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 session. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your host, Kylie 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 first quarter 2021 corporate update and financial results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz; our Chief Development Officer, Matthew Klein; our Chief Business Officer, Eric Pauwels; 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 this 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 10-Q and our annual report on Form 10-K filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We would disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures, and a reconciliation of GAAP to non-GAAP is available in today's earnings release. With that, let me pass the call over to our CEO, Stuart Peltz.

Thanks, Kylie. 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 to adapt to circumstances abound. Our passion for our mission remains; to provide innovative treatments to patients with debilitating, rare diseases that have few or no treatment options. I'm pleased to report that PTC is emerging from this challenging time an even stronger company. 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 Strengths-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 expectations, 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 a substantial 32% growth in revenues, compared to the first quarter of 2020. This is quite incredible considering Translarna was launched in 2014 and Emflaza in 2017, and we expect strong growth to continue into the future. The commercial team continues to deliver impressive growth and has been working hard to bring these treatments to patients around the world. Now let's move to Evrysdi, the first at-home treatment for spinal muscular atrophy. Evrysdi has continued to see strong uptake in the US, with 1,600 SMA patients now on treatment. This represents a remarkable 50% market share in a short period of time post-approval, and we expect this growth to continue. We were pleased to report that Evrysdi received EMA approval and had the first EU sale the following day. This shows the pent-up need for a convenient, orally bioavailable, effective therapy for SMA patients. The first EU sale triggered a $20 million milestone from our partner Roche. We expect additional growth as European markets secure pricing and reimbursement. A Japanese approval is also expected before the end of this year. The success we established with Evrysdi provides a roadmap for future oral, small molecule splicing in therapeutics. The roadmap guides us in our development of PTC518 for Huntington's disease, or HD, which I will now return to. 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 PTC518 is an orally bioavailable small molecule that penetrates the blood-brain barrier, selectively titratable and effectively blocks HTT. Pre-clinically, it uniformly lowered HTT across all sections of the brain and reduces mRNA and protein levels 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 MAD cohorts, PTC518 was found to be well-tolerated, with no safety findings. Rarely are you able to demonstrate you're on target in a Phase 1 trial in healthy volunteers, and analogous to the Evrysdi program, this puts us in a unique position. We're extremely pleased with the progress to date and look forward to sharing additional results and next steps as the study progresses. Based on the mechanism of action and the pharmaceutical properties of PTC518, we believe it has the potential to emerge as the treatment of choice in the first disease-modifying therapy for Huntington's disease. And now I want to touch on our PKU program. As a reminder, a small Phase 2 head-to-head responder study was previously performed with PTC923. The results demonstrated that PTC923 showed a twofold greater reduction of phenylalanine levels in the blood relative to Kuvan. Importantly, the results also show that 50% more patients responded to PTC923 as compared to Kuvan, including patients with classical PKU. We will start a registrational trial evaluating PTC923 in PKU, called APHENITY, mid this year, 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 PTC923 as a clinically differentiated therapy to address this high unmet medical need. With newborn screening and established centers of excellence, we see this as an exciting program. Let me next turn to our bio-e platform. The bio-e platform is a key component of our diversified pipeline because of this novel approach to targeting disorders of oxidative stress and inflammation. As a reminder, we have initiated two registrational trials with vatiquinone, the first compound from the bio-e platform, one for mitochondrial epilepsy and one for Friedreich ataxia. Through its targeted-based action at the enzyme 15-lipoxygenase, vatiquinone reduces the oxidative stress pathology that ends up as mitochondrial epilepsy and Friedreich ataxia. Moving on to our gene therapy platform, we have some updates to share on PTC-AADC. 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 CHMP opinion in the third quarter of 2021. In addition, due to further COVID-related delays to complete the third cannula surgery, we now anticipate the BLA submission to be delayed by at least a quarter. Let's now turn to PTC299 in COVID-19. As a reminder, PTC299 is an oral, small molecule with a dual mechanism of action that demonstrates both antiviral and anti-inflammatory effects. PTC299 inhibits SARS-CoV-2 viral replication and calms the cytokine storm. PTC299 functions by targeting the cellular enzyme dihydroorotate 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 II/III registrational trial consisting of two stages. We expect enrollment to be completed for the full trial in the second quarter of 2021. We're proud to continue to deliver across our global commercial program and our robust development pipeline that currently includes three ongoing registrational trials and one additional to be initiated in mid-2021. We are in a great financial position with a strong cash balance and a number of upcoming 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 our clinical progress.

