PTC Therapeutics Inc (PTCT) 2016 Q3 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the PTC Therapeutics Third Quarter 2016 Earnings Conference Call. (Operator instructions.) As a reminder, today's conference call is being recorded. I would now like to introduce your first speaker for today, Emily Hill, for opening remarks. You have the floor, ma'am.

Thank you. Welcome to our conference call. today we will discuss PTCs third quarter 2016 financial results and provide a corporate update.

Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. These include statements about our future expectations regarding clinical development, regulatory and commercialization timelines and potential outcomes, including statements related to our ability to resolve the matter set forth in the Refuse to File letter we received from the FDA in connection with our new drug application for Translarna for the treatment of Duchenne muscular dystrophy, whether pursuant to continued appeal or otherwise, and statements related to our ability to obtain and maintain marketing authorizations for Translarna, including with respect to our pending request for [new] Translarna's authorization for NM-DMD in the EU and the nature of any conditions or restrictions that may be placed on any such renewal, if such renewal is granted, the potential success of our product and product candidates, addressable patient populations, and financial projections. Actual results may differ materially from those indicated by these statements as a result of a variety of risks and uncertainties, including the timing and outcomes of interactions PTC has with the FDA with respect to Translarna, including whether we are required to perform additional clinical or non-clinical studies of significant cost, whether it's successful, may enable FDA review of the NDA, whether the EMA determines that the risk-benefit balance of Translarna suppose continuation of our marketing authorization in the EEA, the timing and outcome of [ACT CF], the outcome of pricing and reimbursement negotiations in those countries in which we are authorized to sell Translarna, and the price which we are able to sell Translarna, and those risks discussed under the heading, "Special Note Regarding Forward-Looking Statements and Risk Factors" in our most recent Form 10-Q. Such statements represent our judgement as of today, and PTC undertakes no obligation to publicly update any forward-looking statements except as required by law.

Information regarding our use of GAAP and non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's financial results press release.

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

Good afternoon, and thank you for joining us on the call. we are pleased to report on the progress we've made in the third quarter across many fronts. Today I will summarize the ongoing Translarna regulatory activities in the EU and the US. Other important updates include continued progress on our Translarna commercialization efforts, the start of the study in SMA type 2/3 patients, developments in our clinical pipeline, and financial results for the quarter.

Let me start with EMA's review of our current marketing authorization of Translarna for Duchenne muscular dystrophy. As you know, we are seeking to renew the conditional marketing approval of [paying] for Translarna from the European Medicine Agency in 2014. Translarna is now available to patients in countries through commercial sales or reimbursed early access programs in Europe, Latin America, and the Middle East.

As a condition of our approval in Europe, we submitted the results of our ACT DMD phase three clinical trial to the EMA in January. In parallel, we also submitted the request for annual renewal of our marketing authorization. As we previously said, we have been working with the EMA to design an appropriate clinical trial that would affirm the risk-benefit profile of Translarna in nonsense mutation DMD.

At our CHMP meeting in October, the committee requested additional information regarding the risk-benefit profile of Translarna, its efficacy, and the design of a potential study that would provide comprehensive clinical data on these matters. While we have provided information in response to their request and expect to continue to engage in future interactions, recent dialogue has introduced a higher degree of uncertainty as to the outcome.

We are in the process of responding to those requests and anticipate we will participate in another oral explanation meeting before the CHMP this year. We continue to expect that the CHMP will complete its assessment and issue an opinion regarding renewal by the end of the year. We plan to share more detail once the CHMP review is completed. We appreciate all the effort put forth by the CHMP and their dedication and commitment to the DMD patients in this renewal procedure.

I'd like now to turn to our regulatory activities in the United States. As you know, we received a Refuse to File letter in February from the FDA. We submitted an appeal to the Refuse to File in July, and in October the first appeal was denied. As we have previously stated, we expect the appeal process to be iterative. We will submit our appeal to the next level of the FDA as soon as possible, and we intend to continue the appeal to higher levels of the FDA as necessary.

