Q2 2021 Sarepta Therapeutics Inc Earnings Call
[music].
Good afternoon, ladies and gentlemen, and welcome to get US direct us Therapeutics second quarter 2021 earnings call.
Operator: Good afternoon, ladies and gentlemen, and welcome to the Sarepta Therapeutics second quarter 2021 earnings 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 will need to press Star 1 on your telephone.
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 will need to press star 1 on your telephone.
Operator: As a reminder, today's program is being recorded. At this time, I'll turn the call over to Mary Jenkins, Senior Manager of Investor Relations. Please go ahead.
As a reminder, today's program is being recorded.
At this line I'll turn the call over to Mary Jenkins Senior manager Investor Relations. Please go ahead.
Thank you operator, and thank you all for joining today's call earlier today, we released our financial results for the second quarter 2021. The press release is available on our website at drifted out Com and our 10-Q was filed with the Securities and Exchange Commission earlier. This afternoon, joining us on the call today are Doug Ingram Ian asked upon.
Mary Jenkins: Thank you, operator, and thank you all for joining today's call. Earlier today, we released our financial results for the second quarter of 2021. The press release is available on our website at Surrepta.com, and our 10Q was filed with the Securities and Exchange Commission earlier this afternoon. Joining us on the call today are Doug Ingram, Ian Estefan, Fallen Murray, Dr. Gilmore O'Neill, and Dr. Louise Radin
Alan Murray, Dr. Gilmore O'neill and Dr. Louise Rodino quite back after our formal remarks, we'll open the call for Q&A I'd like to note that during this call we were making a number of forward looking statements. Please take a moment to review our slide on the webcast, which contains our forward looking statements. These forward looking statements involve risks and uncertainties many of which are beyond <unk>.
Mary Jenkins: After our formal remarks, we'll open the call for Q&A. I'd like to note that during this call, we were making a number of forward-looking statements. Please take a moment to review our slide on the webcast, which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, many of which are beyond surreptus' control. Actual results could materially differ from these forward-looking statements, and any such risks can materialize and adversely affect the business, the results of operations, and trading prices for Seraptive common stock.
To wrap those control Act.
Actual results could materially differ from these forward looking statements and any such risks can materially and adversely affect the business. The results of operations and trading prices for <unk> common stock for a detailed description of applicable risks and uncertainties. We encourage you to review the company's most recent quarterly report on form 10-Q filed with the SEC.
Mary Jenkins: For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10Q filed with the SEC as well as the company's other SEC filings. The company does not undertake any obligation to publicly update its forward-looking statements, including any financial projections provided today based on subsequent events or circumstances. I'll now turn the call over to our President and CEO, Doug Ingram, who will provide an overview of our recent progress.
As well as the company's other SEC filings the company does not undertake any obligation to publicly update or towards looking statements, including any financial projections provided today based on subsequent events or circumstances on.
Now I'll turn the call over to our President and CEO, Doug Ingram, who will provide an overview of our recent progress Doug.
Douglas S. Ingram: Thank you, Mary. Good afternoon, and thank you all for joining Surretha Therapeutics' second quarter 2021 investor conference. With a large multi-platform genetic medicine pipeline, which spans RNA, gene therapy, and gene editing, and with three approved therapies, we have a significant number of important initiatives underway in 2021, and I and my team are very pleased to share with you this evening our progress in the achievement of our milestone. I am particularly proud of this team's focus on execution and the consistent achievement of our goals this year, which you will see reflected in our results.
Thank you Mary good afternoon, everyone and thank you all for joining us throughout the therapeutics second quarter 2021.
Investor Conference call.
With a large multi platform genetic medicine pipeline, which spans RNA gene therapy, and gene editing and with 3 approved therapies. We have a significant number of important initiatives underway in 2021, and I and my team.
Are very pleased to share with you this evening, our progress and the achievement of our milestones.
I am, particularly proud of this team's focus on execution and the consistent achievement of our goals. This year, which you will see reflected in our results.
Douglas S. Ingram: Now, as pleased as I am with our quarterly performance, I am going to dispense with my usual order and start by updating you on the important and very positive developments for SRP 9-01 this quarter. I am delighted to share with you the progress we've made with respect to SRP-001 and the positive outcome of our recently completed meeting with FDA's Office of Tissue and Advanced Therapies. I'll be referring to that division going forward as OTA.T.
Now as pleased as I am with our quarterly performance I am going to dispense with my usual order.
Start by updating you on the important and very positive developments for SRP 9001 this quarter.
I am delighted to share with you the progress we've made with respect to SRP 9001, and the positive outcome of our recently completed meeting with Fda's office of tissue.
And advanced therapies, I'll be referring to that division going forward.
Okay.
Now as a reminder, earlier in the second quarter, we announced the 12 week results of our first 11 patient cohort for study 1 O..3 also known as endeavor.
Douglas S. Ingram: Now, as a reminder, earlier in the second quarter, we announced the 12-week results of our first 11 patient cohort for study 103, also known as Endeavor. To remind you, study 103 is our trial evaluating the expression and safety of our commercially representative material. This is an extremely important study, and it has confirmed the performance of our therapy using the material process with which we intend to launch SRP 9001. We were pleased to report that on every biomarker, our commercially representative material performs as well as, or better than the clinical supply material we used in our prior study.
To remind you studied 1 O 3 is our trial evaluating the expression on safety.
Of our commercially representative material.
This is an extremely important study as it has confirmed the performance of our therapy.
Using the material process with which we intend to launch SRP 9001.
We were pleased to report that on every biomarker.
Our commercially representative material performs as well as or better.
On the clinical supply material used in our prior study.
Armed with a positive study 1 O 3 results, we scheduled a meeting with <unk> to review, our CMC and our plans for study 301 and that is our proposed pivotal trial for SRP 900, what.
Douglas S. Ingram: Armed with the positive study 103 results, we scheduled a meeting with OTAT to review our CMC and our plans for study 301, that is our proposed pivotal trial for SRP 901. I would like to thank OTAT for what was a very productive and informative meeting. Based on that meeting, we are on track to commence study 301 as proposed by the division, both in the United States and then globally, and we believe we should be able to initiate study 301 in September of this year.
I would like to thank owe tax on what was a very productive and informative meeting.
And based on that meeting we are on track to commence study 301 as proposed to the division.
Both in the United States, and then globally and we believe we should be able to initiate study 301, Inc.
September of this year.
The initiation of study 301 is an important moment not merely for this program, but for families living with Duchenne.
Douglas S. Ingram: The initiation of study 301 is an important moment, not merely for this program but for families living with Duchenne. Following receipt of the final minutes, I will provide detailed information regarding our study design and some of the reasons we are so confident that our program will be successful. Now we've taken a deep dive into part one of study 102, and we are not only very confident in the performance and transformative potential of SRP 901, but we are also very confident that study 301 is well designed with a high probability of success of showing that performance.
Following receipt of the final minutes I will provide detailed information regarding our study design.
And some of the reasons, we are so confident that our program will be successful.
We've taken a deep dive into part 1 on study 102, and we are not only very confident in the performance from <unk>.
Transformative potential with SRP 9 here a zero 1.
But we are also very calm, but if it's 301 is well designed with a high probability of success of <unk>.
Showing that performance.
Once we have the final minutes and are ready to initiate the trial I will share with you the details of the trial.
And the data driven basis for our confidence in this program.
Looking forward study what else she was proceeding and remains blinded and.
And we will have a readout of the second phase of that study, including 1 year and 2 year functional results.
In the first quarter of 2022.
Staying with our pipeline updates, let me now move to limb girdle muscular dystrophy.
As you know we have seen very robust results from our first 2 cohorts.
Our proof of concept study for SRP 900, free that's our gene therapy being developed to treat L. G. M D type 2 weeks.
Douglas S. Ingram: Again, once we have the final minutes and are ready to initiate the trial, I will share with you the details of the trial and the data-driven basis for our confidence in this program. Looking forward, study 102 is proceeding and remains blind. And we will have a readout of the second phase of that study, including one year and two year functional results, in the first quarter of 2022. Stay tuned for our pipeline updates. Let me now move to Lindgirdle Muscular Dispidididid.
I can now report that we have already solicited and received written feedback from both the FDA and EMA.
Regarding our plans for SRP 903, both confirming the possibility of using a protein expression.
As an endpoint for accelerated approval in the U S and for conditional approval in Europe.
From here, we need to gain alignment with the FDA and EMA on the precise clinical and regulatory approach.
Appropriate for L. G M D chewy and appropriate for the rest of the L. G M B pipeline.
And based on the written feedback we have received we are investing time now considering how we might move our entire L. G. M D cycle like in what platform.
Douglas S. Ingram: As you know, we have seen very robust results from our first two cohorts in our proof-of-concept for SRP-0-3, that is, our gene therapy being developed to treat LGM-Ty2E. I can now report that we have already solicited and received written feedback from both the FDA and EMA regarding our plans for SRP 9003, both confirming the possibility of using protein expression as an end point for accelerated approval in the U.
Forward together.
With the successes that we've seen with our gene therapy approach to L. G. M. D. We are expanding our portfolio Doctor O'neal will provide additional color on our license to another RH 74 mediated gene therapy at this stage that's.
1 to treat L. G M D tight 2 way or calpain apathy.
Moving now to our RNA franchise, you will recall that earlier this year, we announced positive results from part a of our momentum trial studying our next generation version of our more pelino platform.
Net guide conjugated PMO or P. P. M O SRP 50 could be 1 which is designed to be an enhanced version of our PMO technology for Duchenne patients who have a mutation amenable.
Douglas S. Ingram: From here, we need to gain alignment with the FDA and EMA on the precise clinical and regulatory approach appropriate for LGMD2E and then appropriate for the rest of the LGMD pipeline. And based on the written feedback we have received, we're investing time now in considering how we might move our entire LGMD-Glycan platform forward together. With the successes that we've seen with our gene therapy approach to LGMD, we are expanding our portfolio. Dr. O'Neill will provide additional color on our license to another RH74 mediated gene therapy in this instance, one to treat LGMD type 2A or calpane opal.
2 exon 51 skipping Dr. Neil will review the positive results of that study at 30 mix per gig and will provide our plans to commence our pivotal phase of our trial for SRP 50.51.
Later this year.
The advancement of our P. P M O technologies solidifies, our singular leadership and evidence driven RNA technology.
Rare diseases, where steric walking can provide benefit.
Our PMO is predictable and a durable platform that has already produced 3 FDA approved therapies that can in turn improve the lives of nearly 30% of duchenne patients.
In the United States and at least for now to a lesser extent outside the United States. Our next generation P. P. M O. If confirmed in upcoming trials will greatly extend the reach and impact of our RNA platform.
Douglas S. Ingram: Moving now to our RNA franchise, you will recall that earlier this year, we announced positive results from Part A of our Momentum trial, studying our next generation version of our Morpelino platform, the peptide conjugated PMO, or PPMO, SRP 5051, which is designed to be an enhanced version of our PMO technology for Duchenne patients who have a mutation amenable to Exxon 51. Dr. O'Neill will review the positive results of that study at 30 mix per Kig and will provide our plans to commence our pivotal phase of our trial for SRP 5050 later this year.
As Dr. O'neill will share with you our PMO platform has the potential of being a leap forward in the treatment of Duchenne.
With the P. P. M O platform, we have the technical ability to construct therapies were well over 80% of duchenne patients.
And with profoundly greater discipline on production.
The opportunity exists to expand our reach far beyond the United States with approvals globally and.
And even as we develop our P. P M O us for Duchenne, we are exploring additional genetic diseases.
First Erik blocking may provide benefit.
We will work with the Neurology division at Cedar and that's the division with an F. D. A responsible for our RNA platform to gain alignment on part D of SRP 50, 51 trial and once confirmed with the Cedar we will commence our part D. Pivotal trial before the end of this year as we also advanced edition.
On a construct for other mutations.
Now, let me comment on our quarterly performance, serving the Duchenne community with our 3 approved RNA therapies.
Douglas S. Ingram: The advancement of our PMO technology solidifies our singular leadership in evidence-driven RNA technology to treat rare diseases where steric blocking can provide benefits. Our PMO is predictable and a durable platform that has already produced three FDA-approved therapies that can, in turn, improve the lives of nearly 30% of Duchenne patients in the United States, at least for now, to a lesser extent, outside the United States. Our next generation, PPMO, once confirmed in upcoming trials, will greatly extend the reach and impact of our RNA blast.
In addition to continuing to adapt to this pandemic. The team is focused on serving our patients with exon to us in late August.
And launching them on us.
No. It was approved back in February of this year.
And their success is reflected in our quarterly numbers.
I am pleased to report that in the second quarter, we achieved net product revenue of approximately $142 million that represents a nearly 27% growth.
Over the same quarter last year.
Since our first approved therapy nearly 5 years ago, we have enjoyed long term compounded annual growth of about 20%.
Douglas S. Ingram: As Dr. O'Neill will share with you, our PBMO platform has the potential to be a leap forward in the treatment of Dushan. With the PBMO platform, we have the technical ability to construct therapy for well over 80% of Duchenpe, and with profoundly greater discipline production. The opportunity exists to expand our reach far beyond the United States with approvals globally. And even as we develop our PPMOs for Duchenne, we are exploring additional genetic diseases where steric blocking may provide benefit.
As a testament to the value of our therapies to the lives of those living with Duchenne.
Even considering that each of our therapies requires weekly infusions amid a troubling pandemic environment.
Adherence rate for our therapies remains well over 90%.
An extremely impressive and.
Telling metric.
Based on this success, we have today increased our full year net product revenue guidance at the commencement of this year our guidance was in the range of $537 million to $547 million.
Today, we are raising that guidance to between 565 and $575 million representing at the midpoint of growth of more than 25% over last year.
Douglas S. Ingram: We will work with the Neurology Division at Cedar, and that's the division with the FDA responsible for our RNA platform, to gain alignment on Part B of the SRP 5051 trial. And once confirmed with Cedar, we will commence our Part B pivotal trial before the end of this year, as we also advance additional constructs for other mutants. Now, let me comment on our quarterly performance, serving the Dushen community with our three approved RNA therapy.
Our Chief commercial officer, Alan Murray, who will provide more color on our quarterly performance performance in a moment.
Now the progress we've made in 2020, 1 demonstrates execution by our team of professionals across our entire fully integrated commercial stage genetic medicine organization.
While not currently reflected in our stock price.
I am proud that the strip the team has executed this year and achieve nearly every 1 of the ambitious goals. We have set for them driving performance of our on market therapies and advancing our industry, leading genetic medicine pipeline.
Douglas S. Ingram: In addition to continuing to adapt to this pandemic, the team has focused on serving our patients with Xondis and Viandis, and launching them on, as you know, was approved back in February of this year, and their success is reflected in our quarterly numbers. I am pleased to report that in the second quarter, we achieved net product revenue of approximately $142 million. That represents a nearly 27% growth over the same quarter last year.
To summarize what's considered to be a complements the accomplishments so far in 2021 and I'll do this quite logically.
