Ladies and gentlemen, thank you for standing by, and welcome to the PTC First Quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer Please be advised that today's conference is being recorded. I would now like to hand the conference over to your host, Tali O'Keefe, Senior Vice President, Commercial and Corporate Strategy. Please go ahead.
Good afternoon and thank you for joining us today to discuss the PTC Therapeutics 1st Quarter 2021 Corporate Update and Financial Results. Joining me on today's call is our Chief Executive with Stuart Peltz our Chief Development Officer, Matthew Klein our Chief Business Officer, Eric Powells and our Chief Financial Officer, Emily Hill. Before we start, let me remind you that today's call will include forward looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward looking statements. Our actual results could materially differ from these forward looking statements as any and such risks can materially and adversely affect our business and results of operations.
For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10Q and our annual report on Form 10 ks filed with the Securities and Exchange Commission as well as the company's other SEC filings. We will disclose certain non GAAP information during this call. Information regarding our use of GAAP to non GAAP financial measures and a reconciliation GAAP to non GAAP is available in today's earnings release. With that, let me now pass the call over to our CEO, Stuart Peltz. Stuart?
Thanks,
Kiley, and thank you for joining us today. As this quarter marks a year into the COVID pandemic, We reflect on the incredible fortitude and determination of our employees, patients and stakeholders during this challenging time. I'm incredibly proud of PTC's success and continued growth despite the pandemic, which I believe is a testament to our people, their resilience That have few or no treatment options. I'm pleased to report that PTC is emerging from this challenging At PTC, we have always taken our environmental, Social and governance initiatives very seriously and as we continue to grow, this has not changed. We pride ourselves on our culture.
We were also honored to have recently received Gallup's Don Clifton Strength Based Culture Award, which reflects our ongoing deep commitment to our employees as they are a key ingredient to our success. PTC received this award alongside Accenture and the Atlantic School System. Let me now speak to the strong performance this quarter. We outperformed revenue projections, delivered on a number of Key objectives and are making substantial progress towards our upcoming milestones in 2021. First, let's focus on the DMD franchise.
The franchise continues to see robust growth with one of our strongest quarters ever in commercial revenue. Translarna and Emflaza saw Substantial 32% growth in revenues compared to the Q1 of 2020. This is quite incredible considering The commercial team continues to deliver impressive growth and have been working hard to bring these treatments to patients around the world. Now let's move to for spinal muscular atrophy. Arisneas continues to see strong uptake in the U.
S. With 1600 SMA patients Now on treatment. This represents a remarkable 15% market share in a short period of time post approval and we expect this growth We were pleased to report that Arissey received EMA approval and had the first EU sale the following day. The first EU sale triggered a $20,000,000 milestone from our partner Roche. We expect additional ex U.
S. Growth as European market Our Japanese approval was also expected before the end of this year. The successfully established In our recent Huntington's disease deep dive, We demonstrated that the splicing platform has proven to be a robust engine to identify therapeutic candidates for a number of key diseases, including SMA and HD. We also demonstrated that PTC-five eighteen is an orally bioavailable small It penetrates the blood brain barrier is selective, titratable and non effluxed. Preclinically and not only uniformly in the periphery.
Most importantly, the preliminary results from the Phase 1 clinical trials were quite profound. In healthy volunteers, we achieved the desired dose dependent lowering of HTT mRNA beyond the targeted 30% to 50%, even with a single dose. We also demonstrated that in the completed SAD And MAT cohort PTC-five eighteen was found to be well tolerated with no safety findings. Rarely Are you able to demonstrate you're on target in the Phase 1 trial in the healthy volunteers and analogous to the Eprisney program, This puts us in a unique position. We're extremely pleased with the progress to date and look forward to sharing And next steps as the study progresses.
Based on the mechanism of action and the pharmaceutical properties PTC-five eighteen, we believe it has the potential to emerge as the treatment of choice and first disease modifying therapy for Huntington's I now want to touch on our PKU program. As a reminder, a small Phase 2 head to head Responder study was previously performed with PTC-nine twenty three. The results demonstrated that PTC-nine twenty three showed a 2 fold greater reduction of phenylalanine levels in blood relative to Kuvan. Importantly, the results also that 50% more patients responded to PTC-nine twenty three as compared to Kuvgang, including patients with classical PKU. We will start a registrational trial evaluating PTC-nine twenty three in PKU called APHINITY mid And we expect to have results by the end of 2022.
There's an estimated global prevalence of 58,000 PKU patients and the vast majority are not well addressed by current therapy. We see potential for PTC-nine twenty three as a clinically differentiated therapy to address this high unmet medical need. With newborn screening and established centers of We see this as an exciting program. Let me next turn to our BioE platform. The BioE platform is a key component of our diversified pipeline because of its novel approach to targeting disorders from the BioE platform, 1 for mitochondrial epilepsy and 1 for free drink ataxi.
Through its targeted base to action at Moving on to our gene therapy platform, we have some updates to share on PTC Due to the inability to complete its pre approval inspection because of COVID related delays, the CHMP has requested a clock stop in the MAA approval process to allow for completion of these inspections. As a result of this clock stop, we now anticipate receiving the CHFP opinion in the Q3 of 2021. In addition, due to further COVID related delays to complete the 3rd cannula surgery, We now anticipate the BLA submission to be delayed by at least a quarter. Let's now turn to PTC299 for COVID-nineteen. As a reminder, PTC299 is an oral small molecule with a dual mechanism of action that demonstrates both PTC299 functions by targeting cellular enzyme dihydroauricase dehydrogenase or DHODH.