FDA's guidance on the process provides for a 30-day timeframe per appeals cycle, but this timing could be extended, for example, to allow for time to respond to FDA requests, for more information, or for a meeting. The first denial was signed by Dr. Robert Temple on behalf of the Office of Drug Evaluation I. Under FDA's internal policies, the next level of appeal would be Dr. Jenkins, the Director of the FDA Office of New Drugs, followed by Dr. Woodcock, the Director of CEDR.

Our appeal is based on a three-pronged argument - one, that there's a legal basis for fair treatment among companies; two, that the totality of our data supports a positive risk-benefit profile for Translarna; and three, that our results can only be fairly assessed with the attention they deserve in the context of a full and fair review. We take the position that a full and fair review would require an Advisory Committee meeting where clinical experts in Duchenne muscular dystrophy and representatives of the patient community can express their views on Translarna treatment. We will provide an update following final conclusion of the appeal process, or if we decide to pursue an alternative regulatory strategy.

We have pioneered clinical development in Duchenne muscular dystrophy, including the characterization of its natural history. Over 400 nonsense mutation DMD boys and young men have participated in our clinical trials dating back to 2005, and the vast majority have chosen to remain on Translarna as of today, foregoing participation in other studies with alternative investigative therapies. We believe this long-term compliance speaks to the benefit Translarna is providing to patients in the United States and around the world. We believe our data to date and feedback from patient support [of] positive risk-benefit profile of Translarna.

We feel strongly that it is in the best interest of patients and the US Duchenne muscular dystrophy community that the Translarna NDA be reviewed by the FDA. We have approximately 130 United States patients in extension studies currently on Translarna therapy for Duchenne muscular dystrophy, some dating back as long as 10 years. We have maintained patients in these extension studies, and they have provided important data. In some countries, we have initiated the closing of these long-term studies.

As these studies come to an end and site closures continue, it is crucial for patients that the FDA gives Translarna a full and fair review in order that the possibility of long-term access can continue. This would include an Advisory Committee, where patients and experts' perspectives can be heard.

Given that we are in the middle of dialogue with the agencies, we are not able to comment further on these matters. As a result, we will not be addressing these regulatory topics in further detail in our Q&A today.

Let's switch gears to discuss Translarna's commercialization outside of the United States. Our global launch of Translarna is tracking well, and the feedback we receive from physicians of patients about Translarna remains very positive. We have seen good growth year-over-year across Europe, Latin America, and the Middle East. We have continued to advance the formal reimbursement process in many countries.

Let me hand the call over to our Chief Commercial Officer, Mark Rothera, for further detail on our commercial efforts.

Thanks, Stu. This was another strong quarter for Translarna sales, reaching $22 million and representing 125% growth over the third quarter of last year. Our goal is to make Translarna available to nonsense mutation DMD patients around the world as promptly as possible, since every day counts for them. Our strategy is to achieve this through both rapid geographic commercial expansion and increasing penetration of markets where reimbursed Translarna is already available.

Increasing penetration is achieved both through the conversion of known nonsense mutation DMD patients onto drug and the continued focus on patient identification through DMD awareness programs and genetic testing activities. In addition, we continue to be pleased with the remarkably high level of compliance to Translarna therapy.

While pricing and reimbursement discussions are ongoing in a number of key European countries, I'm happy to say that we are making great progress at securing access to patients in new countries and at a price level that is sustainable to our organization. And I'd like to speak more to this point on our call today.

Our latest achievement is an agreement on terms with AIFA, the Italian Medicines Agency, which enables commercial access for Italian patients, including switching those patients currently receiving Translarna either through our extension trials or reimbursed early access. These commercial terms will become effective in the new year.

We also achieved agreement on pricing and reimbursement terms with both the Swedish National County Council, as well as the Romanian Ministry of Health, during the third quarter. These developments will enable reimbursed access for additional nonsense mutation Duchenne patients in Europe.

