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spk06: Good day, and thank you for standing by. Welcome to the PTC Therapeutics Third Quarter 2021 Corporate Update and Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star 0. I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Head of Investor Relations. Please go ahead.
spk03: Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics Third 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, and our Chief Business Officer, Eric Powers, and our Chief Financial Officer, Emily Hill. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements. Our actual results could materially differ from these forward-looking statements. As such, statements are subject to risk that can materially and adversely affect our business and results of operation. 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 annual report on Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call. information regarding our use of GAAP to non-GAAP financial measures, and a reconciliation 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?
spk10: Thanks, Kylie, and thank you all for dialing in. I'm excited to tell you about our progress this quarter as we have continued to demonstrate remarkable commercial revenue and have been making good progress across a robust pipeline. At PTC, we are committed to creating both short and long-term value for all our stakeholders. To accomplish this, we have built a company that discovers, develops, and commercializes therapies to treat patients of higher medical needs. We are building a sustainable pipeline that at steady state will develop new therapies that reach commercialization on a continuous basis. This will allow us to substantially grow our revenue base so that it will continue to increase in the years to come. The results of all these efforts are bearing fruit. We see continuous and impressive commercial revenue growth of our products, and we now have five ongoing registration-directed studies with an increasing number of preclinical and clinical studies in progress. We are building a sustainable, enduring, biopharmaceutical companies. Turning to this quarter's DMV franchise commercial revenue, we continue to deliver impressive year-over-year growth. The franchise has grown by 39% compared to the third quarter of 2020, with $114 million in total revenue. This was primarily driven by new patient starts for both Inflaza and Translarna. and geographic expansion for Translarna. I'm pleased to announce that we are raising our 2021 revenue guidance for the DMD franchise to $400 to $420 million from the $370 to $390 million. Eric and Emily will go into more detail shortly. Now, I'd like to highlight the significant milestones achieved in Brazil with both Taxeti and Ray Lever this quarter. In August, we were pleased to announce the approval of Ray Lever in Brazil. This is the first approved treatment for familial chylomicronemia syndrome, or FCS, and we're excited to be able to bring this therapy to patients in need. This was not the only milestone for Brazil this quarter. I'm also happy to report that Taxeti, which is for the treatment of HATTR amyloidosis, received Category 1 pricing. Category 1 pricing is given to innovative treatments that show benefits over current standards of care. Due to the Portuguese descent, there is a higher prevalence of HATTR patients in the Brazilian population. Eric will go into more detail on the remarkable progress of the commercial team later in this call. Now let me turn to Evrizni, which is the first commercial product from our innovative splicing platform. Evrizni continues to show strong revenue this quarter, with approximately 20% total market share in just over a year after launch. Evrizni is the most prescribed SMA treatment in the United States, and Roche expects further growth in 2021, with approval in 63 countries and its continued focus on the pricing and reimbursement efforts outside of the U.S. The success of our commercial portfolio demonstrates our ability to utilize our commercial engine to grow revenues to further invest in the pipeline, which I'll now discuss in more detail. In particular, I'd like to start with our near-term value drivers. I'm excited to announce that we have initiated the registration-directed trial called Affinity for PTC923 in PKU. We view this as a significant opportunity as there is a well-defined patient population through newborn screening, known centers of excellence, and a clear pathway to approval with a blood-based biomarker as an endpoint, as well as having an enriched population through a run-in responder analysis that increases our chance of success. Let me talk about our next two registration-directed trials from our BioE platform. The BioE platform targets excess electrons and the oxidative stress that contributes to multiple disease states. The first compound from this platform, vatiquinone, inhibits 15-lipoxygenase, a key regulator that controls the oxidative stress response. The first of the registration-directed trials with vatiquinone is the MITEE study. in patients with mitochondrial disease associated with seizures. We expect results in the third quarter of 2022, and if positive, will be the basis of our NDA. Our second registration-directed vaticanone trial, MOVE-FA, is in patients with Friedreich ataxia, a mitochondrial disease that affects neuromuscular function. We're grateful for the collaboration and support from the FA community in helping us to drive enrollment. We anticipate results in 2023. We're also moving ahead with the next generation compound from the BioE platform, PTC 857. We have selected ALS as the first indication and are aiming to initiate the phase two trial for PTC 857 in the first quarter of next year. I'll now discuss our innovative splicing platform with a focus on PTC518 for the treatment of Huntington's disease. We recently reported results from PTC518 Healthy Volunteer Trial. We were able to show dose-dependent lowering of both HTT mRNA and protein and achieve the targeted 30% to 50% reduction. We also demonstrated that PTC518 passes the blood-brain barrier and has minimal efflux. These are key attributes to treat Huntington's disease. We remain very excited about this program and are moving as rapidly as possible into phase two. Moving into the phase two trial, we will replicate safety, tolerability, and pharmacology of PTC508, as well as decreases in Huntington mRNA and protein levels in the Huntington's disease patients. Matt will go into more detail on our phase two program shortly. now moving on to AADC. In Europe, we still expect the CHMP opinion by the end of this year and look forward to bringing this transformational therapy to AADC deficiency patients. I'm also pleased that we recently held a ribbon-cutting ceremony for our gene therapy manufacturing center of excellence in Hopewell, New Jersey. Our new state-of-the-art facility is well-equipped and staffed to produce high-quality plasmid and AAV vectors for gene therapy applications. I'm very proud of the progress we've made over the past quarter with exciting commercial achievement and steady state progress across our pipeline. This speaks to the dedication of our people who have worked incredibly hard in the face of the ongoing challenges brought by the pandemic. The past 18 months have required perseverance, and I'm proud to say that we've continued to execute across all fronts. We have all the ingredients, research, development, and commercialization in place that positions us to be a growing, revenue-generating, enduring biopharmaceutical company. I'll now turn the call over to Matt for an update on the development program. Matt?
