 17 in the kidney as designed.
You may recall that we indicated and the press release that eight of the nine patients had completed the study follow up with the remaining ninth patient anticipated and the next couple of weeks.
That night patients trends through day, 44, or end of dosing were very encouraging and as we complete the overall data analysis and have any material updates will be share to share them with you.
We are also planning and earlier scientific presentation at peak and connect in late June of this year with more detailed top line data as well as what we believe our new compelling preclinical data validating the impact of <unk> 43 to six treatments in animal models of the disease.
Joseph P. Hagan: We are also planning an earlier scientific presentation at PKD Connect in late June of this year with more detailed top-line data, as well as what we believe are our new compelling preclinical data valid for the impact of RGLS 4326 treatment in animal models of the disease. Recall that the design of the molecule is to bind a mere 17 in the kidney. This then leads to increased expression of the PKD1 and PK2 genes, and the resultant proteins of these genes code for polycystin 1 and 2.
Recall that the design of the molecule is to bind the mere 17 in the kidney.
This then leads to increased expression of the PK and PD, one and peak at the two genes.
And the result and proteins. These genes encode for polycystic, one and two.
Measured levels of PC, one and <unk> two have been shown to inversely correlates with disease severity and.
Joseph P. Hagan: Measured levels of PC1 and PC2 have been shown to inversely correlate with disease severity and are believed to be directly linked to the underlying genetic drivers of the disease. The overall trend that we saw in polycystin showed increasing levels of both PC1 and PC2 over time, with a sustained effect one month after completion of dosing, suggesting that less frequent dosing could be utilized.
And are believed to be directly linked to the underlying genetic drivers of the disease.
The overall trend that we saw and polycystic showed increasing levels of both PC, one and two over time with the sustained effect one month after completion of dosing, suggesting that less frequent dosing could be utilized.
Understanding patient mutational status may further contribute to understanding impacts on response rates.
Approximately 85% of patients with ADP <unk> are reported to have a mutation in the peak of the one gene with the remaining 15% having the mutation in the <unk>.
Joseph P. Hagan: Understanding patient mutational status may further contribute to understanding impacts on response rate. Approximately 85% of patients with PKD are reported to have a mutation in the PKD1 gene, with the remaining 15% having a mutation in the PKD2G. Additionally, the PICI-1 gene has one predicted binding site for a mere 17, while the PKD2 gene has two predicted binding sites, potentially contributing to differential response rates between the biomarkers. On the safety front, RGLS 4326 was well tolerated by all nine patients with no serious adverse events reported. All reported AEs were mild and generally transient in nature.
Additionally, the PD one gene has one predicted binding site for mere 17, while the peak 82 gene has to predict binding sites potentially contributing to differential response rates between the biomarkers.
On the safety front RJ less force Reto <unk> was well tolerated by all nine patients with no serious adverse events reported.
All reported Aes were mild and generally transient nature.
Overall, the PK profile of RG less force through $2, six and patients with similar to that observed and the prior healthy volunteer study.
Concentrations of the drug and plasma were greater in patients with the C. Max of approximately three micrograms per milliliter relative to healthy volunteers, where the C. Max was approximately two micrograms per milliliter alere.
Which suggests that lower doses may be effective in achieving the desired exposure in the kidney and the target organs of interest.
In this disease or approximately 160000 diagnosed in the U S alone and it is the force leading cause of end stage renal disease.
Joseph P. Hagan: Overall, the PK profile of RGLS 4326 in patients was similar to that observed in a prior healthy volunteer study. However, concentrations of the drug in plasma were greater in patients with a CMAX of approximately three micrograms per milliliter relative to healthy volunteers, where the CMAX is approximately two micrograms per million, which suggests that lower doses may be effective in achieving the desired exposure in the kidney, the target organ of end. This disease, there are approximately 160,000 diagnosed in the U.S. alone, and it is the fourth leading cause of end-stage renal disease.
As I mentioned earlier <unk> is caused by the mutation in either of the peak of the one or <unk> gene.
A mutation in either of these genes and disrupt the normal functions of the encoded proteins play system, one and two and.
And reduces their levels.
And leads to access the proliferation of the kidney epithelium formation of multiple systems, which eventually leads to kidney failure.
50% of <unk> patients eventually develop end stage renal disease, requiring dialysis or transplant by the age of 60.
There is only one recently approved therapy and the U S pointing to the need for new treatment options.
Regulus has evolved the strong foundational technology from its inception for my own us and on the island to develop a specific proprietary kidney targeting technology.
