Q2 2021 Rocket Pharmaceuticals Inc Earnings Call
Welcome to the rocket Pharmaceuticals incorporated Investor Conference call.
Operator: the Rocket Pharmaceuticals Incorporated Investor Conference Call. My name is Vanessa, and I will be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. If you have a question, you can enter the queue by pressing star, then one on your touch-tone phone.
My name is Vanessa and I will be your operator for today's call at.
At this time all participants are in a listen only mode. Later, we will conduct a question and answer session.
If you have a question you can enter the queue by pressing Star then 1 on your Touchtone phone.
Mayor Cassetti: I will now turn the call over to your host, Mayor Cassetti, Director of Business Development and Operations. Thank you, Vanessa. Good afternoon, everyone.
I will now turn the call over to your host.
Eric and study director of business development and operations.
Thank you Vanessa.
Good afternoon, everyone. This is my ear to study director of business development and operations and Investor Relations lead at rocket Pharmaceuticals.
Maier Kassetti: This is Maier Kassetti, Director of Business Development and Operations and Investor Relations Lead at Rocket Pharmaceuticals. Thank you for joining us. The purpose of this call is to share and discuss key updates on our clinical program. Before we begin, I would like to briefly discuss the use of forward-looking statements in this conference call. Statements we make on this call may include statements which are not historical facts and are considered forward-looking within the meaning of the securities laws and which are usually identified by the use of words such as anticipates, believes, estimates, expects, intends, may, plans, projects, seeks, should, will, and variations of such words or similar expressions.
Thank you for joining us.
Purpose of this call is to share and discuss key updates on our clinical programs.
Before we begin I would like to briefly discuss the use of forward looking statements on this conference call.
Statements. We make on this call may include statements, which are not historical facts and are considered forward looking within the meaning of the securities laws and which are usually identified by the use of words, such as anticipates believes estimates expects intends may plans projects seeks.
Should will and variations of such words or similar expressions.
Maier Kassetti: We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements reflect our current views about our plans, intentions, expectations, strategies, and prospects, which are based on the information currently available to us and on assumptions we have made.
We intend these forward looking statements to be covered by the safe Harbor provisions for forward looking statements contained in section 27, a of the Securities Act and section 21 E of the Securities Exchange Act and are making this statement for purposes of complying with those safe Harbor provisions.
These forward looking statements reflect our current views about our plans intentions expectations strategies and prospects.
Which are based on the information currently available to us and on assumptions we have made.
Maier Kassetti: Although we believe that our plans, intentions, expectations, strategies, and prospects, as reflected in or suggested by those forward-looking statements, are reasonable, we can give no assurance that the plans, intentions, expectations, or strategies will be attained or achieved.
Although we believe that our plans intentions expectations strategies and prospects as reflected in or suggested by those forward looking statements are reasonable and we can give no assurance that the plans intentions expectations or strategies will be attained or achieved.
Maier Kassetti: Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control, including, without limitation, those set forth in our earnings release issued earlier today and in item 1A, risk factors, of our annual report on Form 10K for the year ended December 31st, 2020, and as updated by our subsequently filed quarterly reports on Form 10Q and our other SEC filings. be filed We assume no obligation to publicly update any forward-looking statements, whether as a result of new information, future events, or otherwise.
Furthermore, actual results may differ materially from those described and the forward looking statements and will be affected by a variety of risks and factors that are beyond our control, including without limitation those set forth and our earnings release issued earlier today and in item 1 a risk factors of our annual report on form 10.
K for the year ended December 31, 2020, and as updated by our subsequently filed quarterly reports on form 10-Q, and our other SEC filings.
We assume no obligation to publicly update any forward looking statements, whether as a result of new information future events or otherwise.
Maier Kassetti: Participating on today's call on behalf of Rocket are our Dr. Garouv Shum, Chief Executive Officer, Dr. Jonathan Schwartz, Chief Medical Officer and Clinical Development Senior Vice President, Dr. Guy Thrie Rowe, Chief Development Officer and Head of Regulatory Policy, Carlos Garcia, Chief Financial Officer, and Claudine Proust, Senior Vice President of Strategy and Corporate Development. There will be a question and answer session at the end of this call in which we will all participate. I will now turn the call over to GARO. Thank you, Mayor, and thank you everyone for joining us today. We have several updates to take you through. Let me highlight the four key take-home sports.
Participating on today's call on behalf of rocket or Dr. <unk> Shah Chief Executive Officer Dr.
Dr. Jonathan Schwartz, Chief Medical Officer, and clinical development Senior Vice President.
Dr Guide through Brown, Chief Development Officer, and head of regulatory policy Carla.
Carlos Garcia, Chief Financial Officer, and quality and price senior Vice President of strategy and corporate development.
There will be a question and answer session at the end of this call and which we will all participate.
I'll now turn the call over to Garth.
Thank you <unk> and thank you everyone for joining us today.
We have several updates to take you through let.
Let me highlight 4 key take home store today.
Gaurav Shah: First, regarding the Danny Clinic, we are reiterating our previous guidance that, based on our most recent FDA interaction and exercising the best of our judgment and estimation, we continue to anticipate resuming the trial this quarter. Again, the low dose is demonstrating increasing and durable benefits. We will go over key data points, including some B1. Third, for Danin, we are removing the high dose from future dosing plans. Fankonia, Nedia, LAD1, and P-KD remain on track, and we will provide further clinical updates. Those are the key takeaways. We'll now get into some work, starting with Dan.
First regarding the data and clinical we are reiterating our previous guidance based on our most recent FDA interactions and exercising the best of our judgment and estimation. We continue to anticipate resuming the trial this quarter Q3.
Second.
Forget the low dose is demonstrating increasing and durable.
We will go over key data points, including some new ones.
Third for that and we are removing the high dose from future dosing plants.
4.
Iconium EMEA led you'd want and PKU remains on track and we will provide further clinical updates in Q4.
Those are the key takeaways will now get into some more detail.
Parting with them.
We've been working very closely with the FDA over the last several weeks and through our discussions we have agreed to modify our immune suppression and complement inhibition protocols to bolster safety guardrails.
Gaurav Shah: We've been working very closely with the FDA over the last several weeks, and through our discussions, we have agreed to modify our immune suppression and complement inhibition protocols to bolster safety guard. In addition to these protocol updates, we've had a chance to review updated low-dose data with the FDA that Rocket believes is supportive of its potential as a viable phase two dose. Notably, photographic evidence for all three low-dose patients shows improvements, meaning a decrease in autophagic vacuoles, a hallmark of Danden Disease Pathology, as assessed by electron microscopy of cardiac tissue via endomyocardial biocartial biopause.
In addition to these protocol updates we've had a chance to review updated and low dose data set with the FDA that rocket beliefs and supporters of its potential as a viable phase 2 dose.
Notably <unk>.
Photographic evidence for all 3 logos patients show improvements being decreased and our Beijing vacuoles, a hallmark of data and disease pathology.
First by electron microscopy of cardiac tissue and the Atkins and myocardial biopsy.