First additional evidence driven evidence driven confidence.
On the probability of success of SRP 9001.
Even though part 1 on study 102 did not achieve statistical significance on the pool the primary endpoint due to tightening issues in baseline imbalances in.
In the pre specified subgroup analysis of the 4 to 5 year olds, where the baselines were in line.
We saw not merely strong statistically significant benefit, but perhaps the best results.
So far in the trial for Duchenne.
Moreover, an analysis of the complete data set from study 1 or 2 only bolsters, even more our confidence from the transformative potential of SRP 9001.
Douglas S. Ingram: Since our first approved therapy nearly five years ago, we have enjoyed long-term compounded annual growth of about 20% And as a testament to the value of our therapies to the lives of those living with Duchenne, Even considering that each of our therapies requires weekly infusions amid a troubling pandemic environment, The adherence rate for our therapy remains well over 95% and extremely impressive and telling that, Based on this success, we have today increased our full-net product revenue guidance, commencement of this year, our guidance was in the range of 537, $547 million dollars, Today we are raising that guidance to between $565 and $575 million, representing at the midpoint, a growth of more than 25% over last year. Our chief commercial officer, Dallon Murray, will provide more color on our quarterly performance in a moment.
And more than just that the study has informed the design of our next trial greatly.
Greatly enhancing its probability of success.
Next we received FDA approval for and launched our third Eric RNA therapy.
The shut in of course that gives them on this now serving a record percentage of patients as Alan will detail in a moment our performance across all 3 of our RNA based therapies Exxon just by August.
Demand us even in these challenging times.
It's been exceptional.
We also reported over the course of this year several positive clinical data readouts.
That bolstered not only our approach, but the intrinsic value of both.
Our gene therapy, and RNA platforms consider exceptional functional improvement and durability results for SRP 9003 R. L. G M D G E.
Gene therapy, we also reported impressive clinical results for SRP 50, 51, the first of our candidates from our next generation.
P PMO platform.
We also reported exceptional clinical results from the first cohort studying 1 O 3 confirming that the performance of our commercially representative material for SRP 9001, and frankly, the culmination with enormous work and investment to advance our gene therapy manufacturing process over the last few years.
Douglas S. Ingram: Now, the progress we've made in 2021 demonstrates execution by our team of professionals across our entire fully integrated commercial stage genetic medicine organization. While not currently reflected in our stock, I am proud that the Surrepta team has executed this year and achieved nearly every one of the ambitious goals we have set for them, driving performance of our on-market therapies and advancing our industry-leading medicine pipeline. So some summaries, let's consider the accomplishments so far in 2021, and I'll do this chronologically.
And as you've heard today, you've completed a productive meeting with us at.
Regarding our pivotal trial for SRP 9001 that is of course, the study 301, and we are on track to initiate that trial in September of this year in the United States.
Around the world as well.
Looking forward to the rest of the year. In addition to initiating study 301, and continuing study 1 or 2 for SRP 9 heroes zero 1.
We will engage the FDA and ministries of health to align on our clinical and regulatory pathway for our <unk> portfolio and separately, we will align with the FDA and other ministries of health around the world with the goal of advancing our P. P. M. O SRP 50, 51 to a pivotal trial to start this year.
Douglas S. Ingram: First, additional evidence-driven confidence in the probability of success of SRP 9001, even though part one of study 102 did not achieve statistical significance on the pooled primary endpoint due to tying issues and baseline imbalance. In the pre-specified subgroup analysis of the four to five-year-olds, where the baselines were in line, we saw not merely strong, statistically significant benefit but perhaps the best results so far in a trial for Moreover, an analysis of the complete data set from studies one or two only bolsters even more our confidence in the transformative potential of SRP-901. And more than just that, the study has informed the design of our next trial, greatly enhancing its probability of success. Next, we received FDA approval for and launched our third RNA therapy to treat Duchenne. Of course, that is Amondis, now serving a record percentage of patients.
I look forward to updating you as we progress and to continue to execute on our milestones over the remainder of this year and with that let me turn the call over to Ian <unk>, who will provide an update on the financials Ian.
Thanks, Doug good afternoon, everyone.
This afternoon's financial results press release provided details for the second quarter of 2021 on a non-GAAP basis as well as the GAAP basis.
Please refer to the press release available on <unk> website for a full reconciliation of GAAP to non-GAAP financial results.
Total net product revenue for the second quarter 2021 from our PMO exon skipping franchise was $141.8 million compared to $111.3 million for the same period of 2020.
For the second quarter of 2021 individual in net product sales were $112.5 million for exon 51.
$22.4 million for buy on that 53 and <unk>.
$6.9 million from the newly launched a modest 45.
The increase primarily reflects higher demand for our products and the launch of a modest 45.
That said due to the strong performance, we have increased our 2021 revenue guidance range for our RNA franchise.
Douglas S. Ingram: As Dallon will detail in a moment, our performance across all three of our RNA-based therapies, Xonis, My Honor, and among us, even in these challenging times, has been an exception. We have also reported, over the course of this year, several positive clinical data readouts that bolster not only our approach but the intrinsic value of both, gene therapy and RNA platform. Consider exceptional functional functional improvement and durability results for SRP903 are LGMD2E therapy.
In the quarter ended June 32021, we recognized $22.3 million of collaboration revenue compared to $26 million recognized on the same period of 2020, which primarily relates to our collaboration arrangement with Roche the Reimbursable co development costs under the Roche agreement.
$17.7 million for the second quarter of 2021.
The $8.9 million for the same period of 2020.
On a GAAP basis, we reported a net loss of $81.4 million and $158 million or $1, <unk> and $1.93 per basic and diluted share in the second quarter of 2021 and 2020, respectively.
Douglas S. Ingram: We also reported impressive clinical results for SRP 50-1, the first of our candidates from our next generation PPMO plan. We also reported exceptional clinical results from the first cohort of study 103, confirming the performance of our commercially representative material for SRP-001 and, frankly, the culmination of an enormous amount of work in investment to advance our gene therapy manufacturing process over the last few years. And as you have heard today, you've completed a productive meeting with OTAT regarding our pivotal trial for SRP-001, that is, of course, study 301, and we are on track to initiate that trial in September of this year in the United States and around the world as well.
We reported a non-GAAP net loss of $121.2 million or $1.52 per basic and diluted share in the second quarter of 2021 compared to a non-GAAP net loss of 111.
$9 million or $1.51 per basic and diluted share in the second quarter of 2020.
In the second quarter 2021, we recorded approximately $19.5 million and cost of sales compared to $13.3 million in the same period of 2020. The increase in cost of sales is primarily due to increasing demand for the company's products.
On a GAAP basis, we recorded $239.6 million on $188.5 million in R&D expenses for the second quarter of 2021, and 2020, respectively, a year over year increase of $51.1 million.
Douglas S. Ingram: Looking forward to the rest of the year, in addition to initiating study 301 and continuing study 102 for SRP 901, we will engage the FDA and ministries of health to align on our clinical and regulatory pathway for our LGMD port phone. And separately, we will align with the FDA and other ministries of health around the world with the goal of advancing our PMOSRP 5051 to a pivotal trial this year.
This increase is primarily due to an increase in milestone and manufacturing expenses.
On a non-GAAP basis, R&D expenses were $189 million for the second quarter of 2021.
<unk> to $164 million for the same period of 2020, an increase of $28.6 million.
Now turning to SG&A on a GAAP basis, we recorded approximately $72.3 million and $73.7 million or expenses for the second quarters of 2021, and 2020, respectively, a decrease of $1.4 million.
Douglas S. Ingram: I look forward to updating you as we progress and to continuing to execute on our milestones over the remainder of this year. And with that, I will turn the call over to Ian Estepan, who will provide an update on the financial...
Year over year decrease was driven primarily by a decrease in compensation personnel and professional service expenses.
Ian M. Estepan: Thanks, Doug. Good afternoon, everyone.
On a non-GAAP basis, the SG&A expenses were $54 million for the second quarter of 2021 compared to $55.1 million from the same period of 2020.
Ian M. Estepan: This afternoon's financial results press release provided details for the second quarter of 2021 on a non-gap basis as well as a gap basis. Please refer to the press release available on Surruptive's website for a full reconciliation of gaps to non-gap financial resources. Total net product revenue for the second quarter of 2021 from our PMO Exxpings franchise was $141.8 million, compared to $11.3 million for the same period of 2020. For the second quarter of 2021, individual net product sales were $112.5 million for Exx 51, $22.4 million for Viandas 53, and $6. $6. For the newly launched Amondas 45.
A decrease of $1.1 million.
On a GAAP basis, we recorded $16.2 million in other expenses net for the second quarter of 2021 compared to $12.4 million and other expenses net for the same period of 2020.
The increase primarily reflects an increase in interest expense incurred on the company's term loan debt facility due to increase in the outstanding balance partially offset by a reduction of interest expense incurred on the company's convertible debt related to the adoption of ASU 2026.
In February 2021, we entered into an agreement to sell the rare pediatric disease priority review voucher or <unk>, we received from the FDA in connection with the approval of a mark of 25.
In April of 2021, we completed our sale of the PRP and received proceeds of $102 million with no commission costs, which further recorded as a gain from sale of the PRP day not.
Karen any.
It did not have any carrying value at the time of the sale. There was no similar activity during the second quarter of 2020.
Ian M. Estepan: The increase primarily reflects higher demand for our products following the launch of Amondas 45. As that said, due to the strong performance, we increased our 2021 revenue guidance range for our RNA franchise. In the quarter ended June 30, 2021, we recognized $22.3 million of collaboration revenue compared to $26 million recognized in the same period of 2020, which primarily relates to our collaboration arrangement with Roche. The reimbursable co-development costs under the Roche Agreement totaled $17.7 million for the second quarter of 2021, compared to $8.9 million for the same period of 2020. On a gap basis, we reported a net loss of $81.
We had approximately $1.74 billion balance of cash cash equivalents and investments as of June 32021.
And Doug just outline in Gilmar will go over in more detail. We progressed several pipeline programs. This year for this reason, we anticipate running multiple pivotal study in 2022, we will continue to invest in our manufacturing scale up in anticipation of delivering on these therapies to patients and with that I'll turn the call over to Dan 1 for an update on our commercial activities.
Talent.
Thank you Ian and good afternoon, everyone.
The team has yet again exceeded expectations across all 3 of our approved products in the second quarter of 2021.
Due to this strong performance as Doug mentioned, we have increased our guidance range by almost $30 million with the new guidance being $565 billion to $575 billion up from the $5.37 to $5.47 million.
As mentioned total revenue reached approximately $142 million in Q2, representing double digit growth over the previous quarter, and we approached nearly 27% growth versus Q2 of 2020.
The second quarter represents our strongest rate of revenue growth since the Exxon just 51 launch phase.
It's our 19th consecutive quarter of revenue growth since launch in 2016.
Ian M. Estepan: And $150.8 million, or $1.2 and $1.93 per basic and diluted share, in the second quarter of 2021 and 2020, respectively. We reported a non-gap net loss of $121.2 million, or $1.52 per basic and diluted share, in the second quarter of 2021 compared to a non-gap net loss of $11. $7.9 million, or $1.51 cents per basic and diluted share, in the second quarter of 2020. In the second quarter of 2021, we recorded approximately $19.5 million in cost of sales compared to $13.3 million in the same period of 2020. The increase in cost of sales is primarily due to increasing demand for the company's products.
Put that into perspective, that's 1 quarter shy of 5 years of consistent quarter over quarter revenue growth.
Keep in mind that this consistent growth has been achieved without taking a single price increase at any point, making this accomplishment that much more distinct and impressive.
Now transitioning to the details of our performance in the second quarter. Our revenue in Q2 was driven by strong performance across all 3 of our approved PMO based exon skipping medicines I'll review each in chronological order bigger.
Beginning with exon 51, the team has continued to execute driving revenue to over $112 million in Q2, 2021, which represents roughly 8% growth versus Q2.2020.
We've worked hard throughout the COVID-19 pandemic to mitigate the risks 2 weeks on to 51 and have emerged in a strong position.
Our impressive performance from Q1 to Q2.2021 for <unk> 51 was a result of the team driving a robust rate of re authorization during the insurance changes, we typically see at the beginning of each year as such we don't expect to see the rate of growth. We saw on the second quarter with Exxon just 51 to <unk>.
Ian M. Estepan: On a gap basis, we recorded $239.6 million and $188.5 million in R&D expenses for the second quarter of 2021 and 2020, respectively, a year over year increase of $51.1 million. This increase is primarily due to an increase in milestone and manufacturing expenses. On a non-gap basis, R&D expenses were $189 million for the second quarter of 2021, compared to $160.4 million for the same period of 2020, an increase of $28.6 million. Now turning to SG&A on a gap basis, we recorded approximately $72.3 million and $73.7 million for expenses for the second quarters of 2021 and 2020, respectively, a decrease of $1.4 million. The year-over-year decrease was driven primarily by a decrease in compensation and professional service expenses.
Continue at the same rate.
It is important to be reminded that we now see the exon 51 amenable population as mature and well penetrated in the ambulatory setting.
Having had an approved therapy on the market for nearly 5 years.
As a result of any growth that we see for example, 51 will be primary primarily driven by newly diagnosed or incident patients.
Moving now to buy on this 53, although we're still very much in the launch phase I'm happy to report, we are seeing minimal competitive impact on the demand from both patient and physician community.
Revenue totaled over $22 million in the second quarter, representing nearly 30% growth versus the first quarter of 2021.
Reinforcing our leading position our expertise in duchenne and the flawless execution of our team.
The team has done a great job on the second quarter getting patients on therapy and as we work through the start forms from the launch phase we expect more modest growth in subsequent quarters due to a smaller basis start forms to work from.
Overall from what we're seeing to date.
Majority of exon 53 treated patients are on by on this 53 and.
And the competitive launches had limited impact on our overall launch trajectory to date.
And finally, a modest 45.
Perhaps our most exciting news coming out of the second quarter is our stronger than anticipated launch.
While it's early days, we're seeing revenue from a modest 45 tracking ahead of the exon 51 trend, which is even more impressive given the relative size differences of the 2 patient populations.
Ian M. Estepan: On a non-GAP basis, SG&A expenses were $54 million for the second quarter of 2021, compared to $55.1 million for the same period of 2020, a decrease of $1.1 million. On a gap basis, we recorded $16.2 million in other expenses for the second quarter of 2021 compared to $12.4 million in other expenses for the same period of 2020. The increase primarily reflects an increase in interest expense incurred on the company's term loan debt facilities due to an increase in the outstanding balance, partially offset by a reduction of interest expense incurred on the company's convertible debt related to the adoption of ASU 2020 OSCE.
Adjusting for the relative population sizes the rate of new patient start forms from modest 45 are in line with what we saw for the exon 51 launch however, based on our deep experience in Duchenne and constant improvements in terms of the execution of the team the time to getting patient access.