In preclinical models, we have demonstrated that <unk> <unk> six preferentially distribute some of the kidney and collecting duct derived kidney cysts.
Joseph P. Hagan: As I mentioned earlier, ADPKD is caused by a mutation in either the PK1 or PKD2 gene. A mutation in either of these genes disrupts the normal functions of their encoded proteins, polysystem 1 and 2, and reduces their levels, and this leads to excessive proliferation of the kidney epithelium, and the formation of multiple cysts, which eventually leads to kidney failure. 50% of ADPKD patients eventually develop end-stage renal disease requiring dialysis or a transplant by the age of 16.
Treatment with <unk> for three to six inhibits mere 17 function increasing the expression of the PD, one and two genes as well as during COVID-19 proteins polycystic, one and two.
And most importantly.
Slows down and <unk> growth and primary human and ADP <unk> cultures, and multiple ADP <unk> mouse models of the disease.
Additionally, both kidney weight, the body weight and kidney injury markers of reduced compared to untreated mice, both signs of improved kidney health through treatment with this drug and these disease models.
Our ADP <unk> program consists of two compounds.
Our <unk> for three to six the lead molecule, which is being tested and the ongoing phase <unk> study reported last week as well as our next generation molecule, which is moving towards the clinic and should be ready around year end or early Q1 of next year.
Joseph P. Hagan: There is only one recently approved therapy in the U.S., pointing to the need for new treatment options. Regulus has evolved a strong foundational technology from its inception with Ionis and onylam to develop a specific proprietary kidney targeting technology. In preclinical models, we have demonstrated that RJLS 4326 preferentially distributes to the kidney and collecting duck-derived kidney cyst. Treatment with RGLS 4326 inhibits MGLS17 function, increasing the expression of the PKK1 and 2 genes, as well as their encoded proteins, polysystem 1 and 2, and most importantly, slows down cyst growth in primary human ADPKD, cyst cultures, and multiple ADPKD mouse models of the disease.
These molecules are designed to do the same thing and that is inhibits the function of the mere 17 family and micro NACE, which is up regulated and both humans with the disease as well as and mouse models of disease.
So in summary, we are very pleased with these data and look forward to the results from the second cohort later this summer.
And as well as engaging FDA on the remaining hold requirements that would permit us to move for three to six in the phase two and beyond.
The research team at Regulus also continues to advance our platform technology with some exciting earlier stage programs and the laboratory.
And finally before I turn the call back over to Chris I wanted to welcome our recent additions to our board of directors Dr. Alice Wong Dr. Wrong brings an extensive scientific background of the board to help direct the company's drug discovery and development efforts.
Dr. Wong is currently senior faculty associate of Biology, and biologic engineering at the California Institute of Technology. We are pleased to add someone of her caliber to the Regulus Board.
Chris.
Thanks, Jay turning to our financial results, our cash balance totaled $31 6 million at the end of Q1, 2021, which is approximately <unk> 5 million more than our $31 1 million cash balance at the end of Q4 2020.
Joseph P. Hagan: Additionally, both kidney weight to body weight and kidney injury markers are reduced compared to untreated mice, both signs of improved kidney health through treatment with this drug in these disease models. Our ADPKD program consists of two comp.
We expect our cash runway to extend through the first quarter of 2022.
R&D expenses in Q1, 2021, and Q1 2020, we're substantially similar at $3 3 million per Q1, 2021, and $3 1 million for Q1 2020 the.
Joseph P. Hagan: Our GLS 4326, the lead molecule, which is being tested in the ongoing Phase 1B study reported last week, as well as our next generation molecule, which is moving toward the clinic and should be I&D ready around year end or early Q1 of next year. These molecules are designed to do the same thing, and that is to inhibit the function of the MIR 17 family of micronate, which is upregulated in both humans with the disease as well as in mouse models.
These risks these amounts reflect the internal and external costs associated with advancing our clinical and preclinical pipeline.
G&A expenses were $2 $5 million per the first quarter of 2021 compared to $2 4 million for Q1 2020 of these amounts reflect personnel related and ongoing general business operating costs.
Net loss for Q1, 2021, 6 million consistent with the first quarter 2020, net loss of $5 9 million or net loss per share on both a basic and diluted basis decreased two eight per share and the first quarter of 2021 down from the net loss per share.
