Q3 2022 PTC Therapeutics Inc Earnings Call

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Yeah.

Hello, Thank you for standing by and welcome to the PTC third quarter 2022 financial results Conference call. At this time all participants are in a listen only mode. After the speaker presentation, there will be a question and answer session.

I ask a question during the session you will need to press star one one on your telephone. Please be advised that today's conference maybe recorded I would now like to hand, the conference over to your speaker today Karli O'keefe.

Please go ahead.

Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics third quarter 2022, corporate update and financial results.

I am joined today by our Chief Executive Officer Stuart Peltz, our Chief Operating Officer Matthew Klein, our Chief Business Officer Eric Pauwels, and our Chief Financial Officer Emily Hill.

I'm joined today by our Chief Executive Officer, Stuart Peltz our.

Our Chief operating Officer, Matthew Cline.

Our Chief business Officer, Eric Powell.

<unk> Financial Officer Emily Hill.

Today's call will include forward-looking statements based on our current expectations.

Today's call will include forward looking statements based on our 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.

Please take a moment to review the slides 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 risks that can materially and adversely affect our business and results of operation.

Our actual results could materially differ from these forward looking statements as such statements.

Shipments are subject to risks that can be 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 annual report on Form 10-K and quarterly report on Form 10-Q filed with the Securities and Exchange Commission, as well as the company's other SEC filings.

For a detailed description of applicable risks and uncertainties. We encourage you to review the company's most recent annual report on Form 10-K, and quarterly report on Form 10-Q 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.

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.

Let me pass the call over to our CEO Stuart Peltz.

Okay.

With that, let me pass the call over to our CEO, Stuart Peltz.

Thanks Kiley.

Afternoon, everyone and thank you for joining the call.

I'm pleased this year PTC strong third quarter results.

We continue to demonstrate strong execution and are moving forward on our 2022 miles.

Our marketed products.

To generate strong revenue growth and we are advancing a broad and deep pipeline of new therapy to treat diseases with significant.

Medical me.

Stuart?

Our mission at PTC is to discover develop and commercialize innovative therapies and to bring them to patients with rare disorders and in doing so to create significant value for all of our stakeholders.

Today, <unk> has five marketed products and.

Seven development program focused on treating diseases of high unmet.

On that medical need.

We continue to build a robust pipeline.

Potential new therapy.

Steady state, we expect to deliver one therapy every two to three years.

Moving to our performance in the quarter.

G $270 million.

In total revenue, representing a 57% increase over the third quarter of 2021.

Thanks, Kylie.

<unk> revenue was $131 million in the quarter.

An increase of 15% year over year based on continued strong performance across all of our commercial portfolio. We are increasing our 2022 DMD guy.

This allows us to raise the low end of the total revenue guidance and Eric will go into this in more detail shortly.

Good afternoon, everyone, and thank you for joining the call.

I would now like to provide a regulatory update on chegg lineup.

The robust results from our study for <unk>, one as well as the continued evidence of long term treatment benefit from our real world data from the stride registry.

This compares well to convert the European conditional marketing authorization.

Standard market.

I'm pleased to share PTC's strong third quarter results. We continue to demonstrate strong execution and are moving forward on our 2022 milestone.

Getting authorization for.

The regulatory path in the EU as plan, we have submitted a type two variation to convert your authorization to the European Medical agency in September .

Our mission at PTC is to discover, develop, and commercialize innovative therapies and to bring them to patients with rare disorders, and in doing so, to create significant value for all of our stakeholders.

Type two variation procedure typically last for several months.

As such we expect to see HMP opinion in the first half of 2023.

Turning to the U S. We submitted a meeting request to the FDA to gain clarity on the path of filing an NDA.

The FDA has provided initial written feedback that study <unk> one does not provide.

Evidence of effectiveness, we are planning follow up discussion with the agency to understand whether the evidence in the ITT population in study <unk> hundred one along with confirmatory evidence from other studies could support approval.

Clear example of this approach of using trial results along with confirmatory evidence to support NDA filing Hasnt seen recently for rare neurological diseases with amalek and Riyadh.

DMD revenue was $131 million in the quarter, an increase of 15% year over year. Based on continued strong performance across all our commercial portfolio, we are increasing our 2022 DMD guidance. This allows us to raise the low end of the total revenue guidance, and Eric will go into this in more detail shortly.

Let me now turn to discuss the first marketed product from our splicing platform.

He has established market leadership in all major markets and is on track to become the global market leader.

All right.

Growth is being driven by patient switches.

New patient starts.

Label and geographic expansion.

In addition.

<unk> has a 90% retention rate in the first 12 months demonstrating treatment satisfaction.

Late last year ROE submitted a type two variation to the European Medicine agency for use in pre symptomatic infants with SMA under two months of age.

I'd now like to provide a regulatory update on TransLarna. The robust results from our study for 041, as well as the continued evidence of long-term treatment benefit from our real-world data from the STRIDE registry, positions us well to convert the European conditional marketing authorization to a standard marketing authorization. For the regulatory path in the EU, as planned, we have submitted a type 2 variation to convert, the authorization to the European Medical Agency in September.

Our label expansion already approved by the FDA earlier this year.

The type 2 variation procedure typically lasts for several months, and as such, we expect, a CHMP opinion in the first half of 2023.

Finally, based on the interim efficacy and safety data from Rainbow fish Darby and newborn.

Returning to the U.S., we submitted a meeting request to the FDA to gain clarity on the, path of filing an NDA.

While the FDA has provided initial written feedback that Study 041 does not provide substantial, evidence of effectiveness, we are planning follow-up discussions with the agency to understand whether the evidence in the ITC population in Study 041, along with confirmatory evidence from other studies, could support approval.

Clear examples of this approach of using trial results, along with confirmatory evidence, to support NDA filing, has been seen recently for rare neurological diseases with Amilek and Riada.

Note that the majority of pre symptomatic infants treated with <unk> achieved key milestones such as sitting and standing with back of the patient walking after 12 months of treatment with <unk>.

<unk> expansion in Europe is expected to be approved before the end of 2022.

Let me now turn to discuss the first marketed product from our splicing platform.

Let me now move to our Huntington's disease program with our next flagship compound PTC five.

ARISD has established market leadership in all major markets and is on track to become, the global market leader for SMA. Rapid growth has been driven by patient switches, naive patient starts, and label and geographic, expansion. In addition, ARISD has a 90% retention rate in the first 12 months, demonstrating treatment, satisfaction.

Late last year, Roche submitted a type 2 variation to the European Medicine Agency for use in, pre-symptomatic infants with SMA under 2 months of age, a label expansion already approved by the FDA earlier this year. The EU filing is based on the interim efficacy and safety data from Rainbow Fish study in, newborns, which showed that the majority of pre-symptomatic infants treated with ARISD achieved key milestones, such as sitting and standing with half of the patients walking after 12 months of treatment. The label expansion in Europe is expected to be approved before the end of 2022.

Let me now move to our Huntington's disease program with our next splicing compound, PCC518.

As we said before the global pivot HD study is currently enrolling in many European countries and Australia.

As we said before, the global PIVOT-HD study is active and currently enrolling in many, European countries and Australia.

We expect to share results from the 12-week portion of the study in the first half of, 2023.

To share results from the 12 week portion of the study in the first half of 2023, Matt will go into more pivot HD trials specifics shortly.

Matt will go into more PIVOT-HD trial specifics shortly.

Our robust pipeline of drug candidates continues to advance in clinical development towards, commercialization.

Our robust pipeline of drug candidates.

Continues to advance through clinical development towards commercialization.

We remain on target to achieve three important data results over the next nine months.

We remain on target to achieve three important data results over the next nine months.

First, Tepatarian, previously 9.2.3, in PKU in the fourth quarter, for vatiquinone for, mitochondrial disease-associated seizures in the first quarter of 2023, and for vatiquinone in Friedreich ataxia in the second quarter of 2020.

There are separate Terry previously 92, three in PKU in the fourth quarter for particular known for mitochondrion.

Associated seizures in the first quarter of 2023.

We're known and Friedrich <unk> ataxia in the second quarter of 2023.

We are also excited to announce that we have entered into a strategic financing collaboration, with Blackstone Life Sciences. This collaboration will support our mission to build enough programs in our pipeline at, steady state so that we can deliver at least one new therapy every two to three years, and so that we can continue to bring transformative medicines to patients globally and create value for all our stakeholders. As part of the partnership, Blackstone provided an initial $350 million of low-cost, low-dilution, capital with an option for additional $650 million in funding.

We are also excited to announce that we have entered into a strategic financing collaboration with Blackstone life Sciences.

This collaboration will support our mission to build enough programs in our pipeline at steady state. So that we can deliver at least one new therapy every two to three years and so that we can continue to bring transformative medicines to patients globally.

<unk> value for all our stakeholders.

As part of the partnership.

<unk> provided an initial $350 million of.

Our low cost low delusive capital with an option for additional $650 million in funding.

Emily will describe the details of the financing.

Emily will describe the details of a five year three.

With sustained growth in our marketed products and many new products advancing in our pipeline, we continue to build our commercial platform for strong growth for many years to come.

With sustained growth in our marketed products and many new products advancing in our pipeline. We continue to build our commercial platform with strong growth for many years to come.

I'll now hand over to Matt for an update on our development program.

I will now hand over to Matt for an update on our development programs Matt.

Matt?

Thanks, Stu.

Okay.

Over the course of the third quarter, we continue to make progress across all of our platforms, and expect results from several of our ongoing registration-directed trials in the next six to nine months.

Over the course of the third quarter, we continued to make progress across all of our platforms and our spectrum results from several of our ongoing registration directed trial.

Six to nine months.

I'll start with an update on our VLA submission first data.

I'll start with an update on our BLA submission prep state. Please.

We had a type C meeting with the FDA in October to discuss the details of the submission, package. Based on the discussion, FDA has asked for additional bioanalytical data in support of, comparability between drug products used in the clinical studies and commercial drug products.

We had a type C meeting with the FDA in October to discuss the details of the submission package.

Just on the discussion FDA has asked for additional bioanalytical data quite a comparability between drug product used in the clinical studies and commercial drug product we have.

We are currently working with FDA to address this request, and we now expect the VLA submission, will occur in the first half of 2023.

Currently working with FDA to address this request and we now expect the BLA submission will occur in the first half of 2023.

Turning to our ongoing registration-directed Affinity Phase III trial of Cepiastrin, previously known as PCC 923, in patients with PKU, we remain on target to share results by the end of the fourth quarter. The Affinity trial is a six-week placebo-controlled study with a primary endpoint of reduction, in blood phenylalanine levels. To enrich the randomized study population for likely responders, the study includes, a run-in phase during which potential subjects are treated with Cepiastrin for two weeks, and only those demonstrating responses to Cepiastrin are randomized.

Turning to our ongoing registration directed phase III trial of <unk> biggest thing other PTC nicely.

Patients with PKU, we remain on target to share results by the end of the fourth quarter.

The trial is a six week placebo controlled study with a primary endpoint of reduction in blood phenylalanine levels.

To enrich the randomized study population for likely responders. The study includes a run in phase during which potential subjects are treated with <unk> for two weeks and only those demonstrating response to set the actual are randomized.

Following completion of the six-week placebo-controlled study, all subjects will be eligible, to enroll in a long-term extension study.

Following completion of the six week placebo controlled study all subjects will be eligible to enroll in a long term extension study.

Turning to the BioE platform, we have three ongoing registration-directed trials, two, with Vitipinone, the MITEI study for mitochondrial disease-associated seizures, and the MUVEF-A study for Pregipitaxia, and one trial with Utiloxistat, previously known as PTC 857, for ALS. Both the MITEI and MUVEF-A trials are now fully enrolled, and we continue to expect, results from the MITEI trial in the first quarter of 2023 and from the MUVEF-A trial in the second quarter of 2023.