During the third quarter of 2016, Translarna also become available to patients in England following the issuance of final guidance by the National Institute for Health and Care Excellence, or NICE. Since the agreement was published, we are pleased to have seen rapid uptake in England, representing the fastest country launch to date. Furthermore, every region in the UK, which includes Wales, Scotland, and Northern Ireland, has granted reimbursed access to Translarna. We are pleased that the very broad advocacy effort of patients in the UK has enabled all eligible patients to gain access to the therapy through a managed access agreement.

As you will recall, patients in Germany are accessing therapy through the foreign importation pathway. This alternate path has successfully enabled treated patients, prior to de-listing, to stay on therapy, and new patients to start treatment, as well. As a reminder, in May of 2015, German's Federal Joint Committee, or G-BA, the highest decision-making body in the German healthcare sector, granted Translarna an early benefit assessment rating of three, which signifies that the drug provides a quantifiable added benefit to patients.

In the third quarter of this year, the G-BA began a re-analysis of Translarna based on additional data from the ACT DMD study. The outcome of this assessment is expected later this year. After the G-BA reassessment, PTC could choose to revisit reimbursement discussions with the national health insurance body, the GKV.

Translarna net sales continued to grow outside of Europe, and we are confident in our ability to reach sales in line with our stated guidance for 2016. PTC has built a commercial footprint spanning over 40 countries and plans to further expand Translarna's availability on a country-by-country basis over the coming quarters, as well as increase penetration in countries where reimbursement is already available.

With that, let me turn the call back to Stu.

Thanks, Mark. Let me now turn to our program for Translarna in cystic fibrosis. We anticipate the results from our global confirmatory phase three clinical trial, ACT CF, toward the end of the first quarter of 2017. I want to discuss some of the important developments surrounding the trial design and analysis. We actively solicited feedback regarding our statistical analysis plan from the FDA through a type-C meeting during the third quarter of 2016. Following receipt of feedback from the FDA and our CHMP rapporteurs, we revised our protocol and made corresponding changes to our statistical analysis plan for ACT CF. These changes were aimed to align with precedents with respect to the more recent approval of the cystic fibrosis-related therapy.

The primary endpoint was adjusted from a measurement of relative change to an absolute change of FEV-1 over 48 weeks. Additionally, we plan to measure the change in FEV-1 from baseline to the average reading at the last two visits as opposed to baseline versus the final visit. Measuring the average of the last two visits reduces the impact of variability on the endpoint. This change in the primary endpoint to the measure absolute FEV-1 does not impact the statistical power of ACT CF. The trial was originally designed to be powered for a 6% relative change with a 90% confidence, and is now designed for a 3% absolute change.

As a reminder, we submitted a type 2 variation to our marketing authorization in Europe to request approval for Translarna for nonsense mutation cystic fibrosis during the third quarter of 2015. We believe Translarna is the only product candidate in clinical trials to address the underlying cause of nonsense mutation CF, which is considered one of the most difficult-to-treat populations. The submission was based on post-hoc analysis of the results from our previous phase three study. We will continue to respond to questions from the CHMP. However, we believe they may wait for the outcome of the ACT CF to issue an opinion.

I would now like to focus on another program in our clinical pipeline. As we have discussed before, we have developed a platform technology to identify molecules that modulate (inaudible). This technology has been used to discover potential new therapeutics for spinal muscular atrophy, or SMA. SMA is a rare genetic neuromuscular disorder that is caused by a missing or defective SMN1 gene, which results in reduced levels of SMN protein. The disease generally manifests early in life and is the leading genetic cause of death in infants and toddlers.

We have a robust program and collaboration with Roche and the SMA Foundation around oral small molecule SMN2 splicing modifiers as a way to address the disease. And oral therapy, which has exposure to both muscle and nerve tissues, has the potential to provide considerable advantages for patients. We recently announced developments regarding the oral SMN2 splicing modifier, RG7916. Phase one data was highlighted by Roche at the Child Neurology Society meeting in Vancouver showing dose-dependent increase in the SMN2 messenger RNA. The data supported moving into patients, and the program recently advanced into a phase two study in SMA type 2/3 patients.