To end on therapy has been faster for a modest 45 than what we saw for exon 51.
As a result, the team has delivered nearly $7 million in revenue in our first full quarter with a modest 45.
The successful launch of them on this 45 is our third since 2016 and represents the dedication of our team who work every day on behalf of patients.
Our deep experience with Duchenne has enabled us to serve more patients expedite access to drug and offer best in class support through select assist.
Ian M. Estepan: In February 2021, we entered into an agreement to sell the rare pediatric disease priority review voucher, or PRV, we received from the FDA in connection with the approval of Amanda-45. In April of 2021, we completed our sale of the PRV and received proceeds of $102 million with no commission costs, which was recorded as a gain from sale of the PRV did not carry any, and did not have any carrying value at the time of the sale. There was no similar activity during the second quarter of 2015.
We are extremely proud of the team and we will continue to apply learnings towards our number 1 priority, which is serving to nearly 30% of duchenne patients who may benefit from our PMO based.
Exon skipping therapies.
Now looking to the future as Chief commercial officer, I Couldnt be more excited about continuing to leverage our learnings to support the Duchenne community as we rapidly advanced both our gene therapy and P PMO pipeline.
And now I'll turn the call over to Gilmore for an update on our research and development activities Kilmer.
Thank you Donna and good afternoon, everyone.
In the.
In the second quarter, a great deal of progress was made in advancing both our RNA and gene therapy program.
Dallan Murray: We had approximately $1.74 billion of cash, cash equivalence, and investments as of June 30th, 2021. As Doug just outlined in Gilmore, which we'll go over in more detail. We are progressing several pipeline programs this year. For this reason, we anticipate running multiple pivotal studies in 2022. We will continue to invest in our manufacturing scale-up in anticipation of delivering these therapies to patients. And with that, I'll turn the call over to Dallon for an update on our commercial activities.
Before beginning with our RNA based P. P. M O program SRP 5051, I want to Echo Doug's sentiment that we are very pleased with our recent meeting with <unk> regarding the SRP 9 years on 1 program.
Remain on track to initiate our study 301 this September in the United States and globally.
As you recall in early May 2021.
We announced positive clinical data from the 30 Meg per kg arm of the momentum study for SRP 50, 51, evaluating safety and change from baseline at week 12.
Just on skipping and dystrophin expression in both ambulatory and non MDI patients.
Dallan Murray: Thank you, Ian, and good afternoon, everyone. The team has yet again exceeded expectations across all three of our approved products in the second quarter of 2021. Due to this strong performance, as Doug mentioned, we have increased our guidance range by almost $30 million, with the new guidance being $565 to $575 million, up from the $537 to $547 million. As mentioned, total revenue reached approximately 142 million in Q2, representing double-digit growth over the previous quarter, and we approached nearly 27% growth versus Q2 of 2020.
3 of the patients in there were in their late teens on 1 patient was 7 years old at the time of treatment.
The results were impressive.
The third he make per kg cohort showed a significant dose dependent increase in exon skipping.
P 50, 51, when dosed once per month.
Pardon he makes per kg achieved approximately 11% mean exon skipping at week 12.
Compared to the P. P Mod 20, Meg per kg dose.
At the Turkey meat for peak dose, we observed a greater than 4 folds dose dependent increase in exon skipping on only a 50% increase in dose.
Further when compared to the current standard of care at Jefferson, We observed an 18 code increase in exon skipping.
Dallan Murray: The second quarter represents our strongest rate of revenue growth since the Exondis 51 launch phase. It's our 19th consecutive quarter of revenue growth since our launch in 2016. To put that into perspective, that's one quarter shy of five years of consistent quarter over quarter revenue growth.
Now in terms of expression that 30 day peak dose of SRP 50, 51 demonstrated more than 6.5% means a stroke on protein expression as measured by western blot, representing a greater than 100 percentage increase in expression versus the 20 Meg per kg cohort Ashwin when you week 12.
Here are some other notable aspects of the data first.
Dallan Murray: Keep in mind that this consistent growth has been achieved without taking a single price increase at any point, making this accomplishment that much more distinct and impressive. Now transitioning to the details of our performance in the second quarter, our revenue in Q2 was driven by strong performance across all three of our approved PMO-based exon skipping medicines. I'll review each in chronological order.
The results were not driven by a single patient all of the patients response to therapy.
Second based on our predictive modeling, we should comfortably achieved greater than 10% of stroke on with once per month dosing overtime.
Third.
Based on dystrophin levels are not a predictor of post treatment expression. In fact, we observed that 2 patients with the lowest baseline had the highest level of post treatment. This question.
Dallan Murray: Beginning with Exondas 51, the team has continued to execute, driving revenue to over $112 million in Q2, 2021, which represents roughly 8% growth versus Q2 2020. We've worked hard throughout the COVID-19 pandemic to mitigate the risks to Exondis 51 and have emerged in a strong position. Our impressive performance from Q1 to Q2, for Exandis 51, was a result of the team driving a robust rate of reauthorizations during the insurance changes we typically see at the beginning of each year. As such, we don't expect the rate of growth we saw in the second quarter with Exxonius 51 to continue at the same rate.
And for safety.
We continue to believe that the Hypomagnesaemia observed in this study remains manageable and manageable with magnesium supplementation and us not cartilage with changes in renal function.
Our next step is to meet with FDA regarding part D of momentum and based on the outcome of that meeting our intention is to dose part D. By the end of 2021.
We are thrilled with the SRP 50, 51 results and the potential that SRP 5051 hold to offer individuals with duchenne a more convenient once per month treatment option with a manageable safety profile and superior dystrophin expression.
Now.
Shifting to our gene therapy program.
I will begin with our safety and biopsy results reported in mid May from the first 11 patients in study 103, using our commercially represents a material for SRP 9 years every 1.
Dallan Murray: It's important to be reminded that we now see the Exxon 51 amenable population as mature and well penetrated in the ambulatory setting. Having had an approved therapy on the market for nearly five years, any growth that we see for Xonis 51 will be primarily driven by newly diagnosed or incident patients. Moving now to Viandus 53, although we're still very much in the launch phase, I'm happy to report we are seeing minimal competitive impact on demand from both patient and physician communities.
These results are tremendously valuable because they've confirmed the characteristics of the commercially represents material for SRP 9 years or what.
Which achieved robust transduction for a mean of $3.87 vector genome copies per nucleus.
In addition, we reported robust expression of micro dystrophin correctly localized to the sarcolemma membrane and.
And we have measured the 3 different ways.
With a mean of 55, 4% by Western blot.
75% positive fibers.
And intensity of a $116, 9% correctly localized to the membrane.
Dallan Murray: Revenue totaled over 22 million in the second quarter, representing nearly 30% growth versus the first quarter of 2021, reinforcing our leading position, our expertise in Duchenne, and the flawless execution of our team. The team did a great job in the second quarter of getting patients on therapy. And as we work through the initial forms from the launch phase, we expect more modest growth in subsequent quarters due to a smaller base of initial forms to work from. Overall, from what we're seeing to date, the vast majority of Exxon-treated patients are on Viandas 53, and the competitive launch has had limited impact on our overall launch trajectory to date. And finally, Amond is 45.
Furthermore, we observed a consistent safety profile with our clinical and manufacturing process with no clinical complement manifestation.
It cannot be understated that this study 103 results provide confirmation of our manufacturing process and analytics positioning us to happily serve the duchenne.
Population.
I'd also like to remind you about some critical findings from part 1 of our ongoing SRP 9 years or 1.102 study.
I want to emphasize that because of the studies stockpile randomization design and the statistical analysis plan, we can state with confidence that the pre specified subgroup analysis of 4 to 5 year old Duchenne boys Stratham demonstrated that SRP 9 years or 1 treated boys achieved NSA a gain.
Dallan Murray: Perhaps our most exciting news coming out of the second quarter is our stronger than anticipated revenue. While it's early days, we're seeing revenue from Amondis 45 tracking ahead of the Exondis 51 trend, which is even more impressive given the relative size differences of the two patient populations. Adjusting for the relative population sizes, the rate of new patient formation forms for Mondes 45 is in line with what we saw for the Exondis 51 Monge.
That's where both clinically meaningful.
On superior to placebo treated boys with statistical significance.
This means that the SRP 9 years or on micro dystrophin construct is functional in humans and confers physiological on clinical benefit.
Substantially increasing the probability of success for this program.
Now moving to our limb girdle muscular dystrophy portfolio.
Dallan Murray: However, based on our deep experience in Duchenne and constant improvements in terms of the execution of the team, the time to get patients access to and on therapy has been faster for Amondas 45 than what we saw for Exanjus 51. As a result, the team has delivered nearly $7 million in revenue in our first full quarter with Amondis 45.
Our 6 development stage programs have the potential to address approximately 70% of all them guard with patients.
These programs are progressing well and we continue to hold a leading position in limb girdle muscular dystrophy grounded in differentiation science and a deep understanding of the disease.
Dallan Murray: The successful launch of Amundas 45 is our third since 2016 and represents the dedication of our team who work every day on behalf of patients. Our deep experience with Duchenne has enabled us to serve more patients, expedite access to the drug, and offer best-in-class support through select assistance. We are extremely proud of the team and will continue to apply learnings towards our number one priority, which is serving the nearly 30% of Duchenne patients who may benefit from our PMO base, Exxon skipping therapy.
Currently serve to have separate programs in development to treat various subtypes of limb girdle muscular dystrophy.
And this morning, we announced the execution of a licensing agreement with nationwide children's hospital.
For Calpain, 3 a gene therapy candidate to treat limb girdle muscular dystrophy type 2.8 or calpain apathy.
Limb girdle muscular dystrophy type <unk> caused by mutations in the calpain treat Jim and it's the most common form of limb girdle accounting for 1 third of limb girdle muscular dystrophy diagnosis.
We are pleased to report that the preclinical research and safety studies net.
Ed by Dr. <unk> at nationwide Children's hospital have provided early proof of concept for helping tree in limb girdle type to aid and support further advancement.
Dallan Murray: Now looking to the future, as chief commercial officer, I couldn't be more excited about continuing to leverage our learnings to support the Duchenne community as we rapidly advance both our gene therapy and PPMO pipeline. And now I'll turn the call over to Gilmore for an update on our research and development activities.
We will apply the learnings from our SRP 9 user 1 and SRP 9 years, there were 3 development program to the Calpain 3 program and our 5 other limb girdle programs all of which use the same AAV RH 74 vector designed to robustly deliver treatment to skeletal muscle make even a deal tempted to treat muscular disease.
Gil Blum: Thank you, Dallon, and good afternoon, everyone. In the second quarter, a great deal of progress was made in advancing both our RNA and gene therapy programs. Before beginning with our RNA-PMO program, SRP 5051, I want to echo Doug's sentiment that we are very pleased with our recent meeting with OTAT regarding the SRP-901 program. We remain on track to initiate our study 301 this September in the United States and globally.
Now turning to SRP 9003, our lead limb girdle gene therapy candidates in development to treat limb girdle type TUI.
Each demonstrated positive data earlier this year at the 2021.
Muscular dystrophy associations annual clinical and scientific conference.
We presented the first expression data from biopsies of participants in cohort 1 the low dose cohort taken 2 years. After a single administration of SRP 9 days or 3.
The results showed sustained protein expression in muscle tissue.
Gil Blum: As you recall, in early May 2021, we announced positive clinical data from the 30-mig-big-harm phase of the Momentum study for SRP 5051, evaluating safety and change from baseline at week 12 for exon skipping and dystrophine expression in both ambulance and non-ambulant patients. Three of the patients were in their late teens, and one patient was seven years old at the time. The results were impressive. The 30-Meg-K cohort showed a significant dose-dependent increase in ex-skipping.
We are thrilled with these results are the SRP 9 years of Itchy program as they also provide read through to our 9 years were 1 program and any program that utilizes our age 74.
On the MHC K 7 promote.
No.
Turning to our functional results recipe 9 years or 3.
Assessments were taken 2 years following treatment in cohort, 1 and 1 year after treatment and core to the high dose cohort. We were pleased to observe that patients continue to demonstrate stability either Northstar assessment for just fair enough that these or <unk> total score.
Gil Blum: SRP 5051 when dosed once per month, 30 makes per take achieved approximately 11% mean exon skipping at week 12. Compared to the PPMO 20-Pek dose, at the 30-mic-k-dose, we observed a greater than four-fold dose-dependent increase in exon skipping at only a 50% increase in dose. Further, when compared to the current standard of care at Tepper's, we observed an 18thold increase in exxon skipping. Now, in terms of expression, the 30-Mig-D dose of SRP 5051 demonstrated more than 6.5% mean to stroke and protein expression as measured by Western Blots, representing a greater than 100% increase in expression versus the 20-Mig per-Kig cohort at only Week 12. Here are some other notable aspects of the data.
And improvements on time function tests.
The results from both cohorts continue to support a differentiated safety profile.
The Orange 74 vector compared to other AAV serotypes.
In fact between our SRP 9 years, everyone on SRP 9 years with 3 programs, we have dose nearly 80 patients and have maintained a consistent safety profile.
We also believe that the high level of expression observed without construct net to durable outcomes that are critically important for patients receiving a onetime therapy.
All of these therapies are not a coincidence.
<unk> 9 years or 1 was rationally designed and then the learnings from this candidate have been applied and continues to be applied to SRP 9 years or tree and our 5 other named Robert Kennedy.
The SRP 9 years, you treat results represent a solid foundation, a virtual engine to build and advance a steady stream of additional socket like in derived indications in limb girdle muscular dystrophy.
Gil Blum: The results were not driven by a single patient. All the patients responded well to therapy. Based on our predictive modeling, we should comfortably achieve greater than 10% discrophene with once per month dosing over time. Third, baseline dystrophine levels are not a predictor of post-treatment expression. In fact, we observed that two patients with the lowest baseline had the highest level of post-treatment expression, and fourth, We continue to believe that the hypomagnetemia observed in the study remains monitorable and manageable with magnesium supplementation and is not correlated with changes in renal function.
No.
Many of you are likely aware that in early September the cellular tissue on gene therapy. The Advisory Committee meeting to discuss the toxicity risks of admin associated virus or AAV vector based gene therapy.
With the results we have thus far from our SRP 9 years or 1 and SRP 9 usually 3 programs. We expect the discussion with central around vector specific toxicities observed with other serotypes.
We look forward to the meeting and expect that the shared learnings would be helpful and continues to drive the field of gene therapy forward.
Additionally, we look forward to sharing day from our gene therapy on on a pipeline program at the 2021 annual Congress of the World Muscle Society being held virtually from September 20th 24.
Gil Blum: Our next step is to meet with FDA regarding Part B of momentum. Based on the outcome of that meeting, our intention is to dose Part B by the end of 2021. We are thrilled with the SRP 5051 results and the potential that SRP 5051 holds to offer individuals with Duchen a more convenient once-per-month treatment option with a manageable safety profile and superior dystrophin expression. Now, shifting to our gene therapy program, I would begin with our safety and biopsy results reported in mid-May from the first 11 patients in study 103 using our commercially representative materials for SRP 901.