Joseph P. Hagan: So, in summary, we are very pleased with these data and look forward to the results from the second cohort later in the summer, as well as engaging FDA on the remaining hold requirements that would permit us to move 436 into phase two and beyond. The research team at Regulus also continues to advance our platform technology with some exciting earlier stage programs in the laboratory. And finally, before I turn the call back over to Chris, I wanted to welcome our recent addition to our board of directors, Dr. Alice Wong.
On both a basic and diluted basis of 25 per share and the first quarter of 2020.
With that I will turn the call back over to Jay.
Thanks, Chris we're happy to take your questions the operator to open the lines.
Thank you Sir at this time for the participants to ask a question. Please press star one on your telephone keypad.
We will pause for just a moment to compile the Q&A roster.
Thank you.
Sure.
We have our first question from Chevette the dig your line is open.
Joseph P. Hagan: Dr. Wong brings an extensive scientific background to the board to help direct the company's drug discovery and development efforts. She is currently Senior Faculty Associate of Biology and Biologic Engineering at the California Institute of Technology. We are pleased to add someone of her caliber to the Regulus Board.
Hi, and thank you for myself on the analysts that Kelly. Thank you for taking my question.
Oh boy, the RG and less loyalty plans of cohort one data.
Dana achieved the company's main objective of establishing safety and PK to address clinical hold and establish the proof of concept the biomarker.
Unknown Executive: Thanks, Jay. Turning to our financial results, our cash balance totaled $31.6 million at the end of Q1, 2021, which is approximately $0.5 million more than our $31.1 million cash balance at the end of Q4 2020. We expect our cash runway to extend through the first quarter of 2022. R&D expenses in Q1 2021 and Q1 2020 were substantially similar, at 3.3 million for Q1 2021 and 3.1 million for Q1 2020. These amounts reflect the internal and external costs associated with advancing our clinical and pre-clinical pipeline.
The Dol kind of negative reaction post the data with outs can you provide some thoughts around day.
Sure, Yes, further and we were puzzled by that as well.
Frankly going into the dataset we'd spent.
Significant amount of time with them.
<unk> of our institutional investors setting expectations for what we thought we might see and.
Described that if we saw positive trends and Biomarkers, we think that would be of win because this is a very short treatment duration.
Meaning just six weeks of dosing.
And so to see the magnitude of change that we saw and both PC, one and PC too.
Was very encouraging to us and.
Demonstrating proof of concept and hitting the target and.
As I alluded to and my comments would suggest that just based on the trajectory, which we will be sharing at the <unk> connect conference.
That was continued dosing you would expect it to continue going up.
Unknown Executive: GNA expenses were 2.5 million for the first quarter of 2021 compared to 2.4 million for Q1 2020. These amounts reflect personnel-related and ongoing general business operating costs. The net loss for Q1 2021 was 6 million, consistent with a first quarter 2020 net loss of 5.9 million. Our net loss per share on both a basic and diluted basis decreased to 8 cents per share in the first quarter of 2021, down from a net loss per share on both a basic and diluted basis of 25 cents per share in the first quarter of 2020. With that, I will turn the call back over to Jay.
And so.
Of both markers, we could anticipate going up higher than what was recorded.
At the end of this study of day 71.
Also mentioned the highest levels achieved we're at day 71, which was the full 28 days after completion of dosing.
We've known that the half life of the kidney to approximately two weeks and I think this evidence from a pharmacodynamic standpoint supports that understanding of half life and the human kidney and.
And suggest that less frequent dosing could also the utilized which would be obviously much more advantageous and the commercial setting.
And I just have one follow up question.
Thank you.
Updates from the FDA meeting all of the clinical hold.
Yes, so we plan to reach out to them I think we've said in the past they've been very cooperative.
With us are experienced with them and this division is.
Seems focused on health.
Helping sponsors innovate and areas of significant unmet need and so we plan to reach out to them to better understand should this be a formal and informal process of engaging them on the remaining hold requirements. Initially because we want to get their feedback so it could either be and formal or through a type a meeting.
Joseph P. Hagan: Thanks, Chris. We're happy to take your questions now. Operator, can you open the line? Thank you, sir.
Operator: Thank you, sir. At this time, for the purpose of events, to ask a question, please press Star 1 on your telephone keypad. We will pause for just a moment to compile the Q&A roster. We have our first question from Shveta Dick. Your line is open.
And once we get that we'll be prepared to follow either route.
And in the latter route with the type a meeting we'd be submitting a briefing book at the time of the meeting request. So our timing will will materialize. Once we understand that route. The team is busy now finalizing the modeling with these data and finalizing the touches on a potential briefing book.