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, and I am pleased to share our most recent program updates. First, I'll begin with our validated splicing platform. As Stu mentioned, we remain enthusiastic about the potential of PTC518 to deliver a meaningful benefit to Huntington's disease patients. PTC518's broad brain biodistribution and lack of efflux in the CNS are key differentiating properties and reflect PTC's experience in developing selective, specific, and broadly biodistributed oral, small molecule splicing drugs. The PTC518 Phase 1 healthy volunteer study is ongoing. As we shared in the deep dive last month, data from the SAD and first two MAD cohorts demonstrated dose-dependent reduction of Huntington mRNA, the key objective of the Phase 1 study. In addition, we achieved the desired 30 to 50% reduction in HTT mRNA in the lowest MAD dose cohort. Furthermore, we observed that the long half-life of PTC518 resulted in sustained reduction in HTT mRNA levels up to 72 hours after cessation of dose. We look forward to sharing additional data, including pharmacology data from the CSF sampling cohort once available. Turning to our bio-e platform, enrollment is ongoing in our two vatiquinone registrational trials in mitochondrial epilepsy and Friedreich ataxia. As a reminder, the mitochondrial epilepsy trial, the MIT-E 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 six months of treatment. The MOVE-FA 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 FARS score, and a 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 MIT-E study in Q3 2022, and from the MOVE-FA study in 2023. We have completed the Phase 1 study, the PTC857, the next compound from our bio-e platform, and expect to have data available later this quarter. PTC857 is a second-generation 15-lipoxygenase inhibitor being developed for neurodegenerative disorders characterized by pathology of the 15-lipoxygenase response pathway. Turning to our PKU program, we are excited about the potential for PTC923 to meet the persistent unmet medical need of PKU. PTC923 is an orally administered precursor of BH4, the co-factor of the phenylalanine hydroxylase enzyme that is affected in PKU. PTC923 readily crosses the cell membrane and as Stu mentioned, demonstrated significant effects in reducing phenylalanine levels in a Phase 2 trial, including in even the most severe classical PKU patients. We are on schedule to initiate our global Phase 3 placebo-controlled trial, the APHENITY trial, in mid-2021. Next, if I could update on our AADC deficiency gene therapy program. As Stu mentioned, due to an inability to complete pre-approval inspections 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 CHMP opinion in the third quarter of 2021. In addition, the third planned surgery with the commercial cannula has been delayed, and we now anticipate BLA submission to be delayed at least one quarter. Nonetheless, our teams are continuing their global commercial launch efforts, which Eric will describe in more detail. Finally, I want to share the continued progress in our FITE19 trial of PTC299 in COVID-19. We have completed stage one of this registrational trial and are currently enrolling stage two. Despite the great strides in the development of COVID-19 vaccines, there remains a need for effective COVID-19 therapies as we face new challenges due to virus variants, uneven vaccine distribution, and vaccine hesitancy. We expect to have data for FITE19 in the second half of 2021. As you can see, we continue to make progress in advancing our robust and diverse development pipeline. I will now hand the call over to Eric for an update on our commercial execution this quarter.

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 to date. We have 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. The sustain in 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 in DMD patients globally. As a reminder, Emflaza is the first and only FDA approved treatment for all DMD 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 AAF. 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 geography, as well as continued geographic expansion. Following the approval in the fourth quarter of 2020, we are pleased to announce that the Russian Federation has approved a plan to financially support all eligible, ambulatory nonsense mutations, 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-19 and leadership changes in the Ministry of Health, we continue to see increases in newly diagnosed DMD patients and are working towards securing a group purchase order for Translarna in the second half of 2021 to meet the needs of new and existing DMD patients. Now, turning to Tegsedi and Vylibra. The team continues to make progress with disease awareness and patient identification in Latin America for our patients, despite the ongoing COVID-19 challenges in the region. In Brazil, we continue to explore avenues for pricing 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 that we now have some of the first patients benefiting from the treatment with Vylibra in Latin America through early access pathways and are making progress in Brazil, as we anticipate ANVISA approval in Q3. Moving on to AADC. As a reminder, PTC AADC 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 a gene therapy launch for patients with AADC deficiency, which is now expected to occur in Europe shortly after final EMA approval. PTC continues to execute on the patient screening activities with over 100 at-home and saliva-based genetic testing programs in over 20 countries initiated in enriched high-risk populations. We aim to identify more than 300 patients globally, 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 through 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 in 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.