The study, named SUNFISH, is a two-part study investigating the safety, tolerability, and efficacy of RG7916. The first part is a dose escalation study to evaluate safety and tolerability. After dose selection, the study will transition into the pivotal efficacy segment. Initiation of the pivotal second part of the study is expected to begin in 2017 and will trigger a $20 million milestone payment to PTC from Roche.

A similarly designed two-part study called FIREFISH in type 1 SMA patients is expected to begin in the coming months. Furthermore, we have grown our splicing technology platform. We have very specific and important knowledge of the splicing sequences involved in the alternative splicing of various genes involved in the manifestation of disease. Our discovery research team is currently advancing two additional programs based on this knowledge and technology. One of these programs is advancing through a collaboration with Mass General Hospital and is focused on the splicing of the ICAP gene, which is involved in familial dysautonomia.

We are also advancing an exciting program utilizing splicing to address Huntington's disease. Both of these programs are receiving significant attention, with the goal of declaring at least one development candidate by the end of 2017.

On another clinical front, our internally developed oncology compound, PTC596, was recently highlighted at the European Society for Medical Oncology. PTC596 is an orally active small molecule that targets tumor stem cell populations by reducing the function, activity, and amount of BMI1. PTC596 acts by altering and destroying the BMI1 protein through a process called phosphorylation. The poster described the dose-escalating phase one study nearing completion and confirmed that PTC596 is generally well tolerated at doses that achieve or exceed plasma concentrations at which we saw efficacy in preclinical models. We will use the results of this study to move into further clinical development in 2017.

To wrap up, we are working diligently to complete the renewal of the EU marketing authorization. Translarna's commercial presence continues to expand around the world, and we continue to deliver strong commercial results. We remain committed to bringing Translarna to patients in the United States, and are engaging with the FDA to escalate the dispute resolution process. We are immensely proud of the internal research and development, and we have a robust clinical and preclinical pipeline that continues to advance.

With that, let me turn it over to Shane to talk about our financial results for the third quarter. Shane?

Thanks, Stuart. As mentioned earlier in the call, we generated $22 million in Translarna net product sales in the third quarter of 2016. This represents a 125% increase versus the same quarter in 2015. Year-to-date through the first nine months of this year, we have generated over $56 million in net sales, which gives us confidence in our ability to achieve the middle of our revenue guidance of $65 million to $85 million in Translarna net product sales for the full year 2016

We reported a net loss of approximately $35 million for the third quarter of 2016 compared to approximately $43 million for the same period of 2015. Our net loss decreased sequentially versus approximately $39 million in the second quarter of 2016, largely in part due to our growing revenue stream.

Non-GAAP R&D expenses in the third quarter were approximately $27 million, which were relatively flat compared to the same period in 2015, and non-GAAP R&D expenses increased sequentially versus the second quarter of 2016 by approximately $2 million. Non-GAAP SG&A expenses were $19 million for the third quarter of 2016 compared to approximately $17 million for the same period of 2015, and non-GAAP SG&A expenses were relatively flat compared to the second quarter of 2016.

Our net cash burn for the third quarter was $24.6 million, which represents a monthly burn rate of approximately $8 million. We ended the quarter in a strong position, with $248 million in cash and marketable securities on our balance sheet.

With respect to our operating expense guidance, we now anticipate non-GAAP operating expenses to be between $180 million and $190 million for the full year 2016, excluding approximately $35 million in non-cash stock-based compensation expense, for total operating expenses of approximately $215 million to $225 million for 2016, a reduction of approximately $10 million from our prior guidance. And we expect to finish 2016 with approximately $220 million in cash and cash equivalents on our balance sheet.

We will now turn the call over to the operator to start Q&A.

(Operator instructions.) Tazeen Ahmad, Bank of America.