Gaurav Shah: Additionally, two of the three low-dose patients with closely monitored immunosuppressive regimen compliance demonstrated improvements in New York Heart Association class from 2 to 1, which translates to no impairment. These patients also demonstrated a substantial improvement in a key marker of heart failure, BMP, which decreased by 75 and 79% versus baseline levels, as well as improvements in cardiac output by 35 to 62% compared to baseline as measured by invasive hemoglobinase. All three treated low-dose patients continue to demonstrate stabilization or improvements in the BFP 6-minute walk test as well as New York. Given the activity observed in the patients in the low-dose cohort and importantly to mitigate associated safety concerns in the E14 range, we have decided to forego pursuit of the higher doses, meaning 1.1E4T vector genomes per kilogram or higher.
Additionally.
2 of the 3 low dose patients and closely monitor immunosuppressive regimen and compliance demonstrated improvements in New York Heart Association class from 2 to 1 which translates to know compartments and box.
These patients also demonstrated substantial improvements are a key marker of heart failure, DMT, which decreased by 75, and 79% versus baseline levels as well as improvements in cardiac output by 35% to 62% compared to baseline as measured by and basically hemodynamics.
All 3 accretive low dose patients continue to demonstrate stabilization or improvement and VIP 6 minute walk test as well as New York Heart Association class.
Given the activity observed in patients and the low dose cohort.
And importantly to mitigate and associate safety concerns and we eat and 14 range, we have decided to forgo pursuit of the higher doses, meaning $1.1 billion 14 vector genomes per kilogram or higher.
Gaurav Shah: This is a decision that was made in agreement with the FPA and allows us to focus fully on the low dose moving forward. The 6.713 also reduces the total number of patients needed in our phase one study and potentially allows for more rapid progression to phase 2. Now, as disclosed in December 2020, one patient in the high-dose cohort who was the heaviest patient treated today who had highly advanced disease developed complement-mediated thrombotic microangiopathy, which resolved fully with transient hemogialysis.
This is a decision that was made in agreement with the FDA and allows us to focus fully on the low dose moving forward..6 713 also reduces the total number of patients needed and our phase 1 study and potentially allow us to more rapid progression to phase III.
Now as disclosed in December 2021, patient and the high dose cohorts and we have.
And your patient treated to date.
The advanced disease develop complement mediated thrombotic microangiopathy, which resolved fully with transit you can look out.
Gaurav Shah: This patient continued to have progressive disease considered unrelated to gene therapy by the trial investigator as well as transplant cardiologists and successfully went on to receive a heart transplant. The patient is currently doing well, clinically, and, of course, resolution of his baseline biopathy that was present prior to treatment.
This patient continues to have progressive disease considered unrelated to gene therapy by the trial investigator as well as transplant cardiologist and successfully went to answer and receive a heart transplant.
The patient is currently doing well clinically and of course the resolution of this baseline biopsy that was present prior to treatment.
Gaurav Shah: Analysis of the explanted part demonstrates fibrosis that was consistent with end-stage data. Our belief has always been that the onset of fibrosis in the year or so prior to transplant could diminish the efficacy of gene therapy, and this patient exemplifies the importance of earlier intervention in this disorder. We at Rocket do not consider this a safety issue, and it is not considered related to the home.
Analysis of the X blended part derma.
Demonstrated by growth that was consistent and state batten disease.
Our belief has always been that the onset of fibrosis and the year or so prior to transplant could diminish the efficacy of gene therapy and this patient exemplifies the importance of earlier intervention and this disorder.
We had rocket do not consider this a safety issue and it is not considered and related to the whole.
Gaurav Shah: We believe it does highlight the importance of the right timing in order for gene therapy to be fully effective. In discussions with the FDA on this case, we have refined their eligibility criteria to focus on patients earlier in this process. Now, importantly, as of this past week, we have submitted all requested changes to the FDA and have confirmation that we have agreement on the updated program. As mentioned, we expect that we can resume the trial in Q3 with the revised eligibility criteria in place and refined safety measures.
We believe it does highlight the importance of the right timing and order for gene therapy to be fully effect.
In discussions with the FDA on this case, we have refined our eligibility criteria to focus on patients earlier in disease.
Now importantly, as of this past week, we have submitted all requested changes to FDA and have.
Confirmation that we have agreement on the updated protocol.
As mentioned, we expect that we can resume the trial and Q3 with the revised eligibility criteria and place and refine safety measures in place.
Gaurav Shah: Moving forward, we have received interest from more than 20 patients for participation in the trial, and we look forward to progressing rapidly toward phase one completion and a phase two registration. One final point on Dan, throughout the duration of this hold, we have had an exceptionally collaborative discussion and dialogue with people. And with our confidence in the low dose and the modifications to our clinical trial protocol, we are truly excited about the prospects of our DANID program and look forward to presenting longer-term data on both the low and higher dose patients in the fourth quarter of. Now, turning to our Lentiviral programs.
Moving forward, we have inbound interest for more than 20 patients for participation and the trial and we look forward to progressing rapidly towards phase, 1 and completion and the phase II registration trial.
1 final point on that throughout the duration of this hold we would have had exceptionally collaborative discussions and dialogue with the agency.
And with our confidence and the low dose and a modification to our clinical trial protocol. We are truly excited about the prospects of our data program and look forward to presenting longer term data on both the low and higher dose patients and the fourth quarter of this year.
Now turning to our lengthy viral programs, we've provided updates and <unk> for our fans and Tony Indian led day, 1 and PK day programs and continue our momentum towards regulatory filings.
Gaurav Shah: We've provided updates at ASGCP for our Phantonia, LAD1, and PKD programs and continue our momentum towards regulatory for our final lending program. We are deeply saddened that the first patient treated in our infantile malignant osteocotrosis phase one trial has passed away from likely non-gene therapy-related pulmonary complications, with autopsy confirmed evidence of pulmonary hemorrhage that was very likely related to paroptimpedia following conditioning It is also related to underlying osteoctrosis.
For our final Lindsay program, we are deeply pattern that the first patient treated and our infantile malignant osteopetrosis phase 1 trial has passed away from likely non gene therapy related pulmonary complications.
Autopsy confirmed evidence of.
Of pulmonary hemorrhage and was very likely related to thrombocytopenia following conditioning therapy and also related to underlying osteopetrosis.
Claudine Proust: Of note, pulmonary complications occur more commonly in osteopatrosis patients relative to many other non-malignant immunologic diseases, especially in those patients who are undergoing, Consistent with the protocol, we have pausing role, ending a comprehensive evaluation in collaboration with an independent data monitoring, We look forward to providing updates in all of our programs in the fourth quarter of 2020. And finally, as many of you may know, Claudine Krause will be transitioning out of rocket to take on a CFO role at another, Buddy has been with Rocket for three and a half years and has been an integral part of our growth story from the days of ImitTech for those who were there then, from private to a mid-cap public, While we are, and I personally am sad to see Kudin leave us, we are tremendously excited for her and sincerely thank her for her contributions here, a rocket.
Of note pulmonary complications occur more commonly and.
After petros as patients relative to many other non malignant hematologic diseases, especially in those patients who are undergoing a transplant.
Consistent with the protocol, we have paused enrollment and.
And being a comprehensive evaluation and collaboration with an independent data monitoring monitoring committee.
We look forward to providing updates and all of our programs and the fourth quarter of 2021.
And finally as many of you may know Claudine Kraus will be transitioning out of rocket to take on the CFO role at another company.