Thanks, Eric. In the first quarter 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 sheet 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 First Quarter 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 $117.9 million for the first quarter of 2021, a 73% increase over the first quarter of 2020. This was driven primarily by net product revenue from the DMD franchise of $90 million, collaboration revenue of $20 million from the EU first commercial sale milestone payment for Evrysdi, and the royalty revenue of $6.7 million. Turning first to our DMD franchise. Translarna net product revenues were $46.5 million compared to $40.5 million for the first quarter of 2020. For Emflaza, we reported net product revenues of $43.5 million, as compared to $27.5 million in the first quarter of 2020. Moving now to Evrysdi. Our partners, Roche, report in 2021 year-to-date sales of approximately 80 million Swiss francs. As a reminder, PTC retains approximately 57% of Evrysdi royalties until Royalty Pharma receives a return of $1.3 billion after which 100% of the royalties revert back to PTC. Also in our royalty monetization deal, we earn sales-based cash milestones that we fully retain. One milestone this quarter was related to the first European commercial sale with a $20 million payment triggered when this occurred. The royalty monetization transaction not only transformed our balance sheet by bringing forward future cash flow to current $650 million in cash assets, while still allowing PTC to maintain the majority of the royal stream, along with the future potential growth, as Evrysdi could become the preferred global SMA therapy worldwide. Non-gap R&D expenses were $120.8 million for the first quarter of 2021, excluding $13.7 million in non-cash, stock-based compensation expense, compared to $81.9 million for the first quarter of 2020, excluding $8.2 million in non-cash, stock-based compensation expense. The year-over-year increase in R&D expenses reflects increases in spending due to advancing the gene therapy, metabolic, and bio-E platforms. Non-gap SG&A expenses were $49.1 million for the first quarter of 2021, excluding $12 million in non-cash, stock-based compensation expense compared to $51.2 million for the first quarter of 2020, excluding $7 million in non-cash, stock-based compensation expense. Cash, cash equivalents, and marketable securities totaled approximately $988.4 million as of March 31st, 2021, compared to $1.1 billion as of December 31st, 2020. I will now turn the call over to the operator for Q&A.

Our first question comes from Eric Joseph with JPMorgan.

Just a couple from us, primarily on PTC518 for Huntington's. First is, how we should be thinking about the timing of the next updates to their study? So typically the analysis on protein change in the periphery and also drug exposure in the CSF, will you be looking at exposure to the CSF in simply one cohort, and will that be sufficient to inform those selections in a patient study? And then secondly, I guess coming away from some of the presentations from the Roll HD, are you thinking any differently? Or how has your thinking evolved in terms of the feasibility of establishing or looking for therapeutic benefit or proof of concept in the Phase 1 Huntington patient study?

Yes, thank you for the question, Eric. We are in the process of completing additional cohorts, which will include a food effect, multiple ascending doses, and treatments to obtain CSF and protein analysis. We expect to have this information available soon and look forward to sharing it when it's ready. Overall, we are confident about the exposure levels. It’s important to note that our data shows a strong correlation between blood results and brain results, highlighting the advantage of being able to determine drug levels accurately. We are pleased with the results we've seen in reducing targets, even after a single dose. In terms of the Roche data, we believe toxicity is a significant issue for them, and we think it's specifically related to their ASO approach and insufficient deep brain penetration. The hydrocephalus observed with Roche's drug is also something we saw with SPINRAZA, given that both involve ASOs. Roche used a higher volume and significantly more ASO, which likely contributed to the hydrocephalus issue and may affect penetration as well. We maintain confidence in our ability to alter conditions with our drug, which targets splicing and reduces HTT levels. Reducing HTT is essential for mitigating the effects of Huntington's Disease, a monogenic disorder caused by the mutant Huntington protein. We believe that both HTT and the RNA of the protein are key targets, supported by numerous case studies and animal models showing that reducing wild-type HTT is well tolerated and leads to significant clinical benefits. Our orally bioavailable drug, which reaches all tissues, allows us to control drug levels in the brain effectively, making it a promising option with broad tissue distribution. It does not efflux, and we believe it has the potential to be the best in class for this treatment. Does this clarify things for you, Eric?