Finally, and most importantly, I want to thank all the patients their families study sites and coordinators My R&D colleagues on our partners who have done so much work under incredibly different constructive stance is caused by the pandemic to maintain our urgent mission to deliver new highly effective therapies to people of rare disease.
I will now turn the call back over to Doug to open the question and answer session Doug.
Thank you very much Dr O'neill and thank you for the rest of my colleagues May let's open up the lines for the Q&A now.
Absolutely to ask a question you will need to press star 1 on your telephone Covid.
Gil Blum: These results are tremendously valuable because they've confirmed the characteristics of the commercial material for SROP 9001, which achieved robust transduction for a mean of 3. Vector Genome Copies for Nuclear In addition, we reported robust expression of microdiscoporfer correctly localized to the sarcolemal membrane, And we have measured this three different ways, with a mean of 55.4% by Western Blanc. 70.5% positive 5%, and an intensity of 116.9% correctly localized to the membrane.
I think on your question press the pound key.
Minder callers will be limited to 1 question only please standby walbrook on.
Part of the Q&A roster.
Yeah.
Your first question comes from the line of Gena Wang of Barclays. Your line is open.
Thank you for taking my questions I have 1 question regarding study.
1 Doug I know you wish you detail about us trial design, but just wondering if you can share the high level of a trial design now and also regarding study 1 or 2 crossover data in first quarter next year. Just wondering have you defined prespecified Nitro Houston controller.
Yeah. Thank you for that question first of all thank you for the first question because I'm going to get this question a lot. This evening and this gives me an opportunity to frustrate everybody just wants so I am not going to provide details on the study 301 other than of course to let you know that it is it is a.
Gil Blum: Furthermore, we observed a consistent safety profile with our clinical manufacturing process with no clinical complement manifestation. It cannot be understated that the study 103 results provide confirmation of our manufacturing process and analytics, positioning us to aptly serve the Duchenne population. I'd also like to remind you about some critical findings from part one of our ongoing SRP 901 study. I want to emphasize that because of the study stratified randomization design and analysis plan, we can state with confidence that the pre-specified subgroup analysis of 4-to-5-year-old DuCen Boy Stratum demonstrated that SRP 90101 treated boys achieved NSAA gains that were both clinically meaningful and superior to placebo-treated boys with statistical certainty.
Placebo controlled double blinded trial that will be our pivotal.
Trial, there are a lot of nuance behind that the powering of at the end of the age groups et cetera, and we have really put a lot of thought into study 301 informed enormously by study 102, and I'm gonna be I'm very excited to share that with you and I'm very excited that we were able very recently to have met with.
The division and on that basis gain confidence that we're going to initiate that trial in September of this year, but I'm going to frustrate you would not provide a ton of detail other than to know that it is you know it is obviously a robust very well on power double blind.
On placebo controlled trial on study 1 or 2 of course before the team is working on natural history stats on all of the statistics associated with that it is a blinded trial as you know we will have 2 fully.
Gil Blum: This means that the SRP 90101 microdustrofen construct is functional in humans and confers physiological and clinical benefits, thus substantially increasing the probability of success for this program. Now, moving to our limb girdle, we must go to the district portfolio.
Fully to lock all of that down and walk the natural history search down before we on blind, but I think that Jim has still has additional statistical work to do before the stat plan is from fully locked.
And thank you for both of those questions Junior.
Your next question comes from the line of <unk> of Boa. Your line is open.
Gil Blum: Our six development stage programs have the potential to address approximately 70% of all dim girdle patients. These programs are progressing well, and we continue to hold a leading position in limb girdles and muscular dystrophy, grounded in differentiated science and a deep understanding of the disease. Currently, Sarepta has several problems in development to treat various subtypes of limb girdle muscular dystrophy type 2a or calpane option. This morning, we announced the execution of a licensing agreement with nationwide children's hospitals for calpane 3, a gene therapy candidate to treat limb girdle muscular dystrophy type 2a or calpane option. Lim-Gardle muscular dystrophy type 2A is caused by mutations in the Calpane 3 genes, and it's the most common form of limb-gardle, accounting for one-third of all limb-gardle muscular dystrophy diagnoses.
Hey, guys. Good afternoon, thanks for taking my questions and thanks for all the positive updates.
So my 1 question talk us about timing of your study.
I think that's starting in September.
On the Pfizer call that happened recently, they didn't seem to make specific mention of what is happening with their DMD study at least like U S. Enrollment. So I'm curious if you end up on a timeline win here.
Regarding the study everything on the U S.
Any sense around the same time, what's your view on what that overlapping.
Our clinical trial sites, and whether or not it might impact your ability to enroll.
Yes. Thank you for that a couple of thoughts 1 I want to be clear I'm, not I'm going to avoid directly.
Jim.
Comparing to other programs as you can well imagine I have probably.
Gil Blum: We are pleased to report that the preclinical research and safety studies led by Dr. Serifahank at Nationwide Children's Hospital have provided early proof of concept for calpain tree in limb girdle type 2a and support further advancement. We will apply the learnings from our SRP 901 and SRP 9003 development programs to the Calcane 3 program and our five other limb girdle programs, all of which use the Now, turning to SORP 9003, our lead Limgirdle gene therapy candidate in development to treat Limgirdle type 2E, which demonstrated positive data earlier this year at the 2021 Muscular Drip History Association's annual clinical and scientific conference.
Earned reputation for leading towards the competitive so I'm going to fight might naturally and statement, but I will say the fall let me say the following first that.
There is no 1 else that has the amount of clinical.
On data to inform their program and the confidence of their therapy like <unk> the Dutch Dr.
Dr. O'neill I believe mentioned in his opening remarks, we have by now.
At these levels SRP 900 line.
And ambulatory and non ambulatory children and nearly 80 children, if not more than 80 by now so we have an enormous amount of information that informs the confidence of our therapy and informs the next program and gives US a lot of confidence that we're going to do quite well and we've done studying 1 on 1 we've done study 1 or 2 part 1.
We will have study 102 part to that will read out very early next year. We have study 103 in the first cohort of that of course looks brilliant in the performance of that therapy from an expression and safety perspective, and we'll start 301 and initiate that trial on if all goes well in September and we feel very confident about that so we're we're in.
Gil Blum: We presented the first expression data from biopsies of participants in cohort 1, the low-dose cohort, taken two years after a single administration of SRP 9903. The results showed sustained protein expression in muscle tissue, We are thrilled with these results for the SRP-SRP-3 program, as they also provide re-through to our 90-01 program, and any program that utilizes RH74 and the MHCK7 promoter, turning to our functional results for SOP 9023, assessments were taken two years following treatment in cohort one and one year after treatment in cohort two through the high-dose cohort We were pleased to observe that patients continue to demonstrate stability in their North Star assessment for dysferrinopopathy or NSAD, total score, and improvements on timed function tests.
Good shape to drive SRP 9 years Youre on 1 forward and of course, the reason that we want to do that with us.
Enormous amounts of urgency is.
Hopefully everybody that Cheniere. This rare disease knows there are thousands and thousands and thousands of children literally hundreds of thousands of children around the world who are having their muscle stolen from them day after day literally unrelenting and and.
Fortunately invariably fatal so we need to move fast and we will do that on the specific question you asked a second.
Part of your question that you asked us.
Again, there is an enormous need for therapies like this for this gene therapy for a P. P M on others, and therefore understandably an enormous amount of interest and desire that we moved fast.
Cash from families, who are living with and unfortunately invariably dying from Duchenne muscular dystrophy and from physicians.
Physicians and investigators so I stand by the proposition that I've had for some time that that this.
Program once we get going should enroll with significant rapidity.
Gil Blum: The results from both cohorts continue to support a differentiated safety profile of the RH74 vector compared to other AV-serids. In fact, between our SRP 9001 and SRP 9003 programs, we have dosed nearly 80 patients, and I've maintained a consistent safety profile. We also believe that the high-level expression observed with our construct led to durable outcomes that are critically important for patients receiving a one-time therapy. All these therapies are not a coincidence.
Your next question comes from the line on Brian Abrahams of RBC capital markets. Your line is open.
Oh, Hey, guys. Congrats on all the progress and thanks for taking my question on.
I'm just wondering with respect to study 301 are there any additional gating factors to getting that study up and running both in the us and internationally.
Any additional back and forth required the agency and can you confirm that I guess at this point you are aligned on all the necessary potency assays are expected to be in line shortly.
A couple of thoughts 1 is do you have just true.
Gil Blum: As SRP 9001 was rationally designed, and then the learnings from this candidate have been applied and continue to be applied to SRP 9303 and our five other limb girl candidates. The SRP 9003 results represent a solid foundation, a virtual engine to build and advance a steady stream of additional circuit-like and derived indications in Limegerdle Musco Distribal. Now, many of you are likely aware that in early September, the cellular tissue and gene therapy advisory committee is meeting to discuss the toxicity risks of abno-associated virus or AAV vector-based gene therapy.
To initiate the study and roll a study out around the world. There are lots of steps. So I would say this is the team has been frankly in my view fantastic in their execution, but we have a lot to do to get this study fully enrolled around the world. So there's I don't want to create the impression that there's not a lot of additional work to do there is its the teams.
Gary very competent and confident in getting all of that done I'd say the biggest the most significant issue for us to ensure that we could move rapidly and initiate this trial quickly.
Particularly in the United States was to have that meeting with <unk>.
And of course, we have that meeting.
We'll say, although I'm not going to give you the exact day it was.
Recent and as I said, a very positive meeting.
Informative meeting very well prepared meeting on both sides by the way and as a result of that we have an enormous amount of confidence that we're going to be able to initiate this trial very soon and our goal is to have that done in September and we feel confident about that as it relates to the potency assay. We've done a lot of work on the potency assay as you may recall back lash.
Gil Blum: With the results we have thus far from our SRP 9001 and SRP-03 programs, we expect the discussion with central-round vector-specific toxicities observed with other serotoners. We look forward to the meeting and expect that shared learnings will be helpful and continue to drive the fields of gene therapy forward. Additionally, we look forward to sharing date from our gene therapy and RNA pipeline programs at the 2021 Annual Congress of the World Muscle Society being held virtually from September 20th to 24, Finally, and most importantly, I want to thank all the patients families, study sites and coordinators, my R&D colleagues and our partners who have done so much work under incredibly difficult circumstances caused by the pandemic to maintain our urging mission to deliver new, highly effective therapies to people wear diseases.
Last year in September we actually had.
Stalled for a short period of time it turns out.
Based on potency assay on September of 2020 that actually ended up being for us a blessing. It gave us an opportunity to have live dialogue with the division and to really understand at a fairly.
Granular level, what the division was looking for not only them, but in the future on potency assays and so we've done a bunch of work. Since then we've shared our perspective on the potency assays and our approach to potency assay with the division. They have agreed with our approach and endorsed our approach and we gathered the data in.
As I've said before there's a lot still left to do as 1 can imagine to get a trial up and running around the globe, but we feel very confident that we'll be initiating that trial. This year and frankly, we feel confident will be initiated in September.
Your next question comes from the line on Alicia Young of Cantor. Your line is open.
Hey, guys. Thanks for taking my question and congrats on the progress on us.
Gil Blum: I will now turn the call back over to Doug to open the question and answer session. Thank you very much, Dr. O'il, and thank you to the rest of my colleagues. May, let's open up the lines for the Q&A. Absolutely.
Incentive plan, because you may not answer it.
I guess I wanted to get your perspective on like P. P. M on potential endpoints is there potential for similar endpoints with BMO or is it more functional and then if they don't answer that can you just talk about maybe some other indications where it's Derek blocking us associated with BMO on where you might consider going there. Thanks.
Operator: Absolutely. To ask a question, you will need to press star 1 on your telephone; to withdraw your question, press pound. As a reminder, callers will be limited to one question only. Please stand by while we compile the Q&A roster. Your first question comes from the line of Genn-Wang of Barclays. Your line is open. Thank you for taking my questions. I have one question regarding
Yeah, I will start with so.
So on the P. P M O there'll be there'll be essentially 2 there'll be a functional end point of course, as we will eventually need to confirm the benefits of functionally to continue to have the therapy approved around the world, but our goal in the first interest with the P. P M O us too.
Seek an accelerated approval, United States and potentially even a conditional approval in.
Europe on the basis of the robust expression that we're seeing we have a well understood pathway in the United States with accelerated approval pathway. So it will be.
Operator: study 301, Doc, you will share details about the trial design, but just wondering if you can share the high level of a trial design now, and also regarding study 1012, crossover data,
Yeah, it'll be essentially 2 broad things on the functional endpoints with the P. P. M O and then there'll be I don't think we I don't think that we've landed on or disclosed publicly what what particular end point that we'll use for it it will obviously be there'll be some complication because with functional endpoints will have to think about the functional endpoint for the.
Operator: cross-over data in the first quarter next year. Just wondering, have you defined pre-specified natural history control?
Angela 20 population than functional end point potentially for the non ambulatory population, but will also have expression and that'll be dystrophin production and we have a we have a well understood pathway in the United States and we'll have a dialogue with the EMA on that basis as well.
Douglas S. Ingram: Yeah, thank you for that question. Gina, first of all, thank you for the first question, because I'm going to get this question a lot this evening, and this gives me an opportunity to frustrate everybody just once.
And then on additional indications.
I will turn this over either to Dr. O'neill Dr. True, what do you know clay back for that.
Douglas S. Ingram: So I am not going to provide details on study 301, other than, of course, to let you know that it is a placebo-controlled, double-blinded trial that will be our pivotal trial. There are a lot of nuanced details behind that, the powering of it, the end, the age groups, et cetera. and we have really put a lot of thought into study 301, informed enormously by study 102. And I'm going to be, I'm very excited to share that with you, and I'm very excited that we were able, very recently, to meet with the division and, on that basis, gained confidence that we're going to initiate that trial in September of this year. But I am going to frustrate you and not provide a ton of detail other than to know that it is, you know, it is obviously robust and very well-powered.
Since maybe chat about some of the other possibilities.
Your next question comes.
But before we go on I think it was really.
Steve You had another question I want us I want to answer that just created confusion because I'm supposed to be the master of ceremony and called on to people. So I will start with doctor on the L. B.
You answered it or turn it to turn it over to Dr or we didn't have great day.
Yeah. So we're actually very interested in leveraging the assets you might take us beyond.
You must have in muscular dystrophy and are looking at a number of tissues are targets of interest.
Both in muscle.
On muscle indication as well.
Potentially renal indications, but thats the kind of work that we're still.
Performing in our discovery phase and we will be leveraging our learnings from the ongoing 50.51, and then applying those in accelerating those forward. Once we have absolute clarity on our 50.51 progress on the P. P mode.
Douglas S. Ingram: A double-blind placebo-controlled trial. On study 102, of course, before the team is working on natural history sets and all of the statistics associated with that, it is a blinded trial. As you know, we'll have to fully lock all of that down and lock the natural history sets down before we unblind, but I think the team still has additional statistical work to do before the stat plan is fully developed. And thank you for both of those questions, Gina.