Shweta: Hi, this is Shweta speaking on behalf of Leanna Musato. Thank you for taking my question.
And that's why we've guided to sort of of mid summer of interaction with FDA per <unk>.
Joseph P. Hagan: So for the RGLS 436 cohort 1 data, that data achieved the company's main objective of establishing safety and PK to address clinical hold and establish the proof of concept with biomarkers. But the stock had a negative reaction after the data was out. Can you provide some thoughts around that?
Upon request of the type a meeting day of 30 days to grant it.
And so you are set sort of on the clock at that time.
Got it thank you.
We have all of our next question from the Chen Your line is open.
Hi, Thank you for taking my questions Mike.
My first question is.
For patients with the peak of the one gene mutation, which represents 85% of total ADP COVID-19 patients.
Joseph P. Hagan: Sure, yes, Feda. We were puzzled by that as well. You know, frankly, going into the data set, we'd spent a significant amount of time with a number of institutional investors setting expectations for what we thought we might see and describing that if we saw positive trends in biomarkers, we think that would be a win because this is a very short treatment duration, meaning just six weeks of doses. And so to see the magnitude of change that we saw in both PC1 and PC2 was very encouraging to us in demonstrating proof of concept and hitting the target.
Does it matter how.
The much improvement.
Does <unk> 42 to 2006 deliveries for the PC too.
Uh huh.
Expression in order to achieve these improvements.
One could hypothesize that the need in increase and PC to would be less than and PT. One because they don't have a mutation in the peak of the two gene.
And so we.
We've already shared these results with some of our key scientific consultants in the community.
And they are equally enthusiastic for the results and obviously understand the mutational status and they all anticipated debt we're likely the.
Joseph P. Hagan: And as I alluded to in my comments, would suggest that just based on the trajectory, which we will be sharing at the PKK Connect conference, that with continued dosing, you would expect it to continue going up. And so, you know, both markers we could anticipate going up higher than what was recorded at the end of this study at day 71. I also mentioned the highest levels achieved were at day 71, which was a full 28 days after completion of dosing.
These nine patients.
Patients.
Given their Mayo classification of being C's, d's and needs, which is the more and more advanced disease and.
And.
And the reported data that those with the mutation and the PD one gene have more advanced and aggressive disease that these were probably all or nearly all <unk>.
Patients with the PD one mutation.
So.
It is possible debt even for the 2006.
Improve the doesn't increase the.
PC to expression that much.
The trunk of can skew actually achieved.
Joseph P. Hagan: We've known that the half-life in the kidney is approximately two weeks, and I think this evidence, from a pharmacodynamic standpoint, supports that understanding of the half-life in the human kidney and suggests that less frequent dosing could also be utilized, which would be obviously much more advantageous in the commercial setting.
Statistical significance in terms of.
And now.
Achieving the endpoint for Inc.
The patients symptoms with <unk>.
Right.
Yes, here's how I would answer that E. So remember we anticipate this is a chronic treatment that were not going to give 468 doses and it's done and they're cured so right and with the trends that we've observed as I said, we would expect.
<unk>.
Biomarkers to continue to go up with continued treatment.
Reaching statistical significance can be achieved.
Joseph P. Hagan: And I just have one follow-up question. When can we expect updates from the FDA meeting in the clinical halls? Yeah, so we plan to
Through continued dosing or adding more subjects.
Where the disconnect is as well.
And how much does it have to go up to half of clinical benefit there. We have some exciting data and we hope to share soon whereas little of 20% increase in <unk> and <unk> is associated with significant efficacy in animal models.
Joseph P. Hagan: Yeah, so we plan to reach out to them. I think we've said in the past they've been very cooperative with us in our experience with them, and this division seems focused on helping sponsors innovate in areas of significant unmet need.
And obviously, we're pioneering work here of this first in human study with this first in class mechanism.
And the Great News is though we've got a biomarker the downstream of the gene target or the or the micro and a target.
Joseph P. Hagan: And so we plan to reach out to them to better understand whether this should be a formal or informal process of engaging them on the remaining hold requirements initially because we want to get their feedback. So it could either be informal or through a type A meeting. And once we get that, we'll be prepared to follow either route. In the latter route, with a type A meeting, we'd be submitting a briefing book at the time of a meeting request.
That demonstrates that we're hitting the target and having the subsequent genetic changes that this molecule is designed to do.
So how soon can we expect to see results, indicating.
How much increase in the levels of PC, one and or PC too.
And then lead to clinical benefit.