But he has been with rocket for 3 and a half years and has been and integral part of our growth story from the days of <unk> for those who are there then.
Private for a mid cap public company.
We are and I personally and stat to speak on in vivo.
We're tremendously excited for her and sincerely. Thank her for her contributions here a rocket.
Claudine Proust: I'll pass it to Kaudine. Thank you, Gara. Looking back, Brockett has had extraordinary growth, gone public, and the company has already delivered a lot of value to shareholders, and I look forward to seeing Rockets continue success in the future over the long term. I am so truly grateful to be part of this journey. Mayor.
Passenger quality.
Yes.
Thank you Gaurav.
Looking back rocket has had extraordinary growth.
Since going public the company has already delivered a lot and value to shareholder.
And I look forward to seeing rocket continued success and the future over the long term I am truly grateful to the part of this journey.
Sure.
Mayor Cassetti: Thank you, Claudine. That concludes our prepared remarks. The Rocket Executive Team is now happy to address any questions on this update. I'll turn the call back over to the operator for Q&A. And thank you. We will now begin our question and answer session, Sesson. With your question, please press star, then one on your Tuscone phone to enter the queue. If you wish to be removed from the queue, you can press the pound sign or the hash key. If you're using a speakerphone, please pick up the handset first before pressing the numbers.
Thank you Claudine.
This concludes our prepared remarks, the rocket executive team is now happy to address any questions on this update I will turn the call back over to the operator for Q&A.
And thank you we will now begin our question and answer session with your question. Please press Star then 1 on your Touchtone phone to enter the queue. If you wish to be removed from the queue. You can press the pound sign or the Haskins, if youre using a speakerphone. Please pick up the handset first before pressing the numbers and the interest of time.
Operator: In the interest of time, we ask that you please limit yourself to one question and one follow-up question, and we thank you. Our first question is from Greg Harrison with Bank of America. Please go ahead. Hey guys, this is Aspen on behalf of Greg.
We ask that you please limit yourself to 1 question and 1 follow up question and we thank you. Our first question is from Greg Harrison with Bank of America. Please go ahead.
Hey, guys and because Aspen on for Gregg. Thanks for the questions. So it seems like you are pretty much aligned with FDA at this point for resuming denim.
Aspen: Thanks for the questions. So it seems like you're pretty much aligned with FTA at this point for restarting Dan. And I guess is there anything else that needs to be done before getting that study started? And just to kind of tack on to that a little bit, with this upcoming AVA gene therapy atcom with F50A, is there any chance that's a gaining factor? And if not, just what are your general expectations for that atcom? Thank you. Hi, Gorop here.
I guess and is there anything else that needs to be done before getting that study started.
And just to kind of tack onto that a little bit.
With this upcoming AAV gene therapy icon with Epic day is running is there any chance that the gating factor.
And it's not just what are your general expectations for that outcome.
Hi, <unk>. Thanks for the question so as of last week.
Gaurav Shah: Thanks for asking questions. As of last week, we have confirmation of no further clinical context to protocol. We respect the FDA process, and we're waiting for the FDA to complete this full review. And that's what we can stay at the moment.
We have confirmation of no further clinical comex and the protocol, we respect the FDA process.
And we're waiting for the FDA to complete their full review.
And.
And that's what we can stay at the moment with regard to the upfront and Advisory Committee meeting I will actually pass this over to Dr Guide and route who is 1 of the rocket executive team members and who I think they know what's ahead of the office of orphan drug products for 7 years and the FDA and are now working with this Patrick.
Gaurav Shah: With regard to the upcoming advisory committee meeting, I will actually pass this over to Dr. Guy T. Rowe, who is one of the rocket executive team members and who, as you may know, was head of the Office of Orphan Drug Products for seven years at the FDA, and he's now working on this. Thanks for us. Hi, everybody. This is Guy Rowe.
Thanks, Thanks, Chris.
Thank you Ralph and to answer the specific question related to <unk>.
Guy T. Rowe: To answer the specific question related to the advisory committee meeting, as far as we know, we really have no reason to believe that there's any sort of relationship between this clinical hold and the timing of the advisory committee meeting, and it's certainly inconsistent with all the communications that we've had with the agency to date. With respect to the meeting, you know, we're looking forward to engaging in the meeting and listening and learning from the discussion there. Okay, thank you. Thank you. Our next question is from Deghan Ha with People. Great, good afternoon.
The Advisory Committee meeting and as.
As far as we know.
And we really have no reason to believe that there is any sort of relationship between this clinical hold.
And the timing or the Advisory Committee meeting and certainly and consistent with all of the communications that we've had with <unk> today and with respect to the meeting itself.
We're looking for.
To engaging and the meeting unless things change and the discussion there.
Okay. Thank you.
And thank you. Our next question is from Dae Gon ha with Stifel.
Great Good afternoon, and thanks for taking our questions on the thrombotic microangiopathy.
Deghan Ha: Thanks for taking our questions. On thrombotic microangiopathy, are you able to discuss the details behind the reclassification as Sussar? And I guess does that have anything to do with, you know, or has that been reflected in the mitigation strategy as you submitted it last week? And I guess a follow-up to that is, you know, on the May call, you talked about two buckets as it pertains to the resumption of the trial. that being risk mitigation and eligibility criteria. So has anything changed in your view, or anything in that proposal changed since that may update? Thanks, Gawkes.
Are you able to discuss the details behind the reclassification as 2 Saar and I guess does that have anything to do with.
Or has that been reflected and the mitigation strategy as you are.
As you submitted it last week and I guess, a follow up to that is in the May call you talked about 2 buckets as it pertains to the resumption of the trial that'd be and risk mitigation and eligibility criteria. So has anything changed and your view or anything and that proposal changed since that may update thanks Scott.
Absolutely.
Gaurav Shah: Absolutely. So the Sussar Re-Oxification was based on recent guidance that we've gotten from the agency. And it is reflected in certain protocol changes that will, in the future, define such events as SUARs. I think that's the bottom line.
The.
<unk>.
Reclassification was based on.
Recent guidance that we've gotten from the agency.
And it is reflected and certain protocol changes that will and the future defined such events as you saw us I think thats the bottom line and it's really part of the tightening of protocol measures and safety monitoring and with regard to what we had said in may.
Gaurav Shah: It's really part of the tightening of protocol measures and safety monitoring. And with regard to what we had said in May, it's the same thing. We have defined these monitoring parameters more closely.
It's the same thing we have defined these monitoring parameters more closely we define handling and we've tightened some of its safety guardrails and ground immune suppression and cultural inhibition and.
Gaurav Shah: We've defined handling of SAEs. We've tightened some of the safety guardrails around immune suppression and complemented emission and slightly refined the eligibility price to focus slightly earlier in treatments and avoid end-stage disease patients. Those are the same points that we had anticipated in May, based on the initial FDA call, and they remained the exact same. Thank you very much. And thank you. Our next question is from Gil Bloom with Needham and Company. Good afternoon, and thank you for taking our question.
Slightly refine the eligibility criteria.
<unk> focus slightly earlier 3 book that avoid and pages. These patients.
The same points of yet and.
Dissipated and be based on the additional FTE and call and they remain the exact state.
Thanks very much.
And thank you. Our next question is from Gil Blum with Needham <unk> company.
Good afternoon, and thank you for taking our question.