Turning to the bio E platform, we have three ongoing registration directed trials.

The <unk> study for mitochondrial disease associated seizures, and then move that base study.

Got it.

And one trial with future lots of debt previously known as <unk> seven for ALS.

Both the 90 and real estate trials are now fully enrolled and we continue to expect results from the <unk> trial in the first quarter of 2023, and some to move ethane trial in the second quarter of 2023.

Enrollment is ongoing in the Cardinal's global placebo-controlled trial of Utiloxistat, in ALS patients. The Cardinal's trial is a six-month placebo-controlled study, with a target enrollment of approximately 258 subjects. Subjects will be randomized two-to-one to receive eutroloquistat or placebo. The primary endpoint of the study is change in the ALS-FRS disease rating scale from baseline, to six months, with secondary endpoints capturing other aspects of disease morbidity as well as mortality.

Enrollment is ongoing in the Cardinal global placebo controlled trial of each along with that patient the.

The Cardinal trial is a six month placebo controlled.

With a target enrollment of approximately 258 subjects.

Subjects will be randomized two to one to receive your philosophy or placebo.

Primary endpoint of the study has changed any AOS FRS disease rating scale from baseline at six months with secondary endpoints, capturing other aspects of disease morbidity as well as mortality.

Turning to our slicing platform, as we recently shared, we are actively enrolling the PTC, 518 PIVOT-HD Phase 2 trial at our European and Australian study sites.

Turning to our splicing platform. We recently shared we are actively enrolling the PTC <unk> pivot HP phase II trial at our European and Australian study.

Enrollment in the U.S. is paused as the FDA has asked for additional data to support the, proposed PIVOT-HD dose levels and duration.

Enrollment in the U S with Pas, but the FDA has asked for additional data to support the proposed pivot HD dose level and duration.

As a reminder, PIVOT-HD is a 12-month placebo-controlled trial of PTC 518 in Huntington's disease patients, and initially includes two dose levels, 5 milligrams and 10 milligrams, with the potential to study a third dose, which will be based on the findings from the 5 milligram and 10 milligram dosing groups. You will recall that in Phase 1, we observed a ratio of plasma to CSF exposure of approximately, 1 to 2.7, a relationship that could potentially allow us to treat patients at a lower dose and still achieve the desired 30 to 50 percent HTT protein lowering in the brain.

As a reminder, given HD is a 12 month placebo controlled trial in our PTC 508, and Huntington's disease patients.

And initially includes two dose level five milligrams in Canada with <unk>.

Potential for study at third dose, which we based on the findings from the five milligram and 10 milligram dosing.

You will recall that in phase one we observed a ratio of plasma.

Closure of approximately one to two points.

A relationship that could potentially allow us to treat patients at a lower dose.

And still achieve the desired 30% to 50% http protein lowering in the brain.

We have been asked why we have selected 5 milligrams and 10 milligrams as the starting, dose levels for the PIVOT-HD trial, since we studied higher doses in the Phase 1 Healthy, Volunteer study. The PIVOT-HD dose selection was based on both the percent lowering of blood HTT levels and, the ratio of plasma to CSF exposure observed in Phase 1.

We've been asked why do we have selected five milligrams and 10 milligrams as the starting dose levels for the pivotal trial.

A higher doses into phase one healthy volunteer study.

The pivotal dose selection was based on both the percent lowering of blood hcg level and the ratio of plasma the CSF exposure observed in phase one.

In the Phase 1 MAD study, we observed approximately 40 percent reduction in blood HTT levels at, the 15 milligram dose and approximately 60 percent reduction in blood HTT levels at the, 30 milligram dose. Given the observed ratio of 1 to 2.7 of plasma exposure to CSF exposure, we would expect, to have an even higher level of CNS HTT protein lowering at the 15 milligram and 30 milligram dose levels.

And the phase one.

We observed approximately 40% reduction in blood http level at the 15 milligram dose and approximately 60% reduction in blood <unk> levels at the 30 milligram dose.

Given the reserve ratio of one to two points that our plasma exposure to CSS exposure, we would expect to have an even higher level of CNS HGT protein lowering at the 15 milligram 30 milligram dose.

Accordingly, given our stated target HTT protein lowering of 30 to 50 percent in the brain, of HTT patients, we have selected 5 milligrams and 10 milligrams as starting dose levels. If the plasma to CSF ratio in HTT patients observed in PIVOT-HD is consistent with what, was demonstrated in Healthy Volunteers in Phase 1, dosing at 5 milligrams and 10 milligrams may very well achieve the desired 30 to 50 percent HTT protein lowering in the brain.

Accordingly, given our stated target HGT protein lowering of 30% to 50% in the brain of HD patients we have selected.

Less than five milligrams and 10 milligrams is starting dose level.

If the plasma at the CSF ratio in HD patients observed activity HD is consistent with what was demonstrated in healthy volunteers in phase one.

Dosing at five milligrams and 10 milligrams may very well achieved the desired 30% to 50% HGT protein lowering in the brain.

Of course, if the ratio of plasma to CSF exposure in HTT patients is closer to 1 to 1, we have, the ability to study higher dose levels in the PIVOT-HD study. We can also confirm that the protocol approved in Europe and Australia for the 12-month PIVOT-HD, study includes the ability to potentially study a 20 milligram dose level if needed.

Of course that the ratio of plasma and CSF exposure in HD patients is closer to 1% to one we have the ability to study higher dose levels in the pivot HD study.

We can also confirm that the protocol approved in Europe , and Australia for the 12 months pivot HD study, including the ability to potentially study a 20 milligram dose level if needed.

In terms of study design, the PIVOT-HD study includes two parts. An initial 12-week placebo-controlled phase focused on PTC518 pharmacology and pharmacodynamic, effect, as well as CSF exposure, followed by a nine-month placebo-controlled phase focused on biomarkers, including CSF HTT protein levels, brain volume changes on MRI, and plasma and, CSF neurofilament light changes.

In terms of study design activity HD study includes two parts.

Initial 12 week placebo controlled phase focused on PTC, five pharmacology and pharmacodynamics as.

As well as CSF exposure.

Led by a nine month placebo controlled phase focused on biomarkers, including CSF HGT protein levels brain volume changes on MRI and plaza in CSF <unk> element light chain levels.

We look forward to sharing results from the 12-week portion of PIVOT-HD and H1 of 2023.

We look forward to sharing the results from the 12 week portion of pivot HD and each one of 2020.

Overall, we are very excited about our continued progress across our development program and look forward to sharing results from several of our studies in the near future.

Overall, we are very excited about our continued progress across our development program.

I look forward to sharing results from several of our studies in the near future.

I will now hand the call over to Eric to provide an update on our commercial portfolio.

I will now hand, the call over to Eric to provide an update on our commercial portfolio Eric.

Eric?

Thanks, Matt.

Thanks, Matt It is exciting to see the progress from our pipeline.

It is exciting to see the progress from our pipeline, and the commercial team is eager to bring our innovative treatments to patients to address a high number of unmet medical needs worldwide.

And the commercial team is eager to bring our innovative treatments for patients to address a high number.

Our global customer-facing team has delivered yet another outstanding quarter. DMD revenue was $131 million in the quarter, an increase of 15% year-over-year. Our DMD franchise continues to be a key revenue driver and remains robust and geographically diversified. As a result of consistent strong quarterly revenue, we are raising our 2022 DMD revenue guidance to $490 to $500 million.

<unk> needs worldwide.

Our global customer facing team has delivered yet another outstanding quarter DMD revenue was $131 million in the quarter, an increase of 15% year over year.

Our DMD franchise continues to be a key revenue driver and remains robust and geographically diversified.

As a result of consistent strong quarterly revenue, we are raising our 2022 DMD revenue guidance to $490 million to $500 million.

Starting with Emplaza, net product revenue for the second quarter was $55 million, which represented 16% growth over the third quarter last year. Continued strong execution by our Emplaza team drove new patient starts supported by continued favorable access, high compliance, and appropriate weight-based dosing for DMD patients in the U.S., which drove the growth.

Starting with the Plaza.

Net product revenue for the second quarter was $55 million, which represented 16% growth over the third quarter last year.

Continued strong execution by our employee team drove new patient starts supported by continued favorable access high compliance and appropriate weight based dosing for DMD patients in the U S, which drove the growth.

TransLarna delivered $77 million in net product revenue for the third quarter, which represents a 14% increase over the third quarter of 2021. This was driven by growth in all regions.

<unk> delivered $77 million and net product revenue for the third quarter, which represents a 14% increase over the third quarter of 2021.

This was driven by growth in all regions.

Overall, TransLarna revenue continues to be globally diversified, and we continue to make good progress with our expansion into newer markets in Eastern Europe, the Middle East, and Latin America, as well as additional markets in Asia Pacific, which is of strategic importance for future growth.

Overall trend, Florida revenue continues to be globally diversified.

And we continue to make good progress with our expansion into newer markets in eastern Europe , The Middle East and Latin America, as well as additional markets in Asia Pacific, which is of strategic importance for future growth.

Moving to AbstaZa and our ongoing launch activities. Following the approval in Europe for the treatment of AADC deficiency, AbstaZa was launched at the recent 2022 SSIEM meeting in Germany.

Moving to upstate there.

Our ongoing launch activities.

Following the approval in Europe for the treatment of ADC deficiency.

Upstate, though was launched at the recent 2022.

E L F.

Meeting in Germany.

Our team is actively executing on all strategic initiatives of the launch.

Our team is actively executing on all strategic initiatives with the launch.

We are pleased to have already treated our first commercial patient this year under the French Early Access Program, and we anticipate treating additional commercial patients in Germany, France, and Italy in Q4. Treatment center readiness is on track, as well as further preparation for surgical treatment carried out at key European centers.

We are pleased to have already treated our first commercial patient this year under the French early access program and we anticipate treating additional commercial patient.

In Germany, France, and Italy in Q4.

Treatment Center readiness is on track as well as further preparation for surgical treatment carried out at key European centers.

Patient identification is continuing to accelerate, and we are also strongly focused on markets that have early access programs and others via cross-border healthcare.

Patient.

Ratification is continuing to accelerate.

And we are also strongly focused on markets that have early access programs and others via cross border healthcare.

Based on the clinical results and the feedback from the KOLs treating patients to date, we, are confident that the durable efficacy and safety data we obtained from up to 10 years of follow-up with Abstaza will support HTA-DoCEA submissions for reimbursement as the first and only treatment approved for AADC deficiency patients 18 months and older.

Based on the clinical results and the feedback from the Kols treating patients to date.

We are confident that the durable efficacy and safety data, we obtain from up to 10 years of follow up with a state that will support HCA dossier submissions for reimbursement as the first and only treatment approved for ADC deficiency patients 18 months.

And older.

We have guided to $20 to $40 million in revenue from Abstaza and continue to work towards, this in the fourth quarter in France, Germany, and Italy.

We have guided to $20 million to $40 million in revenue from a state that we continue to work towards this in the fourth quarter in France, Germany and Italy.

Shifting gears in Latin America, our team continues to progress with Tegceti and Guadalibre.

Shifting gears in Latin America.

Our team continues to progress with take steady and why Libre.

In Brazil, following the innovative classification for Tegceti, we delivered the first group, purchase order from the Ministry of Health earlier this year.

In Brazil.

Following the innovative classification protect study we delivered the first purchase order from the Ministry of Health earlier this year.

Furthermore, patient identification continues to be strong, particularly in remote areas, where Tegceti's self-administration is a significant advantage over the competition.

Furthermore, patient identification continues to be strong, particularly in remote areas, where tech steady self administration as a significant advantage over the competition.