Yes, so we plan to present some data these data at <unk> connect including the trends as well as additional preclinical data.
Joseph P. Hagan: So our timing will materialize once we understand that route. The team is busy now finalizing the modeling with these data and finalizing the touches on a potential briefing book. And that's why we've guided to sort of a midsummer interaction with FDA. Per PDUFA, upon request of a type day meeting, they have 30 days to grant it. And so you're set sort of on a clock at that time. Got it. Thank
What we know is that all of the preclinical validation which is.
And our view and those of our advisors as well as potential strategic partners quite compelling on this novel mechanism to address the disease and with 40 326, we hit the target.
We see increased PD, one and <unk> two expression, we see increased protein levels of polycystic, one and policies to two and all of that is associated with the reduction insist accounts and size and basically arresting the cystic expansion associated with the disease and animal models now and humans we.
Yichin: We have our next question from Yichin. Your line is open. Hi, thank you for taking my questions. My first question is, for patients with the PKD1 gene mutation, which represents 85% of the total 80 PKK patients, does it matter how much improvement does RGS 43226 deliver for the PC?
We have to advance the program to understand.
How long will it take to lead to a change and in total kidney volume, which would likely be the next marker.
Yichin: to expression.
Joseph P. Hagan: expression in order to achieve disease improvement. You know, one
As well as in.
And as well as in.
Joseph P. Hagan: You know, one could hypothesize that the need for an increase in PC2 would be less than in PC1 because they don't have a mutation in the PK2 gene. And so, you know, we've already shared these results with some of our key scientific consultants in the community, and they're equally enthusiastic about the results. And obviously, understanding mutational status, they all are anticipated to be these nice patients given their Mayo classification of being seized, Ds, and E's, which is the more advanced disease, and the reported data that those with the mutation in the PKD1 gene have more advanced and aggressive disease, so these were probably all or nearly all patients with a PKD1 mutation.
And ultimately in GFR, which we would do and a phase II study after this.
And we didn't and this short duration study measure total kidney volume more or you will calculate GFR with just the view that it would take longer treatment duration to see those kinds of impacts but it would also remind you that there are other markers that are indicative of kidney health.
And where we have seen statistically significant improvements in animal models, particularly in.
And Kim one and and Gal and more aggressive animal models of the disease.
And in this study we we shared last week that although eight of the nine patients had and gal levels within the normal range, which is quite broad I would say as well it goes up to two of <unk>.
Units of.
Zero to 72 nanograms per Mil.
And.
We did have one patient that came in the who had nearly twice the upper limit of normal and saw a.
After each dose reduction and and go back to the normal level.
Joseph P. Hagan: It is possible that even 43226 doesn't improve the doesn't increase the performance of the PC.
And it's the net of one so we don't want to make too much out of it but it does beg the question and a larger study or one where you can enrich for some of those markers of kidney damage might you be able to demonstrate efficacy earlier efficacy than than say, a total kidney volume change or of GFR change.
Joseph P. Hagan: PC2 expression that much, the drug can skew actually achieve statistical significance in terms of achieving the endpoint for improving patient symptoms with PKD1 gene mutation. Yeah, here's how I would answer that, E. So, remember, we anticipate this is a chronic treatment that we're not going to give four, six, eight doses, and it's done, and they're cured. And with the trends that we've observed, as I said, we would expect both biomarkers to continue to go up with continued treatment, reaching statistical significance can be achieved, you know, through continued dosing or adding more subjects. Where the disconnect is, well, how much does it have to go up to have a clinical benefit?
Okay.
So and your view, which biomarker of measurements.
We will likely become the primary efficacy end point in the future of phase two trial.
I think the primary.
We're very encouraged with the divisions.
Cooperation with Sanofi.
The igloo debt, where they are can receive accelerated approval on a change and total kidney volume and.
And the phase II study.
So long as they commit to fully enrolling.
A.
Phase III cohort.
That would continue on and the post marketing setting.
For full approval, if they demonstrate a improvement and GFR.
Over over placebo.
And based on our estimates of trial size and design that would be effectively the phase II accelerated portion would be approximately 250 patients.
Joseph P. Hagan: We have, you know, some exciting data, and we hope to share soon, where as little as 20% increase in PC1 and PC2 is associated with significant efficacy in animal models. And, you know, obviously, we're doing pioneering work here, this first in human study with this, you know, first in class mechanism. And the great news is, though, we've got a biomarker that's downstream of the gene target or the microRNA target that demonstrates that we're hitting a target and having the subsequent genetic changes that this molecule is designed to do.