Gil Bloom: Just about the death that happened in the IMO study, are there really any significant differences between the conditioning regimen seen in transplant in these patients versus gene therapy? Thank you. You mean versus other gene therapy? No, just versus the medical edict stem cell transplant, which is sometimes used as the standard of care. Is there any difference between the conditioning used in osteopatrosis gene therapy versus osteopatrosis transase? Brett Correct. I'll pass that on to Dr. Jonathan Schwartz. Hi, this is Jonathan Schwartz. The conditioning regimen that's used in the osteopatrosis gene therapy study is mylo-abletive bisulfan.
And just about the Dustin Hoffman and the AML study is there really any significant differences between the conditioning regimen and sing and transplant and these patients versus the gene therapy.
And.
Perfect you mean versus other gene therapies.
No just versus them adequate extensional transplant, which is sometimes called me as the standard of care.
Got it.
Are there any differences between the conditioning used and after the <unk> gene therapy versus osteopetrosis transplant and Thats, what youre asking.
Correct Yep.
I'll pass that over to Dr. Jonathan Schwartz.
Hi, This is Jonathan Schwartz.
The the conditioning regimen, that's used and the Osteopetrosis gene therapy study is.
Jonathan Schwartz: That's governed by pharmacokinetic guidance or TBE.
Milo ablative.
Installed fan.
And that's.
Jonathan Schwartz: governed by pharmacokinetic guidance or TDM, therapeutic drug monitoring. In general, this is a less extensive, mild suppressive, and less extensive immunomodulatory regimen that would be utilized in an allergenic transgenic animal for this condition. Typically, your allergenic transplant regimens will utilize combinations of myelobelative therapy, sometimes that's sulfhenicoplastromy, the total biarradiary radiation, and different chemotherapy regimens, and then they also utilize immunosuppressive or lymphosopor therapies as well.
Governed by pharmacokinetic guidance with TD and therapeutic drug monitoring.
In general this is a less.
Extensive.
Myles suppressive and less extensive immuno module at Torrey regimen, and that would be utilized and allogeneic transplant.
And for this condition typical year allogeneic transplant.
And as we'll utilize combinations of Milo and builders therapy.
And sometimes you saw fan and cyclophosphamide and total body irradiation and.
Chemotherapy.
Regiments and then they also utilized.
And the immunosuppressive with Lymphoseek suppressive.
Therapies as well.
Jonathan Schwartz: So this is a less extensive but nonetheless myeloblative conditioning regulator that's part of our gene therapy. Did that answer your question, sir? Do you have a follow-up? No, I do not have a follow-up that answers my question. Thank you. Thank you very much. Our next question is from Your Own Werber with Cowen. Great.
And so so this is.
This is a less expensive, but nonetheless, milo ablative conditioning regimen.
And that's part of our gene therapy program.
And did that answer your question, Sir do you have a follow up.
No I do not have a follow up that does answer my question. Thank you.
Thank you very much.
Our next question is from your own Weber with Cowen.
Great. Thanks for taking my question growth, maybe 2 questions. The first 1 is when you did your echoes did you see any less and tricolor ejection fraction and benefits or where patients essentially sort of normal at baseline and what about stroke volume because it's obviously related to cardiac output and then any update on 6 minute walk testing.
Your Own Werber: Thanks for taking my question. Grover, I have maybe two questions. The first one is, when you did your echoes, did you see any left ventricular ejection fraction benefits, or were patients essentially sort of normal at baseline? And what about stroke volume? Because it's obviously related to cardiac output, and then any update on six-minute walk testing would require longer follow-up. And with all of that in mind, based on what you're seeing, what do you think might be a primary endpoint for a pivotal trial? Thank you.
And with longer follow up and with all of that in mind and based on what you're seeing what do you think might be a primary endpoint for pivotal and thank you.
Gaurav Shah: So on the injection, hi, I'm talking, on the echo for injection fraction, many patients, if not most patients, have preserved ejection fraction until they reach end-spaced disease. This was true for most of the patients that have been enrolled in the trial. We have disclosed previously that the exception here was that last patient who did, as I mentioned earlier, move on to have a transplant because that patient was starting to lose cardiac function. More on that as we update our criteria. Sorry, you have to ask the second one again. Yeah, the second one. What about stroke volume?
So on the injection rates higher revenue.
And the Echo.
And for ejection fraction.
Many patients if not most patients have preserved ejection fraction and until they reach and stage disease. This was true for most of the patients that have been involved and the trial.
We have disclosed previously.
Exception here it was that.
Last patient who did and.
And earlier move on to have and transplant that patient and we're starting to lose cardiac function.
More on that as we update our criteria.
And.
Sorry, it adapt and the second 1 against a couple and there.
The second 1 what about stroke volume because that's obviously a determinant of cardiac output and then 6 minute walk price.
Gaurav Shah: Because that's obviously a determinant of cardiac output, yeah, and a six-minute walk-up, stroke volume, and then we'll get to six minutes. So on cardiac output, the data that was revealed in December, there is the current data set that we're working on that we've also shared with the agency. Some of these patients do start having worsening cardiac output, even before there's a loss of ejection fraction And in two of the three patients that I mentioned, we have started to see increases in cardiac output as measured by the basis in T-Montimatic.
Stroke volume and then we'll get to 6 minute walk at endpoints.
So on cardiac output and the data that was revealed in December there is the current data set that we're working on and that we've also share.
With the agency.
Some of these patients do start having worsening cardiac output even before this loss of ejection fraction and.
2 of the 3 patients had mentioned we have started to see.
Increases in cardiac output as measured by the basics and more dynamics.
Gaurav Shah: In terms of the six minute walk test, we now, and this is new information from before, have demonstrated six minute walk test stabilization or improvement in all three of the low dose patients. And that's a long-term stabilization or improvement in BMP as well as New York Association class. So that's the information.
In terms of 6 minute walk test, we know and this is new information from before.
Demonstrated.
6 minute walk test stabilization or improvement and all of the low dose patients and that's the bauxite stabilization or improvement and DMT as well as New York processes and cost.
So that's that's new information and the endpoints.
Gaurav Shah: And the endpoints, We have cast a wide net in terms of capturing appropriate endpoints to help us guide toward phase two. These include biomarkers of the kind that we discussed, BSP, PEPAACIO, clearance, as well as imaging endpoints such as a subjection fraction, clinical functional endpoints, such as a significant walk test or even quality of life, NYU class. So any of these could be part of the endpoints. We can't speculate on what those will be until we have an end of phase one discussion with the FDA. You know, there's been about a quarter delay in the trial right now.
We have cast a wide net in terms of capturing the appropriate endpoints to help US guide towards phase..2 these include Biomarkers and decline.
<unk> DSP and Pic bacule clearance.
And as well as imaging endpoints, such as ejection fraction and clinical functional endpoints, such as 6 minute walk test or even quality of life and endpoints such as and why.
Hi, a J class.
So any of these could be parts of the endpoints, we can't speculate and what that what those will be until we have and then the phase 1 and discussion with the FDA I think the.
There's been about a quarter delay and you're on the trial right now.
Gaurav Shah: At the same time, we've had a collaborative discussion with the FDA. Sometimes you don't have these discussions about endpoints until later in development. We're hopeful that, potentially, we can expedite the trial based on the conversations we're having right now. And Goroff says, "To something, make sure I got that right."
