Voyager Therapeutics Inc (VYGR) 2017 Q4 法說會逐字稿

Good morning, and welcome to the Voyager Therapeutics Fourth Quarter and Year-End 2017 Financial Results and Corporate Highlights Conference Call. (Operator Instructions) Please be advised that this call is being recorded at the company's request.

At this time, I'd like to turn it over to Matt Osborne, Voyager's Vice President of Investor Relations and Corporate Communications. Please proceed.

Thank you, Shannon. Good morning, and welcome to the conference call. This morning, we issued a press release which outlines the results and corporate highlights for the fourth quarter and year-end of 2017 and provides our corporate goals and financial guidance for 2018. The release is available at voyagertherapeutics.com.

Today on our call, Steve Paul, Voyager's President and CEO, will briefly discuss our recent corporate, and program highlights; Bernard Ravina, Voyager's Chief Medical Officer, will review the Parkinson's disease program; and Jane Henderson, Voyager's Chief Financial Officer and Senior VP of Corporate Development, will review the year-end financials, and then we will open up the call for your questions.

Before we begin, just a reminder that the forward-looking statements included in this call represent the company's view as of today, March 14, 2018. Voyager disclaims any obligation to update these statements to reflect future events or circumstances. Please refer to today's press release as well as Voyager's filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by such statements.

With that, I'll pass the call over to Steve.

Thank you, Matt, and good morning, everyone. Voyager's strong performance in 2017 was evident across many functions of the business, including clinical and preclinical development, manufacturing, operations, human resources and business development. This allows us to enter 2018 with an exciting program in Parkinson's disease that is about to enter a pivotal clinical trial, a group of pipeline programs targeting other severe neurological diseases that continue to advance towards the clinic and an exciting new collaboration with AbbVie to deliver monoclonal antibodies using AAV that allows us to pursue other important CNS disorders, including Alzheimer's disease.

For VY-AADC, we recently reported longer-term follow-up data from the Phase Ib trial that we believe continues to demonstrate that VY-AADC can restore the brain's ability to make dopamine and offer patients better control over their motor function in response to levodopa therapy, the way they initially did during the earlier stages of their disease.

As Bernard will discuss, the goal of this trial and any well-designed Phase Ib clinical trial is to, as fully as possible, explore a range of doses for both safety and efficacy before proceeding into a pivotal placebo-controlled trial, and we have accomplished this with our most recent data set. The results that Bernard will briefly highlight are clinically robust, durable and we believe not due to a placebo effect, and we are confident that the design of the Phase II/III pivotal program allows flexibility with respect to maximizing our chances of success. Achieving success in this placebo-controlled program would set a very high bar in the field of Parkinson's disease to address the hundreds of thousands of patients with a onetime treatment and a unique mechanism of action that could provide durable improvements in motor function and quality of life.

Our pipeline programs continue to advance with 2 IND filings expected from the ALS, Huntington's disease and Friedreich's ataxia programs in 2019. Now simply advancing programs into the clinic is not our goal, but advancing potentially best-in-class programs that have a high probability of success once in the clinic is the goal, and our ongoing efforts to optimize the capsid, transgene and delivery approach applies to each of our preclinical programs, our ALS SOD1, Huntington's disease and Friedreich's ataxia program.

For Huntington's disease, in particular, recent clinical data from antisense oligonucleotide approaches targeting mutant and wild-type Huntington administered monthly by Intrathecal lumbar bolus administration supports further development in our view and encourages us with our own gene therapy lead candidate, which, again will be a one and done approach. However, before proceed -- we proceed into clinical development, it is important for us and others to be able to knock down the Huntington protein in relevant nonhuman primates in both the cortex and striatum. We believe our delivery approach and optimized vector has the potential for achieving greater Huntington knockdown in striatum than other approaches and importantly, sufficient knockdown in the cortex to achieve maximal therapeutic benefit. We look forward to providing you with an update on these preclinical data and advances with this program later this year.

Now for Friedreich's ataxia, we are also progressing our work using several novel AAV capsids to select a lead clinical candidate. We recently presented encouraging data in a very compelling transgenic mouse model of Friedrich's demonstrating that a onetime intravenous dose of a novel AAV capsid and a frataxin transgene led to a rapid halting and reduction of disease progression measured by multiple tests. With increasing IV doses of our vector, we observed complete rescue of the Friedrich's phenotype, which are very, very exciting results. Also, we have identified an AV vector that effectively delivers frataxin not only to sensory neurons, but also to the heart, an important target tissue for potentially treating the cardiomyopathy and heart failure that eventually proves fatal to so many patients with Friedreich's ataxia.