We anticipate to receive an additional group purchase order in the fourth quarter.

We anticipate to receive an additional group purchase order in the fourth quarter.

Finally, discussions continue to progress with CONITECH, the National Commission for, the Incorporation of Technologies, for inclusion of Tegceti in the essential drug list, which will simplify the access to HATTR amyloidosis patients.

Finally discussions continue to progress with contact the National Commission for the incorporation of technology for inclusion of <unk> in the essential drug list, which will simplify the access to <unk> amyloidosis patients.

For Guadalibre, we continue to grow our patient base across Latin America for the treatment, of STF. Patient identification continues to progress, and we are pleased to have received the first, group purchase order from the Ministry of Health in Brazil, which we anticipate to deliver in the fourth quarter. This is an important milestone for our STF patients awaiting treatment.

Before we Libre, we continue to grow our patient base across Latin America for the treatment of Fcs.

Patient identification continues to progress and we are pleased to have received the first purchase order from the Ministry of health in Brazil, which.

Which we anticipate to deliver in the fourth quarter.

This is an important milestone for our FCS patients awaiting treatment.

As a reminder, last December, we submitted an application to INVISA in Brazil for approval, of Guadalibre for the treatment of FTL. If approved, Guadalibre will be the first approved treatment for FTL in Brazil, and, this will mark the first approval globally for this indication. We anticipate a decision later this year.

As a reminder, last December we submitted an application to <unk> in Brazil for approval, we lever for the treatment of FPL.

If approved way Libra will be the first approved treatment for <unk> in Brazil.

And this will mark the first approval globally for this indication.

We anticipate a decision later this year.

In conclusion, this is a very exciting time for PTC, and in particular for our global, customer-facing team.

In conclusion. This is a very exciting time for PTC and in particular for our global customer facing team.

We are laser-focused on delivering a strong finish to 2022 and setting the foundations, for an even more successful 2023.

We are laser focused on delivering a strong finish to 2022 and setting the foundation for an even more successful 2023.

Now let me turn the call over to Emily for a financial update.

Now, let me turn the call over to Emily for a financial update annually.

Emily?

Emily.

Thanks, Eric.

Before turning to third quarter financial highlights, I would like to describe the strategic, financing of up to $1 billion that we have just closed with Blackstone Life Sciences.

Thanks, Zack before turning to third quarter financial highlights I would like to describe the strategic financing of up to $1 billion that we have just closed with Blackstone life Sciences.

This transaction allows PTC to accelerate our revenue and innovative pipeline. This partnership also puts PTC in a strong position to pursue future BD opportunities, and moreover to execute without near-term dependence on market dynamics.

This transaction allows PTC to accelerate our revenue and innovative pipeline.

This partnership also puts PTC in a strong position to pursue future BD opportunity.

And Moreover to execute without near term dependence on market dynamics.

The financing consists of $350 million up front. This includes $300 million in Senior Secured Debt at $7.25 plus SOFR with a 7-year bullet term and an additional $50 million of equity. Additionally, the term loan includes another $150 million in Delayed Draw Debt that can be accessed in the first 18 months after close.

The financing consists of $350 million upfront. This includes $300 million in senior secured debt at seven point.

Two five plus so far with a seven year bullet time.

And then the additional $50 million of equity. Additionally.

Term loan includes another $150 million delayed draw debt that can be accessed in the first 18 months after close.

Lastly, the total financing includes a potential $500 million credit line for mutually agreed-upon business development opportunities.

Importantly, the term loan investment by Blackstone will be secured by a limited assets collateral bucket, including and limited to TransVarna, M-Plaza, Absteza, Sepia Pteran, and Vatiquinone.

Lastly, the total financing includes a potential 500 million dollar credit line for mutually agreed upon business development opportunity.

Importantly, the term loan investment by Blackstone will be secured by a limited assets collateral bucket.

<unk> and limited to Translarna and Plaza.

Data set the upturn in particular now.

We look forward to continuing to deliver on our mission of developing and commercializing breakthrough therapies globally.

We look forward to continuing to deliver on our mission of developing and commercializing breakthrough therapies globally.

I'll now take a few minutes to review our third quarter financial results. Please refer to the earnings press release issued this afternoon for additional details. This was driven primarily by net product revenue from the DMV franchise of $131 million, a RISD royalty revenue of $33 million, and an RISD milestone of $50 million from Roche for surpassing annual sales of $750 million.

I'll now take a few minutes to review our third quarter financial results.

Please refer to the earnings press release issued this afternoon for additional detail.

Beginning with top line results total revenues for 217 million for the third quarter of 2022 50.

57% increase over the third quarter of 2021.

This was driven primarily by net product revenue from the DMD franchise and $131 million.

<unk> revenue was $33 million and that brings the milestone of $50 million from Roche Christa passing annual sales of $750 million.

Our total revenue from the first three quarters of 2022 was $531 million, and consequently, we have narrowed our revenue guidance range to $710 to $750 million from $700 to $750 million. This includes DMV revenue of $490 to $500 million, raised from our previous revenue guidance of $475 to $495, and also includes $20 to $40 million in revenue from Absteza, our recently launched gene therapy.

Our total revenue from the first three quarters of 2022 with $531 million.

Consequently, we have narrowed our revenue guidance range to seven $750 million.

$100 million to $750 million.

This includes AMD revenue of $490 million to $500 million raised from our previous revenue guidance of 475 to 295 and also includes $20 million to $40 million in revenue from.

Our recently launched gene therapy.

Turning now to our DMV franchise, TransVarna net product revenues were $77 million, representing year-over-year revenue growth of 14% compared to the third quarter of 2021. This growth was despite FX headwinds and would otherwise have been approximately 30% growth year-over-year. TransVarna had net product revenues of $55 million, or 16% growth year-over-year.

Turning now to our DMD franchise, Ken on net product revenues were $77 million representing.

Representing year over year revenue growth of 14% compared to the third quarter of 2021.

This growth was despite FX headwinds and what otherwise have been approximately 30% growth year over year.

Plaza had net product revenues of $55 million or 16% growth year over year.

Non-GAAP R&D expenses were $150 million for the third quarter of 2022, excluding $15 million in non-cash stock-based compensation expense, compared to $118 million for the third quarter of 2021, excluding $13 million in non-cash stock-based compensation expense.

non-GAAP R&D expenses were $150 million for the third quarter of 2022, excluding $15 million in noncash stock based compensation expense.

<unk> to $118 million for the third quarter of 2021.

Excluding $13 million in noncash stock based compensation expense.

The year-over-year increase in R&D expenses reflects additional investment in research programs and the advancement of the clinical pipeline. Non-GAAP SG&A expenses were $67 million for the third quarter of 2022, excluding $14 million in non-cash stock-based compensation expense, compared to $56 million for the third quarter of 2021, excluding $13 million in non-cash stock-based compensation expense.

The year over year increase in R&D expenses reflects additional investment in research programs and the advancement of our clinical pipeline.

non-GAAP SG&A expenses were $67 million for the third quarter of 2022, excluding $14 million in noncash stock based compensation expense.

Compared with 56 million for the third quarter of 2021, excluding.

Excluding $13 million in noncash stock based compensation expense.

Cash, cash equivalents, and marketable securities totaled approximately $288 million as of September, 30, 2022, compared to $773 million as of December 31, 2021. We're happy to report our recent financing increases that cash balance to approximately, $635 million on a pro forma basis.

Cash cash equivalents and marketable securities totaled approximately 288 million as of September 32022.

<unk> to $773 million as of December 31, 2021.

We're happy to report our recent financing increases that cash balance to approximately $635 million on a pro forma basis.

I'll now turn the call over to the operator for questions.

I'll now turn the call over to the operator for questions.

Operator.

Operator.

Thank you.

Thank you as a reminder to ask a question you will need to press star one one on your telephone. Please standby we compile the Q&A roster.

As a reminder, to ask a question, you will need to press star 1 1 on your telephone.

Please stand by while we compile the Q&A roster.

Our first question comes from Brian Abrahams with RBC Capital Markets.

Our first question comes from Brian Abrahams with RBC capital markets. You May proceed.

You may proceed.

Hi, this is Joe.

Hi, This is Joe on for Brian . Thank you for taking our question just could you provide us a little more detail about the initial feedback on Translarna and then what do you what do you plan to including the data package to.

I'm for Brian.

Thank you for taking our question.

Just could you provide us a little more detail about the initial feedback on TransLarna and, you know, what do you plan to include in the data package to address this issue?

Thank you.

To address this issue.

<unk>.

Yeah.

Yes.

Thanks for that question.

Thanks for.

To that question.

What we did was, as you know, we had submitted a meeting request to the FDA so we can clarity on the path to the NDA.

What we did was.

As you know we have.

To me there is a meeting request.

To the FDA, so we can get clarity on the path.

So this was a written one.

So this one.

And while the FDA provided us initially some written feedback that study 41 does not meet the substantial evidence of effectiveness. We're now planning to follow up on the discussion with the agency to understand whether the evidence in the ITT population in study 41, along with confirmatory evidence from other studies, could therefore then support approval.

A written one new well.

And the FDA providers.

Initially some written feedback.

Maybe 41 does not reach a substantial evidence of effectiveness.

We're now planning to follow up on the discussions with the agency to understand whether the evidence.

The ITT population in study 41, along with confirmatory algorithms.

Another study could therefore, then support approval.

So I think, as usually is the case with the agency, especially with initial written feedback, it can involve some conversations and some live conversations that we expect to have where we can have some back and forth.

Thank you.

It is the case with behavior.

Especially with industrial and feed.

It can involve some conversations some live conversations that we expect to have where we can.

Can have some back and forth.

You know, particularly given some of the long history of the program, you know, the really unmet medical need of the disease and the interest in the patient community.

Particularly given some of the long history of the program.

But really unmet unmet medical need of the continue button.

So in the patient community.

And the fact that really, most recently, there has been regulatory precedence with other companies in similar situations.

And well.

But really most recently.

<unk> regulatory testing.

The other company.

Similar situations.

And I think a clear example of that, which you've seen recently with NDA submissions, especially in the rare neurological diseases, you saw from companies like Amilex and Riata, where initially they weren't accepting the submissions and subsequently they then did after conversation.

A clear example of that what you've seen recently.

NDA submission, especially in the rare neurological diseases.

So from companies like <unk>.

Initially.

Accepting submissions.

Perfect.

After our conversation so we're looking to this.

So we're looking to, you know, this is the beginning, the first inning of the game here, in which we'll be going back and forth with them.

This is the beginning of the first name of the game here.

We'll be going back and forth with that.

Make sense?

Makes sense. Thank you.

Thank you.

Thank you one moment for questions.

Thank you.

Our next question comes from Kristen <unk> with Cantor Fitzgerald you May proceed.

One moment for questions.

Hi, good afternoon, Thanks for taking my question.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

How do you think that this deal with Blackstone and some of your upcoming potential commercial opportunities if so.

We'll hear with your late stage pipeline could help frame you towards reaching self sustainability and I know Emily mentioned potential BD opportunity exploration as well. So can you give a general framework about what you might be looking for and the future balance of in house innovation as well as outsourcing. Thank you.

You may proceed.

Sure.

I'll start and then pass it as I can.

Said, we and what our plan has been reviewed.

<unk> been building through the combination of both.

External business development as well as internal growth.

Sure.

Drug discovery.

What they bring.

Product to the marketplace every two to three years and that's what we're building to and we're going to do with the combination of both of those two.

Hi.

To be able to both.

Accelerate those processes.

The way we look at this from black to per month from the Blackstone gives us a great opportunity.

Let's say accelerated.

Molecules that we have in fabrication applications and then as well is to look over.

Which we already do for <unk>.