Our next question comes from the line of Alethia Young with Cantor Fitzgerald.

This is Nina on for Alethia. We were wondering what are the remaining steps to file in the U.S. for AADC beyond the one-quarter delay related to COVID? And do you think the delay is potentially longer than a quarter?

Sure. Thanks for the question. So AADC, I think, is obviously a really exciting product, and it's shown really transformational results in being able to take people who are developmentally arrested, kids who are, and to be able to actually see those development, 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, you want to talk a little bit about the steps there?

In the comments made in the call as well and the process we have submitted the MAH, 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 want to remind everyone that that's moving forward and we now expect to have that opinion in the third quarter. For the BLA, as we've talked about, really one of the key gating factors was the agency's desire for us to demonstrate some experience with our specific gene therapy product, with a specific cannula we intend to use commercially, which is the smart goal of cannula. Now of note, that cannula has been fits in marked in the EU, which is why it was not an issue. The cannula was not an issue in the MAA process. On the FDA side, that cannula has been 510K-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 that 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 putamen 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 two 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 discussed before, is to complete that third procedure. And then obviously, we'll take the data along and make sure everything else is in place with the agency and look to move forward at that point.

Our next question comes from the line of Robyn Karnauskas with Truist Securities.

First, just to follow up on expectations for Huntington data. I had two questions. You set the bar low for what we can learn from the CSF. And you said that we'll be getting that CSF data shortly. Can you give us a little bit more color, an updated thoughts on how we should view that data so we don't over-expect too much? Second, on the protein levels, which everyone's really interested in seeing, should we expect a difference, a delay in the lowering of protein? 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 PTC-293. 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 affinity trial?

Thank you for the questions, Robyn. We believe that our extensive research indicates the drug can pass the blood-brain barrier, reach all parts of the brain and various tissue types, and enter the cerebrospinal fluid (CSF). Our observations in non-human primates showed consistent levels in both blood and CSF. In the upcoming clinical trial, we expect a single dose will sufficiently address this aspect. Additionally, we are evaluating RNA and protein levels as part of the cohorts, understanding that the relationship between RNA and protein may not be a direct one-to-one since we won't be at steady state at 14 days. However, we do expect to see a reduction in those levels during this time frame and will determine the percentage of reduction accordingly. We believe there is a strong correlation between RNA reduction and protein synthesis, with no observed regulatory discrepancy. Therefore, a decrease in RNA should also reflect in protein levels. Our findings across various animal models support this confidence. Regarding PTC-923, we are excited because it targets a broader patient population, demonstrating increased efficacy and lower levels of activity, comparable to both Kuvan and Palynziq. As it is an oral formulation and has performed well in Phase 2 trials, we feel optimistic about its potential benefits for these patients. Would you like to add anything further?