And at the same time, we've had a collaborative discussion with the FDA. Sometimes you don't have these discussions about endpoints until later in development.
Hopeful that potentially we can expedite the trial based on the conversations we're having right now and just based.
And growth so just make sure I got that right the 6 minute walk test.
Gaurav Shah: The six-minute walk test? I'm sorry if I missed it. You mentioned you saw an improvement in the six-minute walk in New York Hart class, and I'm sorry, in B&P in New York Hard Class, but did you also say that it was stabilized or improved? Yeah, so I'll go through it in detail.
Sorry, if I missed it you mentioned you saw an improvement and 6 minute walk and New York Heart class and I'm, sorry, and the and BNP and New York Heart Class, but did you also say 6 minute walk you was stabilized or improved.
Yeah. So.
I'll go through in detail all 3 patients have stabilization or improvement and BMP 6 minute walk test and cardiac output and alright.
Gaurav Shah: All three patients showed stabilization or improvement in BNP, 6 minute walk test, and cardiac output. And sorry, BNP, 6 minute walk test, and heart class; all three patients showed stabilization or improvement. The two patients who had an immune suppression regimen that was closely monitored, those two patients specifically had drops in B&P from 75 to 79% versus baseline, and they also had improvements in New York Heart Association class. Those are the two patients who had the monitored immune suppression. But all three patients had stabilization across the Six-minute Walk Test specifically; we haven't revealed those data.
And Pete 6 minute walk test and.
And heart last all 3 patient a stabilization or improvement the 2 patients who had monitored immune suppression regimen and that was closely monitor those 2 patients specifically had drops and BNP from $75 to 79% versus baseline.
And also they had improvements and New York Heart Association costs. Those are the 2 patients who had the monitor immune suppression, but all 3 patients at stabilization across all per items 6 minute walk test specifically we haven't.
Yield those data, we will and fourth quarter, but its been stable or improved in all 3 of those patients as well at this point.
Gaurav Shah: We will in Fort Quarter, but it's been stable or improved in all three of those patients as well. Great, thank you. Thank you. Our next question is from Manny Forohar with SBV Lerink. Please go ahead.
Great. Thank you.
And thank you. Our next question is from Manny for O'hara with SBB Leerink. Please go ahead.
Hey, Thanks for taking the question My first question is.
Are there any changes to the protocol for Dan and disease potentially change the proportion of patients that would be eligible for the trial.
Manny Forohar: Okay, thanks for the second question. My first question is, are there any changes to the protocol for Danden Disease that could potentially change the proportion of patients that would be eligible for the trial? I have a follow-up. Hi Lane.
And then a follow up.
Timeline.
We are.
Identifying patients that we would consider at this stage disease, and <unk> always said that and the last year or so prior to transplant.
Gaurav Shah: We are identifying patients that we would consider M-stage disease. We've always said that in the last year or so prior to transplant, the onset of fibrosis is such that gene therapy probably would not be affected. Those patients were never considered to be part of the treatable population. So overall, the answer does not change the treatable or addressable population. Great.
Non set of fibrosis is such that gene therapy, and probably would not be effective.
Those patients were never considered to be part of the treatable population. So overall and the answer is it does not change the treatable and our addressable market share.
Great you figure looking forward to meeting and listening and learning and September and Tom can you confirm whether or not you're invited Argo group participating and giving yourselves.
Gaurav Shah: You said you're looking forward to meeting and listening and learning about the September adcom. Can you confirm whether or not you're invited or will be participating in the ad litigation yourselves? Yeah, we have had no discussions with the FDA about the adcom. Today, we have not been invited, but we'll certainly be listening. Thanks, that's helpful, guys. Thank you. Our next question is from Raju Prasad with William Blair. Thanks for taking the question.
Yes, we have had no discussions with the FDA and about the AD com.
2 days and you have not been invited and but we'll certainly be listening.
Thanks, that's helpful guys.
Okay and.
Thank you. Our next question is from Raju Prasad with William Blair.
Thanks for taking the question.
With with the agreement the FDA cannot go into the high dose what should we expect for the clinical progression of this program is at the lower dose.
More adult patients and then going into a pediatric population or do you plan on and kind of advancing and the <unk>.
Gaurav Shah: With the agreement from the FDA to not go into the high dose, what should we expect for the clinical progression of this program? Is it the lower dose with more adult patients and then going into a pediatric population, or do you plan on kind of advancing into the pediatric population once you can re-enroll patients into the
Pediatric population once you can re enroll patients into the trial and error.
Question on the and the suppression regimen.
Hi, Thanks for the question Ross.
And our intent is to move forward right away with the pediatric populations logos.
And.
And we will update as that happens.
Gaurav Shah: Patients ended the trial, and I have a question about the immunospression regimen.
Okay, great and and maybe if you could just clarify the changes that were made to the immuno suppression regimen as far as complement activation goes and that'd be helpful. Thanks.
Gaurav Shah: Hi, thanks for the question, Roger. Our intent is to move forward right away with the pediatric population blood dose, and we'll update as that happens. Okay, great. And maybe you just clarify the changes that were made to the immunosuppression regimen as far as complementing is concerned.
Okay.
We will definitely update.
And as as the trial progresses, and certainly in the fourth quarter I don't want to provide too many specifics and during an active FDA dialogue, but yes, we will definitively update there's nothing in there and that that is that and we would consider major.
Gaurav Shah: as far as complement activation goes, that'd be helpful. Thanks.
Refinement revisions tightening of the protocol.
Gaurav Shah: We will definitely update as the trial progresses and certainly in the fourth quarter. I don't want to provide too many specifics during an active FDA dialogue, but yes, we will definitely update.
And nothing that really affects the types of patients that we can treat other than the eligibility points you made.
Or or affects the trial conduct a day.
Great. Thank you.
And we have our next question from Easter relative value with UBS.
Gaurav Shah: There's nothing in there that we would consider major. It's refinements, revisions, tightening the protocol, and nothing that really affects the types of patients that we can treat other than the eligibility point we made or affects the trial context. Great, thank you.
Hey, Thank you for taking my question.
Just a couple of Wanda and on the patients with a high per cent.
Kind of defined the market is about 33000 patients across the U S and then.
And does that mean 2000 and excludes the patients with fibrosis that are in advanced stages or how are you kind of whittling down some day care and closing criteria.
Esther Regivalue: And we have our next question from Esther Regivalue with UBS. Hey, thank you for taking my question. I have just a couple.
Yes, that's a good question, we think that the.
Gaurav Shah: One is on patients with fibrosis. You've kind of defined the market as about 33,000 patients across the US and the EU. And, you know, does that 32,000 exclude patients with fibrosis that are in advanced stages? Or how are you kind of whittling down from their tier enrollment criteria? Yeah, that's a good question.
And number of patients with fibrosis.
Prevalence and the adverse impact of gene therapy is it's very small, it's really going to be boys and.
In the months and maybe a year or so leading up to the actual heart transplants more and unfortunate cases that day.
Males, which has a population we haven't really talked about yet and certainly very viable options and the program forward and have.