The advantage of targeting the cellular enzyme instead of a viral protein is that it's less likely to elicit drug resistance, which is particularly important as the virus continues to mutate. We are currently running a Phase twothree registrational trial consisting of 2 stages. We expect enrollment to be completed for the full trial in the Q2 of 2021. We're proud to continue to deliver across our global commercial program and our robust development pipeline that currently includes 3 ongoing milestones to look forward to in the remainder of the year. With that, I'll turn the call over to Matt, who will further discuss
Thanks, Stu. I would like to start by emphasizing the consistent progress Our development teams have made despite the ongoing challenges of the pandemic. We are very proud of the success that we have had in advancing programs from all of our scientific platforms, forms, and I'm pleased to share our most recent program updates. First, I'll begin with our validated splicing platform. As Stu mentioned, we remain enthusiastic about Distribution and lack of deflux from the CNS are key differentiating properties and reflect PTC's experience in developing selective, specific and broadly biodistributed oral small molecule splicing drugs.
The PTC-five eighteen Phase 1 healthy volunteer study is As we shared in a deep dive last month, data from the SAD and first two NAD cohorts demonstrated dose dependent reduction of Huntington mRNA, the key objective of the Phase 1 study. In addition, we achieved a desired 30% to 50% reduction in We look forward to sharing additional data, including pharmacology data from the CSF sampling cohort once available. Turning to our BioE Enrollment is ongoing in our 2 vitequinone registrational trials in mitochondrial epilepsy and Friedreich ataxia. As a reminder, the mitochondrial epilepsy trial, the MITEI study, is a global placebo controlled trial enrolling approximately 60 children with inherited mitochondrial disease and associated refractory seizures. The primary endpoint is the reduction in observable motor seizures following 6 months of treatment.
The MOVE EPI trial, our Phase 3 study in pediatric and adult Friedreich ataxia patients is also a global placebo controlled trial. The primary endpoint of this study is improvement in the modified BARS score And the key secondary endpoint is improvement in activities of daily living as assessed by the FA ABL scale. As we have discussed previously, this endpoint strategy was developed in consultation with both the FDA and EMA. We expect to have data readouts from the MITEI study in Q3 2022 and from the MOVE FA study in 2023. We have completed the Phase 1 study at PTC8fiveset, the next compound from our BioMe platform and expect to have data available later this quarter.
PTC-eight fifty seven is a 2nd generation 15 Turning to our PKU program, we are excited about the potential for PTC-nine twenty three to meet the persistent unmet medical need of PKU. PTC-nine twenty three is an orally administered precursor of BH4, the cofactor of the phenylalanine hydroxylase enzyme that is affected in PKU. PTC-nine twenty three readily crosses the cell membrane And as Stew mentioned, demonstrated significant effects in reducing phenylalanine levels in a Phase 2 trial, including in even the most severe classical PKU
We are
on schedule to initiate our global Phase 3 placebo controlled trial, the APHINITY trial in mid-twenty 21. Next, I'd to allow for completion of these inspections. As a result of this clock stop, we now anticipate receiving the CHMP opinion in the Q3 of 2020 In addition, the 3rd planned surgery with the commercial cannula has been delayed and we now anticipate BLA submission to be delayed at least 1 quarter. Nonetheless, our teams are continuing their global commercial launch efforts, which Eric will describe in more detail. Finally, I want to continued progress in our FIGHT-nineteen trial of PTC299 in COVID-nineteen.
We have completed Stage 1 of this registrational trial and are currently enrolling Stage 2. Despite the great strides in the development of COVID-nineteen vaccines, there remains a need for effective COVID-nineteen therapies as we face new challenges due to virus variants, uneven vaccine distribution and vaccine hesitancy. We expect to have data from FIGHT 19 in the second half of twenty twenty one. As you can see, we continue to make progress in advancing our robust and diverse I will now hand the call over to Eric for an update on our commercial execution this quarter. Eric?
Thanks, Matt. I'm proud of the remarkable growth of our global DMD commercial franchise. The continued focus on executing with excellence from our customer facing team was instrumental in delivering one of the most successful quarters for commercial revenue We've seen incredible growth in our DMD franchise with Emflaza leading the way at 58% and Translarna at 15% growth. Our total DMD franchise grew 32% compared to Q1 2020. We have seen incredible growth in our DMD franchise with Emplaza leading the way at 58 percent and Translarna at 15% growth.
Our total DMD franchise grew 32% compared to Q1 2020. The sustained Emflaza growth is primarily driven from new patient starts, a reduction in patient assistance and bridge programs maintaining high levels of compliance and lower treatment discontinuations with the largest base of DMD patients globally. As a reminder, Emflaza is the 1st and only FDA approved treatment for all EMD patients ages 2 years and older. Importantly, with multiple publications of Emflaza's real world data, we continue to support Clinically differentiated benefits over prednisone, including the recent switch data presented at MDA and We continue to see strong new prescription growth from patients seeking switches from their healthcare providers. Translarna's strong performance is driven by growth due to ongoing expansion of the patient base in key markets, Continued high compliance and broader access in existing geographies as well as continued geographic expansion.