Assets that are later stage.

Assets or commercial get commercialized, but we'll hope.

Near term commercialization effort to be able to bring it and also to increase revenues.

Add to our later stage.

Pipeline so.

And do you have anything extra or do you want to add.

Yeah, I'll just reiterate that we're obviously very excited about this deal.

As you pointed out it does really provide incredibly attractive financing at favorable terms.

And allows us to create strategic flexibility to drive innovation.

The business added business development, we obviously want to look for further opportunities to leverage our existing commercial drug development infrastructure.

And we will.

Utilize some of this access to capital for those business development opportunities.

Good afternoon.

Thank you both and then for Steve is the agency now comfortable with the cannula and surgical procedural items and I guess, what gives you confidence that this is essentially the last item that you need to check off before submitting.

Thanks for taking my question.

Yes sure.

Matt do you want to take that one.

So how do you think that this deal with Blackstone and some of your upcoming potential commercial opportunities, if successful here with your late-stage pipeline, could help frame you towards reaching self-sustainability?

And I know Emily mentioned potential BD opportunity exploration as well.

Alright, Thanks, Kristen for the question so.

The client related issues appear to be addressed the issue in the past was that there was a desire for us to have experience using our specific drug product with the cannula for the delivery of the product into the brain of the children. There had been no prior experience with that and so there was a set of data.

That included both the bench top testing showing that.

The compatibility of the products with the device and then of course importantly, those surgical procedures, where we now have been able to provide them the data that the.

Drugs can be delivered safely.

Two that children with that device in terms of the ask regarding additional data in support of the comparability.

<unk>, we are well positioned to provide what they want which is just some additional samples from our clinical batch material to be included in the BLA. So we are fully confident that we can provide those data and be able to deliver the package colored with the submission as we said in the first half of 2023.

Yeah.

Thanks, everyone.

So can you give a general framework about what you might be looking for and the future balance of in-house innovation as well as outsourcing?

Okay. Thank you. Thank you one moment for questions.

Our next question comes from Eric Joseph with Jpmorgan You May proceed.

Thank you.

Hi, good evening, thanks for taking my questions.

Sure.

Just a follow up on.

PTC 518 I'm curious.

So whether our readout if the data suggests moving to a higher dose how confident are you that you have.

You know, as I think we, I'll start and then pass it.

As I said, we, you know, and what our plan has been is we've been building through the combination of both external business development as well as internal growth of our drug discovery and development pipeline to bring a product to the marketplace every two to three years.

The clinical pause in the U S can be resolved at that point, allowing you to recruit U S sites as part of that cohort.

And then <unk>.

Leon.

Steve.

I guess im following the progress of other new new gene therapy launches it sounds like some European countries are expressing a desire to reimburse over time I'm wondering if you've encountered.

That kind of resistance with us.

At all and how that might impact revenue recognition there. So thank you.

Great.

Yes, you were growing in and out a little bit on the slide.

I think your question was the ability to go get 20, if you go to a higher dose we got it right.

Not only that if you're able to go to the higher if you have to go to 20 Megs.

At that time point.

Are you able to recruit U S sites, I guess with the pause in the USB resolved.

Resolved at that time, if you need to go to 20 <unk>.

And that's what we're building to.

So maybe just for everybody.

And we're going to use the combination of both of those to, to be able to both accelerate those processes.

So, the way we look at this from Blacks, from a, from the Blacks, which gives us a great opportunity to, you know, to accelerate, to take molecules that we have and have additional indications in them, as well as to look, which we always do for assets that are later stage assets or commercial, commercializable, a near term commercialization effort to be able to bring in also to increase revenues and add to our later stage pipeline.

So, Em, do you have anything extra you want to add?

I'll start.

Yeah, I'll just reiterate that.

We're obviously very excited about this deal. You know, as you pointed out, it does really provide incredibly attractive financing at favorable terms and allows us to create strategic flexibility to drive innovation, the growth of the business and business development.

Yes.

Remind everyone that the.

<unk> is a global study.

It's up and running outside of the U S being multiple sites in multiple countries.

Dose levels and put the durations that we do the higher and just to remind everyone that includes.

Yeah.

The five milligram to 10 milligram 20 milligram. So all of those went through the regulatory bodies throughout Europe and in Australia. So we have.

So in the sense that maybe there was globally the outlier there with the U S in terms of that.

We obviously want to look for further opportunities to leverage our existing commercial drug development infrastructure, and we will utilize some of this access to capital for those business development opportunities.

Obviously, what we do are doing.

Thank you both.

We're we're are.

Our top priority now is really to get this study enrolled and keep the program moving forward.

Also as rapidly as possible.

And then for up stays, is the agency now comfortable with the cannula and the surgical procedural items?

And then in.

In parallel we'll work with the agency to address their concerns.

And I guess what gives you confidence that this is essentially the last item that you need to check off before submitting?

And so.

From our point of view the most likely the most likely thing that we could do in terms of the concerns would be hey, Shlomo.

Dave.

From from the results that we got from there, but what we're doing is that we're moving.

Our goal is to move incredibly rapidly.

It completely all doses of the group.

Within those that approved within Europe .

And in Australia, and there was nothing in our view.

Any more.

Kelly.

Clinical data.

So we will obviously bring them result.

On the subset of patients to try and move forward, but our real priority is really to complete it in.

Moving as rapidly as possible.

Europe . So it didn't move as we don't need their permission to be able to go there, but we will be able to get the result.

The consequence of being able to do the trial and all of these sites.

And in terms of scale.

Maybe kylie and that you can.

Talk about the European.

In terms of pay as you go.

Yes, absolutely thanks, Eric for the question and if I heard you correctly. Eric. Your question was just around that from a contracting perspective understanding the discussions we're having in Europe at the moment.

Okay.

Yes, but also.

There's been some discussion that some countries.

My preferred.

Our paygo.

Paradigm rather than upfront.

Paying all upfront for some gene therapy products I'm, just wondering if that might apply also those phase in and how that might impact your revenue recognition. If it is in fact the paygo.

Uh huh.

Yes.

Structure going forward.

Yes, I think from our perspective, obviously, we're under discussions with a number of health technology assessment agencies in Europe at the moment and I think one of the things that's really important perhaps data. It's not just a strong data package that we have that shows the treatment benefit across all patients, but also the durability data and I think this is what is.

Really important for the pay for you as you go or pay for performance perspective.

And I think that's going to be what we put our emphasis on as we continue this discussion because it's not only that we're able to have that transformational benefit in the patients in the short term, but also the durability of that and as we've talked about in the past we have durability with up to 10 years of follow up and I think that coupled with the strong clinical.

And safety package clinical efficacy and safety package that we have allows us to believe that that we can focus on single upfront payments.

Got it that's helpful. Thanks for taking the questions.

Thanks, Eric.

Thank you one moment for questions.

Yes.

Yeah, sure.

Our next question comes from Joseph Thome with Cowen You May proceed.

Matt, you want to take that one?

Hi, there good afternoon, and thank you for taking my question maybe on.

PTC 93 into the end of the year data I guess ahead of our submission.

Theres always need here a positive pivotal study is there any CMC work that you need to conduct given that came in from center ahead of a submission and then if you can just kind of lay out.

Yeah, sure.

The context of generic to Vancouver that empower the peak.

For biomarker out there what's the what's the success.

And this time of the.

Thank you.

Thanks for the question.

Sure.

Thanks for that question, yes.

Yes, we're pretty excited about.

About 92 three for PKU.

Part of it is because I mean, I think we've discussed this.

Before.

Is one of the bandwidth.

Is that really it.

You said, it's really a better coupe.

And that's because it's far more bio available.

You can get it to a higher concentration.

At the end of the day makes it far more effective.

We're able to see that.

MAA youre able to see that.

And even patients were cool band.

What's not shown to be effective in those set of <unk>.

Page seven.

Right so.

That's an exciting add.

Aspects of the drug is that it.

Early results show that we are able to treat more and more types of patients and so greater reductions.

No.

It's been a already a reduction within that block.

So.

So.

We think.

So because you have to remember while key brand is is there.

There is a huge patient population that hasn't been well treated.

And mainly because it.

For those patients it doesn't work and I think we're going to show that.

The cannula issues appear to be addressed, you know, the issue in the past was that there was a desire for us to have experience using our specific.

A drug product with the cannula for the delivery of the product into the brain of the children.

Within the drug and what it has already shown is that.

Is that it actually can it can actually target patient. So I think there's a really a commercial advantage there.

They had no prior experience with that. And so there was a set of data that included both the bench top testing showing that.

The compatibility of the product with the device, and then, of course, importantly, those surgical procedures where we now have been able to provide that the data that the, the drug can be delivered safely to the children with that device.

In terms of the ask regarding additional data in support of the comparability analysis, we're well positioned to provide what they want, which is just some additional. Samples from the clinical batch material to be included in the.

Okay.

Matt you want to add something else in terms of the PKU enrollment.

So it's progressing.

So we are fully confident that we can provide those data and be able to move the package forward.

Yes, Joe I would just say, yes to answer your question, we expect a positive data will be well positioned to move forward towards the NDA all the other components of the package would be ready and as you mentioned is clearly a significant unmet medical need.

And with the submission, as we said, in the 1st, half of 2023.

For patients with PKU, and we're seeing that manifest in the tremendous enthusiasm for participation in the trial in the U S and around the world across all levels of severity, including as Steve pointed out the classical PKU patients.

Thank you very much.

Thanks everyone.

Thank you one moment for questions.

Thank you.

Our next question comes from David Leibowitz with Citi. You May proceed.

Thank you.

Hi, this is the bonds and on behalf of David So.

One moment for questions.

Welcome to the line of when you see that FDA sees that study.

Okay.

I think we lost him.

Are you there.

Hello, maybe weakness.

Beth.

Yes.

Maybe I'll switch to the next one and then go backwards Uganda.

Hi, sorry, I believe there was something wrong so.

What I wanted to ask was that of all Translarna oven mdc's substantial benefit in studies zeal for Ron I've been looking at the benefit in the primary analysis set.

Along with AGL will data or the IBD population and when can we hear further updates about this.

Yes, so yes, they are talking they took.

Hey.

Feedback really they took.

But they took a pretty rigorous review of things that you did not hit in terms of the <unk> population.

So now what we want to talk about it.

This is Dan.

That would go with it.

Get approval in the ITT population along with confirm.

Confirmatory.

The other way, we can get an approval of them, but I assume there's evidence out there that is.

The ITT population and study over 41, along with the confirmatory evidence from other studies.

It could.

Yes.

Could it could actually.

Have approval and we expect.

To be able to have a series of conversations about that.

To be able to.

To have that particular conversation.

Yes, I think.

When you look again, what we did is I think you can look back and see.

Some of those example, where mines were changed.

<unk> clarity on the pathway and discussing with Amalek can rehab reata were minor changes after discussion.

Thank you and maybe one last question on the PKU program. So what kind of responder rate are you expecting in the upcoming upbeat in patients who have greater than 600, micron once daily dosing nylon and levels.

Okay.

Don.

Yes, sure we haven't provided any specific information on what we're seeing in terms of responder rates other than to emphasize what we've seen in the phase II study and what we expect in this study, which again what we saw in phase II was responses across the full spectrum of patients not only with those of the baseline level of greater than <unk>.

600, micro <unk> per liter, but importantly, also in that subgroup of patients the classical PKU patients with baseline federal OE levels greater than 1200 buy promoted the leader where historically there has been no response to these patients to clear that and we've been able to demonstrate market reductions in blood phenylalanine levels. So we look forward to seeing robot.

The best across the full spectrum of severity.

As well at baseline as well as the different genotype second impact PKU and again, we look forward to sharing those data by the end of the fourth quarter.

But the asset.