Now turning to our goals for this year. 2018 will be an important year for the company as our Parkinson's disease pivotal program will be up and running and advancing our other exciting pipeline programs are well within our reach. Specifically, we plan to complete a Type C meeting with the FDA, incorporating feedback from this meeting into our Phase II/III pivotal program for VY-AADC for advanced Parkinson's disease. We will provide 6-month safety and motor function data from the Phase I trial of VY-AADC using the posterior infusion trajectory. During mid-2018, we plan to dose the first patient in the planned Phase II pivotal program for advanced Parkinson's disease. And during the second half of 2018, we plan to provide longer-term safety, biomarker motor function and quality-of-life data from Cohorts 1 through 3 and from patients in the posterior trajectory trial. We will continue to advance multiple preclinical programs towards clinical trials through further vector optimization and exploration of additional routes of administration leading to filing 2 IND applications from the ALS SOD1 Huntington's or Friedreich's ataxia programs during 2019.

In addition, as we've done with our AbbVie collaboration, we will continue to identify, evaluate and progress business development opportunities including potentially partnering other Voyager programs as well as our technology platform capabilities.

Now before I turn it over to Bernard, earlier in the year, we announced my succession plan, which is well underway. Having been with the company for 6 years since its inception, I take great pride in our accomplishments, with the great progress we've made with our pipeline and in helping to assemble a terrific leadership team. I will continually enroll with Voyager as a member of the board, and as a member of Voyager's Science and Technology Committee. Given my passion for science and discovering new medicines, I look forward to spending more time with the tau antibody program and our collaboration with AbbVie. Both companies are hitting the ground running on this exciting collaboration.

Bernard will now review the progress with our Parkinson's disease program.

Thanks, Steve, and good morning, everyone. We recently provided the Phase Ib interim update with VY-AADC. I'll briefly recap those results and address some questions that have come up since the readout.

At a high level, our first Phase I trial has allowed us to understand the dose response and identify what we think is the maximum tolerated dose or concentration that does not lead to too much dopamine. The second Phase I trial using posterior delivery has shown this approach to be a more efficient infusion strategy to take into the pivotal program than the transfrontal approach used in the first trial. This is exactly what we hope to achieve with the both of our Phase I studies.

The data from the first trial show that onetime administration of VY-AADC increases enzyme activity and decreases the need for levodopa and related medications in a dose-dependent manner, thus confirming the mechanism of action. The recent data continue to show robust durable improvements in patient's motor function along with sustained reductions in daily oral levodopa and related medications in the 2 higher dose cohorts. At 18 months, Cohort 2 generated a 3.5-hour improvement in quality on-time or on-time without troublesome dyskinesia, which is the primary endpoint of the pivotal program. At 18 months, Cohort 2 patients also had a mean increase of 5.1 hours a day of on-time without any dyskinesia and experienced 65% less off time. These are very clinically meaningful results, especially at this time point. These results are above what one would expect for placebo and are in the same range as deep brain stimulation in a similar patient population. But diary data represent only 2 to 3 days of function at a time. For an assessment of how patients are doing over a longer period, we can look at the Unified Parkinson's Disease Rating Scale activities of daily living, in the patient reported 39 item Parkinson's disease questionnaire or PDQ-39. VY-AADC demonstrated dose-dependent, clinically important improvements in both of these measures in Cohorts 2 and 3. These measures indicate overall patient well-being and are reflective of durable and meaningful treatment effects in motor function.

So what does this all mean for patients? It means, they can count on a reliable and robust response to levodopa as they did early in their disease course. In fact, we know patients who are able to return to work or other activities, including a job that involves public speaking. Across the cohorts, patients in the trial have been able to return to meaningful daily activities that reflect a high level of motor control including riding a bike and skating. This is really the goal of the program, to return patients to a stage when they are able to control their motor function with oral levodopa. We're very pleased with the overall results, especially in Cohort 2, given the balance of the durable and improved response in motor function and wider range to titrate oral levodopa. The combination of the more manageable concentration of Cohort 2 with a potentially greater coverage of the putamen and simpler posterior delivery procedure may be the ideal dose and administration to take into the pivotal program.