spk14: Thanks, Stu. I'm happy to provide an update on the continued progress of our pipeline programs. I will begin with our PTC 923 PKU program. As planned, we initiated enrollment in the Affinity Trial, our global Phase III registration-directed trial of PTC923 in pediatric and adult PKU patients. This double-blind placebo-controlled trial will include a run-in phase to identify responders to PTC923 who will then be randomized to receive either PTC923 or a placebo for six weeks. As of previous approved therapies for PKU, The primary endpoint of the affinity trial is reduction of phenylalanine blood levels. Following completion of the placebo-controlled trial, subjects will then be enrolled in a long-term, open-labeled extension study. We expect to have results from the placebo-controlled trial by the end of 2022. Turning now to our PTC518 Huntington's disease program. Following the announcement of the successful Phase I study results in healthy volunteers, we are moving forward with our Phase 2 study in Huntington's disease patients. This study, PivotHD, will include a 12-week double-blind placebo-controlled phase, followed by a one-year open-label extension phase. The study will enroll approximately 100 to 150 subjects who will be randomized to receive placebo for one of two dose levels of PTC518. The primary objective of the placebo-controlled phase is to demonstrate safety, pharmacology, and evidence of HTT, mRNA, and protein lowering in HD patients. In addition, we will collect CSF, plasma, and CNS radiographic biomarker data in both the placebo-controlled and long-term extension phases of the study that could provide evidence of meaningful PTC518 treatment effect. As we discussed in our program update last month, the inclusion criteria for the PIVOT-HD trial were carefully constructed to ensure enrollment of a study population in whom we can demonstrate treatment effect over the course of the study. The criteria for this Goldilocks population were developed based on extensive analyses of the HD clinical and biomarker natural history databases. We look forward to initiating the Phase II study by the end of this year. Next, I'll provide updates on our BioE platform. As Stu mentioned, we are continuing enrollment in the two registration-directed trials of the tiquinone in mitochondrial disease-associated seizures, the MITEI trial, and in frederic ataxia, the MOVE-FA trial. I am proud of the progress our teams have made in activating our global study sites to allow for enrollment of these trials during the pandemic. We expect results from the MITEI trial in Q3 2022 and from the MOVE-FA trial in 2023. As we reported last quarter, we completed the Phase I Healthy Volunteer Trial of PTC-857 and are now moving forward with the Phase II trial in patients with ALS. As a reminder, PTC-857 inhibits the enzyme 15-lipoxygenase, a key regulator of the inflammation and oxidative stress pathway known as pharyptosis. Ferruptosis is a recently described cell death pathway that has been demonstrated to be key to neurodegenerative disease pathology, including ALS and Parkinson's disease. In a series of preclinical studies, we have demonstrated that PTC857 is a potent protector of neuronal cell death and neuropathology in a number of in vitro and in vivo neurodegenerative disease test systems. We plan to initiate the Phase II study in the first quarter of 2022, and we'll provide additional details on the study design once it is finalized. We are excited about the progress we have been making in our ongoing registration-directed trials and look forward to initiating the Phase II trials for PTC 518 and PTC 857 in the near future. I'll now turn the call over to Eric for an update on our commercial business.
spk13: Eric? Thanks, Matt. our PTC customer-facing team has delivered another outstanding quarter in our global DMD franchise. We have built a strong foundation for our potential launch of the PTC AADC gene therapy, which will follow the anticipated EMEA approval and will continue to drive our geographic expansion across the globe to strengthen our commercial engines. Our strong revenue growth continues in our DMV franchise with a 39% increase year over year. This brings our year-to-date sales for the DMV franchise to $306 million. Our 2021 revenue guidance was originally at $355 to $375 million at the beginning of 2021. which in Q2 was raised to 370 to 390 million. Based on the continued strong year-to-date performance, we are pleased to announce that we are raising our 2021 revenue guidance for the DMV franchise to 420 million, a substantial increase over the original guidance. New patient starts, continued high compliance, and a focus in operational excellence has fueled sustained growth of Inflaza. This quarter, we achieved $47 million in revenue, which is a 22% increase over the third quarter of 2020. Turning to TransLarna, we achieved $67 million in revenue this quarter, a 55% growth over the third quarter of 2020. As a reminder, especially in rare diseases, significant international markets like Brazil can produce large orders, create lumpiness due to the uneven government-driven orders that vary over the course of the year. This drives large quarter-over-quarter growth in comparison to others. In this quarter, the successful launch in Russia was a key driver of our growth as we received centralized reimbursement in Russia and obtained a significant order for a large group of nonsense mutation DMD patients. Additionally, we are seeing continued growth in main European markets and driving geographical expansion in Central and Eastern Europe, Latin America, the Middle East, and Asia Pacific, which remains important to our future growth. We are also excited to recently share the real-world results from the STRIDE patient registry, demonstrating that treatment with Translarna delays loss of angulation by more than five years in boys with non-sense mutation Duchenne muscular dystrophy compared to standards of care alone. This is further adding to the totality of evidence for the benefit of Translarna. We are making continued progress for access to Translarna with reimbursement agreements now established for patients in Finland and the Netherlands and broader coverage for two- to five-year-olds for patients in Italy. Despite significant COVID-19 challenges in Brazil, we are pleased with Advisa's approval of expansion of the TransLarner label to include patients in the two- to five-year-old range. Across Latin America, we continue to see increases in newly diagnosed