The dose for one year to see that impact on top of the key volume with perhaps an interim look at six months.
And then and.
The additional 250 that would be.
To be added to that for the full approval.
A year after that two years of follow up.
For the GFR.
So that theoretically could be something that could could could be starting for us.
Sometime next year and.
And obviously if were successful.
The successful is addressing the remaining hold requirements and.
We've got.
Alignment with the division as to what.
Joseph P. Hagan: So how soon can we expect to see results indicating how much increase in the levels of PC1 and or PC2 can lead to clinical symptoms?
That pathway it looks like for moving the product quarter.
Got it got it.
Does the company currently and have sufficient capital to fund the operations into 2020 two.
Joseph P. Hagan: Yeah, so we plan to present some data at PKD Connect, including the trends, as well as additional preclinical data. What we know is that all of the preclinical validation, which is, you know, in our view and those of our advisors, as well as, you know, potential strategic partners, quite compelling in this novel mechanism to address the disease. And with 4326, we hit the target.
Yes, I think as Chris mentioned in her prepared remarks, we ended the first quarter with more cash we ended the year with and so.
Youll see and our and our quarterly filing that we had.
Utilize the ATM in the earlier.
Part of the quarter.
And we're able to add to the balance sheet. So we haven't changed our guidance that we've got cash through Q1, but you can imagine we're burning right now about.
$2 million of bumps and we got $31 million nearly $32 million of the balance sheet. So.
Joseph P. Hagan: We see increased Pek1 and PKD2 expression. We see increased protein levels of polycystin 1 and polycystin 2. And all of that is associated with a reduction in cyst count and size, and basically arresting the cystic expansion associated with the disease in animal, Now in humans, we obviously have to advance the program to understand, you know, how long will it take to lead to a change in total kidney volume, which would likely be the next marker, as well as in, as well as in, you know, ultimately in GFR, which we would do, you know, in a phase two study after this, you know, we didn't, in this short duration study, measure total kidney volume or, you know, calculate GFR with just a view that it would take longer treatment durations to see those kinds of impacts.
My quick math would suggest that thats.
16.
The 16 months or sales.
Got it.
And that's all thank you and without without raising any additional capital right.
Alright, great. Thank.
Thank you.
Thank you.
We have our next question from Jan and Jim Your line is open.
Hi, Thanks for taking my questions and.
So the first question you mentioned continued dosing may further increase the.
The effect the on the PD markers.
When might be the opportunity to see that.
I mean after this the.
The current study the three cohorts, which are all have the same duration.
Is there an opportunity to have a another study to have a longer duration, but.
Not necessarily the the kind of the final.
The Registrational study of that that you've just mentioned.
The we've thought a lot about the euro and that's a really good question what additional derisking could we do at a given dose level and we've considered that after we discuss these results with FDA.
Joseph P. Hagan: But it would also remind you that, you know, there are other markers that are indicative of kidney health where we have seen statistically significant improvements in animal models, particularly in Kim 1 and Ngal, in more aggressive animal models. And in this study, we shared last week that although eight of the nine patients had Engal levels within the normal range, which is quite broad, I would say, as well, it goes up to units of 0 to 72 nanograms per mill. We did have one patient that came in, though, who had nearly twice the upper limit of normal and saw a, you know, after each dose, reduction in Engau back to the normal level.
Perhaps we take an interim step of doing call. It three months study at.
And at a certain dose level to see additional markers and.
And.
So that's all under consideration.
Okay.
Got it and then.
You mentioned the and Gal.
But also I think you.
Attract 10 one.
Could you talk a little bit about the findings on the King one in terms of the baseline and also any changes for all of the patients.
Yes.
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Still of the process of analyzing those data, but I think as Dennis.
Talking with me here internally, we would anticipate that those are probably of all likely within the normal range as well that.
That marker as well as and Gal is used to diagnose acute kidney injury and.
Joseph P. Hagan: And, you know, it's the end of one, so we don't want to make too much out of it. But it does beg the question, in a larger study or one where you can enrich for some of those markers of kidney damage, might you be able to demonstrate efficacy, earlier efficacy, than say a total kidney volume change or a GFR change.
The <unk> that we would suspect would come if we enriched for patients that were even more advanced and their disease.
Right, Okay and then.
You are I think only of our last call you'd mentioned two of the nine patients.
