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. [Operator instructions] Please be advised that today's conference is being recorded.

[Operator instructions] 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.

Stuart?.

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 passing 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 out-performed revenue protection, 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 have 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 XUS 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 in selective titratable and [indiscernible] blocks. Pre-clinically, it not only uniformly lowered HTT across all sections of the brain, but also 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 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 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 2 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 preapproval 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 consisted of 2 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 3 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.

Matt?.

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 broad brain biodistribution and lack of efflux in the CNS, are key differentiating properties and reflect PTCs 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 2 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 2 vatiquinone registrational trials in mitochondrial epilepsy and Friedrich 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 6 months of treatment.

The MOVE-FA trial, our Phase 3 study in pediatric and adult Friedrich 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 write an 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 plan 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 PTP299 in COVID-19. We have completed stage one of this registrational trial and are currently enrolling stage 2.

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 variance, 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.

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 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. 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 group 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 processes, 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 EMEA 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 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 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. Emily..

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 longterm 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 a hundred percent of the royalties revert back to PTC. Also in our royalty monetization deal, we earn sales sales-based cash milestones that we fully retain.

One milestone this quarter was related 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 a current $650 million 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 and 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. [MPPC299] and COVID-19, as well as increased investment in research programs and advancement of our clinical pipeline.

Non-gap SGNA 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.

Operator?.

[Operator Instructions] Our first question comes from the line of 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. Thanks Eric. Thanks for the question. And so we're in the process of completing the additional cohorts. And as we've said, that will include a food affect, the multiple ascending dose, the treatment, so that we get the CSS as well as protein analysis. 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 that was in what we see in blood is equal to the equivalent that we meant to the CSF. I remind you that that's really a major advantage in terms of being able to be able to find what the drug levels are and be able to do that.

So we have a lot of data on that. 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, thinking in terms of the results based on that, we think that the question there is more on...

The issue, at the end of the day, what we think in terms of what we saw in the Roche data, it seems to be a real issue.

We think it's the toxicity, and so do they, by the way, in terms of the issue, in terms of the reason that it went wrong, was that as thing we think it's an ASO specific problem that we think is due to the toxicity, as well as insufficient deep brain penetration.

And I think the hydrocephalus that was observed with the Roche drug was also seen with SPINRAZA which are both with ASOs. So I can remind you that the Roche drug, they had 4x the volume and about 10x the amount of ASO in there, 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 our drug effects splicing, reduces the level of HTT.

And there's a plethora of data that shows that reducing the HTT levels is critical for preventing the effects of the disease to occur. And we've seen that both in patients who have lower levels of that. I want to remind everyone that Huntington's Disease is a monogenic disease, and it's a consequence of the immune Huntington protein.

It's not like it could be from something else. And we definitely think that both HTT and the RNA of the protein are the best targets for that, and there are plenty of case studies showing both in animal models that lower in wild-type HTT is well tolerated, and that lowering Huntington's Disease by 50% is demonstrated clinical benefit.

So the fact that we have an orally bioavailable drug 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 does not efflux. And we think -- this has really, we think, the potential to be the best in class for this treatment.

Does that help 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 Q 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 [indiscernible] 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 feet 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 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 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 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?.

Robyn, thank for the questions. 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 gets into the CSF.

We've seen that in the non-human primates where we saw equals We've seen that in the non-human primates, where we saw equal amounts. So what we'll do is in the clinical trial, we think it will be sufficient where we'll -- and we know, by the way, of what 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're 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 we anticipate it may not be a perfect one-to-one in the sense that you're not yet at steady state at 14 days but we're expecting to see reduction within that time.

So 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, it's pretty proportional to the level of RNA reduction that you see, you see a production of the proteins, there's a pretty good correlation.

There's no regulation that we've observed that as you reduce the level of RNA, you see a protein synthesis. So we're pretty confident that when you see a reduction of the RNA and that you'll also see a reduction within the protein. So we're very comfortable.

That's what we've seen throughout all our work, when we've looked at the reduction of both RNA and protein within the animal models that we've tested. So we're very comfortable with that. And then with 923, obviously we think we're excited about it that it 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 Kuvan as well as Palynziq. So the fact that it's an oral molecule that it's quite active, that we've seen it perform well, it gets proven in the Phase 2 trial.

We feel pretty comfortable that this is going to be quite helpful to these patients.

Next, you want to add anything to that?.

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. You know, PKU treatment requires activating phenylalanine hydroxylase enzyme, which is dysfunctional in the disease.

And PTC923 is a precursor to BH4, which is the cofactor for the enzyme. And giving that precursor allows it to effectively cross plasma membranes, get into the cell where it's readily activated into BDH4.