As you continue your discussions with CHMP, you've mentioned that you're going to have another oral meeting with them. Given the fact that your drug has been on the market now for quite some time, and the agency should be relative familiar with the attributes of it, can you give us a little bit more color on what topics they've been wanting to discuss, particularly since your phase three data came out?

And then, maybe one question for Mark. How is the sales trend going in Germany? Not having an official price there, has that been a meaningful deterrent for uptake, in your view? Thanks.

As I said in our prepared remarks, given that we're really in the middle of the dialogue with the agency, and that we're completing this process, we really provided all the information that we can on the call today. So, we're not able to comment further. And given that we're so close to completing this, we expect to participate in a call later on once we get a final decision. So, I think we've said all we could say right now in terms of where we are, and we expect to get an oral explanation and complete by the end of the year, as we said.

Has the agency told you that they will have an answer for you by the end of the year, or do you feel that you will have one just based on where you are?

I think it's based on where we are. We think we'll complete the process by the end of the year.

And then maybe on the commercial question.

In fact, as you know, the foreign importation pathway exists where there's a very high unmet medical need, and the product is not accessible within the German marketplace. And as we mentioned before, since we de-listed, all patients have been able to transition onto that pathway that were on drug, and in fact, since then, we've added new patients, as well. So, in fact, we are seeing growth in the German market.

And do you think that this growth can continue even in the absence of a negotiated commercial price there?

That's what we're seeing. That's our current expectation. Now, in addition, we've submitted the G-BA dossier with the updated data from ACT DMD, and that will be going through a further assessment, and we'll get the outcome of that by the end of this year.

And then, following that, we can take the decision to reengage with the umbrella health insurance organization and potentially think about coming to an agreement on a sustainable pricing model to get back into the German market, which might be easier for all parties. But, that's a choice we can make down the line.

But, there wouldn't be any potential disruptions should you end up getting to agreement on a commercial price with supplying the patients that you already have in Germany, is that right?

No, we don't believe so, because what we've already shown is there was no disruption really to the supply in the first place going through the foreign importation pathway. And it's clearly in the interest of all parties, that if we negotiate to come back into the German listing, that we don't want patients to go off-drug. So, I don't think that would be the case.

Geoff Mitchum, Barclays.

This is Evan on for Geoff. One on the commercial performance. So, if I look at sequential quarter-over-quarter growth, if I take the midpoint, it seems that we're actually going to be down in fourth quarter. Am I thinking about this correctly, or am I missing something?

And then, with the new G-BA analysis, what has changed in their assessment? What else are they looking at to potentially get a more favorable view of Translarna? And then, how is enrollment going for the SMA program, given the updates from Biogen Ionis recently?

On the first part, in terms of the guidance, I think we're updating our guidance somewhat to say that we anticipate our ability, or our confidence in our ability to hit the middle of the range. And therefore, as you point out, we're $56 million through the first nine months, therefore the middle of the range being in around $75 million. I think we have our confidence in our ability to achieve that. Is there potential for upside? We'll see, but I think that would certainly indicate a fourth quarter in the same area as this quarter. We have talked previously about fluctuations from quarter to quarter depending on ordering patterns from certain countries, and in particular Latin America.

And then, about the new G-BA analysis, or assessment?

Would you mind repeating what the question on the G-BA was?

What new information, or what are they reassessing? What's going to potentially change their view of Translarna? And you said we'd get that by the end of the year?

Yes. the point here was that we actually made a commitment to go back to the G-BA with our ACT DMD data, which they hadn't previously integrated into their evaluation. The initial evaluation was done on the phase 2B study alone. So, we promised to go back to provide that data so they could do the fuller assessment, which includes the ACT DMD data.

And probably (inaudible) to remind them that the G-BA assessment was a score of three, which is actually it was a good score. The issue wasn't really in terms of the score, because we got a score that said that it was a quantifiable benefit. And so, the issue was the insurance company, we couldn't come to agreement on a sustainable price, but the G-BA gave it a very good score.