Following the approval in the Q4 of 2020, we are pleased to announce that the Russian Federation has approved Plan to financially support all eligible ambulatory nonsense mutation DMD children in Russia with Translarna. We also look forward to continued expansion into additional geographies in Central and Eastern Europe, Latin America, the Middle East and Asia Pacific. Despite ongoing administrative challenges in Brazil driven By COVID-nineteen and leadership changes in the Ministry of Health, we continue to see increases in newly diagnosed BMD patients and are working towards securing a group purchase order for Translarna in the second half of twenty twenty one to meet the needs of in DMD patients. Now turning to TEGSEDI in WAYLIVRA. The team continues to make progress with disease awareness and patient identification in Latin America for our patients despite the ongoing COVID-nineteen challenges in the region.
In Brazil, we continue to explore avenues for Pricing of TEGSEDI and during this process, we continue to provide medical education, genetic testing and patient program support to make TEGSEDI available in certain countries within Latin America through early access programs. We are pleased We anticipate an Endesa approval in Q3. Moving on to AADC. As a reminder, PTC AAVC is a transformative gene therapy that has the potential to produce meaningful changes in AADC deficiency patients. PTC has had a continued focus on preparing for our gene therapy launch for patients with AADC deficiency, which is now expected to occur in Europe shortly after final EMEA 300 patients globally by large and we remain confident with this goal.
In addition to patient identification, The team has a continued focus on identification and preparation of expert pediatric neurosurgical centers of excellence, which is underway to the U. S, the European Union and Latin America, as well as continued disease awareness and educational activities. PTC generated one of our strongest quarterly revenues ever and I continue to have pride and our customer facing team and their ability to execute against their strategic priorities. I will now turn the call over to Emily for a financial update. Emily?
Thanks, Eric. In the Q1 of 2021, we saw strong continued revenue growth and progress across multiple platforms of our pipeline. In addition, given current market conditions, we are proud to have strategically and proactively strengthened our balance last year through the royalty monetization deal. This combined with our impressive revenue growth puts us in a strong cash position to continue to advance our diverse pipeline. We are executing on a number of fronts to deliver on many potentially value creating milestones this year for long term growth.
The press release issued earlier this afternoon summarizes the details of our Q1 2021 financial results. I'll take a few minutes now to review these financial results. Please refer to the press release for additional details. Beginning with the top line results, Revenues were $117,900,000 for the Q1 of 2021, a 73% increase over the Q1 of 2020. This was driven primarily by net product revenue from the DMD franchise of $90,000,000 collaboration revenue of $20,000,000 from the EU first commercial sale milestone payment for Eversi on the royalty revenue of $6,700,000 Turning first to our DMD franchise.
Translarna net product revenues were $46,500,000 compared to 40 point $5,000,000 for the Q1 of 2020. For Emflaza, we reported net product revenues of 43,500,000 as compared to $27,500,000 in the Q1 of 2020. Moving now to Aprizdi. Our partners, Roche, reported 20 21 year to date sales of approximately CHF 80,000,000. As a reminder, PTC retains approximately 57 percent of Averdzi royalties until Royalty Pharma receives a return of 1,300,000,000 after which 100% of the royalties revert back to PTC.
Also in our royalty monetization deal, we earned sales based Cash milestones that we fully retain. One milestone this quarter was related to the 1st European commercial sale with a $20,000,000 payment triggered when this occurred. The royalty monetization transaction not only transformed our balance sheet by bringing forward future cash flow to a current $650,000,000 cash While still allowing PTC to maintain the majority of the Royal Stream along with the future potential growth as ebrinci could become the for Preferred Global SMA Therapy Worldwide. Non GAAP R and D expenses were $120,800,000 for the Q1 of 2021, excluding $13,700,000 in non cash stock based compensation expense, compared to $81,900,000 for the Q1 of 2020, excluding $8,200,000 in non cash stock based compensation expense. The year over year increase in R and D expenses reflects increases in spending due to advancing the gene therapy, metabolic and BioE platforms and PTC299 and COVID-nineteen as well as increased investment in research programs and advancement of our clinical pipeline.
Non GAAP SG and A expenses were $49,100,000 for the Q1 of 2021, excluding $12,000,000 in non cash stock based compensation expense, compared to $51,200,000 for the Q1 of 2020, excluding $7,000,000 in non cash stock based compensation expense. Cash, cash equivalents and marketable securities totaled approximately $988,400,000 as of March 31, 2021, compared to $1,100,000,000 as of December 31, 2020. I will now turn the call over to the operator for Q and A. Operator? Thank
you. Our first question comes from the line of Eric Joseph with JPMorgan. Your line is now open.
Hi, good evening and thanks for taking the questions. Just a couple from us, primarily on PTC-five zero eight for Huntington's. First is how we should be thinking about the timing of the next updates in the healthy volunteer study, specifically the analyses on protein change in the periphery And also drug exposure in the CSF, will you be looking at Exposure of the CSF in more than 1 or simply one cohort and will that be sufficient to inform dose selection in a patient study? And then secondly, I guess looking at coming away from some of the presentations from EnrollHD at AAN, Are you thinking any differently or how has your thinking evolved in terms of, I guess, this feasibility of Establishing or kind of looking for therapeutic benefit or proof of concept in a Phase 1 Huntington patient study. Thanks.
Yes. Thanks, Eric. Thanks for the other question. And so we're We're in the process of completing the additional cohorts. And as we've said, that will include a food effect, a multiple Ascending dose, the treatment so that we get the CSS and well as protein analysis and then So we'll be getting that relatively soon and then we look forward to share this information when it becomes available.