Gaurav Shah: We think that the number of patients with fibrosis, That's prevalent about the event's impact of gene therapy, is very small. It's really going to be boys in the months and maybe year or so leading up to the actual heart transplant or, in an unfortunate case, death. Females, which is a population we haven't really talked about yet and certainly very viable as you move the program forward, have different sorts of heart disease and certainly would not be affected in the same way. So I think that if you're looking for exact numbers within those 30,000, those numbers are general. We think, if anything, they're going to be validated by a third party now. And as we capture even more tax mutations, there's a possibility that those numbers could expand.
Have different sorts of heart disease, and certainly would not be affected and the same way.
I think that the.
And <unk>.
And if you're looking for exact numbers and those 30000 and those numbers are general there.
We think if anything there and they've been validated by a third party now.
And as we capture even more types of mutations there's a possibility that those numbers can expand so I don't think that.
Sliver of.
Sort of.
Patients.
Baseline characteristics that would eliminate and stage diseases.
You are going to get into that.
Probably this number too much.
Yeah, Thank you and we.
And you've kind of mentioned females and consistently since the start of the trial.
What are what is that we do need to see and the kind of patients that are involved too.
Gaurav Shah: So I don't think that that sliver of sort of, patient baseline characteristics that would eliminate end-state disease is going to be, you know, get into that, trouble is number too much. Thank you. And we kind of, you know, you've kind of mentioned females consistently since the start of the trial. What are, you know, what exactly do you need to see in the current patients that are enrolled to, you know, to move forward with, with girls? with females? With female. Yeah.
And to move forward with that.
With females and let's see.
Yeah, sorry.
And we don't really need to see that much I think we want to get a little bit growth.
Further into the phase 1.
And start thinking about what the phase III design and would look like and.
Boys first.
There's nothing more we really need to see to start a trial and females and we have not given any guidance and when that trial will start, but it's certainly in the near to medium term plans.
Got it okay, and just to clarify the phase 2 trial of our channel will be only and voice 1.
The current phase II was not the currency and the upcoming phase and will be based on the current phase 1 and we would want to extrapolate what we've learned from phase 1 to apply to phase III. So that first trial, which we hope will be registration and nature.
Gaurav Shah: No, no, we don't really need to see that much. I think we want to get a little bit closer to phase one and start thinking about what phase two design would look like in boys first. But there's nothing more we really need to see to start a trial in females. We have not given any guidance of when that trial will start, but it's certainly in the near future. Got it. Okay, and just to clarify, the phase two trial you are planning will only
Would be limited to voice and in parallel we would start exploring a trial and females that would support a separate trials and registration and neighborhood.
Okay. Thank you that's very helpful.
Thank you. Our next question is from Jack <unk> with Evercore.
Gaurav Shah: The current phase two would, you know, not the current, the upcoming phase two would be based on the current phase one, and we would want to extrapolate what we've learned from phase one to apply to phase two. So that first trial, which we hope will be registration in nature, would be limited to voice, and in parallel, we would start exploring a trial in the emails that would support a separate trial as registration or neighborhood. Okay, thank you. That's very helpful.
Great. Thanks for taking the questions just continuing on the topic of the phase II registration study for and for Dana and what kind of data and so that you are looking to capture from.
And the pediatric pay.
Patients enrolled in the and the Phase 1 study and how do you think that'll ultimately in the form.
The design of the phase 2 what are the different parameters youre considering that are still not yet determined that that will be informed by the phase 1 and then separately.
Josh Schimmer: Thank you. Our next question is from Doc Zimmer with Evercore. Great, thanks for taking the questions. Just continuing on the topic of the Phase 2 registration study for Dana, what kind of data is it that you are looking to capture from the pediatric population? Patients enrolled in the phase one study, and how do you think that will ultimately inform the design of phase two? What are the different parameters you're considering that are still not yet determined that will be informed by phase one?
And unfortunately patient and pass with <unk>, who passed away is there any unique features about that patient.
That.
Might have explained and see.
And to the unfortunate outcome, whether they were older or more advanced disease and patients who might have otherwise gone for a traditional stem cell transplant and things.
Great.
Thanks, Josh so.
In terms of what we would need to see and the pediatrics.
Phase 1 low dose to start the phase 2 I think thats a discussion that obviously, we will have with the agency at the end of phase 1 meeting.
Josh Schimmer: And then separately for the unfortunate patient with IMO who passed away, are there any unique features about that patient that might have explained the unfortunate outcome, whether they were older or more advanced in disease than patients who might have otherwise gone for a traditional stem cell transplant? Thanks. Right. Thanks, Josh.
If we see more of what we saw and the low dose adults and confirmation of potential prospect of direct benefit and pediatrics. If we can confirm that and then.
And we'll be moving towards phase 2 relatively rapidly.
Gaurav Shah: In terms of what we would need to see in the pediatric phase one low dose to start phase two, I think that's a discussion that obviously we'll have with the agency at the end of phase one meeting. I think if we see more of what we saw in the low dose adults and confirmation of the potential prospect of direct benefit in pediatricians, if we can confirm that, then we'll be moving towards phase two relatively rapidly.
And in terms of how to define and final endpoint for the phase 2 trial I think that's still a discussion that will be as soon as possible I think the dialogue and we've been having over the last several weeks hopefully programs. The end of phase, 1 dialog and accelerate space and development plans for pediatrics as well and adults protection.
On the osteopetrosis patients I will defer to Jonathan if there were any differences and that patient versus other osteopetrosis patients that might have predisposed.
Gaurav Shah: And in terms of how to define the final endpoint for the phase two trial, I think that's still a discussion that will be had as soon as possible. I think the dialogue we've been having over the last several months hopefully primes the end of phase one dialogue and accelerates space to development plans for pediatric as well as adults. On the osteopatrosis patient, I will defer to Jonathan if there were any differences in that patient, other osteoprotin patients that might have predisposed him.
Can you repeat the question with respect to the osteopetrosis patients.
Yes, Jonathan just wondering if there are any clinical features that might've portended.
The outcome that they had whether it was more advanced disease older patients, who maybe have not been eligible for and earlier stem cell transplant that might explain and Lam.
Gaurav Shah: Can you repeat the question with respect to osteopatrosis? Yeah, Johnson, just wondering if there are any clinical features that might have portended the outcome that they had, whether it was more advanced disease, an older patient who maybe had not been eligible for an earlier stem cell transplant that might explain why I am when they had that event. Yes. Yeah, so we'll provide more comprehensive information regarding specific individual as we disclose.
But they had that.
So we will provide more comprehensive income.
And.
Regarding the specific individuals as.
And as we've disclosed.
Clinical data.
And at.
Relevant conferences later this year.
I don't think that there was necessarily anything.
And that we would identify and this patient is.
Jonathan Schwartz: clinical data at relevant
Jonathan Schwartz: relevant conferences later this year. I don't think that there was necessarily anything that we would identify in this patient as either either low or high risk. One thing that we're we're very much aware of is that in osteopatrosis, many of these patients do have chronic lung compromise that's related to the bone abnormalities that the ribs cause a restrictive lung pattern, and some of the sinus abnormalities creates sort of a chronic inflammation in the bronch eye and pulmonary parankhama, which is probably why these patients do have a high degree of pulmonary complications in allergenic transplant setting, Obviously, our intent is to provide a therapy that's less overall chemo than you'd have in an allotransplant.
Either the low or high risk 1 thing with it.