Thank you thanks for taking my question.

Okay.

Thank you one moment.

One moment for questions.

Our next question comes from Eric Joseph with, J.P. Morgan.

Our next question comes from Alexander <unk> with <unk> you May proceed.

You may proceed.

Hi, Thanks for taking my question.

One entre in Florida in Europe can you remind us if you get full marketing approval does that change anything with the story as far as.

Hi.

Will you be forced to go.

From the renegotiated price, perhaps or do you expect additional uptake in patient identification or treatment that the story change at all.

If you get full marketing authorization and then second question on upstairs in Europe .

Can you remind us as we progress in the launch what types of metrics Youre considering providing in addition to revenue will you be providing the number of patients treated or active sites that are full and ready to go.

Or there would be appreciated thanks.

Good evening.

Sure. Thanks.

Thanks for the question.

For.

The transition in Europe from a conditional approval to full approval.

Thanks for taking the questions.

I have just a follow-up on PTC 518.

Interesting.

We've been pretty good about.

Okay.

I'm curious whether I can read out if the data, suggests moving to a higher dose.

Communications will bring me my mantra trends line. So we have a large number of patients already on <unk>.

The transition to the from the conditional to the full approval.

So just preventative.

We don't have to report every year for five years.

In terms of.

In terms of the HCA and such maybe.

Sure.

Eric you may want to comment.

Yes sure. Thanks for the question I think a full marketing approval only helps of course, but every contract.

Great.

Actually has their own systems by which they will evaluate the HCA assessment and so in many cases, a fuller conditional approval doesn't really affect too much any of those discussions we believe that the <unk> hundred one results along with stride and along with.

All the previous studies combined will not only strengthen the current value proposition that we have but I think it will give us even a stronger position to add continually add new patients will strengthen our current pricing structure throughout Europe and the international corridor.

So essentially while this is primarily as we said a regulatory.

We don't have to file every year for five years. It certainly does strengthen our value proposition and we will continue to leverage all of the data to ensure that we maintain.

The best possible price at this point in time.

Does that answer your question.

It does yes, and then and then on the <unk> launch.

Any additional color on future metrics.

Yes.

Yes.

I think the major metric that we were trying to deal with.

With revenues.

Yeah.

Right. So probably do you want to comment anymore on that.

Yes, absolutely I think as we've shared in the past we were able to identify a number of patients globally and I think as we achieved approval the team.

Is working full steam ahead, and being able to work with the different incentives that we have.

In Europe to be able to schedule the saturates and have these patients treated as soon as possible we were extremely pleased.

Have already traded Alpha commercial patient this year under the French early access program and we do anticipate a number of additional commercial patients in Germany, France, and Italy in the fourth quarter and I think we've done a good job of having treatments that he is ready to go.

Across a number of countries and this has been crucial to ensuring that we have the patients identified the treatment centers ready to guy and being able to schedule. The factory. So we're able to treat the patient and making sure that we have the right market access environment to do that so from that perspective, we're focused shifting the focus towards revenue we have said that.

We will.

I hope to achieve or anticipate achieving 20% to $40 million in revenue this year and we're still on track to do that.

Okay.

Alright, thanks for taking my questions.

Thank you.

Thank you one moment for questions.

Yes.

Our next question comes from Raju Prasad with William Blair You May proceed.

How confident are you that the clinical pause in the U.S, could be resolved at that point, allowing you to recruit U.S. sites as part of that cohort?

Thanks for taking the question just wanted to get some clarity on.

FDA strategy with regards to trends Lorena.

So did you guys request.

<unk> meeting or has it not been clarified.

What type of interaction with the agency and then going into this meeting.

If there is a request for Toronto.

Supplementary study or something of that nature would that be something that you'd be willing to do to try and support approval or is it really just trying to.

Get the FDA to understand the data set as it stands today.

And then secondly, I guess from following the progress of other new gene therapy launches, it sounds like some European countries are expressing a desire to reimburse over time.

Thanks.

I'm wondering if you've encountered that kind of resistance with Avesta at all and how that, might impact revenue recognition, if so.

Thank you.

Great.

Yes.

Maybe I'll start out in a couple of points as well.

Clearly what's critical here that we believe is that.

Hey, there.

Just ever since Cobra and it's been very difficult.

Actually.

<unk>.

Person to person or for that matter you will recall.

Things have been through written communications.

That's a relatively slow way.

Yes.

Exchange of ideas to make some changes.

I do want to emphasize however.

That the comprehensive nature of the data set that we have right as you think about it.

359 patients with <unk>.

Statistically significant results.

<unk> data in the six minute walk test.

Time function test.

North Star the registry data demonstrating.

Some of the hard endpoints like emulate preservation of emulation.

<unk> function.

Really.

Strong package in our view.

And I think if we in a sense so that in a way that one of them.

The first studies that have a statistically significant.

Endpoint.

And the overall population.

Datasets that we have.

Not to mention.

Paul dataset of all the patients.

Massively statistically significant.

So we think we can.

Certainly to have a discussion with them and getting an approval for that.

That's the way we want to work.

<unk> towards.

Getting in getting approval for transplant in the U S.

Matt is there anything else you want to add.

Yes, Ross I would just say that.

As Tim mentioned, the things that are a bit different in COVID-19. The traditional cadence with agent team as always you can get written comments that are often quite conservative and maybe don't completely address all aspects of the data package and then you have the advantage of that in person meeting to really volley back and forth in spine sort of a middle ground to make sure.

That the agency is fully understanding that.

Data packages and I think that's particularly true in wireless complex.

As as the transponder data package and so we are in a position now where we've got lot first written feedback that seems to have focused on our on our potential interest of using 741 alone to meet that aided substantial evidence of effectiveness criterion that the agency has held that held out for <unk>.

Their disorders, where a single study can suffice rather than seeding we focus on the clear evidence of benefit in the overall ITT population along with the confirmatory evidence we can clearly offer whether it be for the pooled analysis of those seven post that in 'twenty, one and $27 one with a P value of zero point year over year.

<unk> showing that these findings are significant treatment benefit clearly are not affected by chance or offset of course, the stride registry, where we cannot confirm that what we're observing in the clinical trials in terms of slowing of progression are manifesting themselves in important delays and the key morbid transitions of the disease, whether that be the four year delay.

And loss of ambulation compared to matched natural history cohort. The one eight years in terms of loss of pulmonary function. So where we are now is really I think it's early innings, what could very well be a series of back and forth, where we are certain that theyre seeing the data and the potential with the data to satisfy what has been used.

For other sponsors and other rare disorders to meet the.

Criteria for allowing for the submission.

Thank you one moment for our next question.

Our next question comes from Gena Wang with Barclays. You May proceed.

Thank you maybe just a quick follow up would you just comment I wanted to have clarification for your initial interaction with sbe rigs.

Regarding the study.

One did FTC your ITT analysis, along with the others.

Analysis.

Okay.

Yes.

Go ahead, Matt.

Yes.

Clarify all of the data were submitted.

They their comments and to focus on the primary analysis the primary.

Analysis method, which is in the ITT population emphasizing the fact as we all know that we did not achieve significant in that.

Pre specified subgroup of 300 and greater than five and savings given that that did not need significant statistical significance. We didn't meet the criteria of substantial evidence of effectiveness.

And so I think where we didn't see a clear.

It's clear feedback is on that Super set of ITT population and again. This is the limitations of written feedback and that's why we look forward to having a conversation with the agents.

Okay.

Another question is regarding the.

HD study since you submit the nine months nonhuman primate data to the FDA.

After your initial clinical study so just wondering any concerning safety that could trigger FTE pasta clinical trial in other words was the highest dose.

You dose in the nine months nonhuman Primate study and what was the toxicity you have seen so far.

Yes, so we.

Look I think what's important is.

Obviously when thinking about how.

The role of safety toxicology is always to identify.

None of the ruble.

Effects level and then to be.

It could be multiple between that and the.

And the drug and so well.

Well, we don't really give the details of toxicology program, we were multiple multiples.

From from the <unk>. So we felt pretty comfortable that you could see was.

Well consistent with.

The same feelings from the regulatory bodies from all the countries that we're in as well.

Australia, and then I'll remind you though.

Obviously in the rollover safety.

Safety toxicology is to get an idea and so no.

What you wanted to be looking for that being said I want to make it clear that it.

These are because you go to higher doses.

We have not seen any treatment emergent.

I would say he's our aes.

Thus far.

No.

What was observed had nothing that we've seen in the clinic.

Part of the reason, we think about that like we've never seen.

For example, with <unk>.

<unk> I think there is a great example.

Yes.

Obviously, I've talked to corelogic or finding in nonhuman primates.

Everyone talked about for quite some time, but 7000 commercial pace of play either it turned out as we suspected to be specific to 90.

<unk> non human primate for wasn't seen in other species or patient. So we try and be very careful and not try and Ted of drug.

In terms of any safety issues, because we haven't seen any right now so our goal.

And our top priority.

It's a global study and it's opened up the sites around the world is really to get to keep moving it keep this getting enrolled.

And moving forward.

The result of the data because we think thats the key here.

And then.

Some point for the subset of result.

Clinical data to talk to the FDA that I think could be doing because there's nothing like clinical data of the Trump everything.

Thank you.

Our next question comes from Danielle Brill with Raymond James You May proceed.

So, I think Eric, you asked – you were going in and out a little bit on the 518, but I think your question was the ability to go to a higher dose.

Is that right?

Hi, guys. Thanks, so much for the questions I have a couple on PTC, probably run it as well.

First.

Are you planning to show CSF HGT protein levels now that the data are pushed to early next year and then.

I think youre running it sounds like you are running the full 12 months study outside the U S. Pivotal HD shows a functional benefit is there a mechanism or a pathway for a streamline development path in the U S available still.

<unk>.

Sure Thanks for that.

For the question.

Yes, so I think just to remind you to read.

Again, the pivotal <unk> study is a two part placebo controlled study where the first 12 weeks are really focused on the pharmacology and pharmacodynamic effects in the second part.

Is focused on the.

The biomarkers and outcome measures.

So from our perspective, the first 12 weeks, what's really going to be critical there is going to provide the data and the relationship.

In between those.

Exposure <unk> mrna and protein reduction in the <unk>.

Love at steady state and then we'll also know the exposure.

Exposure in the plasma and CSF.

And I think thats ultimately critical because.

What.

The five and 10 milligram doses are a reflection of what we've seen in healthy volunteers, which is basically a close to three to one ratio.

We.

Observe so.

So it tells us about the exposure in that range.

The.

The CSF protein I think will be.

I think we will have a longer time over the duration of the full year study to look not only at the HPT and the CSF, but also euro fill them.

It changes MRI.

And other outcome measures as well, so I think from that perspective.

In a sense I think it's important to realize that.

There are patients in Europe , and Australia are no different than patients in the U S and it's well accepted that.

Similar patients so the results that you get.

The study are no different.

The results that you get from.

Treating patients in the United States and so.

The mere fact that Hugh.

The mere fact that you could use this data and then if there's any way where we can use a combination of biomarker whether filament http changer.

In the blood and see it back as well.

This is Greg volume as measured by MRI measures as SME was for a potential accelerated approval.

And certainly.

That would be viable I think regardless of where you are collected.

The good data.

That's our view of the world in terms of cadence potentially to you.

For a particular either accelerated approval or identifying what's the best way to do the phase III.

It changes regardless of whether those U S patients in there or not.

Thank you.

Okay.

Thank you one moment for questions.

Not only that.

Our next question comes from Kelly <unk> with Jefferies. You May proceed.

Thank you for taking my questions.

Regarding can you. Please file one eight for the patients already in vote from the U S.

Have they all completed study of that first.

Wake portion just wanted to quickly confirm on that and also for the.