In the Phase 2 study we referenced, there was a direct comparison with Kuvan, and the main reason for the superior effect observed is the bioavailability. PKU treatment requires the activation of the phenylalanine hydroxylase enzyme, which is impaired in this condition. PTC923 serves as a precursor to BH4, the cofactor for that enzyme. This precursor effectively crosses plasma membranes and enters the cell, where it is rapidly converted into BH4. In contrast, Kuvan is poorly absorbed because it is a highly lipophobic molecule, resulting in much of the BH2 formed from Kuvan being excreted by the kidneys with only a small amount entering the cells. The evidence from the Phase 2 study illustrates this point, highlighting a significant reduction in phenylalanine levels in classical PKU patients treated with PTC923, whereas no reduction was observed in those receiving Kuvan. Although we did not conduct a direct comparison with Palynziq, it has shown effectiveness in some patients, but it comes with safety and tolerability concerns. Additionally, Palynziq takes time to show full efficacy and requires an epinephrine auto-injector due to anaphylaxis risks, which raises tolerability issues and may explain its limited adoption. Moreover, it is not recommended for children, an important demographic. Looking at the existing PKU market, there remains a significant unmet medical need. Regarding the diet, while it's not a specific focus of our study, we are ensuring diets are controlled to avoid confounding factors in a placebo-controlled study. However, we do anticipate that with an effective therapy, dietary restrictions could be relaxed.

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

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 pre-clinically 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 that was demand-based or were there any other changes in ordering patterns gross-to-net or inventory that may have also factored in?

Yes, thank you for the question. I want to remind everyone that the key aspect here is our ability to proceed without any increase in the CSF. In our measurements, we did not observe any hydrocephalus in the non-human primates. Regarding the issue of disentangling, that's a valid point; our drug data from non-human primates did not reflect the observations you mentioned. We believe that the effects we see are primarily due to the toxic impact of the oligonucleotide. Furthermore, from our perspective, the oral bioavailability of the molecule is crucial. There are two main considerations: the toxic effect and distribution, which doesn't reach every area as effectively as an orally bioavailable molecule does. Similar to our experiences with SMA, we're able to see favorable distribution throughout the body and brain tissues. We incorporated this into PTC518 and ensured it had an efflux mechanism, which has allowed us to observe that the levels in the blood correspond to those in the brain. This consistency gives us confidence that measurements in the blood reflect what reaches the brain, as shown by our previous data. Therefore, we believe we can effectively disentangle these issues. We're confident that the question is not whether we have the right target, as we are certain it is the correct one, considering it's a monogenic disease. We aim to reduce the toxic form. Eric, could you provide some insight into the Emflaza breakdown?

Yes, sure. Yes, Brian, we had an excellent quarter for the DMD 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. To your specific question about in Emflaza, the base of patients that we've been able to accrue, that we started to build in 2020 and 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 and refills, and that's incredible. But what we've also seen is, back in the last quarter, we saw that new prescriptions really continued with its momentum and 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, 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 kinds of tailwinds will continue throughout 2021.

Our next question comes from the line of Danielle Brill with Raymond James.

So I know you talked a lot about how you think the toxicity that Roche is seeing in their Huntington's program is ASL-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.

Certainly. We've had extensive discussions on this topic, and we believe that Huntington's disease is a monogenic condition caused by the mutant Huntington protein. This makes it a prime target for our efforts. Data from animal models indicates that we can significantly reduce the levels of this protein, by at least 50%. Additionally, lowering mutant HTT has been shown to extend the duration before patients experience disease symptoms. There is ample data supporting this. The prevailing theory appears to relate to the toxic effects observed not only with Tominersen but also with Spinraza. In our case, we have ten times the quantity of oligonucleotides and four times the volume, which could be contributing to potential issues. Moreover, we know that oligonucleotides tend to lower levels disproportionately in certain areas of the brain, which complicates measurement assessments of mutant Huntington in cerebrospinal fluid. If our assumptions hold true, it’s possible that excessive reduction occurs in specific locations while being insufficient in others. This isn’t a concern with small molecules that distribute evenly throughout the brain, allowing for balanced titration. Regardless of the hypothesis considered, it seems this issue stems from the oligonucleotides. Roche has acknowledged that the oligonucleotide approach comes with challenges, particularly in terms of distribution. This reinforces our belief in the advantages of an orally bioavailable small molecule, such as PTC518. Higher concentrations of oligonucleotides can lead to complications, which we are aware humans generally do not tolerate well. We’re optimistic about our advancements so far and haven’t observed any notable differences in animal models concerning ventricular volume. Thus, we feel confident that we are in a strong position to develop what we believe to be a best-in-class solution.

That's actually really helpful. And then just quickly, I was wondering if you could comment on where things stand with the Friedrich's ataxia gene therapy program. Can you remind us when you're expecting to enter the clinic with that asset?