We are very much aware of this.
Last year for process.
Many of these patients.
Do you have a.
Chronic.
And long compromise that's related to the bone abnormalities.
And the ribs cause a restrictive lung pattern and.
Some of the sign of soft and maladies creates sort of a chronic inflammation.
And the pronghorn and pulmonary per income up which is why probably why these patients to have a high degree of pulmonary complications and Pat.
Allogeneic transplant settings.
Obviously, our intent is to provide a share.
Therapy, it's less.
Less overall chemo and then you would happen and allo transplant, but nonetheless, you are still talking about many of these patients having.
Jonathan Schwartz: But nonetheless, you're still talking about many of these patients having fairly complex lung environments. I don't think we can comment right now that there was anything specific about this patient that we'd be able to say made him or her different from, typical osteopatrosis patients. All of these kids have pretty severe underlying disorders. May I ask one quick follow-up on the Dane and pediatric patients?
Fairly complex.
And <unk> environment.
I don't I don't think we can comment right now that there was anything specific about this patient that we'd be able to say.
Made and more hurt different from from a.
Typical osteopetrosis patient all of these kids have.
Pretty severe underlying disorder.
Okay May I ask 1 quick follow up on the on the Dana and pediatric.
Gaurav Shah: patients and the next phase of the trial, if they are younger, they are unlikely then to have baseline abnormalities that would be amenable to improvement. And I guess, you know, for older patients, you could see improvement in BNP and performance status, and heart failure. But if you're enrolling younger patients, are you unlikely to see that just because they have not deteriorated to a degree that they would have meaningful baseline abnormalities? Hi Josh, Goro here.
Patients and next phase of the trial.
If they are younger are they unlikely then to have.
Baseline abnormalities that would be amenable to improvement.
And I guess Kurt.
And for older patients you could see the improvement and BNP and performance status and heart failure, but if youre enrolling younger patients or you're unlikely to see that just because they have not deteriorated to a degree that they would have meaningful baseline abnormalities.
Hi, Josh Goldberg here.
There are.
Gaurav Shah: There are a number of pediatric patients who have the onset of cardiac disease even earlier than the adolescents that we've been treating. And remember the cutoff here is age 15 for young adults, plus those who have it less and below that that are pediatric. And the disease, although inexorably leads to heart failure around the age of 19 or 20, on average, is heterogeneous.
A number of pediatric patients who have onset of cardiac disease, even earlier than the adolescence and treating and remember the cost here is 815.4.
Young adult clubs and it lessens and below that interest and there are pediatric and the disease is although inexorably and leads to heart failure around the use and vaccine or 20 on average. It is heterogeneous. So there are many pediatric patients who do have some signs or symptoms of cardiac disease. Those are the ones that would be and.
Gaurav Shah: So there are many pediatric patients who do have some signs or symptoms of cardiac disease. Those are the ones that would be involved in phase one. Ultimately, we may want to move the therapy even before the onset of cardiac disease as a preventive measure, but that's not what this trial is about. All pediatric patients will have some signs or symptoms.
<unk> and the pediatric phase 1 and ultimately we may want to move the therapy, even before onset of cardiac disease and preventative measure, but that's not what this trial and Scott all pediatric patients will have swung to sign or symptom.
Gaurav Shah: Class 2, heart failure or higher disease. Okay, got it. Thanks very much.
Class II heart failure or tires.
Okay got it thanks, very much and before we.
Gaurav Shah: And before we move to the next question, Josh, I also wanted to add an IMO that the protocol has defined measures by which we are part of the trial. We have shared the information with the FDA, and we have not been asked to put the trial on hold. It's a self-mandated pause based on the program. And also, Josh, I know we're spending a lot of time; you asked about what other information could help us move the trial, the pediatric trial, forward into phase two. We're also developing a final version of our natural history output.
Moving to the next question, Josh I also wanted to add and I and mode.
That.
And the protocol has defined measures by which we are part of the trial.
We have shared that information with the FDA and we have not been asked to put the trial.
And starting to sell mandated pause based on the protocol.
And also Josh asked and I know, we're spending a lot of times you had asked about what other information could help us.
Trials and pediatric trial forward into phase 2 and we're also developing a final version of our natural history output and we're learning a lot about how patients decline, especially in the early teenage years, and we hope that that side by side with activity that we're starting to see and the law.
Gaurav Shah: And we're learning a lot about how patients decline, especially in the early teenage years, and we hope that, side by side with the activity that we're starting to see at a low dose, can justify a trial that could potentially be a single-arm trial. So that's the idea here moving forward. Thanks, girls.
Jos and justify a trial that could potentially and be a single arm trial.
So that thats the idea here and moving space.
Got it thanks guys.
David Hong: And thank you. Our next question is from David Hong with SMBC. Hi, thanks for taking the questions. So I want to ask about, you know, the decision to discontinue the high dose. I mean, clearly, it makes sense for all the reasons we've talked about.
And thank you. Our next question is from David Hong with SMB CLEC.
Hi, Thanks for taking the questions.
So I wanted to ask about.
The decision to discontinue the high dose I mean clearly.
Makes sense for all the reasons, we've talked about but I remember you had pursued it in part because you thought there may be some extra cardiac benefits.
Gaurav Shah: But I remember you pursued it in part because you thought there may be some extra cardiac benefits. So, you know, without, I guess, maybe capturing those now that they can have the option of a high dose, do you think that that impacts the overall value proposition of the gene therapy to any significant degree? So Gannon disease is multi-organ, as you say. It would be nice to treat the full spectrum of the disease if possible.
So without I guess, maybe capturing does now debt.
And a high dose.
Do you think that that impacts the overall value proposition of the gene therapy to any significant degree.
Yes.
So Dan and disease is multi organ and as you say.
It would be nice to treat the full spectrum of disease if possible. However.
Gaurav Shah: The mortality in this disease is cardiac in origin. So if we're able to address the cardiac aspects of the disease, extending life is, in our estimation, the ultimate value proposition, and especially if we can achieve normal longevity in these patients who would otherwise pass away or have a heart transplant by age 19 or so. It was a strategy that we had in place, but I think we go with what works and what works in a very major way. understood. Thanks for that!
And mortality and this disease and <unk>.
Cardiac and origin. So if we're able to address the cardiac aspects of the disease.
Extending life is and our estimation of the ultimate value proposition and especially if you can confirm normal normal longevity on these patients who would otherwise pathway or the heart transplant by age 19 airplanes.
So it was a strategy that we had in place, but I think we go with what works and what works and a very major way.
Understood Thanks for that and.
Gaurav Shah: And then I just was wondering, as you tease out what the appropriate endpoints for phase two in Shannon, is your baseline assumption that the approval that you'll probably get would be an accelerated approval? Or do you think, you know, you'd be able to get a full approval out of the dates? You know, basically, do you just do additional clinic work after the initial approval? Yeah, it's hard to speculate at this point, I think that we have a range of biomarkers that could support an accelerated approval plan at the same time. We also recognize that a mortality benefit is the ultimate market of success here.
And I guess what.
Hearing with the.
As he's out what's the appropriate endpoints for our phase II and Daniel.
Is there a baseline assumption that the approval that youll get would that be accelerated book.
Or do you think you'd be able to get a full approval.
A basic.
And basically do you anticipate.