And so that's working well. So in terms of the update, in terms of how we're thinking, And we do think the exposure will be well enough. You've got to remember, we have a lot of results demonstrating That what we see in blood is what we see in the brain and what we see in blood is equal to the equivalent that we meant to the CSF. And so we And that I remind you that that's really a major advantage in terms Of being able to define what the drug levels are and be able to do that. So we have a lot of data on that.
So we're Obviously, we're excited to have seen the results that we've seen in terms of the lowering the target even with a single dose. And so we're going to be completing that. So in terms of the questions, in terms of what we are thinking in terms of The results based on that and we think that the question there is more on the issue really well, at the end of the day, what we think in In terms of what we saw in the Roche data, it seems to be a real issue in terms of the we think it's a toxicity on the and so do they, by the way, In terms of the issue, in terms of the reason that it went wrong was that it's been we think it's an ASO specific problem that we think is due to toxicity As well as insufficient deep brain penetration. And I think the hydrocephalus that was observed with the Roche drug was also What's been RASA, which are both at ASOs, I can remind you that the Roche drug they had 4 times the volume and about 10 times the amount of So I'm not surprised that they're seeing the hydrocephalus and I think that's probably interfering as well with the penetration.
And I think this is consistent with what Roche has reported. So from our point of view, I really don't want to make an argument that this is a statement about the ability to actually alter that. We're pretty confident that you can That our drug effects splicing reduces the level of HTT and there's a plethora of data that shows that reducing HTT levels is critical for elongating the preventing the effect of the disease to occur. And we've seen that both within patients who have lower levels of that. I want to remind everyone that Huntington disease is a monogenetic disease, and it's a consequence of the mutant Huntington protein.
So it's not like it could be from something else. And we definitely think that both HTT and the RNA and the protein are the best targets. 4th, and there's Plenty of case studies showing both in animal models that lowering wildtype HCT is well tolerated and that lowering mutant Huntington disease By 50% is demonstrating clinical benefit. So the fact that we have an orally bioavailable That gets to every tissue that you can control the precise level of the drug within the brain Really is a promising small molecule with broad tissue distribution. It's not e flux and we think this is really we think has the potential to be the best in class for this treatment.
Does that help you,
I'm sorry, I was on mute there. No, that's very helpful. Thanks for taking the question.
Great.
Thank you. Our next question comes from the line of Alethia Young with Cantor Fitzgerald. Your line is now open.
Hi, thanks for taking my question. This is Nina on for Alethia. So we were wondering, what are the remaining steps to filings in the U. S. For AADC beyond the 1Q delay related to COVID?
And do you think the delay is potentially longer
Sure. Thanks for the question. So AADC, I think, was It's obviously a really exciting product and has shown really transformational results enabled and being able to take People who are developmentally rested, kids who are and be able to actually see those developmental, being able to be seen in terms of Being able to ultimately sit and stand and walk. So we're really pretty excited about that. Matt, do you want to talk a little bit about the steps that we'll release?
Yes, absolutely. So just the comments made on the call as well, The as everyone knows, we have submitted the MA to the EMA and that's moving forward and we've now been asked to take a clock stop by the EMA So that they can complete the pre approval inspections. So just wondering whether that's moving forward and we now expect to have that opinion in the Q3. For the BLA, as we've talked about, really one of the key gating factors was their desire for us, the agency desire for us to demonstrate some with our specific gene therapy product with a specific cannula we intend to use commercially, which is the SmartCoal cannula. Now of note, that cannula has been marked in the EU, which is why it was not an issue The cannula was not issued in the MAA process.
On the FDA side, the cannula has been 510 cleared for a number of CNS procedures. It's been used in gene therapy procedures before, but just not specifically to the administration of our gene therapy products. And I think as we've talked about before, the way the gene therapy product is administered is through a complex stereotactic surgery. So what the surgeons do is before the procedure, they get a Google map that basically tells them how to get from the outside world safely into the where we provide a direct infusion of the gene therapy product. The cannula is that piece of equipment that follows the path and instills the gene therapy into the exact place.
So we've done 2 of the procedures already. As we previously reported, those procedures went well. We had a third scheduled and that's been delayed and our plan as we've Before is to complete that 3rd procedure and then obviously we'll take the data online and make sure everything else is in place with the agency and look to move
Thank you. That was helpful.
Thank you. Our next question comes from the line of Robyn Karnauskas with True Securities. Your line is now open.
Hi, guys. Thanks for taking my question. I guess first just to follow-up on expectations for Huntington data. I had two questions. So You set the bar low for what we could learn from the CSF and you said that we'll be getting that CSF data shortly.
Can you just sort of give us a little bit more color, updated thoughts on how we should view that data, so we don't over expect too much? 2nd, on the protein levels, which everyone's really interested in seeing, should we expect a difference, sort of a delay in the lowering of protein? Like should we expect in other words the protein levels to not be lowered as much as the RNA because of a delay? Or should we expect them to be similar if and true it's working that way? And then lastly, I just had a question on PTC293.
So you talked a lot about how that compares to Kuvan. What about how it compares to Palynziq? And do you think you'd be able to use this drug without the diet? Are you incorporating that into your APHINITY trial? Thanks.