DMD patients and expect to fulfill an order for TransLarner in Brazil in the fourth quarter of this year. to treat both new and existing DMV patients in the country. Now, turning to Tegceti and Waymingra, we are excited to announce that we have successfully received category one innovation classification from CMED, the Drug Market Regulation Chamber in Brazil. CMED price categorization is the first critical step in getting pricing and reimbursement in Brazil. Category 1 classification is given to innovative treatments that provide greater efficacy than current standards of care and allows for pricing in line with international markets. Tyseti's categorization as an innovative treatment is a key milestone towards optimizing the value in Latin America. We will continue to provide named patient access and now commence reimbursement negotiations with Conitex. Brazil's health technology assessment body, for inclusion of Tegceti in the Brazilian public health system, or SUSE. As a reminder, there are an estimated 5,000 patients with ATTRM ligosis in Brazil. Tegceti is the first antisense medicine available for patients in Brazil to address the underlying cause of the disease. We were thrilled to announce that Wayliva was approved by Invita in Brazil as of August 2021. Following the approval, we have commenced discussions with CMED, the Brazilian pricing authorities. Wayliva is the first treatment for FCS in Brazil. FCS is a rare metabolic genetic disease which results in a significant disease burden to patients, including potentially fatal pancreatitis and other chronic complications. We have been engaging in patient finding in Latin America with ongoing success and now have patients on treatment in LATAM through early access programs. I will now touch on the preparations for PTC's first gene therapy launch for PTC-AADC. We have built the foundation to support a strong launch, which we anticipate to occur in Europe shortly after final approval. PTC continues to accelerate patient screening activities in enriched high-risk populations. Significant progress has also been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the United States and the EU to ensure treatment center readiness at the time of launch, and we remain focused on identifying patients globally in markets where gene therapy access is available. We are proud to have commemorated October 23rd as AABC Deficiency Awareness Day, together with the AABC Family Network, and look forward to bringing this much-needed treatment to patients very soon. The third quarter has been yet another strong quarter with sustained growth in the DMD franchise. I am looking forward to a strong Q4 as our global customer-facing teams continue to execute flawlessly against their strategic initiatives. I will now turn the call over to Emily for a financial update. Emily?
spk04: Thanks, Eric. We have continued to see substantial revenue growth from our commercial portfolio this quarter, and we remain in a strong position to continue to support strategic advancement across our diverse pipelines. We look forward to continuing to deliver on important milestones across all of our programs. The press release issued earlier this afternoon summarizes the details of our third quarter 2021 financial results. I will take a few minutes now to review these financial results, but please refer to the press release for further details. Beginning with top line results, total revenues were $138.7 million for the third quarter of 2021. a 17% increase over the third quarter of 2020. This revenue includes $115.6 in net product sales and $23.1 in royalty and collaboration revenue. The strong growth of the DMD franchise continued this quarter with Transvarna net product sales of $67.2 million compared to $43.4 million in the third quarter of 2020. Continued geographic expansion, particularly in Russia, has been driving this growth. Year-over-year Enflaza revenue is also up this quarter, with net products revenue of $47.1 million, over $38.5 million in the third quarter of 2020. This has primarily been driven by better compliance and new prescription starts. Due to this strong performance, we have raised revenue guidance for the DMD franchise to $400 to $420 million, from 370 to 390 million. Turning now to Evrizdi, where our partner Roche has reported year-to-date revenue of 396 million Swiss francs, resulting in 33.3 million in year-to-date royalties to PTC. Royalties to PTC for the third quarter were 13.1 million in royalty revenue. As a reminder, PTC also retains sales-based cash milestones, and the 10 million milestone payment for the first commercial sale in Japan was received by PTC this quarter. In addition to this, PTC has an additional 325 million in sales-based milestones remaining, with a 25 million payment expected when the threshold of 500 million in revenue is reached. Non-GAAP R&D expenses were 117.8 million for the third quarter of 2021. excluding $13 million in non-cash stock-based compensation expense compared to $83.8 million for the third quarter of 2020, excluding $9.2 million in non-cash stock-based compensation expense. Non-GAAP SG&A expenses were $56.4 million for the third quarter of 2021, excluding $12.8 million in non-cash stock-based compensation expense compared to $50.3 million for the third quarter of 2020, excluding $7.6 million in non-cash stock-based compensation expense. We have lowered and narrowed the range of our non-GAAP R&D and SG&A expense for the full year 2021 to $715 to $735 million from $725 to $755 million. Cash, cash equivalents, and marketable securities totaled $867.9 million as of September 30, 2021, compared to $1.1 billion as of December 31, 2020. I will now turn the call over to the operator for Q&A. Operator?
spk06: Thank you. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Eric Joseph with J.P. Morgan. Your line is open.
spk07: Hi, good afternoon. This is Hannah on for Eric. Thanks for taking the question. Just a few from us. So first, with respect to your oral swiping platform, just wondering if there are any other CAG trinucleotide repeat disorders that you might be looking to expand into over the near term, such as mitonic dystrophy or aphrodisiac axia. And then next, with regard to PTC 299, the fight 19 COVID-19 study, just wondering if you're able to talk about powering assumptions for your primary endpoint of time to respiratory improvement, and just maybe what some of the entry criteria are as it relates to prior vaccine exposure or COVID-19 and seropositivity. Thank you.