Additional clinical work after you know after the initial approval.
Yes, it's hard to speculate at this point I think that.
We have a range of biomarkers that could support an accelerated approval plan.
At the same time we.
And also recognize that.
And a mortality benefit and the ultimate markers of clinical success here so at the moment.
Gaurav Shah: So at the moment, we can't really speculate, but we hope to have answers as we start having phase one dialogue for the agency. And I will also ask John from the way in here and also comment on some of the other extracurcordian meditation points that were. Thank you, Garav. Jonathan Schwartz here again.
Can't really speculate, but we hope to have answers as we start having industry and 1 biologic agency and.
I will also add sharpened and weigh in here and also to comment on.
Some of the other extra cardiac manifestations points.
Okay.
Thank you Gaurav, Jonathan Schwartz share again.
Jonathan Schwartz: I think it's important to emphasize that although, obviously, cardiac disease is what is... fatal in essentially all of the male damage disease patients, and that's where we'll build the endpoint around, I don't think we can yet discount whether the low dose can or cannot affect the non-cardiac manifestation. Importantly, if you look at Dan in the female face, they don't have substantive extra-carriac manifestations. So we may well see benefit in neuromuscular or neurocognitive aspects of the disease in these male Danin patients with the levels of transduction and protein expression that have been seen in the low dose adults treated to date.
And I think it's important to you.
To emphasize that although obviously.
The cardiac.
Disease is what is.
Middle and.
Essentially all of the nail down and disease patients and that's where we'll build the endpoint around.
I don't think we can yet discount and whether the low dose.
Can or cant effect.
The non cardiac manifestations and importantly, if you look at them and female patients.
And don't have substantive extra cardiac manifestations.
So we may well see benefit and neuromuscular neuro cognitive aspects of this disease.
These males and and patience.
With the levels of transduction.
And that has and protein expression and that has been <unk>.
And the low dose adults.
<unk> treated to date likely that we will take a little bit longer to determine and.
Jonathan Schwartz: Likely that will take a little bit longer to determine than the cardiac benefits that we believe we have seen to date, but certainly it is possible that we may also substantively affect the non-cardiac elements in these patients, just as the females who likely have 30 to 50 percent of normal lab results expression largely are unaffected by those aspects of this disorder. Okay, thanks so much for taking the question. And thank you. Our next question is from Patrick Dildall with Lifesai Capital.
And the cardiac benefits that we believe we are seeing.
Since that day.
But certainly it is possible that.
We may also substantively effect.
And the non cardiac elements.
And these patients just as the females, who have likely 30% to 50% of normal lab, 2 expression largely unaffected by those aspects of this disorder.
Okay. Thanks, so much for taking the question.
And thank you.
Next question is from Patrick <unk> with <unk> capital.
Patrick Dildall: Hi, thanks for taking the questions. As it relates to the patient that underwent a heart transplant, you mentioned fibrosis as a parent. However, was there any worsening myocarditis observed in the explanted heart or evidence that an immune response contributed to the need for a heart transplant? And if so, has there been anything similar observed in biopsies from patients at the low dose?
Hi, Thanks for taking the questions as it relates to the patient underwent heart transplant, you mentioned and fibrosis was apparent however was there any worsening and myocarditis observed and the express and hard or evidence that and immune response contributed to the need for transplant and if so has there been anything similar observed and biopsies from patients.
Seth a low dose thanks.
Gaurav Shah: Thanks.
Gaurav Shah: Hi Patrick, no, no mycarotitis, and no inflammatory changes in the explanted heart, and we also didn't see
And Patrick No no myocarditis and no inflammatory changes and next plant and Mark and we also didn't see any of them.
Gaurav Shah: those technologies on other low-dose patients that we've Got it, thanks.
Those technologies on the other low dose patients and we've looked at.
Got it thanks.
Eric William Joseph: And thank you. Our next question is from Eric Joseph with D.P. Morgan.
And thank you. Our next question is from Eric Joseph with Jpmorgan.
Eric William Joseph: Hi, good evening. I've taken the question. I joined late, so sorry if the question's already been addressed, but maybe just a clarification question as it relates to the potential pivotal phase two for Danins. Should we be, are you contemplating a single program that addresses both adolescents and pediatrics, or would they be programs when run in parallel? And I guess, to the extent that it's the latter, can maybe just articulate what some of the gating factors would be to... an end of phase one meeting.
Hi, good evening, Thanks for taking the question I joined late so sorry.
And as has already been addressed but maybe just a clarification question as it relates to <unk>.
Potential pivotal phase II for Dan and Chewy and B are you.
We're planning a single program that addresses both adolescence, and pediatrics or would they be programs when and in parallel and I guess to the extent, it's the latter.
And just maybe just.
Articulate what some of the gating factors would be too.
And.
And then the phase 1 meeting or the data that you have so far.
Eric William Joseph: Are the data that you have so far in terms of patient numbers and follow-ups efficient, or would you need to see incremental data with the revised protocol or new patient data with the revised protocol? Yeah, so, with regard to phase two. What we need to see is, Number one, some data in pediatrics, for sure, and we need to see the outputs from our natural history so that we can define the protocol design and also figure out what the right thing to do is going to be in collaboration.
In terms of patient numbers and follow up sufficient or would you need to see incremental data.
With the revised protocol or new patient data and with the revised protocol. Thanks.
Yeah.
Yes so.
With regard to.
The.
Startup phase III.
What we need to see.
Number 1 some data and pediatrics.
Sure.
And we need to see the output from our natural history. So that we can define and the protocol design and also figure out what the right endpoints are going to be and collaborations with the FDA.
Eric William Joseph: And those are the things that are. We don't think that we need to add more patients to get there, if anything, actually. Since we've cut out the high dose now, the number of patients needed at the end of phase one meeting is likely going to be smaller. So that's one winner. For your first question, we anticipate one trial for pediatric patients and adolescents; we don't anticipate two-step. So right now, the gating factors are the ones you describe, and we hope to move
And those are the things that are on gaming, we don't think that we need to add more patients to get there if anything actually since we've cut out the idose down the number of patients needed to be end of phase 1 meeting is likely going to be smaller.
So that's 1 point and I want to make.
And your first question, we anticipate 1 trial for pediatrics and adolescents, we don't anticipate 2 separate ones there and so right now the.
Gating factors of the Onesies and once you described and.
And we hope to move forward pretty bad.
Gaurav Shah: Okay, I got it. Very helpful. And thanks for the question.
Okay got it very helpful and thanks for taking my question.
Operator: And thank you, sir. And we have no further questions in queue.
Hi, Eric.
And thank you, Sir and we have no further questions in queue I will turn the call over to Gaurav Shah CEO for closing remarks.
Gaurav Shah: I will turn the call over to Gerov Shah, CEO, for closing remarks. Thank you everyone for participating in today's call, and we look forward to updating you again soon. And thank you, ladies and gentlemen. This concludes our conference, and we thank you for your participation. You may now disconnect.
Thank you everyone for participating in today's call and we look forward to updating you again soon.
And thank you ladies and gentlemen, this concludes our conference and we thank you for your participation you may now disconnect.
Okay.
[music].
Sure.
Okay.
Okay.
Okay.
And then.
And so.
And.
[music].
Operator: and you know, I'm going to