Mike Rehaut.

We got in the first quarter of next year.

You have to set expectation.

Honda.

On page change in.

The numbers of observed of motors tasers from baseline would be considered clinically meaningful. Thank you.

Sure, Matt do you want to take that.

If you're able to go to the higher – if you have to go to 20 megs, at that time point, would you be able to recruit U.S. sites?

Sure.

Thank you very much Kelly for questions. Your first question was on PTC 518.

I guess, would the pause in the U.S. be resolved at that time if you need to go to 20 megs?

And the pause in enrollment to the USD impact on U S patients.

So, maybe just for everybody, I'll start and remind everyone that PIVOT-AHP is a global study, that's up and running outside of the U.S. in multiple sites in multiple countries.

Just to contextualize the situation in Iraq as we mentioned we had started the three month study as we had the three month tox support that with the plan that we would be getting the nine month Tox results and look to amend the protocol.

The us but globally for the full 12 months study to include the 510 and potentially up to the 20 milligram dose levels.

At the dose levels and for the durations that we desire. And just to remind everyone, that includes, the 5 milligram, the 10 milligram, and the 20 milligram.

So, all of those went through the regulatory bodies throughout Europe and in Australia.

Obviously, we were very cognizant of not wanting to have any patients have a lapse between the first 12 weeks and we had in the second line months. If there were delays in getting the clearance of the full 12 months protocol and as such we while we initiated enrollment of that study sites up and running we were able to.

So, we have the – so, in a sense, that's made – it was only the outlier there was the U.S. in terms of that.

Limit enrollment and instead that we have.

Several we had several patients that enrolled in the U S. Because we wanted to make sure that we didn't put too. Many patients are in a situation that can be a lot. So by the time. The pause has occurred the patients have completed that.

We're completed the 12 week portion of the study so.

There was no.

Additional impact to those patients because of the way we paced enrolments until we were certain that we can provide enrolment in the full 12 months without disruption.

Turning to the mining question as you mentioned, we expect to have results from the <unk> study in <unk> associated seizures in the first quarter and then just as a reminder.

About seizures in patients with mitochondrial disease, there are calling in about 30% to 50% of all children of mitochondrial disease highly morbid and often the cause of death in patients with mitochondrial disease.

Unlike other seizures seizures don't respond with typical anti epileptic agents because they are usually result from disturbances in the energetic pathways that are common mitochondrial disease and of course that are targeted by the <unk>.

We're in a situation where you have these children, who are having severe seizure burden, including up to hundreds of day in some severe cases, given the lack of therapies for these refractory seizures I think most physicians view, even at 25% lowering in daily.

Here's a monthly seizure rate thats will be reported would be a significant clinical benefit to these patients and we of course design a study and power for a change it.

40% between treatment and placebo groups. So we empower right around 50% lowering of the treatment group a 10% change in the placebo group, which is consistent with what's been observed in other pediatric epilepsy syndrome studies again, I think even if we were able to capture and 25% reduction in seizure burden that would.

<unk>.

Impactful.

Clinical effect, given the enormous seizure burden high morbidity and mortality associated with the severe seizure burden in these children, who have no cherokees typically effective for them.

Thank you.

Thank you one moment for questions.

Okay.

Our next.

Question comes from Judah Frommer with credit Suisse. You May proceed.

Hi, guys. Thanks, just a quick one on the Blackstone collaborations.

Could you give us a little color on the on the Genesis of the arrangement, where there other financing transactions being considered and this was the most attractive and.

Did you feel that this was the time to raise capital or did this kind of fall into your lap.

Thank for that.

Steven.

Emily you want to take that one.

Yeah sure happy to take that one thanks for the question.

This is a long competitive process, we evaluated several options obviously looking at options that were equity related further royalty options that options and frankly.

It came out as the best cost of capital and Louis dilution option for the company.

We're also very happy to be able to structure Taylor deal with Blackstone that.

<unk> eliminate collateral basket.

And therefore excludes some of our.

Other assets in the pipeline.

And I guess.

As far as it comes to timing as Jim mentioned, we do have we have identified assets in the pipeline, where we want to extend.

There are indications and so.

The sooner the better should be able to accelerate that innovation.

Sure.

<unk> developed the pipeline.

Okay, Perfect and then just on that 500 million in potential credit facility. When you say mutual agreement does that mean Blackstone would potentially take ownership with you or its just that they need to.

Prove it.

Business development that Youre planning on taking on.

I mean that was an important part of the transaction and I think thats where were.

Really excited to have such a highly respected partner with such a broad network. So.

We will work with Blackstone, we've obviously demonstrated our ability as a proven consolidator to create values for business development, we will work with Blackstone to further those efforts to leverage their their network and then yes. They will be mutually agreed upon transactions that can be structured in a.

Number of ways trail, either upfront funding or royalty financing that will allow us to accelerate our momentum.

Got it thanks.

Yes.

Thank you and as a reminder to ask a question you will need to press star one one.

Our next question comes from <unk> with Bank of America, You May proceed.

Hi, good afternoon. Thank you for taking my questions.

P. J you can you give us a sense about how youre thinking about the market opportunity.

I know.

The goal is is to present data that is looking to be a better kuban, but given that prevent a generic.

Where do you think at least initially the job would place in terms of.

Where in the treatment regimen that would fall.

Maybe it's early to talk about that but to the extent that you have this year would love to hear it and then.

On the Blackstone deal or a second question.

Was the trend lineup path to U S approval part of the discussion.

They get a chance to see that written feedback from the FDA under CDA.

Thanks.

Great. So maybe let's start with.

We.

The PKU, maybe I'll start and then pass.

I think that the.

The.

T. J you I think I think one thing that I think we should make very clear is that.

Well there is cool.

And maybe this isn't as well known should be looked at the majority of patients.

PKU patients.

<unk>.

Either untreated or not really well controlled while on prove that.

Even with the two commercial products are available.

So there is a large.

Population locations, but above.

About 58000, PKU patients globally of which a very small percentage.

Our actually.

Controlled by Google. So the consequence of that is that there is a huge opportunity here.

And the huge opportunity with a better Kuban location, probably treat it and therefore, that's that's really the big opportunity here and so maybe to <unk>.

Go through in more detail.

<unk>.

The market why that's the case.

Charlie do you want to go through and sort of explain how you think about slicing and dicing the.

The patients who who.

Respondents.

Yeah, absolutely. So thanks for the question I think as Steve said, we see this is a really unique opportunity while there's about 58000 PKU patients globally and two approved therapies, there's still substantial unmet need so we sort of think of the marketplace and in broad strokes and defenses.

About 30% of patients that are therapy naive today in the U S.

And all of those patients that includes the classical PKU patients. Those that are typically severe and have baseline <unk> levels of 1200 micro molar per liter of mall and in the past. These have not been able to see benefit from <unk> or other treatments and so from that perspective, they remain therapy naive.

In addition to that the remaining 70% of the patients that have tried to that many of them as Jay said, I know Andre van and that could be because they either initially fail because theyre wholly controlled at the time and so there's a substantial opportunity when you look across those three main segments and if you think about the data that give.

This confidence going on from the phase two into the phase three.

Three study from the phase III head to head.

<unk> 93, with <unk> was able to demonstrate benefit in that classical PKU patient, which had not been able to be seen with <unk> and previously opening up an opportunity for this therapy naive.

We were able to save 50% more responded with 93.

Then kuban.

Opening up the opportunity for those that initially filed on <unk> and then even in those that were previously treated with <unk> than we saw a 200% greater risk.

The reduction <unk>.

Demonstrating data points across all those different patient segments, and if you think about requirements to step edit for example in the U S.

Obviously normally around providing documentation for trying to treatment and failing on certain aspects of that and if you look across that 70% of the population they've already done that and so it's a market opportunity that's able to be captured very quickly upon launch and obviously as I mentioned in the therapy naive there's no mechanistic rate.

And why they should be put on prevents a failed state.

We think there's a unique opportunity and we think we able to capture upon it very quickly upon launch.

And then for the Blackstone deal Emily you want to.

Talk about the due diligence.

Yes sure.

Thank you for the question Justin.

I think everyone on this call can attest that Blackstone conducted a very thorough due diligence on the.

Company.

Avi please stand or diligence on the data we have today, a regulatory correspondence or forecast our commercial assessment.

And so yes. They have reviewed all of our regulatory correspondence is that we have received in writing I think.

This is really a statement to.

Blackstone's beliefs in the robust long term potential of our pipeline and our commercial products.

Okay, great. Thanks Emily.

Of course, thank you.

Thank you and I'm not showing any further questions. At this time I would now like to turn the call back over to Stuart Peltz for any further remarks.

Yes.

Yes.

So.

First of all let me.

Thank you all for joining us on the call today.

So, you know, obviously, what we do – are doing is we're – our top priority now is really to get the study enrolled and keep the program moving forward and get the results as rapidly as possible.

Obviously, what you can see we've made significant progress this year.

And moving forward to delivering on a number of milestones.

Throughout this year and the lag in the last three quarters.

We've also had a number of.

Critical we also have a number of critical registration.

Good studies that are ongoing now and we look forward to sharing the results of the next six to nine months.

I think are going to continue to really transform.

Transform and create value for all our stakeholders.

So as you can see we're working hard to continue our mission to both discover and develop innovative therapies.

For rare disorders. So again, thanks for joining the call.

Thank you. This concludes today's conference call. Thank you for participating you may now disconnect.

Okay.

Oh.

And then, in parallel, we'll work with the agency to address their concerns.

And so, you know, from our point of view, the most likely – the most likely thing that we, could do in terms of the concerns would be to show them a subset of the data from the results that we get from there.

The conference will begin shortly to raise your hand during Q&A you can dial star one one.

So, what we're doing is that we're moving quite – you know, our goal is to move incredibly rapidly.

And the good news is that we're able to complete all doses of the group within those that are approved within Europe and Australia.

And there's nothing, in our view, any more, you know, tally than actually human clinical data.

So, we'll obviously bring them results on a subset of patients to try and move forward, but our real priority is really to complete it in – is to move it as rapidly as possible in Europe.

So, the good news is we don't need their permission to be able to go there, but we'll be able to get the results as a consequence of being able to do the trial in all these other sites.

Then in terms of upstasa, maybe Kylie and Matt, you can talk about the Europeans in terms of pay-as-you-go.

Yeah, absolutely.

[music].

Thanks, Eric, for the question.

And if I heard you correctly, Eric, your question was just around sort of from a contracting perspective, understanding the discussions we're having in Europe at the moment.

Yes, but also, there's been some discussion that some countries might prefer a pay-go paradigm rather than paying all up front for some gene therapy products.

I'm just wondering if that might apply also to upstasa and how that might impact your revenue recognition if it is, in fact, a pay-go structure going forward.

Yeah, I think from our perspective, obviously, we're under discussions with a number of health technology assessment agencies in Europe at the moment.

And I think one of the things that's really important for upstasa is not just the strong data package that we have that shows the treatment benefit across all patients, but also the durability data.

And I think this is what's really important for the pay-for-as-you-go or pay-for-performance perspective.

And I think that's going to be what we put our emphasis on as we continue these discussions because it's not only that we're able to have that transformational benefit in the patients in the short term, but also the durability of that. And as we've talked about in the past, we have durability with up to 10 years of follow-up.

And I think that, coupled with the strong clinical efficacy and safety package that we have, allows us to believe that we can focus on single up-front payment.

Got it.

That's helpful.

Thanks for taking the questions.

Thanks, Eric.

Thank you.

Sure.

[music].

One moment for questions.

Our next question comes from Joseph Thorne with Cowen.

You may proceed.

Hi, there.

Good afternoon.

Thank you for taking my question.