Yes, thank you for that. We're excited about the program. We've faced some delays due to COVID, but we continue to make progress and anticipate the first human dosing before the end of the year. Our current focus is on completing certain necessary steps before moving into clinical trials. We've already started some start-up activities and plan to leverage our global infrastructure to focus on sites in the U.S. and worldwide. Our aim is to find the quickest route to achieve the first human dosing. Does that help?

Our next question comes from the line of Joe Thome with Cowen and Company.

First, regarding vatiquinone, in the Phase 2/3 study for seizure disorder patients, are you evaluating a reduction in motor seizure frequency compared to placebo? Have there been any efficacy benchmarks established by the FDA that would classify this as a pivotal study? Second, concerning the Friedrich's ataxia gene therapy, are there specific patients who might benefit more from a gene therapy approach rather than vatiquinone? How are you considering the differentiation between these two therapies in the patient population?

Thanks for those questions, they were good questions, and I'll have Matt talk more about it, but it's obviously we've seen 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're seeing survival as a consequence of this. But you know, there currently is a placebo controlled study, but worldwide, do you want to talk a little bit about how we thought of the during the trial, Matt?

Yes, absolutely. Thanks, Tim, and thanks, Joe, for the questions. In terms of mitochondrial epilepsy, this refers to refractory seizures experienced by children with mitochondrial disease. Approximately 40 to 50% of patients with inherited mitochondrial diseases also suffer from seizures, which are often resistant to existing anti-epileptic treatments. This is largely because current therapies do not address the energy pathways that lead to seizures in these patients. In fact, many seizure medications can worsen oxidative stress and the underlying mitochondrial issues, further complicating the situation. In contrast, our therapeutic approach specifically targets these pathways. Both preclinical and clinical studies have shown a significant reduction in seizure frequency, as well as fewer seizure-related complications, such as status epilepticus. In one case series, we noted a marked decrease in disease-related hospitalizations and mortality risk. By addressing the underlying energy disturbances that manifest as seizures, we also see broader impacts on the patients' overall health, particularly concerning seizure thresholds. Our analysis indicated a target reduction of around 50%, which is usually seen as clinically meaningful. Regulatory authorities we spoke with understand the severe nature of this disorder, where seizures can be life-threatening. Therefore, a meaningful improvement is likely to be assessed in the context of the disease rather than a specific numerical reduction. Some children experience up to 150 seizures a day, resulting in a substantial burden. In one case series, we observed a decrease in seizure incidents from 125-250 per day down to 20-30, which is significant. Besides focusing on the primary endpoint of motor seizure frequency, we will also assess secondary endpoints, including other seizure activity metrics, rescue medication usage, and other morbidity aspects, to provide a comprehensive understanding of the therapy's impact on both motor seizures and overall disease burden. Regarding Friedreich ataxia, it's important to note that it affects the entire body and brain, particularly the cerebellum, which is key to the ataxia associated with this disease. With our FA gene therapy, we are taking a targeted approach by delivering the gene directly to the dentate nucleus, focusing on a crucial neurological aspect of the disease. However, since this is a systemic disorder with broader neurological and cardiac implications, an adjunctive systemic therapy like vatiquinone could enhance the benefits of the direct gene therapy. We see these treatments as complementary, working together to provide benefits for patients with ataxia.

Our next question comes from the line of Colin Bristow with UBS.

Congrats on the quarter. I think it's just a quick one from me on, on PTC 923. Can you walk us through your anticipated involvement timelines and then the timeline to subsequent data readout?

Sure. One of the advantages of 923 is that the measurement period is fairly short, approximately 6 weeks, regarding the reduction of phenylalanine levels. Matt, would you like to discuss the timelines a bit more?