So, if the G-BA gave it a good score, what's the rationale for potentially getting a better price from the insurance company, and the insurance provider in Germany?

Well, it appears, at the beginning of this year, we were kind of caught up in a tension between the G-BA rating system and the health insurance system, and slightly different views on how to deal with orphan drug price. There's kind of a public debate going on.

Now, we're in a different place today, and there may well be the possibility of coming to a different agreement with the health insurance umbrella organization now that more time has passed and the drug is already being made available within the German market. So, it could be in the interest of all parties to have the drug supplied within the German market itself.

My final one on SMA and enrollment, given Nusinersen?

Let me just remind you that RG7916 is orally bioavailable compound [of that] compared to the (inaudible). So, Roche has done a lot of work and have analyzed this, and it's clear really that there are sufficient patients available globally to enroll these studies. So, they're confident that they'll be able to enroll these studies.

Heather Behanna, Wedbush Securities.

The first is a follow-up on the guidance on revenue. And if you could comment if there were any -- I know you had commented that Brazil would be every six months potentially, if there were any Latin American payments in the third quarter that contributed to the revenue from the third quarter?

Sure. So, during the third quarter, we did receive both individual and new patient orders from Brazil, and also a bulk national order. However, just to put that in a relative sense, the overall impact of any particular given order this quarter of that nature was not as significant as what we saw in Q1 this year.

And then, just switching gears for a second for an SMA question, I think for RG7916, I was just curious about the preclinical package, and if the nine-month toxicology work is done, and if there's potential for some of those data to be shared at a meeting so we can try to understand the difference between the two potential SMA compounds in the future.

And so, Roche has completed a significant part of the non-clinical tox studies with RG7916, although there are additional work that's ongoing, and they do anticipate presenting the results at a scientific meeting next year. I think one point, though, that's important is that, based on the fact that we're moving forward in the clinical development of RG7916, I think it's clear that we're comfortable with the improved pharmacological properties of the molecule with its wider therapeutic window. So, importantly, we're now moving beyond the phase one into the clinical studies with the SMA patients.

Anupam Rama, JPMorgan.

I was just thinking a little bit about the volume growth for Translarna, if you could give a little bit of color on the breakdown of deeper penetration in the existing markets [and] some of the new geographies that you kind of layered on recently. And maybe you could talk a little bit about if there've been any differences in what you're seeing on compliance rate. Thanks so much.

As I mentioned on the call earlier, the real drivers of our growth are a combination of geographic expansion, but also continued penetration in our existing market. And so, whilst we're not giving specific breakdowns by region, we are seeing considerable growth in all regions, in Europe, in Latin America, and more recently in the Middle Eastern region.

And when we do an analysis of compliance rate by looking at repeat ordering patterns for patients, we're seeing a very high compliance rate of over 90%, which I think is a really good level for a chronic everyday therapy, particularly one that's taken three times a day. And we're getting positive feedback from physicians and patients about the benefits they're feeling when they're on therapy.

Alethia Young, Credit Suisse.

This is Ellie on for Alethia. Just on the commercial side of things, can you characterize what proportion of DMD patients in Europe have been genotyped, and also what strategies are you currently using to increase the number of diagnosed and genotyped patients? And can you update us on how this has all been going? Thanks.

Yes. So, perhaps the best way to answer that is to focus on the Big Five EU countries, just to give you a sense where we've already identified approximately 80% of the expected prevalence of on-label patients in those countries. And now, we're working through getting those patients through to access the therapy, and that depends on the different country systems. Globally, we're putting a lot of assets still behind patient identification work through both DMD awareness, but also putting in place genotyping resources. So, I think previously we've talked about Latin America and Brazil, where we really help the community put in more resource to enable that to happen.

Joel Beatty, Citi.

For the SUNFISH trial, just tell us what data will Roche be looking for from the patients in the first part of the trial, and their assessment on whether to move on to the pivotal portion of the trial?