spk10: Sure. Okay, I'll start with the oral splicing. I think that the splicing one and the platform and as what we've been talking about in terms of the splicing, it's really quite interesting that we've been able to build an informatics program that allows us to identify which sort of U1 sites that we can monitor. We've been particularly interested in the nucleotide repeats as well. I'll speak more generally and just say we've built the platform that's capable of looking at those, and we have a high interest in multiple other repeats like myotonic dystrophy, as well as others. And we think that we can use the platform in interesting ways to be able to tackle other ones. We've talked previously about what we've disclosed as SCOT-3 and MAPTOW. So we have a bunch of other, and then we probably have uh five or six more programs that we haven't disclosed yet but we've always been interested in the ability to be able to reduce the expression of these using our technologies so that we can so i think uh that's being used quite well in the case of 299 and fight 19 i'll pass that over to either matt or kylie on that one
spk14: I have a question on the FITE-19 trial. So, as you mentioned, our primary endpoint in that trial is time to sustain respiratory improvement, which is defined as an oxygen saturation of 94% on Romare, which is sustained until discharge from the hospital, or the end of the study, which is day 28. Basically, the powering assumptions here were based on a of median time to respiratory improvement in the placebo group, which we've taken based on existing data, which was roughly 11 days, and then we had a hypothesized treatment effect, and then basically looked at a hazard ratio of about 1.38, you know, two-sided type 1 error, which got us to our sample size of 380 subjects, which we believe gives us more than 80% power to detect that difference. In terms of your question regarding the vaccination, we don't have any criteria that include or exclude that previous vaccination or anything that relates to seropositivity.
spk07: Okay, great.
spk06: Thanks for taking the question. Thank you. Our next question comes from Danielle Brill with Raymond James. Your line is open.
spk01: Hi, guys. Good afternoon. Thanks so much for the questions. I guess first on the doses for Phase 2, the 518 study, I'm presuming 30 milligrams will be one of the two doses you're thinking of using. Are you contemplating going higher or lower for the second dose? And then do you think it's reasonable to assume we may have data, 12-week data next year? Thanks.
spk10: Yeah, maybe I'll start and then I'll pass it on to Matt. You might remember that we did the Phase I study where we did a 15 and 30 milligram, and we saw in the 30 milligram up to 65% of the RNA that was reduced, and we would anticipate that at steady states the protein levels would go down as well as the numbers. I think what we'd be initially targeting is what we've said is the 30% to 50% of that to be able to get to that. And the way we're thinking about this as well is probably also thinking about taking advantage of some of the fact that we see a bit higher levels in the CSF. So that gives us really an opportunity to actually look at a range of doses. So, Matt, maybe I'll pass on to you to give the thinking on this. Yeah, absolutely.
spk14: So the 30 milligram dose was the dose that we used for the protein cohort, as Stu said, which really got us to the 65% mRNA and novel protein reduction. And again, as Stu said, all along we've been using the inputs from phase one, which was the blood mRNA and protein reduction as well as plasma exposure and CSF exposure to come up with a range of dose levels that would put us into that 5 to 20, I'm sorry, the 30 to 50% range, which we believe will be somewhere target doses, somewhere between 5 and 20. We generally don't give out all the details of the design until the protocol is up and running and we're ready to start. So we'll have more specific information on that as we get closer. But needless to say, we'll be leveraging the titratability of the molecule. And as we learned from that first placebo control phase about the relationship between dose So PKPD in terms of Huntington mRNA and protein reduction in patients will have the opportunity to titrate that dose if, in fact, there's any differences between what we observed in phase one and what we observed in HD patients. In terms of the design and data, you alluded to the 12-week placebo control phase. We said that we're looking to plan to start that study for the end of the year. Those subjects will then roll over into a long-term extension where we'll be focusing on measuring changes in important biomarkers of disease, including the reduction in Huntington mRNA and protein in the blood, as well as in the CSF, and look at other important biomarkers of disease, including NSL, as well as volumetric changes on MRI. In terms of time of the data, I think we'll have more detailed information on time to results once we get the trial started. So we'll give you more information on that in the future.
spk01: So, sorry, just to clarify, Matt, would you intend to provide data after the placebo-controlled portion, or would you wait until the one-year crossover completes?
spk14: Yeah, I expect we'll share the data after the placebo-controlled phase, because that first part of the study is very important in terms of establishing the PK-PD relationship in Huntington disease patients, and will be very important and informally the dose level for the efficacy trial, whether that's done as a phase three or we were able to take advantage of the accelerated approval pathway as opposed to marketing. So we do believe that data set's very important. We'd share that.
spk01: Okay, makes sense. Thank you so much for clarifying.
spk06: Thank you. Our next question comes from with Bank of America. Your line is open.
spk05: Hi, good afternoon. Thanks for taking my questions. A question for you, Stu. How are you thinking about the Translarna franchise in Europe? Specifically, given that it's a relatively mature product now, where do you see most of the new uptake coming from these days? And then I have a couple of follow-ups. Thanks.
spk10: Yeah, sure. So I think you're seeing still growth, which is predominantly a new patience and geographic expansion, which we're continuing to do, and it's been going quite well. Eric, why don't you go through what your team has been doing? Yeah, sure. Hi.
spk13: Yeah, thanks, Drew. Sorry, can you hear me okay?
spk05: Yeah. Hi, Eric.
spk13: Yeah, hi, Dazeen. How are you? Sorry, I'm having a little connection problem here. So, Dazeen, yeah, you know, right now a lot of our growth, that we've seen in the quarter has continued to come from a lot of the main markets. We're seeing very high compliance. We're also implementing a lot of dose adjustments as patients are getting older and heavier. And we're seeing growth in many of the main markets where we have been quite mature and have launched the product over at least five, six, seven years. But we're also seeing growth in other parts of Europe and in international markets. As I mentioned earlier, during the call, we have recently launched in Russia. And very quickly, we were able to get centralized reimbursement in Russia. And also very quickly, a significant order came in for a group of patients. So that dynamic is quite interesting as it's similar to Brazil. So they're large orders for a number of patients, which creates a little bit of lumpy revenues quarter over quarter. But what we see continued growth with Translarna is that patients are staying on drugs for a long period of time. They're adjusting with the dose. There are patients that we are seeing new patients that are coming in in areas in Central and Eastern Europe and Latin America and many others, many other areas. So the collective around Europe and international is extremely important. And in some of the tough payers, even some payers that we've had to fight with for a number of years have opened up and signed new agreements. So even smaller countries like the Netherlands and Finland have shown that they're willing now to pay, which have been more restrictive in the past. And then there's obviously a lot of the label expansions that have occurred. We had label expansions for children as beginning of two years. and really broadening the number of eligible patients. And then the number of less restrictions that are going on right now in terms of patients who go non-ambulatory. So physicians are making, if you will, a sort of risk-benefit decision before taking patients who are off-drug before non-ambulatory. So if I had to actually look at it collectively, it is a combination of good patient compliance, dose and adjustments, geographic expansion, and particularly in key markets. And this quarter, clearly Russia and our main markets have really driven Translarna in what is probably one of our strongest revenue quarters to date.