The conference will begin shortly to raise your hand during Q&A you can dial star one one.

Maybe on PPC-923 into the end-of-the-year data, I guess, ahead of a submission, is all we need here a positive pivotal study?

Is there any CMC work that you need to conduct, given that this came in from SAMHSA ahead of a submission?

And then, if you can just kind of lay out, you know, under the context of generic QVAN, QVAN and PALM-ZEKE from Biomariner out there, what does success, I guess, look like in this study at the end of the year?

Thank you.

Sure.

Thanks for that question.

Yeah, we're pretty excited about the, you know, about 923 for PKU. And part of it is because, and I think we've discussed this before, is one of the advantages is that really, it's that it's really a better QVAN, and that's because it's far more bioavailable.

[music] okay.

And you can get it to higher concentrations, which, at the end of the day, makes it far more effective.

And that you're able to see that in a, you're able to see that in even patients where QVAN was not shown to be effective in those sets of patients.

I think that's an exciting aspect of the drug is that the early results show that we're able to treat more types of patients and show greater reductions of phenomenality reduction within the blood.

So, you know, we think that in itself, because, you know, to remember, while QVAN is there, there's a huge patient population that hasn't been well treated, and mainly because it does, for those patients, it doesn't work.

And I think we're going to show that, you know, within this drug, and what it's already shown, is that it can actually target more patients.

So I think there's a real commercial advantage there.

Matt, you want to add something else in terms of the PKU enrollment and how it's progressing?

Yeah, Joe, I would just say that, to answer your question, we expect that positive data will be well positioned to move forward towards NDA and all the other components of the package will be ready.

And as Stu mentioned, there's clearly a significant unmet medical need for patients with PKU, and we're seeing that manifest in the tremendous enthusiasm for participation in the trial in the U.S. and around the world, across all levels of severity, including, as Stu pointed out, the classical PKU patients.

Great.

Thank you very much.

Thank you.

One moment for questions.

Our next question comes from David Leibowitz with Citi.

You may proceed.

Hi, this is Devanjana on behalf of David.

So, about TransLuna, when you say that FDA says that study...

I think we lost her.

Are you there?

Hello?

Maybe we can get her back.

Maybe we'll switch to the next one and then go back when she's on.

Hi.

Sorry, I believe there was something wrong.

What I wanted to ask was that about TransLuna, when FDA says there isn't substantial benefit in study 041, are they looking at the benefit in the primary analysis set, along with the real-world data or the ITP population?

And when can we hear further updates about this?

Yeah.

So, yes, they took the feedback.

Really, what they took is a pretty rigorous view of things that you did not hit in terms of the MITT population.

So now what we want to talk about is the evidence that would go with the get approved on the ITT population along with confirmatory.

So the other way we can get an approval on this, and there's evidence of this out there, that is on the ITT population in study 041, along with the confirmatory evidence from other studies, certainly could actually have approval.

And we expect to be able to have a series of conversations about that, to be able to have that particular conversation.

And that's, I think, you know, when you look, again, what we did is, I think you can look back and see some of those examples where minds were changed once clarity on the pathway and discussion, like with Amaleks and Reata, where you see minds were changed after discussion.

Thank you.

And maybe one last question on the PKU program.

So, what kind of responder, rate are you expecting in the upcoming update in patients who have greater than 600 micromoles per liter phenylalanine levels?

Oh, okay.

And, Matt, do you want to...

Yes.

Yes, sure.

Yeah.

We haven't provided any specific information, on what we're seeing in terms of responder rates other than to emphasize what we've seen in the Phase 2 study and what we expect in this study, which, again, what we saw in Phase 2 was responses across the full spectrum of patients, not only with those with a baseline, phenylalanine level of greater than 600 micromoles per liter, but importantly also in that subgroup of patients, the classical PKU patients with baseline phenylalanine levels greater than 1,200 micromoles per liter, where historically there's been no response in these patients, to Kuven, and we've been able to demonstrate marked reductions in blood phenylalanine levels.

[music].

So, we look forward to seeing robust effect across the full spectrum of severity as well, at baseline, as well as the different genotypes that can impact PKU.

And, again, we look forward to sharing those data by the end of this fourth quarter when we have that.

Thank you.

Thanks for taking my question.

Thank you.

One moment for questions.

Our next question comes from Alexander Xenakis with Truist.

You may proceed.

Hi.

Thanks for taking my question.

One, on TransLarna in Europe, can you remind us, if you get full marketing approval, does that change anything with the story as far as will you be forced to go and renegotiate price, perhaps, or do you expect additional uptake in patient identification or treatment?

Does the story change at all if you get full marketing authorization?

And then a second question on Upstaza in Europe.

Can you remind us, as we progress in the launch, what types of metrics you're considering providing?

In addition to revenue, will you be providing the number of patients treated or active sites that are full and ready to go?

Or that would be appreciated.

Thanks.

Sure.

Thanks for the question.

For the transition in Europe from conditional to approval to a full, approval, you know, it's interesting.

We've been pretty good about, you know, identifying patients and bringing them out to TransLarna.

So, we have a large number of patients already on.

I think the transition from the conditional to the full approval also just prevents us from, we don't have to report every year, be it every five years.

And I think in terms of HTA and such, maybe, Eric, you may want to comment.

Yeah, sure.

Thanks for the question.

I think full marketing approval only helps, of course, but every country, is different, actually has their own systems by which they will evaluate the HTA assessment.

And so, in many cases, a full or conditional approval doesn't really affect too much any of those discussions.

We believe that the 0401 results, along with STRIDE and along with all the previous studies combined, will not only strengthen the current value proposition that we could have, but I think it will give us an even stronger position to continually add new patients and strengthen our current pricing structure throughout Europe and the international corridor.

So, essentially, while this is primarily, as Sue said, a regulatory where we don't have to file every year for five years, it certainly does strengthen our value proposition, and we'll continue to leverage all of the data to ensure that we maintain the best possible price at this point in time.

Does that answer your question?

It does, yeah.

And then on the up-to-date launch, any additional color on future metrics would be helpful.

I think the major metric that we were trying to get was revenues, right?

So, Kylie, do you want to comment any more on that?

Yeah, absolutely.

I think as we've shared in the past, we were able to identify a number of patients globally, and I think as we achieved approval, the team is working full steam ahead in being able to work with the different centers that we have in Europe to be able to schedule these surgeries and have these patients treated as soon as possible.

We were extremely pleased to have already treated our first commercial patient this year, under the French Early Access Program, and we do anticipate a number of additional commercial patients in Germany, France, and Italy in the fourth quarter, and I think we've done a good job of having treatment centers ready to go across a number of countries, and this has been crucial to ensuring that we have the patients identified, the treatment centers ready to go, and being able to schedule the surgeries so we're able to treat the patients and making sure that we have the right market access environment to be able to do that.

So, from that perspective, we're shifting the focus towards revenue.

We have shared that we hope to achieve or anticipate achieving $20 million to $40 million in revenue this year, and we're still on track to do that.

All right.

Thanks for taking my questions.

Thank you.

One moment for questions.

Our next question comes from Raju Prasad with William Blair.

You may proceed.

Thanks for taking the question.

I just want to get some clarity on the FDA strategy with regards to trans-LARNA.

So, did you guys request, like, a type A or B meeting, or has it not kind of been clarified what type of interaction you'll have at the agency?

And then, you know, going into this meeting, if there's, you know, a request to run a supplementary study or something of that nature, would that be something that, you know, you'd be willing to do to try and support approval, or is it really just trying to get the FDA to understand the data set as it stands today?

Thanks.

Yeah, so maybe I'll start out in a couple of points is what, you know, clearly what's critical here that we believe is that a, that it's, you know, just ever since COVID has hit, it's been very difficult to have actually in, you know, person to person, or for that matter, even calls, most things have been through written communications.

And, you know, that's a relatively slow way to, you know, exchange of ideas and make some changes.

I do want to emphasize, however, that the comprehensive nature of the data set that we have, right?

If you think about it, 359 patients, we saw statistically significant results in the ITT data and the six minute walk test, the time function test, the North Star, the registry data demonstrating, you know, some of the hard end points like ambulation, preservation of ambulation and lung function.

It's a pretty strong package in our view.

And I think if we, in a sense, so that, you know, in a way that 1 of the 1st study is to have a statistically significant.

Endpoint in the, in the overall population, and then with the.

Data sets that we have, not to mention, you know, a full data set of all the patients.

And how massively statistically significant it is.

That we think we can certainly have a discussion with them on getting an approval for that.

So that's that's the way we want to work on work towards getting, getting approval for translating the US.

Matthew, is there anything else you want to add to that?

Yeah, I would just say that, you know, as you mentioned the.

Things have been a bit different and the traditional cases with the agency was always you'd get written comments that are often quite conservative and maybe don't completely address all aspects of a data package.

And then you have the advantage of that in person meeting to really volley back and forth and find sort of a middle ground to make sure that the agency is fully understanding of the data packages.

And I think that's particularly true in 1 is complex as as the trans wanted data package.

And so we're in a position now where we've gotten that 1st, written feedback that seems to have focused on our.

On a potential interest of using study 41 alone to meet that stated substantial evidence of effectiveness criterion that the agency has held that held out for rare disorders where a single study can suffice.

Rather than seemingly focus on the clear evidence of benefits in the overall population, along with the confirmatory evidence, we can clearly offer, whether it be from the pools analysis of those 70721 and 20 and study 41 with the P value of 0.002 showing that the findings of significant treatment benefits clearly are not a 1st by chance.

Or of course, the shrine registry, where we can confirm that what we're observing in the clinical trials, in terms of slowing of progression are manifesting themselves in important delays in the key morbid transitions of the disease.

Whether that be the 4 year delay and loss of emulation compared to a match natural history cohort, the 1.8 years in terms of loss of pulmonary function.

So, where we are now is really, I think, in the early innings of what could very well be a series of back and forth where we are certain that they're seeing the data and the potential with the data to satisfy what has been used for other sponsors and other rare disorders to meet the criteria for allowing for the submission.

Thank you.

One moment for our next question.

Our next question comes from Gina Wang with, Barclays.

You may proceed.

Thank you.

Maybe just a quick, you know, follow what you just commented.

I wanted to have clarification.

For your initial interaction with the FDA regarding the study 041, did the FDA see your ITT analysis along with the other analysis?

Go ahead, Matt.

Yeah, to clarify, all of the data were submitted.

I would say their comments seem to focus on the primary analysis group and primary analysis method, which was in the MITT population, emphasizing the fact, as we all know, that we did not achieve significance in that pre-specified subgroup of 300 and greater than 5, and stating that given that that did not meet statistical significance, we didn't meet the criterion of substantial evidence of effectiveness.

And so I think where we didn't see a clear, the clear feedback is on that superset of our ITT population.

And again, this is the limitations of written feedback, and that's why we look forward to having a conversation with the agents.

Okay.

Another question is regarding the PIVOT-HD study.

Since you submit the nine-month non-human primate data to the FDA after you initiate clinical study, so just wondering any concerning safety that could trigger FDA-positive clinical trial? In other words, you know, what was the highest dose you dosed in the nine-month non-human primate study, and what was the toxicity you've seen so far?

Yeah, so we've, look, I think what's important is, you know, obviously when thinking about how, you know, the role of safety toxicology is always to identify the non-observable effect level, and then to be, you know, to be, you know, have multiples between that and the drug.

And so the, well, we don't really give the details of toxicology program.

We were multiple multiples from the NOAL.

So we felt pretty comfortable, and that, you can see, was consistent with the same feelings from the regulatory bodies, from all the countries that we're in, as well as Australia.

And then I remind you, those, you know, the, you know, obviously, and the role of safety toxicology is to get an idea and to know, you know, what you want to be looking for.