Across the exon skipping amenable population for Duchenne Louise I don't know if you want to add anything to that.
No I think you've covered it well Inc.
Yes.
But we do have we do have preclinical work ongoing exploring a number of different.
Disease areas, where steric blocking might be interesting, but that isn't dishes and then of course I should say just to remind everybody. You know you are working on P. PMO 50.51.
But we've got a number of other construct for additional mutations that at least theoretically.
We can build construct with a high probability of success that could treat.
Operator: Your next question comes from the line of Dazine Amaz of Boa. Your line is open. Hi, good afternoon.
Patients you know at least from a technical perspective, it could be well over 80% of patients that we could build therapies. There is a small percentage of very rare exxon's very rare mutations where this start blocking the technology in exon skipping isn't available, but the good news, it's a very small percentage of duchenne patients.
Operator: Thanks for taking my questions, and thanks for all the positive updates. So my one question, Doug, is about the timing of your study. You're expecting to start in September. On the Pfizer call that happened recently, they didn't seem to make specific mention of what is happening with their DMD study, at least with U.S. enrollment. So I'm curious, if you end up on a timeline where you're starting to study enrollment in U.S. patients around the same time, what's your view without overlapping clinical trial sites and whether or not it might impact the ability to enroll? Yeah, thank you.
Your next question comes from the line on our new from Rama of Jpmorgan. Your line is open.
Hi, guys. Thanks, so much for taking the question and congrats on the progress just on study 301 and the initiation here in September how do you think about getting sort of global sites up and running particularly with the pandemic.
<unk> in different regions, and how you think about the enrollment curve here. Thanks, so much.
Douglas S. Ingram: Yeah, thank you for that. A couple thoughts. One, I want to be clear. I'm not, I'm going to avoid directly comparing to other programs, as you can well imagine. I probably have a well-earned reputation for leaning towards the competitive, so I'm going to fight my natural instinct, but I will say the following.
I think we're well so I'll save the broad strokes again, I think enrollment you raised an interesting point about.
We live and on certain times every time, we think we have clarity on this pandemic. There you know new information comes out it forces us to continue to be humble in our prognostication about the future.
Would still broadly say that I am very confident that seems very confident that this is going to be a.
Robustly very robustly enrolled therapy and even in the height of the pandemic, we have experienced net sites ex U S and us, but ex U S is that kind of thing I think a lot of us on worrying about have been able to stay up and running and continue to execute without.
Douglas S. Ingram: Let me say the following first: that, you know, there is no one else that has the amount of clinical data to inform their program and the confidence of their therapy likes to rep for it. You know, as Dr. O'Neill, I believe, mentioned in his opening remarks, we have, by now, Dost at these levels, SRP 9-001, and ambulatory and non-ambulatory children and nearly 80 children, if not more than 80
Much of a problem in the absolute Youre raging.
Most difficult part of the pandemic, we were running a very significant as you know.
The other trials you are running a very significant global trial, which is the essence trial to confirm the benefits of.
From my understanding them on this.
You know us very even in the most difficult times with very few exceptions, we were able to continue to execute on patients were able to get in and got there.
Douglas S. Ingram: So we have an enormous amount of information that informs the confidence of our therapy and informs the next program and gives us a lot of confidence that we're going to do quite well. And, you know, we've done study 101, and we've done study 102, part one. We will have study 102 part two out very early next year. We have study 103, and the first cohort of that, of course, looked brilliant in the performance of that therapy from an expression and safety perspective, and we'll start study 301 in initiation. That trial
Got their infusions and this is gonna be that's even more complicated because of course those infusions on.
Weekly and then got the functional results there were a few missed visits but not very many so I think we'll be able to navigate through things of course, I will say again, what I've said that Jim about 1 billion times, we have to remain humble in our prognostication about the pandemic, but.
I don't think that's going to be the limiter on things I think.
The most significant limiters, just our ability to get up execute get sites up and running get them qualified and going recruitment will go very very well.
[laughter].
Your next question comes from the line of Celgene Investor of Goldman Sachs. Your line is open.
Hey, Thanks for taking my questions on in your meeting with <unk> was there any discussion about the potential for 9 years or on 1 approval on in the 4 to 5 year olds with DMD just based on on data to date and then secondly can you help us understand how these 2 limb girdle Michael muscular.
Douglas S. Ingram: The fall semester goes well in September, and we feel very confident about that. So we're in very good shape to drive SRP 901 forward. And of course, the reason that we want to do that with enormous amounts of urgency is, you know, hopefully everybody that's near this rare disease knows there are thousands and thousands and thousands of children, literally hundreds of thousands of children around the world who are having their muscles stolen from them day after day, literally unrelenting, and unfortunately, invariably fatal.
Muscular dystrophy type <unk> programs will coexist within your portfolio.
Yeah. So I'll answer the first 1 on I'll, probably leave it conductor.
No quite back to touch on the company on apathy limb girdle. So so let us since were.
Straightforward about this we were very clear about our goals by end of the meeting with <unk>. We did we asked very specific questions.
Rod strokes. The specific question was here's our CMC review, our CMC Here's our protocol for study 301 do you object to US commencing study 301 was that discussion we had absolutely.
Douglas S. Ingram: So we need to move fast, and we will do that. On the specific question you asked, the second part of your question, again, there is an enormous need for therapies like this, for this gene therapy, for our PPMO and others, and therefore understandably an enormous amount of interest and desire that we move fast, both from families who are living with and unfortunately invariably dying from Dushan Lusker Districts and from physicians and investigators. So I stand by the proposition that I've had for some time that this program, once we get going, should enroll with significant rapidity.
No discussions we didnt broached the issue of.
Something else like an accelerated approval for the 4 to 5 year olds are the 4 to 7 year olds.
Based on the data, we've seen already or coming up the data that we might see early next year and part 2 study 1 or 2 just to remind everybody we're going to get some really exciting data well some interesting data at a minimum and hopefully exciting data in the first quarter of next year, because we'll have 2.
2 cohorts 1 core with 1 year functional results in part 2 and another with 2 years from store results that is not an issue that we broke through the agency that would no discussions around that this was really.
Operator: Your next question comes from the line of Brian Abraham of RBC Capital Markets. Your line is open.
Very very much.
Round in study 301, and the commencement of study 301, and I'd say very excited that we are we had a very very productive very positive meeting with the agency on.
Operator: Hey, guys, congrats on all the progress and thanks for taking my question. I'm just wondering, with respect to study 301, are there any additional benefits to getting that study up and running, both in the U.S. and internationally?
On that basis, we're going to initiate that trial very soon.
And we believe it'll be in September.
Now on limb girdle, I'll turn it over to Dr. <unk>.
Way back to touch on Comping up a day.
Thank you for that question I think that there's some confusion we only have 1 <unk> program. We did have an option doctors or anything programs for quite some patents that we've been talking about it in the context on our portfolio on that we recently executed a license on that program.
Douglas S. Ingram: Any additional back and forth required with the agency, and can you confirm that, I guess, at this point, you're aligned on all the necessary potency assays are expected to be aligned shortly? Thanks. A couple thoughts. One, you know, just to initiate a study and roll a study out around the world, there are lots of steps. So I want to say, I don't, this is, you know, every, the team has been, frankly, in my view, fantastic in their execution, but we have a lot to do to get this study fully enrolled around the world. So there's, I don't want to create the impression that there's not a lot of additional work to do; there is. It's the team that's very, very competent and confident in getting all of that done.
1 <unk> program, which now round out our portfolio on we're really excited about it.
Back to think from working.
Quite tirelessly do complete the preclinical data, which shows efficacy data from logically functionally and caffeine knockout mice.
And both young and old line.
And then I guess, there's a lot of confidence moving forward in our development program for a pivotal program.
Thanks for the question.
We're particularly we're very excited about the fact that this is another RH 74 mediated gene therapy, because as you can imagine with the amount of data that we've developed over the last few years, we are only more confident in the differentiated aspects of our 874 SB.
Vector delivery mechanism for gene therapy.
Your next question comes from the line of Brian <unk> of Baird. Your line is from fans.
Douglas S. Ingram: I'd say the biggest, the biggest, the, the most significant issue for us to ensure that we could move rapidly and initiate this trial quickly, particularly in the United States, was to have that meeting with OTAT. And, of course, we had that meeting, and we'll say, although I'm not going to give you the exact date. It was very recent, and as I said, a very positive meeting, a very informative meeting, a very well-prepared meeting on both sides, by the way.
Hey, guys congrats on getting clients to go into phase III.
Yes.
The question is most appropriate protector.
Or do you not quite pack or Dr. O'neill, but I know you guys have been exploring certain AAV re dosing strategies.
You have a partnership with select on and will also discuss some other potential strategies in terms of us.
Colorado patient on silver.
Free dosing and any thoughts on on the progress there I know based on the LTE M. D day. It is home from work like Theres really waning.
Protein expression here about sort of in the long term.
Where are you in terms of looking at the potential for re dosing EPS.
I'd say on let me say a couple of.
Preface remarks, and then I'll turn it over to Dr. Dowdy on playback assurance to make any broad statements I suspect we're not on a stage, where we're going to probably provide.
Douglas S. Ingram: And as a result of that, we have an enormous amount of confidence that we're going to be able to initiate this trial very soon, and our goal is to have that done in September, and we feel confident about that. As for the potency assay, we've done a lot of work on the potency assay. As you may recall, back last year in September, we actually had been stalled for a short period of time, it turns out, based on potency acid. That was September of 2020. That actually ended up being a blessing for us.
Any detail other than this is important.
Theres a lot of reasons why this is important it's important for re dosing, it's important for knocking down neutralizing antibodies to bring into frame. The number of children that can benefit from our therapies, it's important for the ability.
There was ever.
A topic was needed it would really be on a.
Fascinating opportunity than we have in a number of different programs that we've been advancing them and we're pretty excited about it from at least from a preclinical perspective.
We're going to provide a tiny more information on that but if you have any other.
Comments, you'd like to make a luis too.
Yeah, I'll just reiterate there we've.
Any thoughts about having a comprehensive strategy to be able to treat patients with preexisting antibody.
Operator: gave us an opportunity to have live dialogue with the division and to really understand at a fairly granular level what the division was looking for not only then but in the future for potency assays. And so we've done a bunch of work since then. We've shared our perspective on the potency assays and our approach to potency assays with the division. They have agreed with our approach and endorsed our approach, and we've gathered the data, and we've As I said before, there's a lot still left to do, as one could imagine, to get a trial up and running around the globe, but we feel very confident that we'll be initiating that trial this year Hey guys, thanks for taking my question and congratulations on the progress.
And if needed.
To read out.
We have both internal programs on that partnership's upon some selected that really on track.
What aspects of that Mark.
I can go on antibody.
And that's essentially preventing antibody in patients on occasion for the first time, that's something that we're working very aggressive on.
I think this is important for the entire field of gene therapy. Eventually go knocking down preexisting neutralizing antibodies.
Extraordinarily important now we are fortunate were in a fortunate position but.
But I think compared to many others are screen out rate for neutralizing antibodies is relatively low.
15 to 17, maybe 1%.
So on that.
But that's still 15% to 17% of kids that until we find a solution for them would be screened out. So it gives us a real opportunity to bring those kids back in frame.
If all works well.
On a much better life. So that's you know that's why this is extraordinarily important including re dosing as well.
Your next question comes from the line of Gil Blum of need have on company. Your line is open.
Operator: Your next question comes from the line of Alitia Young of Cantor. Your line is: Hey guys, thanks.
Hello, everyone and congratulations on a great quarter.
Just a quick 1 from us.
So.
If theres going to have on.
Douglas S. Ingram: Yeah, I will start with, so on the PPMO, there will be essentially two, and there will be a functional endpoint, of course, as we will eventually need to confirm the benefits functionally to continue to have the therapy approved around the world. But our goal, in the first instance with the PPMO, is to seek an accelerated approval in the United States and, potentially, even conditional approval in Europe on the basis of the robust expression that we're seeing. We have a well-understood pathway in the United States with the accelerated approval pathway.
On the advisory meeting on the safety of AAV is is there any potential for new guidelines coming out of this meeting that might.
Require amendments to protocols.
No.
Well I will let Dr. O'neill touch on that if he has additional comments. The 1 thing I would say is that this is not an issue that we just had a discussion with the division.
Just had a meeting on that.
The all parameters of CMC and protocol on the like regarding non 001 on our next study and certainly none of these issues were.
Any state, where we're even part of that discussion and frankly, we don't have any data preclinical or clinical that would give us any concern around these issues as we understand them that are being raised in this.
Douglas S. Ingram: So it'll be, it'll be simply two broad things. There'll be functional endpoints for the PPMO, and then there'll be, I don't think we've, I don't think that we've landed on or yet disclosed probably what particular endpoint that we'll use for it. It'll obviously be, there will be some complications with functional endpoints. We'll have to think about the functional endpoint for the ambulatory population and then a functional end point, potentially, for the non-ambulatory population.
In this upcoming Advisory Committee meeting, we're very interested in it would love to provide whatever information we have but we're not particularly concerned that this would have an impact on therapies that we're working on right now Dr.
Dr. <unk> do you have any any other comments or.
Contract cabinets.
I think you said it nicely I would guess.
Yes.
And it is our belief and I think the data that we have on others have support the view that different serotypes and the group of capsid.
Our difference and behave differently and our differentiation and I think we have a robust data set that is true our differentiation and how we anticipate.
Douglas S. Ingram: But we'll also have expression, and that'll be district in production. And we have a, you know, we have a well-understood pathway in the United States. We'll have a dialogue with EMA on that basis as well. And then on additional indications, I turn this over either to Dr. O'neill or Dr. Lidina for that, to maybe chat about some of the other possibilities.
Designing our protocols on how do we design is based on the Greek datasets that we have generation and as Doug said.
Dose.
Around 80 or in excess of 80 patients by now so those are the key things we will.
You used to drive our study designs and.
I will also say that we are looking forward to learning more.
Operator: Your next question: Oh, wait.
Douglas S. Ingram: But before we go on, I think there was Lee had another question I wanted to answer. I just created confusion because I'm supposed to be the master of ceremonies and called on two people.
From this advisory group. It is also probably worth reemphasize the FDA guidance are actually registry recently published.
And.
I think can speak in broad suite, but as I said different serotypes different datasets and so we believe and continue to believe that we will be designing our protocols.
Douglas S. Ingram: So I will start with Dr. O'Neill to be answered or turn it over to Dr. O'Neino. Yeah, we're actually very interested in leveraging P2Metica beyond muscle and muscular dystrophy and are looking at a number of tissues that are targets of interest, both in, with a muscle indication, as well as potentially renal indications. But that's the kind of work that we're still, you know, performing in our discovery phase, and we will be leveraging our learnings from the ongoing 50-50s.