spk05: Okay. That was super detailed, and thank you for that. So related to what you just said, the guidance and sales that you introduced today, would you say that's coming more from confidence in Translarna or from uptake for M-Flaza? And then my last question, probably for Emily here, is... Can you just talk to us about your expense estimates? It looks like they're going lower relative to last year, and why is that? Thanks.
spk10: Sure. Okay, so, yeah, obviously there's a lot of confidence in both TransLondon and Plaza, and they both have been growing. So, Eric, do you want to talk a little bit about growth of both of those two?
spk13: Yeah, absolutely. I mean, we saw 22% quarter over quarter growth with Implaza. I mean, we've got $47 million in the quarter. We've seen that as, again, a combination of different things, but primarily, again, very high compliance. We've been also working on dose adjustments. We've minimized dropouts, but we've also seen a lot of new patients that have gone on to Implaza. Not only new patients who are naive, but many patients who are switching based on a number of key publications and scientific data now. And of course, the experience that we've generated that shows that Implaza is superior to prednisone. So we see a lot of those tailwinds of Implaza continuing as the base of patients is growing with Implaza. For Translurna, I think we are equally confident based on the things that I mentioned. And we're looking forward to continued geographic expansion. Keep in mind, all the work that we did over the last probably year, year and a half to expand in many of these markets is paying off. And we continue those investments in Asia Pacific and also in other places in Latin America. And we expect those to continue to provide us growth. So overall, I think we're very confident.
spk04: And then this is Emily. When it comes to your OPEX question, I think it's really just a result of 2021 being a full year impact of COVID versus 2020. So obviously we've greatly reduced our travel expense. And then Eric's team has very successfully transitioned to holding most of their physician seminars and consortiums virtually.
spk05: Helpful. Thank you.
spk06: Thank you. Our next question comes from Alethea Young with Cantor Fitzgerald. Your line is open.
spk02: Hi. Thanks for taking our questions and congrats on all the progress. This is Nanon for Alethea. We are wondering what gives you confidence in the MIE readout in the third quarter of 2022 and how do you think of risks for that trial? And also another one, We are curious how you were planning to update us on the FDA feedback for the Phase 2 PTC518 trial next year. Thanks.
spk10: Sure. The MITEI, Matt, you want to go through that?
spk14: Yeah, absolutely. So the MITEI trial is the registration-directed trial on children with mitochondrial disease-associated seizures. And as we talked a bit about before, this is a highly morbid, and severe symptom mitochondrial disease that occurs across many different of the disease subtypes. And so the trial, this Phase 2-3 trial, was really constructed based on a number of mechanistic data as well as previous clinical data we have in the treatment of mitochondrial disease children with seizures who have a variety of different genotypes and phenotypes. And so what we've been able to demonstrate in our previous studies is that we are able to reduce seizure frequency, reduce the occurrence, and arrest the occurrence of status epilepticus, which is the condition of continued seizures in one specific subtype of mitochondrial epilepsy. We've been able to demonstrate that we can reduce disease-related hospitalizations. In that cohort, the children on average had 52 days in the hospital over the course of the year. That was reduced to zero days in the hospital, the following two and three years on therapy. And in that cohort, we were also able to demonstrate mortality benefit. So when we looked across not only that one subtype, but then across all the different subtypes we've treated, we've been able to demonstrate that we're able to affect seizure frequency and seizure-related morbidity in these children. And again, the fact that vitiquinone targets the 15-life oxygenase enzyme and the oxidative stress response pathway that is common to the disease pathology, regardless of the underlying genotype and phenotype, is what gives us further confidence that we're able to demonstrate the treatment benefit across the whole family of mitochondrial disorders, again, independent of the specific mutations. So that trial is enrolling 60 children at centers around the world. We've been able to work closely with that global network and close relationships with patient foundations around the world that we've been able to develop over the course of many years and are moving forward with enrollment in that trial. And as we said, expecting the data and results in the third quarter of 2022. You know, I missed the second part of your question. If you could just repeat it related to that trial.
spk02: Just how do you think about risks for that trial?
spk14: Yes, I think obviously in constructing a trial, we leveraged our many years of experience in doing trials in children with mitochondrial disease. And I think when you talk about mitochondrial disease, one of the biggest challenges in drug development is the heterogeneity of disease, not only heterogeneity and genotype, but also heterogeneity and genotype phenotype relationship. And so we took that into careful consideration in designing this trial. And to overcome that, we, again, are pleased that we're focused on a symptom that's common to all of these different subtypes. So we don't have to worry about different constellation of symptoms. We know that all the children in the trial have the symptoms of seizures, and we're also employing a strategy that has been used in several successful approval trials for pediatric epilepsy syndromes. That's utilizing a run-in phase to ensure a minimum frequency of seizures and then having the subsequent parallel arms only enrolling those children who met that threshold. In addition to account for any heterogeneity that might still come into play, we're stratifying the randomization for the most common subtypes so we ensure balance across both the placebo and the control group. And we think all of those are very good measures at addressing what we know could be potential risks in the design of that trial.