They'll be looking at obviously exposure, safety, and then the change of the SMN2 RNA to make the SMN RNA, and then of course the protein levels, as well, to identify the best level -- the compound that will demonstrate the protein [will be made]. So, that will be the first part, and then it will seamlessly transition with the appropriate dose into the pivotal portion of the study to look at efficacy in those patients.

One other question on Translarna in Europe. In the event that CHMP decides not to renew the authorization, are there any alternative ways that Translarna could sustainably be provided to patients in Europe?

In the event of an opinion from the CHMP not to renew our marketing authorization, our intention would be to appeal that decision. The appeal process I guess is around a four- to six-month period. And during that period, we can continue to market and sell Translarna until the EC ratifies that final opinion. So, essentially, we would maintain in the status quo until a final decision. And if in the eventuality that leads to a continued negative decision, then we may be forced at that point to withdraw the drug

Simos Simeonidis, RBC Capital Markets.

This is Matt on for Simos. So, I wanted to ask if you could comment a little more on specifically what has introduced the higher degree of uncertainty to the outcome of the Translarna renewal in Europe. Is this based upon recent dialogue that you're referring to, or is this subsequent dialogue to the most recent regulatory update that you provided on October 17?

Yes, thanks for the question. As we've commented, we're in the middle of the process. And given that we're so close to the meeting next we expect to participate in, that we're so close to completing this process that we're really refraining from answering any other thing other than what we've already made the comments on for the regulatory discussion.

And then, you mentioned an alternative regulatory strategy for Translarna in the US. Could you talk any about what that potentially may be?

Well, as we said, we're in the middle of the appeal process, and again, that's what we're doing right now. And so, as we're in the middle of that, this is all we're going to comment on at the moment.

I wanted to ask a little bit about the change in the endpoint for ACT CF. specifically, what prompted this meeting with the FDA? And was this based upon any points that may have been raised during prior discussions with the CHMP?

Thanks for that. This was really based on what we've been thinking about the changes in light of designs from other cystic fibrosis trials that have been performed and how they recently approved therapies. So, what we've done is we took the time to go back and talk to both the FDA and the CHMP on this, so that's what that came to, and that's what these changes were a consequence of.

Gena Wang, Jefferies.

This is (inaudible) for Gena. So, just a quick follow-up on the SMA program. So, just wondering if you can remind us what level of [full SMN2 was] produced in the healthy volunteer during the phase one? And also, what would be the threshold that you think would be required to achieve clinical benefit in SMA patients? Thank you.

Yes, so as you might remember from the previous presentation, this was from a single dose patient where we saw a significant increase in terms of the amount of SMN2 that went to SMN1 transcription. You might remember from the RG7800 where we saw somewhere between a 50% and 100% increase in that range. So, when we go to the next study, we'll be able to, on continuing dosing, will be able to see where that [lands up]. We'd certainly, if you would like, send you the poster from the CNS, the Child Neurology meeting, so that you could see those more directly.

Yes, that would be great. So, for the 100% increase, do you think that would be sufficient in the SMA to achieve the clinical benefit? So, (inaudible) the primary endpoint would be a milestone, like (inaudible)? So, just wondering what would be the threshold that you expect to achieve.

Yes, and this is obviously when we had done this before in plasma. But, you may remember from the preclinical studies where we had animal studies where we saw the net range, where we saw substantial improvement in the animal SMN model. So, that's what makes us quite excited about those results. So, yes, so in that sense, if they reflect what happens in an animal model, that we would think these would be important changes.

Thank you. Ladies and gentlemen, that now concludes our question and answer session. I would like to turn the call back over to Management for closing remarks.

I'd like to thank everyone for being on the line today. As you can see, we've had a lot of important developments and progress across many fronts, and that we look forward to sharing more information with you upon the completion of the (inaudible) opinion. So, we expect to be able to talk to you more in the near future. Thank you for taking the time to be on.

Ladies and gentlemen, thank you again for your participation in today's conference call. This now concludes the program, and you may all disconnect at this time. Everyone have a great day.