Around the empiric data that we're generating from our clinical experience with our Orange 70 forecasted.
Thanks, Don.
Okay.
Your next question comes from the line of redo morale of Cowen Your line is open.
Hi, guys. Thanks for taking the question Doug did I hear you right in your conversations with FDA around the L. G. M D soccer Oakley I cannot preclude us.
Douglas S. Ingram: and then applying those and accelerating those forward once we have absolute clarity on our 5051 progress and the PPMOs across the Exxon Skip and Menable population for Duchenne. Louise, I don't know if you want to add anything to that.
Well soccer like can levels.
Sufficient to drive accelerated approval and does that apply do you think that applies to all of the second line.
Like off the fees.
Louise R. Rodino: I think you cover it well, thanks.
It applies to.
How things as well.
Operator: We do have preclinical work ongoing exploring a number of different disease areas where steric blocking might be, that isn't the shent, and then, of course, I should say just to remind everybody that we are working on ppmO 50 51, but we've got a number of other constructs for additional mutations and, at least theoretically, we can build constructs with a high probability of success that could treat patients, you There is a small percentage of very rare exons, very rare mutations where this stark blocking technology and exon skipping isn't available, but the good news is that there is a very small percentage of Duchenne.
Yeah.
Yes, yes, yes.
When I say dialogue because it was a great response, so we haven't had direct line.
<unk>.
Dialogue with the division yet.
But the written.
Dialog that we've had the written feedback that we've had from the division is that it is.
But you know it is possible to us protein expression levels for 2 way, presumably its beta cycles like in levels as a basis for an approval and that's obviously consistent both with the.
It's because of a number of guidance as it exist at the FDA, but on <unk>.
Zero side of things. So we're very excited about that.
That guidance.
Excited us about the C that we've got and there really is no reason on the face of it why that wouldn't apply to the <unk> to all of the stocks. They are very similar in a number of regards and I think there and similar number of guards and in some ways less complicated than some other genes.
Operator: Your next question comes from the line of Anupam Rama of J. J.
Operator: Hi, thanks so much for taking the question and congratulations on the progress. Just on study 301 and the initiation here in September, how do you think about getting sort of global sites up and running, particularly with the pandemic?
Gene therapies, you know 1 of the issues with AAV mediated gene therapy is that of course, the packaging ability of AAV is limited in a lot of times the gene is larger than the.
Then the packaging and you have to do interesting things like we have with micro dystrophin.
Through a lot of great work.
Similar thing with respect to each of these circle glad cans is that the gene is actually comfortably.
Douglas S. Ingram: the pandemic, very variable in different regions and how you think about the enrollment curve here. Thanks so much.
Able to sit inside the D. So we are making the gene that codes from the native protein in all of the startup of the line cans, but right now that's alpha beta.
Douglas S. Ingram: I think the, well, so I'll save the broad strokes again. I think enrollment you raised an interesting point about, you know, We live in uncertain times. Every time we think we have clarity on this pandemic, new information comes out that forces us to continue to be humble in our prognostication about the future. I would still broadly say that I am very confident, and the team is very confident that this is going to be a robust, very robust therapy.
And gamma we're making the actual native protein on altered that is the sole cause of the disease that is causing the demise of these days.
These children and teens and adults in some cases with respect to some of these <unk> and so I think it's.
It's not unreasonable for the agency to US suggested to us that we can use protein as us.
Surrogate endpoint reasonably likely to lead to clinical benefit for purposes of of.
Douglas S. Ingram: And even in the height of the pandemic, we have experienced that cites X-U.S. and U.S., but XUS is the kind of thing I think a lot of us are worrying about, have been able to stay up and running and continue to function without much of a problem. In the absolute, you know, raging, most difficult part of the pandemic, we were running a very significant, as you know, among other trials, we were running a very significant global trial, which is the essence trial to confirm the benefits of Andamondis.
Considering that there is still work we have to do we have more conversations to have we have to have a broader conversation both with emphasis on by the way I should say and we've had similar feedback from EMA. So there's the opportunity for accelerated approval in the U S opportunity for conditional approval.
In Europe as an example, and now from there we've got to get more concrete about the plans and thinking about what this means for <unk>, what the clinical program should look like what the regulatory pathway will look like for that both for the.
Approval and then also obviously for the post approval confirmatory.
Douglas S. Ingram: And, you know, even in the most difficult times, with very few exceptions, we were able to continue to operate, and patients were able to get in and get their infusions. And this is going to be even more complicated because, of course, those infusions are weekly and then they get their functional results. You know, there were a few missed visits, but not very many. So I think we'll be able to navigate through things, of course.
On the data that we're going to need and we need to do that not only for <unk>, but for gamma and for for Alpha as well and so that's why when on things we're working on right now.
Your next question comes from the line of day say, Yeah of Mizuho Securities. Your line is open.
Good afternoon, and thanks for taking our questions. So just a clarifying questions at the Oh that meeting did the FDA provide any guidance guidance specific guidance.
How to construct the natural history cohort for study 1 or 2.
Yeah.
Oh, no that wouldn't be an issue that came up there.
Douglas S. Ingram: I will say again, as I've said to the team about one billion times, We have to remain humble in our prognostication about the pandemic, but I don't think that's going to be the limiter on things. I think the most significant limiters are our ability to get up, execute, get sites up and running, get them qualified and going, and then I think recruitment will go very, very well.
The meeting was the.
Division <unk> was all about the commencement of our pivotal trial study 301 on that of course isn't going to have a natural history cohort. It's a placebo controlled trial. So that wasn't an issue that was we didnt broached. The question on the did.
Come up in the meeting.
Okay, and then can you just to follow up on that and do you think eventually you'll need to have FDA buying on.
On the natural history comparator song.
Well no I think what I think that's on us to make sure that it's done with the that's done and done robustly enough that it that it's that.
Operator: Your next question comes from the line of Selveen Richter of Goldman Sachs. Your line is OK.
Operator: Thank you. Thank you for taking my questions. In your meeting with OTAT, was there any discussion about the potential for 9-001 approval in the 4-to-5-year-olds with DMD just based on data-to-date? And then, secondly, can you help us understand how these two limb girdle, micomuscular dystrophy type 2A programs will coexist within your portfolio?
But it's meaningful and it and insightful, but generally speaking I think we are the we are the masters of ours, our stat plan for.
For purposes of 1 or 2 we just have to make sure that it's robust.
And it meets the statistical muster and that's of course, what we're doing I have to say, we have a great team on that.
<unk> team.
And obviously I think a very expert development achievements, considering all of those issues.
Your next question comes from the line of Tim Lugo of William Blair. Your line is open.
Douglas S. Ingram: Yeah, I'll answer the first one, and I'll probably leave it to Dr. Goudina Clayback to touch on the calpenopathy, Lynn Grydle. So let's be very straightforward about this. We were very clear about our goals going into the meeting with OAT. We did, we asked a very specific question, and in broad strokes, the specific question was, here's our CMC, review our CMC, and here's our protocol for study 301. Do you object to us commencing study 301?
Hi, guys. This is John on for Tim Congrats on the quarter and thanks for the question.
Was just wondering if you could provide any update on your views on longer term competition or maybe even opportunity from CRISPR based therapies in neuromuscular diseases.
Yeah.
So we're very excited.
Excited about CRISPR technology, let me be very clear about that where we're making significant investments and Christopher cash 9 hopefully everyone knows we have essentially 3 platforms. We've got our RNA therapy, We've got gene therapy I think by now we are.
Douglas S. Ingram: It was that discussion that made me think. We had absolutely no discussions. We didn't broach the issue of something else like an accelerated approval for the four to five-year-olds or the four to seven-year-olds based on the data we've seen already or, you know, coming up with data that we might see early next year in part two of studies one or two. Just to remind everybody we're going to get some really exciting data, well, some interesting data at a minimum and, hopefully, exciting data in the first quarter of next year because we'll have two cohorts, one cohort with one-year functional results in part two and another with two years.
It's not the leaders in.
Portfolio of gene therapy, we are certainly 1 of the top couple of of leaders in gene therapy, and then we've got this Jim Gene editing Innovation Center in Durham, North Carolina, where we're looking at looking at CRISPR cash side and the ability to directly edit the genome is another long term mark.
Opportunity to bring a better life to people with.
With genetic disease, including neuromuscular genetic disease and I'm excited about that I am very excited about for instance, the fact that we have as our leader of our gene editing Innovation Center Doctor, Charlie Gerspach, who is brilliant.
Douglas S. Ingram: That is not an issue that we broke through the agency. There were no discussions around that. This was really, very much around study 301 and the connection to study 301. And I'd say I'm very excited that we had a very, very productive, very positive meeting with the agency. And on that basis, we're going to initiate that trial very soon, and we believe it will be insip Now, I'll turn it over to Dr. Ludina-Claybac to talk about Tampaign-Up.
Brilliant and I think 1 of the significant world leaders and Christopher cast on generally.
Neuromuscular, specifically I will you'll notice that us searches Google search of the articles Youll see that day.
It is all the time, it probably would embarrass doctor Gerspach, but I know that day.
Louise R. Rodino: Thank you for that question. I think that there was some confusion.
Dr. Doudna I think we all know won the Nobel Prize for Christopher gas 9 was asked us.
Louise R. Rodino: We only have one LGMD2A program. We did have an option for a doctors' research program for quite some time, so we've been talking about it in the context of our portfolio, and then we recently executed the license for that program. So it's just one LGMD2A program, which now rounds out our portfolio, and we're really excited about it. Dr. Sanks has been working quite tirelessly to complete the preclinical data, which shows efficacy both biologically and functionally in calcane knockout mice, both in both young mice and old mice, and really gives us a lot of confidence in looking forward to our development program for this program. Thanks for the question.
Not too long ago, I think earlier this year, who she was excited about and Christopher cash 9 states for the future and are on Dr. Charlie Gerspach was 1 of the name. She she gave I think it was the only name she gave in relation to biotech. So we are very focused and very excited about it now.
Christopher cash 9 certainly for full body infusion neuro muscular diseases is challenging today. So from our perspective. This is a research project right now we are not yet ready to translate the fascinating work on Christopher cash 9 into a clinical.
Program right now in patients.
There are a lot of things that have to be a locked before you consider full body infusion. This is not trying to do Christopher cash 9 and let's say ocular or you know in the liver, where it's sort of you know where these AAV mediated.
Operator: We're particularly, you know, we're very excited about the fact that this is another RH74-mediated gene therapy because, as you can imagine, with the amount of data that we've developed over the last few years, we are only more confident in the differentiated aspects of R874 as the vector delivery mechanism for gene therapy.
Therapies, you know significantly go this is asking a lot more of.
Editing and so we've got a lot more work to do so.
I don't I think Christopher cash that's exciting.
It could be very exciting for neuromuscular diseases as well.
Potentially even including Duchenne muscular dystrophy.
I don't see this as a near term competition.
Operator: Your next question comes from the line of Brian Scornie of Bird. Your line is open.
2 for instance, gene therapy, which is right in front of US today I think this is a research project that we've got some work to do before we can translate this into clinical programs, but that is not to say we're not excited about it. We definitely are we think theres going to be an enormous.
Operator: And congrats on getting clearance to go into Phase 3.
Operator: I guess I know the questions most appropriate for Dr. Houdini Claypack or Dr. O'Neill, but I know you guys have been exploring certain AV redosing strategies. I think you have a partnership with Select, and we've also discussed
The time is now for RNA and gene therapy, and we think gene editing or something that could be very exciting for the future, where we actually directly go in and start thinking about how to edit the genome.
Your next question comes from the line of Matthew Harrison of Morgan Stanley. Your line is open.
Operator: Some other potential strategies in terms of polarizing patients for redosing.
Operator: Any thoughts on the process?
Operator: on the progress there, I know based on the LGMD data, it doesn't look like there's really waning of protein expression here, but sort of in the long term, where are you in terms of looking at the potential for redosing AAP?
Hi, This is Max score on for Matthew Harrison. Thank you for taking our question. So how should we think about the crossover arm in terms of the findings from study 102 that is would you expect it to replicate some of the age differences and other factors compared to baseline. Thank you.
Douglas S. Ingram: I say, let me make a couple of preface remarks and then I'll turn this over to Dr. Radia Klepec if you want to make any broad statements. I suspect we're not at a stage where we're probably going to provide any detail other than that which is important. There are a lot of reasons why this is important. It's important for redosing. It's important to knock down neutralizing antibodies to bring in to frame the number of children that can benefit from our therapies.
Yes, thank you for that so.
So no. The good news is that the 1 so the there were.
2 flaws in part 1 on study 102.
1 of the 2 of course is the tighter it is.
<unk> of the the kind of PCR title that was done from a nationwide childrens hospital material, which is a supercoil TCR.
Some of the kids wear had less than the target dose and a significant number of 60% of the kids had lessons on the target dose that's correct, but just to be clear. That's correct. It ended for the crossover patients fully corrected we were using our current tighter method, we do not have that issue the second.
Douglas S. Ingram: It's important for the ability, you know, if there was ever, you know, a topping up was needed, it would really be a fascinating opportunity. And we have a number of different programs that we've been advancing, and we're pretty excited about them from, at least from our pre-clinical perspective. I doubt we're going to provide a ton more information than that, but if you have any other comments you'd like to make, Luis, please, too.
And probably really significant.
The problem with part 1 was this enormous baseline imbalance because even with those titling issues. When we had the baselines right and we did in the 4 to 5 year olds, you saw clinically meaningful and very strong statistically significant.
Louise R. Rodino: Yeah, I'll just reiterate that we've been very thoughtful about having a comprehensive strategy to be able to
Improvement.
In the kids that were on treatment was it 16 kids so so.
Louise R. Rodino: to be able to treat patients with pre-existing antibodies and, if needed, the ability to redose. We have both internal programs and then partnerships with Hanson selected that really will address both aspects of that. So knocking down antibodies and patients that have them and potentially preventing antibodies in patients that are treated for the first time. So it's something that we're working on very aggressively.
Clearly getting the baseline right is important and the problem was in the 6 to 7 yogurt is enormous.
Delta between the active and the treated where the active kids were all very severe in the placebo kids were far more miles I mean significant like the P value on that was 0.004. So 4 times out of a thousand you would have even had this problem.
The good news is that of the.
The crossover is that there's no way to look at a placebo arm anymore of course, all the kids will be on therapy. Some of them will be on therapy for 2 years, some will be on therapy for 1 year sort of a good question that was asked previously we need to make sure we build a strong natural history before we ever on blind build a natural history model that is appropriate.
Operator: I think this will be important for the entire field of gene therapy eventually. You know, knocking down pre-existing neutralizing antibodies is extraordinarily important. Now, we are fortunate. We're in a fortunate position, but I think compared to many others, our screenout rate for neutralizing antibodies is, you know, relatively low. It's, you know, 15 to 17, maybe a percent maximum. But that's still 15 to 17 percent of kids that, until we find a solution for them, would be screened out.