spk02: Got it. Thank you. And I guess for the second question, just how do you plan on updating us on the FDA feedback for the Phase 2 trial for PTC 518 next year?
spk10: So I think what we'll be doing is obviously once we initiate the trial, we'll be telling you. We'll let everyone know. And also after we we get the results after the 12 weeks, we would actually talk about that as well.
spk02: Okay, thank you. That was helpful.
spk06: Thank you. Our next question comes from Raju Prasad with William Blair. Your line is open.
spk08: Thanks for checking the question. I know you guys recently opened the gene therapy facility. Can you talk a little bit about your plans for scaling it up with obviously the ADC program as well as some of the follow-on gene therapy programs, just kind of getting a sense of, you know, what type of scale you'll have and GMP compliance and things of that nature. Thanks.
spk10: Yeah, sure. In terms of compliance, it's a fully operating facility. We have about 220,000 square feet of both suites where we can, you know, grow and prepare the viral vectors as well as the ability to do both GMP plasmids as well in that manner. And so the team is now fully capable of not only preparation of our own plasmids in-house, but also preparation of all the viral vector that's required to do that. And we have all of the manufacturing capabilities to do that in-house, quality and analytical to be able to perform those as well. So that's all being done, and we've been doing this for our other programs that are going on, like what we talked about for FA as well as for, you know, Angelman Syndrome and others as well. So the team's capable of doing that both in the GMP manner, can do it from 30 liters to 1,000 liter facility and make the plasmids as well. We've also been, as I said, and I think I talked about in the past, we'll be doing it for external, potential external customers. We don't anticipate yet we'll be, you know, it will take a little bit of time to be fully functional, and so we'll use some of the extra space we have to be able to bring in potential customers, especially with classes where, you know, in a sense we'll be able to, bring in not only, you know, work through that, but also be able to bring in revenue as well. So the system itself is now all, the site is all up and running, capable of making both plasmids and DNA, and we've been making both vectors as well as plasmids now. And we're confident we can do this, and so we're going to be doing, fulfill all the needs we have as we grow and do more and more, and then also be able to have some customers on the outsides.
spk08: Great. And with regards to affinity, I may have missed this, but do you have a sense of the number of patients that you're going to try and enroll in the arms? And just given kind of the penetration of generic Kuven into the market, just wondering if you think the delta that you've seen kind of phase two, if you recapitulate that, do you think that'll be enough to convert most patients over? Or do you think that you'll need kind of a bigger effect or You know, you're going to go into CUVAN failures. Just kind of curious to know the strategy based on, you know, what you may see in the registration trial. Thanks.
spk10: Yeah, so I think that's an excellent point in that while there's a large number of patients, there's both patients that have been on CUVAN and have failed or have never shown any improvement on it. So there's a large number of patients where CUVAN doesn't do – well for patients. So we don't think, even with the generic, that it's going to be a problem to bring in, to be able to bring in enough patients to do this. We're targeting about 80 patients for the primary analysis cohort. You know, obviously, just to remind everyone, we'll have a run-in for that, so we'll know people will be responsive to it. So it's already set up, I think, for a high chance of success. We've enriched the study population of patients who respond to them. And just to remind everybody, we had done a previous phase two study directly comparing Kuven to our drug. And I think what we've shown is that we see a higher number of patients, about 50% more who responded, and they had a greater effect of reducing finality than we saw patients on Coovent. So we think it's obviously better. We view this as really quite a significant opportunity. You know, really, if you think about it, it's a very well-defined patient population. There's newborn screening centers of excellence. There's a, you know, the pathway to approval is well known. It's a blood-based biomarker where you can measure phenylalanine and a large number of patients in which many of them are in need for improvement of a better drug. So we're excited about that. And we think that this obviously will see increasing success because we have a run in the responder analysis in the affinity study. So in our view, there's a very high amount of medical need in PKU, you know, as the majority of patients remain untreated and are not well controlled, even though there are two commercial products that are available. So we think this is a significant opportunity.
spk08: Great. Thank you.
spk06: Thank you. Our next question comes from Brian Abrams with Arby's Capital Markets. Your line is open.
spk09: Hi, this is Steve on for Brian. Thanks for taking our question. On 518 and building off an earlier question, I'm curious, can you speak a bit more on what you might have to show for safety there? How long you might have to follow patients for potential accelerated approval? And have you looked at differences in transcriptome or proteome caused by 518 in preclinical models or clinical tissue comparing healthy and Huntington samples? And does that hint at any possible differences in safety?
spk10: Yeah. So we make a couple of points. One is obviously safety is usually dependent upon both how it does in patients as well as the safety toxicology. I will say that these molecules are highly selective molecules. And I think we spend a lot and I think that's really a differentiating factor for us. It's an orally bioavailable small molecule where we really worked on the have selectivity and specificity of 518 so that it's very highly specific for HTT and for that particular U1 site. And so obviously what we're going to do is we'll review the results in terms of, you know, the safety will be following that. And what we're going to be doing is in the placebo-controlled study, we'll review the results on the Phase II study to see how patients do in terms of the levels of reduction both within the blood of ATTR and protein and the levels that change within the CSF as well. And we'll be monitoring a number of other biomarkers as well. And then to your question of potential accelerated approval, that's why we're actually going beyond the 12 weeks. Following that, they transition on to an open label study in which they'll be on for a total of 15 months, and that gives the long-term safety as a consequence of that. So we think if there's a potential for an accelerated approval, and what we're interested in that is that we'll have not only the looking at the HTT RNA and protein levels, but other biomarkers as well. What we've found in the transcript, we've looked in a lot of cells, and we've seen that at concentrations, we see really only very few changes in gene expression or in alternative splicing. So it's highly selective and specific.