Thanks, Robin. Thanks for the questions. Yes, so the yes, we think that the Look, we've done a lot of work on this and we know the drug is capable of passing the blood brain barrier, gets into all Aspects of the brain and all tissue types get into the CSF, we've seen that in the non human primates, Where we saw the equal amount. So what we're what we'll do is in the clinical trial, we think it will be sufficient where we'll and we know what by the way We've seen before that the amount that we saw in the blood is what we saw in the CSF that the same levels were observed of the free drug within that both in the non human primates, rats, other that we looked at. So We feel pretty comfortable about that, and so that will be coming up.
And so that's one I think We'll do one dose that we think should be sufficient to answer the question, that particular question. And then in terms of the RNA and protein levels, What we're doing is to as part of the cohorts is to look and see the levels of proteins. And since the We would anticipate it may not be a perfect one to 1 in the sense of that you're not yet at steady state at 14 But we are expecting to see reduction within that time. So we're going to we'll know the levels based on that And we'll be able to calculate what percent we think we have in terms of reduction. So we'll be pretty confident that we'll be getting to that.
I wouldn't make the point. I know there's been a lot of discussion about the protein, but if you think about it, you make protein from the RNA. And as the RNA level goes down, You're seeing you're going to it's pretty proportional to the level of RNA reduction that you see. You see the production of the protein. There's a Pretty good correlation.
There's no regulation that we've observed that as you reduce the level of RNA, you see increased protein synthesis. So it's we're pretty confident that the level when you see a reduction of the RNA and that you'll also see A reduction within the protein in that. So we're very comfortable. That's what we've seen throughout all our work We looked at the reduction of both RNA and protein within the animal models that we tested. So we're very comfortable with that.
And then with 923, obviously, we think we're excited about it. That is actually targets more Patients, so it's more active in a greater number of patients as well as it actually causes a lower level. And we think that's true both with Pruvan as well as Palynziq. So we're pretty we think that this is going the fact that it's an oral molecule That is quite active that we've seen it perform well against Kuvan in the Phase to trial. We feel pretty comfortable that this is going to be quite helpful to these patients.
Matt, do you want to add anything to that?
Yes. So I would just say that in the Phase 2 study, which we referenced, that was a head to head comparison with Kuvan. And part of the reason the clear reason for the superior effect is really bioavailability. PKU treatment requires activating the phenylalanine hydroxyase enzyme, which is dysfunctional in the disease And PGC-nine twenty three is a precursor to BH4, which is the cofactor for the enzyme. Giving that precursor allows it to effectively cross plasma membranes get into the cell where it's readily activated into BH4, Whereas alternatively Kuvan itself is actually poorly absorbed, it's a highly lipophobic molecule And much of the BH2 that's formed from Kuvan goes on to either just get excreted by the kidneys and with only a small amount getting a bit of cells.
So this is really a story of Superior bioavailability and therefore much superior actions seen or superior actions seen in the Phase 2 study, including activity in the classical PKU patients, which in our study had almost 200 Reduction of 200 points of phenylalanine in the classical BKU patients where there was really no reduction seen in the Kuvan on treating patients with in the classical BKU. Now you had also got a Palynziq. We didn't do a head to head comparison with Palynziq. And While Palynziq has shown efficacy in some patients, obviously, it's one of their safety and tolerability concerns. It also takes time for Palynziq to be fully effective.
Palynziq requires you to have an epinephrine auto injector in case of anaphylaxis risk. So There really is a tolerability concern, which may be in part attributable to its lack of universal uptake. It's also not used by kids, which obviously is an important part of the population. So we think when you look at the existing PKU Marketplace is still large on that medical need really because the current therapies aren't adjusted. In terms of the diet question, that's not We're looking at explicitly in the study, but obviously within we're focused as the agency likes you to make sure those diet controls, so you don't have any cofounding factors in a placebo controlled study.
But obviously, we expect with an efficacious therapy that diet could be
Great. Thank you.
Thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.
Hey, there. Thanks so much for taking my questions. Two questions from me. I guess first on the evolving Huntington's space. Have you guys assayed ventricular volumes in non human primates or Done any analyses of cellular protein or RNA expression, either ones that maybe have done preclinically or clinically or can do To maybe help disentangle any potential off target ASO construct inflammatory response versus maybe some adverse effect of lowering HTT itself.
And then Secondly, on Emflaza, obviously, you showed a strong quarter over quarter growth in sales. Just wondering if you could maybe break that down
a little bit in terms of how much
of that Was demand based or were there any other changes in ordering patterns, gross to net or inventory that may have also factored in? Thanks.
Yes. Thanks, Brian, for the question. Just to remind everybody, right, it's The whole nature of this and being able to get through without any increase in the CSF. And so when we measured, We didn't see any hydrocephalus in the non human primate. So there was in terms of disentangling, I think that's a really good point that Our drug in terms of the naive primate data, we have not seen any of what you're seeing.
So I think it's again, it's pretty clear to us that we think The effect is really almost a toxic effect of the oligonucleotide. That's our point of view on this. Again, from our point of view, just the fact that it's an orally bioavailable molecule that it gets, I think there's 2 issues, the toxic effect and then the distribution, it just doesn't get everywhere. And that's just not the case With an oral biovital molecule. So just like we saw for SMA, how well it was able to distribute throughout the body and throughout the Brain and tissues, we see the same thing and we built that in to PTC-five eighteen.
And not only did we build that in, we've also built it That it was an e flux and that it really allowed us to see the level of what we see in the blood is equal to the brain, which gives us a lot of confidence of When we measure what we see in the blood just like we did previously with the RISD, you know what's getting into the break. So I think there's lots of reasons for us to think that we, In a sense, as you said, disentangle one issue from the other. So we're pretty confident that that's it's not really a Question on, is it the right target? We're very certain that that's the right it's a monogenetic disease, and we think It's that reducing this into the toxic form of that just happened to let you know that is indeed what you want to do. So In terms of the in the block or breakdown, Eric, do you want to talk a little bit about that?