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, with only a small getting into the cells.

So this is really a story of superior bioavailability and therefore much superior action seen in the Phase 2 study including activity in the classical PKU patients, which in our study had an almost 200 -- reduction of 200 points in phenylalanine in the classical PKU patients, where there was really no reduction seen in the Kuvan-treated patients in the classical BKU.

Now you had also got a Palynziq. We didn't do a head-to-head comparison of Palynziq and while Palynziq has shown efficacy in some patients, obviously it's one -- there are 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 risks.

So there really is a tolerability concern which may be in part attributed to its lack of universal uptake. It's also not to be used by kids, which obviously is an important part of the population. So we think when you look at the existing PKU marketplaces, there's still a large unmet medical really [indiscernible].

In terms of the diet question, that's not something we're looking at explicitly in the study, but obviously we're focused, as the agency likes you to make sure those diets are controlled so you don't have any [indiscernible] factors in a placebo-controlled study. But obviously, we expect within a efficacious therapy, that diet could be lucid..

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 ASL 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. 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 in terms of disentangling, I think that's a really good point, that our drug, in terms of the non-human primate data we had not seen any of what you're seeing. So I think, again, it's pretty clear to us that we think the effect is really almost the toxic effect of the oligonucleotide, that's our point of view on this.

And again, from our point of view, just the fact that it's an orally bioavailable molecule -- 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 bioavailable molecule.

They're just like we saw for SMA, how well it was able to distribute throughout the body and throughout the brain tissues, we see the same thing.

And we built that in to PTC518 and not only did we build that in, we also built that it was an efflux, and that really allowed us to see the level of what we see in the blood was equal to the brain, which gives us a lot of confidence, when we measure what we see in the blood, just like we did previously with the [indiscernible], you know what's getting it to the brain.

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 it's not really a question of, is it the right target, we're very certain that that's the right target. It's a monogenetic disease.

And we think that reducing this in the toxic form of that [indiscernible] is indeed what you want to do.

So in terms of the Emflaza breakdown, Eric, do you want to talk a little bit about that?.

Yes, sure. Yes, Brian, we had an excellent quarter for 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 a 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..

Sure. Yes. I mean, we've had a lot of discussions on that and what we think about this is that HD is a monogenetic disease, right? And it's the consequence of the mutant Huntington, right? So from our view, that makes it the best target.

Then from the question of "how much can you lower it and 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 certainly the reduction of mutant HTT also has been shown to actually elongate the time where patients shows disease effect.

So I think there's plenty of data out there. And then I think the most likely hypothesis is, in the sense of what we said, the toxic effects that you've seen this not only in Tominersen, but also in Spinraza. Now you have 10x the amount of the oligonucleotides as well as 4x the volume. So you're already creating an issue there.

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 oligonucleotides show a disproportionate lowering in animals, you see more in one part of the brain than the other crop.

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 in 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 getting everything, you may hit maybe.

Let's take your point, let's say it's true, you might be overhitting as a consequence a particular area. That's the hypothesis, that you're really bringing down too much in one spot and not enough in another. That's not a problem when you have a small molecule that gets distributed equally around the brain.

And you can titrate it, you can get to every part of the brain tissue and the levels are highly controlled and we've shown that, indeed, to be the case. So from my point of view, no matter which sort of hypothesis you take, it's still a consequence of 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 let's take the other least likely hypothesis is 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 the orally bioavailable, small molecule. So I think for us, it's reinforced our belief in the importance of the advantages of an orally bioavailable small molecule and it's something that we've been talking about PTC518.

Not only is it -- obviously, the biodistribution. So when we put all this together -- and we really do believe it's likely to just high levels of oligonucleotides, 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 differences when we've looked at in animal models, in terms of the volume within the ventricles. So we feel pretty good that we're in a pretty good spot that we have the potential best in class..

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. Thanks for that. So we're excited about 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. So we -- our goal is -- and what we're doing now is just completing some of the gating items.

So the preclinically ahead of moving into clinic and that's going on now and that we've already begun some start-up activities and we're going to be looking to utilize 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 so that we can get the first in human dosing.

Does that help?.

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

First one -- both on vatiquinone. 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 2/3 versus placebo? And are there been 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 Friedrich's ataxia gene therapy, are there patients that would benefit more specifically from a gene therapy approach versus vatiquinone? How are you thinking about segmenting those 2 therapies in the 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.

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 mitochondrial disease also have seizures and the 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 oxidative stress and the underlying mitochondrial pathology. So that further contributes to the problem that they have.

Whereas, obviously the tickling 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 occurrences of status epilepticus.