spk09: Great. Thanks for that. Really helpful. Appreciate it.
spk06: Thank you. Our next question comes from with Barclays. Your line is open.
spk11: Hi, this is for Tina. Thanks for taking our question. We have maybe two questions. First, congrats on the good quarter. Could you frame for us how big is the Brazilian order and also the Russian launch contribution in Q3 number? And how should we think about the going forward run rate? And my next question is about 518 phase two trial. Have you got any feedback from FDA on what biomarkers will be deemed good predictor of clinical benefit? Thanks.
spk10: Yeah, sure. So, you know, obviously, you know, in terms of the FDA for Huntington's disease, we have not yet talked to them on the biomarkers. Clearly, it's important that we think so. we will be measuring the biomarkers of both RNA and protein in blood, as well as the changes in Huntington protein in the CSF, and then other biomarkers like neurofilament, and then we'll be looking at other MRI measurements and volumetric measurements as well, both NFL and the CSF and plasma as well. So I think, you know, that along, you know, and obviously if you think about Huntington's disease versus, say, you know, Alzheimer's. It's a monogenetic disorder that we know is a gain of function, and we know that it's a consequence of the HDT with the CAG repeat and that lowered levels. And there's both animal data as well as natural history and clinical from patients that show that reducing that improves the outcome for patients. So I think, you know, if there's ever a biomarker where you could show reduction of HTT levels and you know that the consequence of the disease is due to the HTT RNA and protein, and that lowering that level actually helps patients in terms of lower levels delays the progression of the disease, you're in a pretty good spot to be able to say that you know you're hitting the, in a sense, lowering the levels of the protein and RNA, and the result of that should be better outcomes. So I think there's pretty good arguments that one can make. And that then coupled with looking at the CSS and other biomarkers, preservation of brain volume, and others, there's a package of information that we think would be important. In terms of the growth, yes, I think Eric already gave a little bit saying that, you know, we're obviously, you know, the beauty of continuing to grow and have geographic expansion is that while things may be lumpy, different groups are ordering at different times. That helps smooth it out a little bit more. And so while Brazil, you know, in this year was hit relatively hard, With COVID, the commercial team has been working tirelessly with the Minister of Health to secure group purchase. We do expect one in the fourth quarter of this year. And maybe, Eric, you want to talk a little bit about this, Russia?
spk13: Yeah. Yes, Stu. I think you have to characterize Russia in this quarter very similar to what perhaps four or five years ago was Brazil. So in some of these countries, the government will order or will provide access and reimbursement and will provide a single order for a very large number of patients for a number of months. So that creates the lumpiness. And while we don't necessarily provide a specific, you know, the size of the orders and the revenue of the orders within that quarter, you can easily go back four or five years and start to look at where we've had some lumpy quarters particularly when we started adding new patients in Brazil and getting multiple orders or at least one or two orders a year for a large group of patients. The dynamic in this quarter was that Russia was a key driver of that growth, and its centralized reimbursement in that order is what helped us have one of our best quarters ever. And as Steve mentioned, we anticipate, and we're working tirelessly right now, We have an agreement in Brazil, and we anticipate filling that order for a large group of patients as well in the fourth quarter. So it's very hard to predict. These governments tend to have erratic buying patterns, and they do sometimes pick the number of patients and the number of months, which is not always predictable. So it's kind of hard to say what would that be in sort of long quarter-to-quarter forecasts, but what I'd like to emphasize is that on an annualized basis, you see Translona growing consistently.
spk10: And we're seeing, like what Eric said before, so we opened up new areas in, like, Russia, but also Central and Eastern Europe, Middle East, North Africa. We just got, you know, in Latin America, Asia Pacific we're working on. So on top of maintaining all the patients who've been on it, we've had incredible compliance. And there's just continuous amount of data that we're adding too, like the stride data that Eric talked about, where kids are at five and a half years longer in terms of ambulation, better capabilities in terms of lung function. If the data is becoming, you know, it's just so strong that patients are on for a long time, we keep those, we maintain them, and then we're getting more and more patients as we get geographic expansion.
spk11: Got it. Thank you very much.
spk06: Thank you. Our next question comes from with Kellan and Company. Your line is open.
spk12: Hi there. Good afternoon. Thank you for taking my question. The first one, just on the AADC submissions in the U.S., can you just let us know sort of the cadence of interactions with the FDA, if there are any expected before the BLA submission? Have they signed off on the surgeries that have happened? And then second, just in the Friedreich Ataxia study, can you just remind us a little bit how you arrived at that, the 72 endpoint? I know at six months, we maybe saw a little bit of a high placebo response in the prior study. So to me, what were the changes that were made in this pivotal to potentially limit that placebo response? Thanks.
spk10: Yeah, thanks for the question. Matt, you want to take some of this? Yeah, sure.
spk14: So first to the question about the BLA, as we talked about, we were going to complete the surgeries, collect those data, and then meet with the agency to align on the package, ensure everything's in place to make the submission. We have not had that interaction yet. We expect that we'll have the interaction and be able to submit the BLA in the first quarter of 2022. In terms of the MOVE-FA study, As you alluded to, we have based a lot of this study on our previous phase two trial of the tiquinone and phytocataxia, which had the six-week placebo control phase, followed by the long-term treatment duration where patients were treated out to 24 months. Importantly, we recorded a placebo effect in that six months, which prevented us achieving statistical significance. And by the way, that's common. If you look across, for example, even the IATAS trial, had that trial been stopped at six months, they would not have hit their primary endpoint, again, because of a known placebo effect on that FARS outcome measure. But also importantly, when we looked at the patients in our Phase II study, we found that over a two-year period, we were able to demonstrate an overall improvement in disease that is a reversal in disease progression. And that really reinforced the important concept that, one, we're able to achieve a therapeutic benefit, and two, that over longer treatments of time, you can actually see a meaningful impact. And so, When we put that together along with the concern of a placebo effect, we believe that the 72-week study put us in a very strong position to not only have limited and perhaps no placebo effect that would impact our results, but importantly be able to reinforce the long-term potential benefit of the 2.0 therapy in Friedreich ataxia with regards to not only disease progression as measured by the MFAR scale, but other of the key secondary endpoints that were collected in this study.