Yes, sure. Yes, Brian, we had Excellent quarter for D and D franchise all around. I mean, it was one of our strongest quarters commercially. And Emflaza led the way with almost 60% growth year over year. Emflaza, to your specific question about Emflaza, The base of patients that we've been able to accrue that we started to build in 2020 has been very, very strong.
We've really minimized a number of key dropouts. Patients have been benefiting on treatment longer. There's been lower discontinuations and extremely high compliance. We've had thresholds of well over 90% compliance in refills and that's incredible. But what we also seen is back in the last quarter, we saw that new prescriptions really continued with its momentum.
New prescription growth has been some of the best. And so we have had some of our best months in Q1 in terms of new prescription growth. And our market access teams have been working and our commercial teams have been working very, very hard to, if you will, bring down the time from the time of new prescription to the time of where there's a commercial fill. So we've been able to reduce that time on patient assistance programs as well as Bridge programs, which are technically free of charge type programs, and we've been able to reduce that time. And we're also seeing a sort of fundamental change with many of the plans right now that are have over the last years have had restrictions on Emflaza that have removed those, which has helped as well.
So it's a combination of a strong base as well as continued new prescription growth and the time that we get from the time we get a prescription to the time it gets filled. And we continue to see that these kind of tailwinds will continue throughout 2021.
That's really helpful. Thanks, Eric, and thanks, too.
Sure.
Thank you. Our next question comes from the line of Danielle Brill with Raymond James. Your line is now open.
Hi, guys. Good evening. Thanks so much for the questions.
Stu, I know you talked
a lot about how You think the toxicity that Roche is seeing in their Huntington's program is ASO related. But given that we can't completely rule out The potential role of wild type Huntington or the possibility of maybe a narrow therapeutic window. I'm just curious if this has impacted your thoughts on the development strategy for 518 at all? And I have another follow-up. Sure.
Yes. So I think the way we think about I mean, we've had a lot of discussions on that and the way we What we think about this is that HD is a monogenetic disease, right? And it's the consequence of the mutant hunting, Right. So from my view, that makes it the best target. Then from the question of How much can you lower than do the wild type Huntington?
There is data already out there that shows from both animal models that you can reduce it Substantially, 50% for sure. And then certainly the reduction of mutant HTT also has been shown to actually elongate the time where a patient shows a disease effect. So I think there's Plenty of data out there. And then I think the most likely hypothesis is in the sense what we said, The toxic effects that you've seen this not only in, in tamilirsen, but also in SPINRAZA. Now you have 10 times the amount of the oligonucleotide as well as 4 times the volume.
So you're already creating an issue So let's okay. So that's, I think, the most likely hypothesis. But let's take the other point of view. The other question is, we already know that the oligonucleotide show a disproportionate lowering In animals, you see more in one part of the brain than the other part. So you already have a disproportionate part and then you're measuring You're trying to make those levels of measurement using the mutant Huntington and the CSF, which I'm not sure we know exactly what that means.
So you already know you have an issue there. You're not hitting everything. You may hit maybe let's take your point, let's say it's True. You might be over hitting as a consequence of particular areas. That's the hypothesis that you're really bringing down too much in one spot Not enough and another.
That's not a problem with the when you have a small molecule that gets Distributed equally around the brand and you could titrate it, you can get to every part of the brain tissue and the levels are Highly controlled and we've shown that since EtaB the case. So from my point of view, no matter which sort of hypothesis It's still a consequence of the oligonucleotide. It seems to me that the most promising reason that And even Roche said this themselves is that the oligonucleotide is the real problem. But even if you let's take the other least likely hypothesis, It's probably against it's probably then it still doesn't distribute very well and therefore it's probably a problem of too much in one place and not enough in another. You wouldn't see that with Orally bioavailablesmallmolecule.
So I think for us, it's reinforced our belief in the importance The advantages of an orally bioavailable small molecule is something that we've been talking about PTC-five eighteen is Not only it's obviously the bio distribution. So when we put all this together and we really do believe it's likely to Just high levels of oligonucleotide, which we know by the way, humans don't like and high levels can cause problems. So I think we're pretty much very confident in the progress that we've made thus far. We're not seeing any volumetric Any differences when we've looked in Animal Model. So in terms of the volume within the venture call, so We feel pretty good that, we're in a pretty good spot that we have the potential best in class.
Okay. Thanks. That's actually really helpful. And then just quickly, I was wondering, if you could comment on where things stand with the Friedreich's ataxia gene therapy program. Can you remind us when you're expecting to enter the clinic with that asset?
Thank you.
Yes. Thanks for that. So yes, we're excited On that program, we have had, as we've talked about, some delays as a consequence of COVID, but The progress keeps going on and we expect the first human dosing really before the year end. Our goal is and what we're doing now is just completing some of the gating items of the preclinically ahead of moving into clinic and That's going on now and that we've already begun some startup activities and we're going to be looking to utilize our The global infrastructure that we have to focus on sites in the U. S.
And globally. So we're really working on the fastest path To bring that in bring that so that we can get the first in human dose. Does that help?
Yes, it does. Thanks so much again for the questions.