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 manifests in seizures, there's also having other overall impact on the patients and their disease in terms of specific seizure threshold.

For our analysis, we looked at a target reduction of about 50%, which is typically regarded as being clinically meaningful, though I think most regulatory authorities we've discussed acknowledge that given the incredible seizure burden in this disorder that it's serious refractory, and 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, so the disease, these are kids that have sometimes 50, 100, 150 seizures a day, which is a significant burden.

And in one of our case series, we had a reduction from 125, 250 seizures a day down to 20 to 30, which is obviously significant in addition to the motor seizure frequency, which is the primary endpoint, we'll also be capturing other secondary end points looking at other aspects of seizure activity, use of rescue meds, and other aspects of morbidity that will help paint that fuller picture of impact of the therapy.

Not only in deserving motor seizures, but overall disease morbidity in terms of frequent attacks, yes. When you think about Friedreich ataxia, it's a whole body disease, it's a whole brain disease. It's well-known that the cerebellum is really one key aspect of the disease.

It's really ground zero for the ataxia, which is obviously 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 targeted approach just as an ADC and delivering the [indiscernible] 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 vatiquinone can obviously be adjunctive to the direct cerebellar administration, gene therapy.

So we really view this as complimentary to each other and the ability to deliver benefit for all patients with treated 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. But yes, that's one of the beauties of 923 that it's a very short -- the time is, what, about 6 weeks, I think, in terms of the measurement, in terms of looking at phenylalanine 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, Colin. Just to follow up on Stu's comments on the design here, certainly when you look at doing a clinical trial and PKU, it has many advantages. One is you have an end point of phenylalanine reduction, which is an 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 move quite quickly.

So the study itself we're really capturing efficacy is a 6 week placebo control phase, importantly as well, we've been able to follow the path of previous successful clinical trials with who had, for example, where we know that the ideal way to set up these trials is to first enroll patients in a 2 week running phase where we ensure that they're responders to PTC 923.

So all the enrolled subjects who meet criteria will get treated with PTC 923 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 who then get randomized to receive either 923 or placebo for 6 weeks.

So that upfront 2 week running really allows us to knowingly enrich that the placebo controlled phase 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 for targeting somewhere in the area of 160-180 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 are existing centers of excellence, and quite frankly, they're able to leverage PTCs 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 at in a pretty rapid fashion and then get data we're expecting 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 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?.

Sure. So obviously we're doing the single, we'll send these out as well as the multiple ascending dose.

So I'm actually already pretty excited 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 extremely, it was well-type tradable.

We can determine the level that we wanted to get to that. So we're in a pretty good position here to be capable of defining a dose that leads to reduction to the RNA, which we were pretty confident that a steady state will lead to reduction of protein.

So we're in the process of doing a pretty thorough job to make sure completing the additional cohorts, the food effects, the finishing up of 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 we'll and probably we will have done what I really like about what we're doing is that it allows us to actually 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 that we're not flying any plane blind here. We're going in knowing exactly what the dose and exposure is that leads to reduction in HTT RNA. So we're pretty excited about that.

And then the next steps we'll do will be to show the similar type of work both levels of mRNA in 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 in the future design as well as that clinical benefit in HD patient and then where possible we're obviously we 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. And so we look at this analogous to the SMA story where we've defined it, and it's great that we're on target to find a roadmap of going into patients. And then that shows clinical benefit. So that's our plans for now..

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 read outs expected in the near term?.

Yes, sure. I think so a lot of efforts put into vaccination and we're really happy about that. I can say right now that I'm fully vaccinated and most of my team is in that, but having something that attacks the virus 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 in this, 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 variants that come on and the advantage of both of a drug like PTC 299, where it hits both things, it inhibits SARS, COVID 2 viral replication, and because of its mechanism of action, also attenuates [indiscernible].

So incredibly valuable drugs for the treatment of COVID-19, 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 dihydroorotate dehydrogenase or DHODH it's a cellular enzyme.

So the anticipation is that it's going to also be less susceptible to variants of the virus because it's targeting a cellular enzyme versus a viral one. So it would be more resistant to mutation. So we think that's actually good. I generally believe that this is going to be with us for quite some time.

And so we're currently running a phase 2, 3 registrational trial, as we said, it's in 2 stages where we expect enrollment to be completed in the second quarter of this year. And it's that the data from that should be not too far after that. It should be in the second half of this year. So that's our, and then 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..

Sorry. I was just going to say, and obviously we're working toward rapid pathways for approval..

Thanks. And any update on update discussions regarding the transplant disruption site..

Yes. So we're working through this now and 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 go and have a conversation with the FDA..

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 [indiscernible] commercial avenue.

The development team continues 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 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..