Matches, and then you'll look at the this therapy versus natural history. So that's essentially self correcting that second issue is self correcting on that.
On the part 2 and then on all the crossovers. The titling issue was corrected with our more precise tighter net that was used for all of the doses in the crossover.
Operator: So it gives us a real opportunity to bring those kids back into the picture and, if all works well, you know, give them a much better life. So that's, you know, that's why this is extraordinarily important, including redoing this. Wow.
Your next question comes from the line of Joseph Schwartz of SVP Leerink. Your line is open.
Thanks, very much I was wondering beyond those 2 flaws that you were just talking about Doug.
Operator: Your next question comes from the line of Gil Blom of Needham and Company. Your line is open.
How much have you been able to learn from your analysis of study 102 that you can use to implement in study 301 in order to improve the.
Operator: Just a quick one from us. The FDA is going to have an advisory member. Is there any potential for new guidelines coming out of this meeting that may require amendments to protocols? Well, I will let Dr. O'Neill touch on that if he has additional comments. The one thing I would say is that this is not an issue that we just had a discussion about with the division. We just had a meeting on all the parameters of CMC and protocol and the like regarding 9-001 in our next study, and certainly none of these issues were any sick patients were even part of that discussion.
Probability of success do you have any examples that you can give.
Give us to help us appreciate how the.
Mike.
Rising going forward.
Well will you know.
I'm going to apologize I'm going to beg off the detail and we'll talk about that a little bit later, when I have the minutes and we're closer to initiating the trial, because we will come back and talk about the trial and how we become even more confident in the program on pause.
Douglas S. Ingram: And frankly, we don't have any data preclinical or clinical that would give us any concern around at least the issues as we understand them that are being raised in this upcoming advisory committee meeting. We're very interested in it. We'd love to provide whatever information we have, but we're not particularly concerned that this would have an impact on therapies that we're working on right now. Dr. Neil, do you have any other comments or a contract question? No, I think you said it nicely.
But I'll give you the summary answer Joseph and I know this is frustrating, but I'll give you a summary at least from that is that there's an enormous amount of insight that we got from part 1 of 1 or 2 I mean.
We did have stat Sig.
Some of US myself certainly included we'll watch for a while and then immediately realize that we had an enormous amount of opportunity in front of us and I'd say 2 things that came out of that part 1 in summary fashion and we will talk about some of this in more detail when we get the minutes and we talk about the 301 trial.
Gil Blum: I would guess that it is our belief and I think the data that we have and others have support the view that different stereotypes in the AV group of capsids are different and behave differently and are differentiated and I think we have a robust data set that show our differentiation and how we anticipate designing our protocols and how we design it is based on the empiric data sets that we have generated and as Doug said we have a dose around 80 or in excess of 80 patients by now so those are the key things that we will will use to drive our study designs and I will also say that we are looking forward to learning more from this advisory group it is also probably worth reemphasizing the FDA guidance are actually relatively recently published. And, you know, I think can speak in broad swades, but as I said, different serotypes, different data sets. And so we believe and continue to believe that we will be designing our protocols around the empiric data that we are generating from our clinical experience with our RH74. Thanks, Doc.
1 is that that we're just we're just very confident is our people and our program and the probability of success of the program on the transformative potential of SRP 9001, we feel very confident for instance, if we didn't have the baseline.
The issues that we had with those kids.
Unfortunately, we would have had a very different outcome on.
Part 1.
Hum.
Do you want us to and the second thing I would say is.
Then it has informed US 301 in ways that should significantly increase the probability of success.
Your next question comes from the line of Colin Bristow of UBS. Your line is open.
Hi, This is Tim on okay. Thanks for taking on question congrats on the corner. So we have a follow up question relative to the potential accelerated filing funai on 1 I understand it wasn't on discussed over the meeting you had with Oh that.
Operator: Your next question comes from the line of Ritu Baral of Cowan. Your line is: Hi, thanks for taking the question. Doug, did I hear you write in your conversations?
Just want to get an idea on where do you stand now on the potato finding on micro dystrophin compression like biomarker, especially now with depending on the approval were updated take on much more flexible much.
Operator: with FDA around the LGMD sarco-blackanopathies, um,
Douglas S. Ingram: Will sarcoglycan levels be sufficient to drive accelerated approval? Do you think that applies to all of the sarco-gopopathies? Could it apply to A and calpane as well?
For this new royalty does this with high on non us.
Douglas S. Ingram: Yeah, so yes, I want to say dialogue because it was a written response. So we haven't had direct live dialogue with the division yet.
And any possibility on finding ways of preliminary expression data from 3 O.
On 1 and of course with on the downside.
Douglas S. Ingram: But the written dialogue that we've had, the written feedback that we've had from the division is that it is, you know, it is possible to use protein expression levels for 2E, presumably, it's beta-circle glycan levels, as a basis for an approval. And that's obviously consistent both with the, it's because it with a number of guidance that exist at the FDA, both Cibur and the NERO So we're very excited about that guidance, and we're excited about the written feedback that we've got. And there really is no reason, on the face of it, why that wouldn't apply to the Sarks. To all of the Sarks. They're very similar in a number of ways.
While long term Wow great.
We also have a follow up question on a separate question on the competitive landscape, where we didnt notice Pfizer announced plans to start a phase 3 trial in non ambulate a patient.
With no restrictions on a bit too early to know.
Patients aged 2 to 3 years out.
From your side to initiate studies in this population in near term I think you.
Yeah I'll, let me answer the second question for US certainly you know 1 of the what are the things that has happened historically with them.
For for good understandable reasons, but not for good results is that the non ambulatory patient population has been underserved in the clinical trial setting, we certainly will be looking to do trials and the non ambulatory population and I should tell you right now in study 103, and we've already dosed a lot of kids and what else we are dosing.
Douglas S. Ingram: And I think they're similar in a number of respects and somewhat less complicated than some other gene therapies. You know, one of the issues with AAD-mediated gene therapy is that, of course, the packaging ability of AAD is limited, and a lot of times the gene is larger than the packaging, and you have to do interesting things like we have with microdisturcin through a lot of great work. The simpler thing with respect to each of these sarco-glycans is that the gene is actually comfortably able to fit inside the AAD. Thus, we are making a gene that codes for the native protein in all of the sarcoglaclycans. Right now, that's alpha, beta, and gamma.
Non ambulatory patients from larger kids as well in study 1 or 3 so that is a big part of our plans on the <unk>.
All of us approval pathway I'm going to say 2 things.
The first of course is that we understand that kids are getting damaged every day by this disease and that we need to think about how we could urgently move our therapies forward as fast as possible and so I wouldn't.
No 1 should assume that we're not willing to be thoughtful and creative about things and the second thing I would say in broad strokes unrelated to 9 years. There 1 is that accelerated approval as a pathway has been.
Douglas S. Ingram: We're making the actual native protein, unaltered, that is the sole cause of the disease that is caused in the demise of the disease in these children and teens and adults, in some cases, with respect to some of these SARCs. And so I think, you know, it's not unreasonable for the agency to have suggested to us that we can use protein as a surrogate endpoint reasonably likely to lead to clinical benefits for purposes of considering that.
An enormously valuable on the innovative approach to bringing better lives to patients over the course of many years because of accelerated approval has existed long before.
It was in the 20 <unk> century Cures Act. It has brought a better life to countless patients because you just you could literally just real off the cancer patients and age patients and others, whose lives have been bettered or saved US a result of this wonderful approach when it's appropriate.
Douglas S. Ingram: There's still what we have to do. We have more conversations to have. We have to have a broader conversation both with MS, and, by the way, I should say, and we've had similar feedback from EMS. So there's the opportunity for accelerated approval in the U.S., and opportunity for conditional approval in Europe, as an example. And now, from there, we've got to get more concrete about the plans and think about what this means for 2E, what the clinical program should look like with the regulatory pathway will look like for that, both for the approval and then also, obviously, for the post-approval confirmatory data that we're going to need And we need to do that not only for 2E but for approval gamma and for alpha as well. So that's one of the things we're working on right now.
But I will say that it's finally, when I get to 90 day zero, 1 I want to say 2 things about it. The first is that it just so we're very clear we've had no conversations with the division about it there's nothing that would have come out of our meeting with the <unk> that would have given us any.
Any reason to be more or less confident in that as a concept, but the second thing I would say is that study 301 is our pivotal trial.
And we have built it as our pivotal trial and it's robust and us.
People control and it's from our perspective, very well powered and if I wasn't a investor I would presume that that 301 is the pathway to success from a clinical perspective and from an approval perspective, both in the United States and around the world and I wouldn't want on over promise on other things because that's our focus right.
Now our focus right now is getting 301 initiated up and running fast and rolls and confirming the results that we've seen already on that and what we presume we're going to see an early next year and so I just wanted to make sure. We don't we're not creating the wrong impression I think 300 ones our pivotal trial.
Operator: Your next question comes from the line of Fay Yang of Missououou securities. Hi, good afternoon, and thanks for taking our questions. So just clarifying some questions at the ODEP meeting, did the FDA provide any guidance with regard to how to construct the natural history cohort for study 102?
That's what I think people on 2 to focus on us the pathway for approval right now for SRP line shows here 1.
And maybe just moving and just 1 quick point of clarification I don't believe Pfizer started a pivotal study in the non ambulant patient population. The last update I think they gave us that.
Douglas S. Ingram: No, that wouldn't be an issue that came up. The meeting with the division, OTA, was all about the commencement of Octavital Trial Study 301, and that, of course, isn't going to have a natural history cohort in the placebo-controlled trial. So that wasn't an issue that we didn't broach the question on, and that didn't come up.
Yeah, and that's a in that population and they were doing a protocol change and adding so unless to their protocol.
On a dosing more patients so I don't believe they're in it.
Pivotal study with that population.
No I think they're not even I think they are there.
Douglas S. Ingram: Okay, and then, just to follow up on that, do you, does just to follow up on that, do you think eventually you'll need to have FDA's buying on the natural history, the comparators on? Well, no, I think what,
Phase 1 study that was going to explore non ambulatory patient apart I didn't realize you had suggested they had started I think they're actually not moving forward right now because they're gonna do a protocol amendment to add another prophylaxis.
Douglas S. Ingram: Well, I think that's on us to make sure that it's done and done robustly enough that it's meaningful and insightful. But, generally speaking, I think we are the masters of our statistical plan for purposes of 102. We just have to make sure that it's robust, and it meets the statistical muster, and that's, of course, what we're doing. I have to say we have a great team on that; we have a strong support team. And obviously, I think, a very expert development team that's considering all of those issues.
They already have Soliris, we're not mistaken I think they're now, suggesting they're going to have around <unk> as well as a prophylactic in advance of pretreatment.
Your next question comes from the line of Danielle Brill of Raymond James Your line is open.
Hi, This is Alex on for Danielle. Thanks for taking my question I just want to expand on your point on 1 of 3 when can weeks back to us.
See the expanded dataset and if you can comment on how many patients have you dosed in those non ambulatory and the older cohorts.
Cohort.
Operator: Your next question comes from the line of Tim Lugo on behalf of William Blair. Your line is open. Hi guys.
<unk>.
So we will find an appropriate medical meeting down the road to provide additional.
Information and insight into study 1 O 3 so we haven't we haven't selected.
Operator: quarter and thanks for the question. So I was just wondering if you could provide any updates on your views on longer-term competition or maybe even opportunity from CRISPR-based therapies in neural. So we're very excited about Krisper technology. Let me be very clear about that. We're making significant investments in CRISPRCast 9. Hopefully, everyone knows we have essentially three platforms.
From a medical meeting yet, but it will be very interested to show that information and I don't have the details on the number of the complete number but we've done a number of ambulatory patients in a number of.
Large larger.
On kids with with Duchenne muscular dystrophy with SRP 9 zones are on 1 so that is proceeding very well right now.
Your next question comes from the line of Jim Jong of BT I E. Your line is open.
Yes, Thanks, Paramount's would take that question <unk> on.
Limb girdle to E.
Douglas S. Ingram: We've got our RNA therapy, we've got gene therapy. I think by now we are, if not the leaders in the field of gene therapy. We are certainly one of the top couple of leaders in gene therapy. And then we've got this gene editing innovation center in Durham, North Carolina, where we're looking at CRISPRCast 9 and the ability to directly edit DNA. The genome as another long-term opportunity to bring a better life to people with genetic disease, including neuromuscular genetic disease. And I'm excited about that.
It was very encouraging to see to hear the surrogate endpoint discussion but.
Sure they were positive.
Functional data even after 1 year of treatment then.
My question is why don't you go for full approval was the function of data.
The pathway relying on surrogate endpoint would that.
Allow you to maybe avoid running placebo controlled study where would that allow us to talk to the FDA on potential approval, maybe even before.
1 year after treatment.
Douglas S. Ingram: I'm very excited about, for instance, the fact that we have as our leader of our gene editing innovation center Dr. Charlie Gerstbach, who is brilliant and I think one of the significant world leaders in CRISCast9 generally and neuromuscular, specifically. I will, you know, you'll note if you did a Google search of articles, you'll see that, I say this all the time, it probably would embarrass Dr. Gersbach, but, you know, I know that Dr. Doudna, I think we all know, won the Nobel Prize for CRISPR Cast 9, was asked not too long ago, I think earlier this year, who she was excited about in the CRIS And our own Dr. Charlie Gersbach was one of the names she, she, she gave, and I think it was the only name she gave in relation to biotech.
Well, we're going to have to it let's go.
There are many of them we wanted to ask you.
Dose children using the commercially.
Presentative material, so let's start there I understand the data that we have right now for the first 2 cohorts to I agree with you completely it's really a data. It's brilliant on expression is great on safety and it's great on functional signals as well, but that's in the that is in the clinical supply material, we've got to get all of the <unk>.
On process development analytical development and dose kids on the commercially representative material as a predicate day approval that's good news.
Is it as the first part and then the.
And then once we do that why do why would we be interested in looking at expression as opposed to just looking at function and short answer is this is a very rare disease and it is more heterogeneous than duchenne muscular dystrophy, and so that it would just be.
It would.
Douglas S. Ingram: So we are very focused and very excited about it. CRISPR cas9, certainly for full body infusion, neuromuscular diseases, it's challenging. So, from our perspective, this is a research project right now. We are not yet ready to translate the fascinating work of CRISPRC-9 into a clinical program for patients because there are a lot of things that have to be unlocked before you consider full body infusion. This is not, you know, trying to do CRISPRCast 9 in, let's say, the eye or, you know, in the liver, where it's sort of, you know, where these AV-Daited therapies significantly go.
We would make people wait far too long in our view is if we had to.
<unk> for a statistically significant functional readout on <unk>. This is to be direct this is.
Perfect.
Place for the use of a surrogate endpoint and accelerated approval you got a well characterized disease at least the mechanism of action of the diseases, well characterized which is it is a single gene mutation a lack of a structural protein that lack of structural protein that is causing the demise and Anna.
Actual.
Fatality for these for these patients these kids and adults.