That being said, I want to make it clear that if these were, these are, because you go to higher doses, we've never, we've not seen any treatment emergence SAEs or AEs thus far.

And so, you know, what was observed had nothing to be seen in the clinic.

You know, and, you know, and part of the reason we think about that, like, we've never seen an example with, of RISD, I think, is a great example where there was, obviously, a toxicological finding in non-human primates that everyone talked about for quite some time.

But, you know, 7,000 commercial patients later, it turned out, as we suspected, to be specific to non-human primates and wasn't seen in other species or in patients.

So, we try and be very careful and not try and tag a drug, you know, in terms of any safety because we haven't any issues because we haven't seen any right now.

So our goal is, and our top priority is, since, you know, it's a global study and it's opened up the sites around the world, is really to get, to keep moving and keep this getting enrolled and moving forward and, you know, get the results of the data, because we think that's the key here.

And then at some point, with a subset of results, clinical data to talk to the FDA.

That's, I think, the easiest way to do it, because there's nothing like clinical data to trump everything.

Thank you.

Our next question comes from Danielle Brill with Raymond James.

You may proceed.

Hi, guys.

Thanks so much for the questions.

I have a couple on PTC 518 as well.

I guess, first, are you planning to show CSF HCT protein levels now that the data are pushed to early next year?

And then, since you're running, it sounds like you're running the full 12-month study outside the U.S., if PivotHT shows a functional benefit, is there a mechanism or pathway for a streamlined development path in the U.S. available still?

Thanks.

Sure.

Thanks for that answer, for the question.

Yeah, so I think just to remind you, we've, again, the PivotHT study is a two-part placebo-controlled study where the first 12 weeks are really focused on the pharmacology and pharmacodynamic effects.

And the second part is focused on the biomarkers and outcome measures.

And so, from our perspective, the first 12 weeks, what's really going to be critical there is going to provide the data on the relationship between dose, exposure, HTT mRNA, and protein reduction in the blood at steady state.

And then we'll also know the exposure in the plasma and the CSF.

And I think that's ultimately critical because, you know, the 5 and 10 milligram doses are a reflection of what we've seen in healthy volunteers, which is basically a close to 3-to-1 ratio that we observed.

And I think from that perspective, you know, in a sense, I think it's important to realize that, you know, patients in Europe and Australia are no different than patients in the U.S., and it's well accepted that they're similar patients.

And so the results that you get with this study are no different than the results that you're going to get from treating patients in the United States.

And so the mere fact that you, you know, the mere fact that you could use this data, and if there's any way where we can use a combination of biomarker, whether it's neurofilament, HTT changer, in the blood and CSF as well as changes in brain volume as measured by MRI and other measures.

If that's a means for a potential accelerated approval, certainly that would be viable, I think, regardless of where you collected the data.

That's our view of the world in terms of can this potentially be used for a potential, either accelerated approval or to define what's the best way to do the phase three.

We don't think it changes regardless of whether there's U.S. patients in there or not.

Understood.

Thank you.

Thank you.

One moment for questions.

Our next question comes from Kelly Shi with Jeffrey's.

You may proceed.

Thank you for taking my questions.

So regarding PDC 518, for the patients already enrolled from, the U.S., have they all completed the study of their first wake portion?

I just want to quickly confirm on that.

And also for the MITE-E results in the first quarter of next year, can you help to set expectation on what kind of a percentage change in the numbers of observed motor seizures from baseline would be considered clinically meaningful?

Thank you.

Sure.

Matt, you want to take that?

Sure.

So thank you very much, Kelly, for the questions.

Your first question was on, PDC 518 and the pause in enrollment to the U.S., the impact on U.S. patients.

Now, just to contextualize the situation in the U.S., as we mentioned, we had started the three-month study as we had the three-month top support that with the plan that we would be getting the nine-month top results and look to amend the protocol, not only in the U.S., but globally for the full 12-month study to include the 510 and potentially up to the 20 milligram dose levels. Now, obviously, we were very cognizant of not wanting to have any patients have a lapse between the first 12 weeks and the second nine months if there were delays in getting the clearance of the full 12-month protocol.

And as such, while we initiated enrollment, got study sites up and running, we were able to limit enrollment. And so we had several patients that enrolled in the U.S, because we wanted to make sure that we didn't put too many patients in a situation where there could be a lapse. So by the time the pause has occurred, the patients had completed the – they were completed with the 12-week portion of the study.

So there was no additional impact, to those patients because of the way we paced enrollments until we were certain that we could provide enrollment in the full 12 months without disruption.

Turning to the MITEI question, as you mentioned, we expect to have results from the MITEI study in mitochondrial disease-associated seizures in the first quarter.

And maybe just as a reminder about seizures in patients with mitochondrial disease, there are common in about 30 to 50 percent of all children with mitochondrial disease, highly morbid and often the cause of death in patients with mitochondrial disease.

And unlike other seizures, these seizures don't respond to typical antiepileptic agents because they usually result from disturbances in the energetic pathways that are common in mitochondrial disease and, of course, that are targeted by the tiquinone. So you're in a situation where you have these children who are having severe seizure burden, including up to hundreds a day in some severe cases.

Given the lack of therapies for these refractory seizures, I think most physicians would view even a 25 percent lowering in daily seizures or monthly, seizure rate, as we'll be reporting, would be of significant clinical benefit to these patients.

And we, of course, designed the study and powered for a change of a difference of 40% between treatment and placebo group, so we powered it around a 50% lowering in the treatment group, a 10% change in the placebo group, which is consistent with what's been observed in other pediatric epilepsy syndrome studies.

Again, I think even if we were able to capture a 25% reduction in seizure burden, that would, be viewed as a really impactful clinical effect, given the enormous seizure burden and high morbidity and mortality risk associated with the severe seizure burden in these children who have no therapies that are typically effective for them.

Thank you.

One moment for questions.

Our next question comes from Judah Frommer with Credit Suisse.

You may proceed.

Yeah, guys.

Thanks.

Just a quick one on the Blackstone collaboration.

Could you give us a little color on the genesis of the arrangement?

Were there other financing transactions being considered and this was the most attractive?

Operator: The conference will begin shortly.

And did you feel that this was the time to raise capital, or did this kind of fall into, your lap?

Operator: To raise your hand during Q&A, you can dial star 11.

Thanks.

Yeah, thanks for that, Judah.

Emily, you want to take that one?

Yeah.

Sure.

Happy to take that one.

Thanks for the question.

This is a long, competitive process.

We evaluated several options, obviously looking at options that were equity-related for the, royalty options and secured debt options.

And frankly, this came out as the best in cost of capital and lowest dilution option, for the company.

We were also very happy to be able to structure a tailored deal with Blackstone that holds, a limited collateral basket and therefore excludes some of our other assets in the pipeline.

And I guess, you know, as far as it comes to timing, as you mentioned, we do have – we, have identified assets in the pipeline where we want to extend their indications.

And so, you know, the sooner the better to be able to accelerate that innovation and, develop the pipeline.

Okay.

Perfect.

And then just on that $500 million in potential credit facility, when you say mutual agreement, does that mean that Blackstone will potentially take ownership with you, or it's just that they need to, you know, approve business development that you're planning on taking on?

I mean, that was an important part of the transaction, and I think that's where we're, you know, really excited to have such a highly respected partner with such a broad network.

So, we will, you know, work with Blackstone.

We've obviously demonstrated our ability as a proven consolidator to create values for, business development.

We'll work with Blackstone to further those efforts to leverage their network.

And then, yes, they will be mutually agreed upon transactions that can be structured in, a number of ways, you know, through either a front funding or royalty financing that will allow us to accelerate our momentum.

Got it.

Thanks.

Thank you.

And as a reminder, to ask a question, you will need to press star 11.

Our next question comes from Tazeen Ahmad with Bank of America.

You may proceed.

Hi, good afternoon.

Thank you for taking my questions.

Operator: The conference will begin shortly.

Just on PKU, can you give us a sense about how you're thinking about the market opportunity?

Operator: To raise your hand during Q&A, you can dial star 1-1.

I know the goal is to present data that is looking to be a better KUVAN, but given that KUVAN is generic, where do you think at least initially the drug would place in terms of where in the treatment regimen it would fall?

Maybe it's early to talk about that, but to the extent that you have it, we would love to hear it.

On the Blackstone deal, as a second question, was the TransLarna path to U.S. approval part of the discussion, and did they get a chance to see that written feedback from the FDA under CDA?

If so, thanks.

Great.

So maybe let's start with the PKU.

Maybe I'll start and then pass this.

I think that the PKU, I think one thing that I think we should make very clear is that while there is KUVAN, and maybe this isn't as well-known as it should be, but that the majority of patients, of PKU patients, remain either untreated or are not really well-controlled while on KUVAN, even with the two commercially products available.

So there's a large population of patients, that's about 58,000 PKU patients globally, of which a very small percentage are actually controlled by KUVAN.

So the consequence of that is that there's a huge opportunity here, and the huge opportunity is with a better KUVAN, more patients will be treated, and therefore that's really the big opportunity here.

And so maybe to go through in more detail the market, why that's the case, maybe Kylie, do you want to go through and sort of explain how you think about slicing and dicing the patients who respond and don't?

Yeah, absolutely.

So thanks to Dean for the question.

I think, as Stu said, we see this as a really unique opportunity.

While there's about 58,000 PKU patients globally, and two approved therapies, there's still substantial unmet need.

So we sort of think of the marketplace in broad strokes, in the sense there's around 30% of patients that are therapy naive today in the US.

And of those patients, that includes the classical PKU patient, those that are typically severe and have baseline fee levels of 1200 micromolar per liter or more.

And in the past, these have not been able to see benefit from KUVAN or other treatments.

And so from that perspective, they remain therapy naive.

Operator: The conference will begin shortly.

In addition to that, the remaining 70% of the patients that have tried KUVAN, many of them, as Stu said, are not on KUVAN, which has not been able to be seen with KUVAN previously, opening up an opportunity for the therapy naive.

We were able to see 50% more responders with 923 than KUVAN, opening up the opportunity for those that initially failed on KUVAN.

And if you look across that 70% of the population, they've already done that.

And so it's a market opportunity that's able to be captured very quickly upon launch.

And obviously, as I mentioned in the therapy naive, there's no mechanistic reason why they should be put on KUVAN to fail.

So we think there's a unique opportunity and I think we're able to capture upon it very quickly upon launch.

And then for the Blackstone deal, Emily, do you want to talk about the due diligence?

Yeah, sure.

I'm happy to.

Thank you for the question, Tazeen.

I think everyone on this call can attest that Blackstone conducted very thorough due diligence on the company.

Obviously, standard diligence on the data we have to date, our regulatory correspondence, our forecast, our commercial assessment. And so, yes, they have reviewed all of our regulatory correspondences that we have received in writing.

I think this is really a statement to Blackstone's belief in the robust long-term potential of our pipeline and our commercial products.

Okay, great.

Thanks, Emily.

Of course.

Thank you.

Thank you.

And I'm not showing any further questions at this time.

I would now like to turn the call back over to Stuart Peltz for any further remarks.

Yes.

So, first of all, let me thank you all for joining us on the call today.

Obviously, what you can see, we've made significant progress this year and moving forward and delivering on a number of milestones throughout this year and the last three quarters.

We've also had a number of critical – we also have a number of critical registration directed studies that are ongoing now.

And we look forward to sharing the results of these in the next six to nine months that I think are going to continue to really both transform and create value for all our stakeholders.

So, as you can see, we're working hard to continue our mission to both discover and develop innovative therapies for rare disorders.

So, again, thanks for joining the call.

Thank you.

This concludes today's conference call.

Thank you for participating.

You may now disconnect.

Hold on.

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