Yichin: So in your view, which bow marker or measurement will
Joseph P. Hagan: will likely become the primary future face of two. I think the primary, you know, we're very encouraged by the divisions, cooperation with Sanofi on Van Gloustad, where they are, can receive an accelerated approval for a change in total kidney volume in a phase two study, so long as they commit to fully enrolling a phase three cohort, that would continue on in the post-marketing setting for full approval if they demonstrate an improvement in GFR over placebo.
Hum.
Have a PC to increase more than 50%.
So that certainly looks consistent with your estimate of 15 per cent of the patient might be PC true mutations of course, you would do the phenotype and genotype and millwork or look for the.
The the past and molecular diagnosis to pinpoint and that but before.
That data is available and just wondering.
Joseph P. Hagan: And, you know, based on our estimates of trial size and design, that would be effectively the phase two accelerated portion would be approximately 250 patients dosed for one year to see that impact on total K volume, with perhaps an interim look at six months. And then an additional 250 that would be added to that for the full approval, you know, a year after that, two years of follow-up for the GFR. So that theoretically could be something that could start for us sometime next year. And, you know, obviously, if we're successful in addressing the remaining hold requirements, and we've got, you know, alignment with the division as to what that pathway looks like for moving the product forward.
The two patients what's their PC, one increase look like.
And if the <unk> also.
It was also and we'll share all of this at the.
Upcoming scientific conferences, but they also had an.
Increase and PC one debt was quite notable.
Wasn't as if the.
The.
PCT goes up and PC one doesn't go up they had those patients had low low baseline levels of both too.
I see.
And lastly, and maybe can you give a sense of.
The PC one patient for example.
The level.
The level of PC wires and PC too.
Relative to the normal level.
It's approximately.
I think three to five fold lower.
In patients with the disease.
Then in healthy volunteers, and we have that on our investor deck and where.
And you could see that its variable amongst the disease severity.
The lower of the level of polycystic.
Joseph P. Hagan: Does the company currently have sufficient capital to fund operations into 2022? Yeah, I think, as Chris mentioned in her prepared statement.
It looks to clearly correlate with the higher disease burden as measured by how the adjusted total kidney volume.
And so and we see that so the most advanced patients with.
Joseph P. Hagan: Yeah, I think Chris mentioned in her prepared remarks that we ended the first quarter with more cash we ended the year with. And so, you'll see in our quarterly filing that we utilized the ATM in the earlier part of the quarter. And we're able to add to the balance sheet. So we haven't changed our guidance that we'll have cash through Q1, but you can imagine we're burning right now about $2 million a month, and we have 31 million, nearly 32 million on the balance sheet. So, you know, my quick math would suggest that that's months or so. Yeah. And that's obviously without raising any additional capital.
<unk> E mail classification and have the lowest levels of polycystic.
And then amongst healthy and you've got.
Quite a bit of variability so.
The trend of up we think is good and we believe it is good and.
And we know that.
And with fairly minimal changes, we see an impact and animal oils.
Great just a quick clarification.
Or a PC one patient piece of one mutation patient.
And.
And it's a piece of <unk> two down.
For the.
The decreased similar or piece of why is down much more than PC too.
PC, one tends to be more down than PCT piece of two is.
More of abundant.
Operator: We have our next question from Yananzu. Your line is open.
And as you I think know these form these hetero dimers and a ratio of one to three.
Yananzu: Hi, thanks for taking my question. So first question, you mentioned continued dosing may further increase the effect on the PD markers. When might the opportunity to see that occur?
And of colleagues just did one and poly system too and then.
And our symbol of on cilia and involved in flux.
Got it and my last question is.
Joseph P. Hagan: I mean, after this, the current study, the three cohorts, which all have the same duration, is there an opportunity to have another study for a longer duration, but not necessarily the kind of a fine or registration or Yeah, we've thought a lot about that, Yana, that's a really good question. You know, what additional de-risking could we do at a given dose level? And we've considered that, you know, after we discussed these results with FDA, perhaps we should take an interim step of doing a, call it, a three-month study at a certain dose level to see additional markers. And so that's all under consideration. Got it. And then you mentioned Engel. But also, I think you should attract Kim one.
With regard to the assay that you use to measure of piece of MPC too on the Exosomes.
And it gets out of the assay I understand it's the immuno assay does that is that.
Hey.
Does that also pick up of the mutant.
Form of the protein.
Yes on the less the mutant.
Paul truncation of mutations, but could there be a possibility that the part of.
Part of the truncated protein or a point mutation protein and get expressed on the excess of them and being detected by the assay.