And we are able to deliver that that exact approaching the literal native protein in robust amounts to the muscles. So there's this as you know.
Douglas S. Ingram: This is asking a lot more of editing, and so we've got a lot more work to do. So I don't think CRISPRCast9 is excited. I think it could be very exciting for neuromuscular diseases as well, potentially even including Dushan Muscle or dystrophy.
This is the kind of place where accelerated approval was intended where you can bring this therapy, because it's going to have such a high probability of being clinically meaningful to patients you can bring it to patients and then.
Have an ongoing study that confirms those clinical results over time. So that you don't have to wait to bring this therapy to patients and so that's going to be our approach and we've got more work to do with the FDA and EMA on that but I am happy to say that at least at a philosophical policy level. The division agrees that that is a potential.
Douglas S. Ingram: But I don't see this as a near-term competition for, for instance, gene therapy, which is right in front of us today. I think this is a research project that we've got some work to do before we can translate this into clinical programs. But that is not to say we're not excited about it. We definitely are. We think there is going to be an enormous, the time is now for RNA and gene therapy, and we think gene editing is something that could be very exciting for the future, where we actually go directly in and start thinking about how to edit the genome.
Both EMA and FDA, okay on inquiries as well.
There are no question at this time I will now turn the call over to <unk>.
Doug Ingram for closing remarks.
Thank you very much I I will just extemporaneously say, a few things, but not many of US I know people its getting late for everyone. Thank you very much for joining us. This evening I am very proud of the work. This team has done both to serve the patients that we have with the therapies available to us today and I think the team has just done a brilliant job of that.
What other people have and ask questions about our revenue, but that revenue is impressive because it reflects.
Operator: Your next question comes from the line of Matthew Harrison of Morgan Scanley. Your line is open. Hi.
Operator: Hi, this is Max Cora speaking on behalf of Matthew Harrison. Thank you for taking our question. So how should we think about the crossover arm in terms of the findings from study 102? That is, would you expect it to replicate some of the age differences and other factors compared to baseline? Thank you.
Commercial expertise in the field based expertise that I got to tell you I'm extraordinarily proud of them is going to benefit us enormously when we watch some of these gene therapies and as we don't take price increases as a company.
We've.
Price all of our therapies at parity. It is a reflection of our ability to serve patients and bring a better life to patients. So I'm really thrilled with that I'm, obviously thrilled with the team.
Douglas S. Ingram: Yeah, thank you for that. So, so no, the good news is that the one, so the, the, there were two flaws in part one of study 101. One of the two, of course, is tittering. As a result of the kind of PCR tittering that was done in the nationwide children's hospital material, which is a super-coiled PCR, some of the kids had less than the target dose, and there was a significant number of 60% of the kids had less than the target dose. That's corrected, let's just be clear; that's corrected.
For the great work, we've done in advancing our portfolio and pipeline over the course of this year. We've made a lot of great progress and we are a multi platforms to do that on we've got our RNA <unk> got our PMO next generation version of the PMO, We've got our gene therapy line yours or the 1903.
The list will go on with the circle glad cans in the remainder of the LG on DM and you've got a bunch of therapies behind us that we don't have time, even to speak about today. So I'm excited about that I'm looking forward to updating people across the course of this year and I want us Echo the words of Dr. Gilmore I want to also thank the patients and their families, particularly those.
Douglas S. Ingram: And for the crossover, patients fully corrected. We were using our current titering method, so we do not have that issue.
<unk>, who have been willing to participate in the clinical trials that have created so much insight and I think in the end will provide so much hope to patients living with Duchenne muscular dystrophy limb girdle on the other.
Douglas S. Ingram: The second, and probably really significant, problem with part one was this enormous baseline imbalance. Because even with those tidering issues, when we had the baselines right, and we did in the four to five-year-olds, you saw clinically meaningful and very strong, statistically significant improvement in the kids that were on treatment. It was 16 kids.
And the other diseases that we're fighting to try to renew.
To reduce the impact of hopefully save lives for people. So thank you for that and we look forward to additional updates over the course of this year.
Douglas S. Ingram: So, you know, clearly getting the baseline life is important. And the problem was, in the 6-year-old grid, this enormous delta between the active and the placebo kids where the active kids were all very severe, and the placebo kids were far more mild. I mean, significant. Like the P value on that was 0.004. So four times out of 1,000, you would even have had this problem.
This concludes today's conference call. Thank you for participating you may now disconnect.
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Yes.
Yes.
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Douglas S. Ingram: The good news of the crossover is that there's no way to look at a placebo arm anymore, of course. All the kids will be on therapy. Some will be on therapy for two years. Some will be on therapy for one year. Sort of the good question that was asked previously; we need to make sure we build a strong natural history before we ever run blind, build a natural history model that is appropriate and matches, and then we'll look at this therapy versus natural history.
Douglas S. Ingram: So that's essentially self-correcting, that second issue is self-correcting on part two. And then on all the crossovers, the tithering issue is corrected with our more precise tithering method that was used for all of the doses in the crossover.
Operator: Your next question comes from the line of Joseph Schwartz of SBP Learing. Your line is open.
Operator: Hi, thanks very much. I was wondering, beyond those two flaws that you were just talking about, Doug, how much have you been able to learn from your analysis of study 102 that you can use to implement in study 301 in order to improve the probability of success?
Douglas S. Ingram: Do you have any examples that you can give us to help us understand?
Douglas S. Ingram: help us appreciate how the POS might
Douglas S. Ingram: Rising going forward. Well, you know, you know, I'm going.
Douglas S. Ingram: Well, you know, I'm going to, apologies, I'm going to beg off the details and we'll talk about that, you know, a little bit later when I have the minutes and we're closer to initiating the trial because we will come back and talk about the trial and how we've become even more confident in the program and POS. But I'll give you the summary answer, Joseph, and I know this is frustrating, but I'll give you the summary at least.
Douglas S. Ingram: And that is that there's an enormous amount of insight that we got from part one of 102. I mean, you know, the rocks for a while, some of us, myself certainly included, hit Stetsig, you know, some of us hit the rocks for a while, and then immediately realized that we had an enormous amount of opportunity in front of us. And I'd say two things that came out of that part one, in a summary fashion, and we'll talk about some of this in more detail when we get the minutes and we talk about the 301 trial.
Douglas S. Ingram: One is that we're just very confident as a people in our program and the probability of success of the program and the transformative potential of SRP 9-001. We feel very confident, for instance, if we didn't have the baseline issues that we had with those kids, unfortunately, you know, we would have had a very different outcome in part one of study 102. And the second thing I would say is that it has informed 301 in ways that should significantly increase its probability of success.
Operator: Your next question comes from the line of Colin Brifto of UBS. Your line is: Hi, this is Teng, Ansel Collins. Thanks for taking our question. Congratulations on the caller.
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Operator: So we have a follow-up question related to the potential accelerated filing for 901. We understand it was not discussed at the meeting you had with ODAD. Just want to get the idea of where you stand now on the possibility of filing microdistrofen expression like biomarkers, especially now with AdiCaniomachian approval, where FDA did take a much more flexible approach for these neurological diseases with high-on-madmagnose and any possibility of filing with preliminary expression data from 301 and, of course, with all the data you have with 101, 1-1-2, and 103.
Operator: We also have a full-up question, a separate question on the competitive landscape where we did notice Pfizer announced plans to start a 6-3 trial in non-ambulatory patients with no age restrictions and a fifth two for early symptomatic patients age 2 to 3 years old. Any plans for your side to initiate studies in this population during your term? Thank you.
Douglas S. Ingram: Yeah, I'll answer the second question first. Certainly, you know, one of the things that have happened historically with, for good understandable reasons, but not for good results, is that the non-ambulatory patient population has been underserved in the clinical trial setting. We certainly will be looking to do trials in the non-ambulatory population. And I should tell you right now, study 103, and we've already dosed a lot of kids in 103, we are dosing non-ambulatory patients large. Kids as well in study 103.
Douglas S. Ingram: So that is a big part of our plans. On the accelerated approval pathway, I'm going to say two things. I'm going to say three things. The first, of course, is that we understand that kids are getting damaged every day by this disease and that we need to think about how we can urgently move our therapies forward as fast as possible. And so I wouldn't, you know, no one should assume that we're not willing to be thoughtful and creative about things.
Douglas S. Ingram: And the second thing I would say, in broad strokes, as I'm related to 9-0-01, is that accelerated approval as a pathway has been an enormously valuable and innovative approach to bringing better lives to patients over the course of many years because accelerated approval existed long before it was in the 21st Century Cures Act. It has brought better lives to countless patients. You could literally just reel off the cancer patients and AIDS patients and others whose lives have been bettered or saved as a result of this wonderful approach when it's appropriate. But I will say this.
Douglas S. Ingram: Finally, when I get to 901, I want to say two things. The first is that, just so we're very clear, we've had no conversations with the division about it, and there's nothing that would have come out of our meeting with OTAC that would have given us any reason to be more or less confident in that as a concept. But the second thing I would say is that study 3101 is our pivotal trial, and we have built it as our pivotal trial, and it's robust, and it's a placebo control, and it's, from our perspective, very well-powered.
Douglas S. Ingram: And if I were an investor, I would presume that 301 is the pathway to success from a clinical perspective and from an approval perspective, both in the United States and around the world. And I wouldn't want to overpromise on other things because that's our focus right now. Our focus right now is getting 301 initiated, up and running, fast and rolling, and confirming the results that we've seen already and what we presume we're going to see early next year. And so I just want to make sure we're not creating the wrong impression. I think 301s are a pivotal trial. That's what I think people ought to focus on as the pathway for approval, right? SRP 9-
Ian M. Estepan: And maybe Ian, just one quick point of clarification. I don't believe Pfizer started as the pivotal study in the non-ambulant population. The last update I think they gave was that the NSAE in that population, and they were doing a protocol change in serolumus to their protocol for dosing more patients. So I don't believe they're in a pivotal study.
Ian M. Estepan: No, I think they're not even, I think they're a phase one study that was going to explore an unambulatory patient. I apologize you had suggested they had started. I think that they're actually not moving forward right now because they're going to do a protocol amendment to add another prophylactic. I think they already have Saliris, if I'm not mistaken, and I think they're now suggesting they're going to have rabamysine as well as a prophylactic in advance of pretreatment.
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Operator: Your next question comes from the line of the Eneill of Raymond James. Your line is open.
Operator: Hi, this is Alex on behalf of Danielle. Thanks for taking a question. I just want to expand on your points on 103. When can we expect to see the expanded data set? And, if you can comment, how many patients have you dosed in those non-ambulatory and the older?
Operator: cohort So
Douglas S. Ingram: So we will find an appropriate medical meeting down the road to provide additional information and insight and study 103. We haven't selected a medical meeting yet that will be very interested in showing that information. And I don't have the details, the number, the complete number, but we gross out the number of non-ambiatory patients and a number of... large, larger kids with I'm actually that must be distributed with SRP 9001. So that is proceeding very well right now.
Operator: Your next question comes from the line of Yung of B-P-E. Your line is open. Yeah.
Operator: Yeah, thanks very much for taking the question. And on Lin Girdle 2E, it's very encouraging to see, to hear the surrogate endpoint discussion, but you show very positive functional data even after one year of treatment. Then, my question is, why don't you go for full approval with the functional data? Does the pathway rely on a surrogate endpoint? Would that allow you to maybe avoid running a placebo control study? or would that allow you to talk to the FDA about potential approval, maybe even before one year after treatment?
Operator: But we're going to have to, let's go, at the bare minimum, one has to dose children using commercially representative material. So let's start there, and understand the data that we have right now for the first two cohorts. I agree with you completely, it's brilliant data. It's brilliant for expression, it's great for safety, and it's great for functional signals as well.
Douglas S. Ingram: But that's in the, that's in the clinical supply material. We've got to get all of the work done process development, and analytical development, and dose kids on the commercially representative material as a predicate to any approval, as the first part. And then once we do that, why would we be interested in looking at expression as opposed to just looking at function? The short answer is that this is a very rare disease, and it is more heterogeneous than Duchenne muscular dystrophy.
Douglas S. Ingram: And so, you know, it would just be, it would, you know, we would make people wait far too long in our view if we had to wait for a statistically significant functional readout on two E-Kids. This is, you know, to be direct, this is a perfect place for the use of a surrogate endpoint and accelerated approval. You've got a well-characterized disease, at least the mechanism of action of the disease is well-characterized, which is it is a single-gene mutation, a lack of a structural protein, and that lack of structural protein is causing the demise and eventual fatality of these patients, these kids and adults, and we are able to deliver that exact, that Act approach, the literal native protein in robust amounts to the muscles.
Douglas S. Ingram: So this is the kind of place where accelerated approval was intended, where you can bring this therapy because it's going to have such a high probability of being clinically meaningful to patients. You can bring it to patients and then, you know, have an ongoing study that confirms those clinical results over time so that you don't have to wait to bring the therapy to patients. And so that's going to be our approach.
Douglas S. Ingram: I have got more work to do with the FDA and EMA on that, but I am happy to say that, at least at a philosophical policy level, the division agrees that that is a potential, both EMA and FDA agree, and FTAOTA.
Operator: There are no questions at this time. I will now turn the call over to Dog Ingram for closing remarks.
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Douglas S. Ingram: Thank you very much. I will just extemporaneously say a few things, but not many, because I know people; it's getting late for everyone.
Douglas S. Ingram: Thank you very much for joining us this evening. I am very proud of the work this team has done both to serve the patients that we have with the therapies available to us today, and I think the team has just done a brilliant job of that. You know, one of the people hasn't asked questions about our revenue, but that revenue is impressive because it reflects commercial expertise and field-based expertise that, I've got to tell you, I'm extraordinarily proud of and is going to benefit us enormously when we launch some of these gene therapies.
Douglas S. Ingram: And as we don't take price increases as a company, and we've priced all of our therapies at parity, it is a reflection of our ability to serve patients and bring a better life to patients. So I'm really thrilled with that. And I'm obviously thrilled with the team.
Douglas S. Ingram: for the great work we've done in advancing our portfolio and pipeline over the course of this year. We've made a lot of great progress, and we have multiple platforms to do that on. We've got our RNA. We've got our PPMO, the next generation version of the PMO. We've got our gene therapy, 901, 903. And, of course, the list would go on with the sarco glycans and the remainder of the LGND, and then we've got a bunch of therapies behind that that we don't even have time to speak about today.
Douglas S. Ingram: So I'm excited about that, and I'm looking forward to updating people throughout the course of this year. And I want to echo the words of Dr. Gilmore. I want to also thank the patients and their families, particularly those who have been willing to participate in the clinical trials that have created so much insight and, I think, in the end, will provide so much hope to patients living with Dushamaskerishti, Limgirdle, and the other diseases that we're fighting to try to reduce the impact of, and hopefully, save lives of people. So thank you for that. We look forward to additional updates over the course of this year. This concludes.
Operator: This concludes today's conference call. Thank you for participating. You may now disconnect.
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