Thank you. Our next question comes from the line of Joe Thome with Cowen and Company. Your line is now open.
Hi there. Thank you for taking my questions. First one, I guess you're both on vitequinone, but the first one in the seizure disorder patients. Is there a reduction in motor seizure frequency that you're looking for in that Phase twothree versus And are there any efficacy measures that the FDA has kind of set out as a benchmark for this to be one pivotal study? And then second, kind of following up on the Friedreich ataxia gene therapy.
Are there patients that would benefit more specifically from a gene therapy approach versus vitequinone, or how are you thinking about segmenting those 2 therapies in the population? Thank you.
Yes, I think those are thanks for those questions. Those are Questions. And so just I'll have Matt talk more about it, but it's obviously we've seen where a reduction in seizures And based on this, and we've had long term data on this and patients who normally are in real trouble, we've seen survival as a consequence of this. But and so currently it's a placebo controlled study that's worldwide. Do you want to talk a little bit about how we thought of the Doing the trial, May.
Yes, absolutely. Thanks, Steve. And thanks, Joe, for the questions. So in terms of Mitochondrial epilepsy, so that refers to that symptom of refractory seizures in kids with mitochondrial disease. And it turns out About 40% to 50% of patients with inherited autochromesals also have seizures and these seizures are typically Refractory to existing anti epileptic therapies for the simple reason that existing anti epileptic therapies don't target the energetic pathways that are causing seizures In these cases, in fact, many of the seizure medications actually exacerbate obtractive stress and the underlying mitochondrial pathology.
So that further contributes to the problem that they have, whereas obviously, vatipinone targets those pathways. And what we've seen in both preclinical and more importantly the clinical studies is a significant effect on seizure frequency as well as other seizure Related complications like the occurrence of staphylopithecus and in one case series we observed a market reduction in disease related hospitalizations and mortality risk. Again, given that what we're targeting the underlying energy disturbance in these kids, which is obviously manifest in seizures that is also having other overall impact on the patients and their disease. In terms of specific seizure threshold For our analyses, we looked at a target reduction of about 50%, which is typically regarded as being clinically meaningful. Bill, I think most regulatory authorities we've discussed acknowledge that given the incredible seizure burden in this disorder that it's Serious refractory in the seizures are life threatening.
It's really a significant improvement or significant reduction is really going to be looked at maybe independent of a specific number, but in the context of the disease. And again, these are kids that have sometimes 50, 100, 150 seizures a day, which is a significant burden in one of our case series. We had a reduction From 120 to 150 seizures a day down to 20 to 30, which is obviously significant. In addition to the motor seizure frequency, which is the We'll also be capturing other secondary endpoints looking at other aspects of seizure activity, use of rescue meds and other aspects of morbidity that will help paint that Full picture of impact of the therapy, not only in reserve motor seizures, but overall disease morbidity. In terms of prescriptive ataxia, When you think about atresia cataxia, it's a whole body disease, it's a whole brain disease.
While it's well known that the cerebellum is really one key aspect of the disease. It's really ground 0 for the ataxia, which is obviously in the name of the disease and a serious component of the neurological pathology. And so with our FA gene therapy, we're again taking a targeting approach just as an AADC and delivering the fataxin gene directly to the dentate nucleus with the idea that we'll be targeting a key aspect of the neurological aspect of disease. That being said, it's still a whole brain disease and a whole body disease with peripheral neurological impact, cardiac impact. We're having a systemic therapy like betiklinone can obviously be adjunctive to the direct to cerebellar administration of gene therapy.
So we really view this as complementary to each other and the ability to deliver benefit for all patients with treated cataxia. Great. Thank you very much.
Thank you. Our next question comes from the line of Colin Bristol with UBS. Your line is now open.
Hey, good evening and congrats on the quarter. I think just a quick one for me. On PTC-nine twenty three, can you walk us Through your anticipated involvement timelines and then the timelines of subsequent data readout? Thanks.
Sure. So yes, that's one of the beauties for Nancy's 3 is
that it's a very short,
The time is what about 6 weeks, I think in terms of the measurements, in terms of looking at the amount of the reduction. And so Matt, do
you want to go through a
little bit of The timelines?
Yes, absolutely. Just to follow-up on and again, thanks for the questions, Collin. Just to follow-up on Suh's comments on the design here. Certainly, when you look at doing a clinical trial on PKU, it has many advantages. One is you have an endpoint of phenylalanine reduction, which is Objective metric, it's a blood test, it's easy to measure.
Obviously, a bit different than traditional neurological diseases where you have composite scales and things that aren't Readily administered or objectively assessed and moved quite quickly. So the study itself for really capturing efficacy is a 6 week placebo control phase. Importantly as well, we've been able to follow the path of obviously previous successful clinical trials with HUVAN, for example, where we know that the ideal way to set up these trials is to first enroll patients in a 2 week run-in phase where we ensure that they're responders to PTC-nine twenty three. So all the enrolled subjects who meet criteria will get treated with PTC-nine twenty three for 2 weeks And we'll then be able to we've established a threshold where we say that you're a responder and if you're a responder, you then get randomized to receive either 923 or So that upfront 2 week run-in really allows us to knowingly enrich The placebo controlled base population with those who have already responded to 923. So that's really obviously a big advantage in terms of increasing the probability of success of the clinical trial.