spk10: Yeah. I think we're learning a lot in terms of neuromuscular diseases where you're not necessarily seeing kids improve, but you're stabilizing that you're going to need more time within the trial to be able to get better clinical results.
spk12: Yeah, I think that makes a lot of sense. And then just last quick one, now that the gene therapy facility is up and going, and we were on phrygic ataxia. Are there any updates to the phrygic ataxia gene therapy program when we can maybe see that one enter the clinic?
spk10: Yeah, there's that one was, you know, obviously hit by COVID as well in terms of getting the animals completed. The long term toxicology studies is ongoing and we, as we said, we were still on track and expect to dose the first patient in the first half of 2022. So that's where we're at right now. Obviously, the key here will be demonstrate safety of the gene therapy product and then the stereotactic surgical procedure that we'll be using within the pivotal trial. So that's the goals of those experiments, and it's ongoing. It's just we're looking forward to get this going as rapidly as possible. Perfect. Thank you, and congrats on the progress.
spk12: Thanks a lot.
spk06: Thank you. Our next question comes from Karnascus with Truist Securities. Your line is open.
spk15: Hey, guys. This is Kripa on for Robin. Thank you so much for squeezing me in, and congrats on the progress this quarter. I had a question about the Huntington's program. So in deciding, you know, what you call the Goldilocks population for your study, you said that you've looked at natural history databases. Firstly, how comfortable are you that, or what sort of feedback did you get from the FDA if you've already talked to them about it, that a natural history study that you do yourself does not need to be a part of the package? And when we see data from the controlled part of the trial, the 12-week part, what can we expect in terms of readouts? Will it be safety and the Huntington RNA and protein levels, or do you think that is enough time to see a separation in some of the other biomarkers, for example, like NFL? Thank you.
spk10: Yeah, thanks for the question. In terms of the, you know, for the study in natural history, obviously the HD community has a lot of natural history that helps us define the where there's over, you know, in one database, there's over 20,000 patients that one could look at, and it will help us define that. Obviously, within the trial that we're doing, we're doing a placebo control to compare within the first 12 weeks, and then it goes over, so we'll have that much information. So the natural history, what we're using is, and what is critical is really to help us inform the criteria of which patients you can actually see a change in response, right? Because what you need to, you know, and the GobiLox, you know, as Matt has talked about for some time now, is like it's very much true in many of these types of diseases where there's an area, there's a time where if they don't change, you won't see a change, and that's not useful. And then there's a, you know, what normally happens is a If they're so far down the line, it's very hard to see any changes that are too far gone. Very similar to how we've seen this in DMD, so we're trying to make sure we pick the right population where there's a decline, but the decline isn't so, is that you can actually, if you change the course of that, that you would see the, you would be able to measure that difference. The Gobi-like population really helps to ensure that we're enrolling those subjects that are not too early in the disease progression, but have a higher risk of declining over the course of the trial. And therefore, treatment versus that gives you the possibility to see that. And so we're hopeful that as we measure that, obviously we'll measure the biomarkers and we'll see the reduction in CT RNA and protein. That will be important. But we would also then anticipate seeing changes in the CSF, as well as neurophysiologic light changes. We'll look in both the CSF and plasma. And then, of course, monitor the preservation of brain volume as assessed by MRI imaging. So we think that package will be quite interesting. And so the short-term 12 weeks will allow us to get that, and the longer-term of safety and pharmacology and pharmacodynamic measurements of all the others that will go on for a year, we think we'll be able to see something there in terms of the biomarkers.
spk15: Great. Thank you. That was very helpful. And then I had a quick follow-up question on the PKU program. You know, Bymerin has said that a lot of the PKU clinics are still not operating at full capacity. Do you see any, you know, any challenges in terms of being able to find enough patients for the trial, for your pivotal trial? Or are you seeing that it's easy to enroll?
spk10: So we just initiated the trial. So it's hard to give you any hard numbers of what we're looking at. But we think, and this we're doing is, you know, the good news, obviously, we have a global infrastructure program. So we'll be able to get only sites not only in the U.S., but globally as well. And, you know, we have a lot of investigators. And so, you know, obviously I think that's one of the things to make sure is that if you have an expanded number of investigators that will help pull through so that you can get those patients. And that's why we're doing that. So we still expect the results by the end of 2022. Okay.
spk15: Great. Thank you so much.
spk10: Thank you.
spk06: Thank you. And I'm sure enough questions at this time. I like trying to call back over to Stuart Pelts for closing remarks.
spk10: Well, great. So, you know, thanks for joining us today. And I think as you can see, we're continuing to build PTC into a revenue generating company. And I'm proud that the PTC has made what we've done this quarter. I think you can see we've delivered substantial continued year-over-year revenue growth and once again raising our DMD franchise 2021 revenue guidelines. The revenue growth in addition to the continued advancement of our pipeline with the initiation of our fifth registration-directed trial in BKU. This progress really allows us to continue the mission that we have in delivering life-changing therapies to patients around the globe. So thanks for taking the time to listen, and thanks for your questions.
spk06: This concludes today's conference call. Thank you for participating. You may now connect.
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