Yes, absolutely. Thank you for the questions, Colin. Following up on Stu's comments about the design, conducting a clinical trial for PKU has many benefits. One key advantage is that the endpoint is the reduction of phenylalanine, which is an objective metric and easy to measure through a blood test. This is quite different from traditional neurological diseases that rely on composite scales which can be difficult to administer or assess objectively and efficiently. The study is structured to capture efficacy through a 6-week placebo-controlled phase. Additionally, we have been able to base our approach on previous successful clinical trials, like that of PTC 923, which indicates that the optimal way to set up these trials is to first enroll patients in a 2-week running phase to confirm their response to PTC 923. All enrolled subjects meeting the criteria will receive PTC 923 treatment for 2 weeks, after which we will confirm who are responders. Responders will then be randomized to receive either 923 or placebo for the following 6 weeks. This initial 2-week phase allows us to effectively enrich the population for the placebo-controlled phase with those who have already responded to 923, significantly enhancing the probability of success for the clinical trial. For enrollment, we aim to include a larger cohort of approximately 160-180 subjects globally, with expectations that at least 80% will satisfy the enrichment threshold, thereby sufficiently powering the trial for success. Given that this is a global disease, we leverage existing centers of excellence and are actively collaborating with our country teams to identify these centers and ensure patients are ready for participation. We plan to initiate the trial in 2021 and expect to enroll participants quickly, aiming to have data available by the end of 2022.

Our next question comes from the line of Gena Wong with Barclays.

This is Sheldon on for Gena. I have a question about the 518 Huntington's program. So right now you're continuing dosing on healthy volunteers. And what type of data do you need to determine that those that will be recommended for inpatient testing and when do we expect to move into real patients, and what type of patient population are you considering?

We're currently focused on the single and multiple ascending dose studies. I'm quite excited that we've already met our initial objectives, as indicated by preliminary results showing over 50% reduction in HTT mRNA levels in the blood, which were well-tolerated. We plan to finalize the dose that will effectively reduce the RNA, with confidence that this will subsequently reduce protein levels. We're thoroughly completing additional cohorts, food effect studies, multiple ascending dose analyses, CSF measurements, and protein evaluations. Our approach allows us to have a clear understanding of the dose we’re administering, which correlates with the reduction of Huntington RNA. Moving forward, we aim to assess mRNA and protein levels in Huntington's disease patients, while also considering the design of trials to evaluate clinical benefits. We want to ensure we have the right patient population to demonstrate benefits effectively within a reasonable timeframe. We're optimistic about defining the appropriate dose and patient criteria and see parallels to how we approached the SMA program, aiming for a roadmap that leads us to demonstrate clinical benefits. That's where we stand with our plans.

Our last question comes from the line of Raju Prasad with William Blair.

Thanks for taking a question. On 299, how are you thinking about the data disclosure for that and how are you thinking about that program? Kind of in the context of increasing vaccine distribution and some anti-viral readouts expected in the near term?

Yes, I'm optimistic about the efforts put into vaccination, and I'm pleased to share that I am fully vaccinated, as is most of my team. However, having a treatment that directly targets the virus remains highly important since a significant number of people will remain unvaccinated. As we've observed globally, COVID-19 continues to affect many individuals, and new variants are emerging. The benefit of a drug like PTC 299 is that it inhibits the replication of the SARS-CoV-2 virus and also helps mitigate the cytokine storm due to its mechanism of action. This makes it a highly valuable treatment option for COVID-19, particularly in outpatient settings. Moreover, because PTC 299 targets the cellular enzyme dihydroorotate dehydrogenase, it is anticipated to be less vulnerable to the virus's mutations compared to treatments that target viral proteins, which is a positive aspect. I believe COVID-19 will be part of our lives for some time, and we are currently conducting a phase 2/3 registration trial in two stages. We expect to complete enrollment by the second quarter of this year, with results following in the second half of the year. We are hopeful and excited about the possibility of introducing one of the first therapies specifically for this disease. Sorry. I was just going to say, and obviously we're working toward rapid pathways for approval.

This concludes today's question-and-answer session. I will now turn the call back to Stuart Peltz 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 avenue. The development team continues to execute across all the platforms, including the three 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 PTC 518. One healthy volunteer trial for on each disease program, and we're going to continue to provide updates as we complete the study. So we're focused on translating the science into the innovative therapies and really to bring it to patients that transformed their lives. And the team is working hard towards this mission. And obviously the patients are waiting. So thank you for your time today. And that concludes this call.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.