So when we do enrollment, we're going to be enrolling obviously a larger number of subjects. We're targeting somewhere in the area of 160 to 100 and E subjects globally, and we expect from there to get it have at least 80% that will meet that enrichment threshold that would more than adequately power the trial for success. Again, given that this is a global disease, there are existing centers of excellence And quite frankly, we're able to leverage PTC's existing global infrastructure and we're right now working with our country teams to identify centers of excellence and be able to have patients at the ready to go. And so we expect to initiate the trial into 2021 and Enroll it in pretty rapid fashion and then get data we're expecting by the end of 20
Thank you. Our next question comes from the line of Jatin Wang with Barclays. Your line is now open.
Hi, thanks for taking our question. This is Sheldon on for Jita. I have a question on the 5/18 Hi, Linda. This is our program. So right now you're continuing dosing the healthy volunteers.
And what type of data do you need to determine the dose that will be recommended for inpatient testing? And when do you expect to move into real patients? And what type of patient population are you considering? Thanks.
Sure. So Obviously, we're doing the single ascending dose as well as the multiple ascending dose. I'm actually already pretty excited that we've also that we've already achieved the objectives that we set out in terms of With the preliminary results that we demonstrated to everyone that we can reach as measured in blood Even greater than 50% reduction of htc mRNA lowering based on the dose. And what you saw that it was It was well tight, tradable. We can determine the level that we wanted those to get to that.
So we're in a pretty good position here To be capable of defining the dose that leads to reduction in the RNA, which we were pretty confident that a steady state will lead to reduction in protein. So we're in the process of complete doing a pretty thorough job to make sure completing the additional cohorts that includes The food effects, the finishing of the multiple ascending dose, the CSF measurements as well as complete the protein analysis. So that's what we'll have to go into from there. Well, and probably we will have done what I really like about what we're doing is that it allows us to actually be have a very clear vision of A dose that we're giving that gives us an exposure that we know gives the level of reduction of Huntington RNA as a consequence of that. So we're not flying any plane blinds here.
We're going in knowing exactly What the dose and exposure is that leads to the reduction in htRNA. So we're pretty excited about that. And then the next steps we'll do We'll be to show the similar type of work in both levels of mRNA and Huntington's in HD patients themselves, both the RNA and protein levels, as we also are then beginning to think about What is the trial for clinical benefit? So the future design is we'll assess clinical benefit in HC patients. And then in where possible, we obviously want to enrich the patient population, so that we Demonstrate the benefits in a reasonable timeframe with a reasonable sample size.
So I think we're going to be in a really great position to have The right dose and then we're working hard to define what's the right patient What's the right set of patients and what we'll measure? So we look at this analogous to the SMA story where we defined it and other than 50 basis points that were on target to find the roadmap of going into patients And then that shows clinical benefit. So that's our plans for now.
Got it. Thanks.
Thank you. Our last question comes from the line of Raju Prasad with William Blair. Your line is now open.
Thanks for
taking the question. On 299, how are you thinking about The data disclosure for that, how are you thinking about that program kind of in the context of Increasing vaccine distribution and some antiviral readouts expected in the near term.
Yes, sure. I think so a lot of efforts have been put into vaccination and we're really happy about that. Right now that I'm fully vaccinated and I'm moving my team is and that but having something that attacks the virus that's a small That's a treatment I think is still incredibly valuable. There's going to be a fair number of people who are not going to be vaccinated. I believe and as you're probably seeing here that what's going on in other parts of the globe, there's continue Significant numbers of people having COVID, there's additional variance that come on.
And the advantage of both of a drug like PTC299, where it hits both things and inhibits SARS CoV-two viral replication and because of its mechanism of action also attenuates the cytokine So incredibly valuable drugs for the treatment of COVID-nineteen, but and also to the outpatient treatment. So we think this is going to be And frankly, the other advantage of this is because of the target dihydroauric dehydrogenase or DHODH, It's a cellular enzyme. So the expectation is that it's going to also be less susceptible to variance of the virus, right, targeting a cellular enzyme versus a viral one, so it would be more resistant to mutation. So we think that's actually good. We I generally believe that this is going to be with us for quite some time.
And so we're currently running a Phase 3 registrational trial, as we said, it's in 2 stages where we expect enrollment to be completed in the second quarter This year. And it's that the data from that should be not too far after that and should be in the second So that's our and we'll be able to look at the effect. So we're certainly quite hopeful and excited about Perhaps having one of the first therapies that's a therapy for this disease.
Great. And obviously Sorry.
No, I was just going to say, and obviously, we're going to go rapid Pathways for approval.
Yes. Thanks. And any update on FDA discussions regarding the Translarna Distrucutence study?
Yes. So we're as we said, we're working through this Now, once we complete some work that we need to do, then we'll be talking to them. So we're in the process of Finishing that up so that we can then go and have a conversation with the FDA.
Thank you. This concludes today's question and answer session. I will now turn the call back to Stuart Prowse for closing remarks.
Okay. So, look, I wanted to thank everyone for joining us today. And I think As you heard that PTC has really had an incredibly strong performance this quarter through, I think all aspects of the company from discovery to through commercial revenue. The development team We continue to execute across all the platforms, including the 3 registrational trials, which I think are really near term value drivers. We're also very excited to have recently shared the preliminary data from our PCC-five eighteen We take 1 healthy volunteer trial for Huntington's disease program and we're going to continue to provide updates as we to complete the study.
So we're focused on translating the science into the innovative therapies and Really to bring it to patients to transform their lives and the team is working hard toward this mission and obviously the patients are waiting. So thank you for your time today. And that concludes our this call.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.