This is Dennis <unk> and the CSO and I'll take this question. So we have just recently had the kind of conference with key opinion leaders in the field and they told us that they do not believe are there is there is no evidence that any of those truncated proteins.
Hanging around enough basically there is because of their nature. There is stability is very low and they are being rapidly degraded.
Joseph P. Hagan: Could you talk a little bit about the findings on Kim 1 in terms of the baseline and also any changes for all. Yeah, we're still in the process of analyzing those data, but I think Dennis is talking with me here internally. We would anticipate that those are probably all likely within the normal range as well. You know, that marker, as well as Engel, is used to diagnose acute kidney injury. And, you know, that we would suspect would come if we enriched for patients that were even more advanced in their disease. Right?
Yes, so the Elijah wood.
And so we would expect to realize it.
Yes.
Okay, great. Thank you.
Thank you.
There are no further questions at this time.
And I would like to turn the call over back to Jay Hagan.
Great. Thank you and thanks, everyone for joining us today I do want to mentioned on the Investor front, we will be participating and oppenheimer's upcoming rare and orphan disease Summit later next week and we appreciate your time and support of Regulus. Thank you the.
Yananzu: And then you, I think on your last call, you mentioned two of the nine patients have PC2 increases of more than 50%. So, you know, that certainly looks consistent with your estimate of, you know, 15% of the patients might have PC2 mutations. Of course, you would do the genotyping work or look for the past molecular diagnosis to pinpoint that, but before that data is available, just wondering in those two patients, what their PC1 increase looks like. I guess, if they...
That concludes the call.
Ladies and gentlemen. This concludes today's presentation. Thank you for participating you may now disconnect.
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Joseph P. Hagan: It was also, and we'll share all this at the upcoming scientific conferences, but they also had an increase in PC1 that was quite notable. It wasn't as if the, you know, PC2 goes up, and PC1 doesn't go up. They had those patients had low, low baseline levels of both, too. And lastly, maybe you could give a sense of, in a PC1 patient, for example, what's the level of PC1 and PC2, relative to the normal level?
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Joseph P. Hagan: It's approximately, I think, three to five-fold lower in patients with the disease than healthy volunteers. And we have that on our investor deck, Yon, where you can see that it's variable amongst the disease severity. The lower the level of polycystin looks to clearly correlate with the higher disease burden as measured by height-adjusted total kidney volume.
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Yananzu: And so, and we see that the most advanced patients with, you know, one e-male classification have the lowest levels of polysistants. And then amongst healthies, you know, you've got, you know, quite a bit of variability. So the trend of going up, we think, is good, and we believe it is good. And we know that, you know, with fairly minimal changes, we see an impact on animal laws. Right, just a quick clarification. For a PC1 patient, a PC1 mutation patient, is a piece of cake.
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Joseph P. Hagan: is PC1, PC2 down through the decreased similar, or PC1 is down much more than PCT? PC1 tends to be more down than PC2. PC2 is more abundant. And as you probably know, these form these heterodimers in a ratio of 1 to 3 of PolySystem 1 and Polysystem 2, and then they are assembled on cilia and involved in flux. Got it. And my last question is... with regard to the essay that you use to measure PC1, PC2 on the exosome, if that assay, I understand it's an immune assay, did that, if that essay,
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Yananzu: Does that also pick up the mutant?
Dennis Dredge: form of the protein, I guess unless the mutant is all truncation mutations, but could there be a possibility that part of the truncated protein or a point mutation protein gets expressed on the exosome and is detected by the essay? Thanks.
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Dennis Dredge: This is Dennis Dredge, and the CSO will take this question. So we have just recently had a teleconference with key opinion leaders in the field, and they told us that they do not believe, or there is no evidence, that any of those truncated proteins are hanging around enough. Basically, because of their nature, their stability is very low, and they are being rapidly degraded. Yeah, so the Eliza wouldn't.
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Dennis Dredge: Yeah, so the Eliza wouldn't, we wouldn't expect the Eliza. Yes. Okay, great. Thank you.
Operator: There are no further questions at this time, and I would like to turn the call over to Jay Higgan.
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Joseph P. Hagan: Great, thank you, and thanks everyone for joining us today. I do want to mention on the investor front that we'll be participating in Oppenheimer's upcoming Rare and Orphan Disease Summit later next week, and we appreciate your time and support of Regulus. Thank you. Thank you, thank you. Ladies and gentlemen, this concludes today's presentation. Thank you for participating. You may not just be coming.
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