Now to address a couple of the questions raised since the release of the data. First, on durability of response with respect to increase in L-dopa doses observed in Cohort 1 from years 2 to 3. Data on Cohort 2 and 3, now at 12 and 18 months, show stable responses over time across multiple measures. Cohort 1 received the lowest dose of VY-AADC, which we believe is minimally active based on a small increase in fluorodopa PET signal and modest initial reductions in levodopa. The uptick in levodopa doses after 3 years is driven by a single subject and must be taken in the context of their overall clinical improvement. Unlike a placebo response, over time, this cohort evolve to have clinically relevant benefits as shown by their diary data. And 3 years after dosing, the cohort, on average, is better or similar to baseline on all of the relevant motor measures. Given that PD progresses over time, these 3-year data are very compelling.

Now to Cohort 3 and the plateau from 6 to 12 months on on-time without troublesome dyskinesia. It appears at this one time point, 12 months, we have reached a maximum effective dose with the Cohort 3 concentration. Patients in Cohorts 3 on average entered the trial with more severe dyskinesia than patients in Cohorts 1 and 2. They received a higher dose of VY-AADC, which resulted in more conversion of oral levodopa to dopamine and more levodopa-induced dyskinesia. This resulted in larger reductions of levodopa and less improvement on diary than Cohort 2. This was not the case in the 1 patient each in Cohort 1 and 2, who had similar dyskinesia at baseline. This suggests a logical and expected interaction of baseline dyskinesia severity and dose of AADC that's consistent with dopamine pharmacology. For example, in order to balance dyskinesia with good motor control, 1 patient in Cohort 3 reduced their levodopa dose to 25 milligrams or less at a time. This is striking evidence of a clinical response given that patients generally take 100 milligrams at a time when they are first treated. Such small doses, however, can lead to erratic absorption and instances of variable motor control. These reductions in levodopa resulted in less improvement in off-time and on-time as measured by diary compared to Cohort 2.

These results may evolve over time as we've seen in other cohorts and in the preclinical data, and underscores that clinical benefit of AADC will be driven by balancing both enzyme or AADC levels in management of the substrate oral levodopa. Importantly, we'll apply the lessons from this trial to the design of the pivotal program, including dose selection and management of levodopa doses posttreatment.

Finally, to the pivotal program. Given the data from Cohort 2, we're pleased with the design of the program. As a reminder, this is a staggered parallel design with a Phase II and a Phase III portion. The Phase II is powered at 80% to detect a 2-hour improvement in on-time without troublesome dyskinesia from baseline to 12 months versus placebo. The Phase III is powered at 90% to detect a 1.5-hour improvement in on-time without troublesome dyskinesia from baseline to 12 months versus placebo. We're within that range for the Phase II and well above that for the Phase III, given that Cohort 2 data that generated a 3.3-hour improvement from baseline at 12 months. Drawing from past placebo-controlled gene and cell therapy trials in Parkinson's disease, it showed less than an hour of improvement. This provides us with nearly a 1-hour buffer going into the Phase III trial. In addition, the pivotal program will capture many secondary endpoints that are important to regulators, payers and patients themselves.

In summary, we're very pleased with the safety, pharmacology of VY-AADC, the durability and magnitude of effect, the results in particular with the Cohort 2, and the plans going forward with the program.

I'll now pass the call over to Jane, who can walk you through our financials in more detail.

Thanks, Bernard, and good morning. I'll spend the next few minutes reviewing the financials and guidance before we move to Q&A.

Voyager reported a GAAP net loss of $11.8 million or $0.40 per share for the fourth quarter ended December 31, 2017 compared to $14.7 million or $0.57 million per share for the same period in 2016. For the full year ended December 31, 2017, we reported a GAAP net loss of $70.7 million or $2.64 per share compared to a net loss of $40.2 million or $1.59 per share for the same period in 2016.

Collaboration revenues were $6.3 million for the fourth quarter 2017 compared to $2.4 million for the same period in 2016, and $10.1 million for the full year ended December 31, 2017 compared to $14.2 million for the full year ended 2016. Collaboration revenues reflect recognition of payment for research and development services provided by Voyager for various programs under the Sanofi Genzyme collaboration agreement. These revenues can vary based on quarterly assessments of anticipated efforts under the collaboration. The increase in collaboration revenues for the fourth quarter of '17 compared to '16 reflect revenue recognition as a result of Sanofi Genzyme's decision to not exercise its license option to the ex-U. S. rights to the Parkinson's program and then Voyager's recognition of the portion of the agreement allocated to the Parkinson's option.

For the full year 2017, the decrease in collaboration revenues compared to the same period in '16 reflects the changes in the estimated periods for reaching development milestones for certain preclinical programs under the ongoing Sanofi collaboration agreement.

As of January 1, 2018, the company has adopted FASB's new guidance on revenue recognition, known as ASC 606. So going forward, we will make changes as to how we recognize revenue related to our collaboration agreements. We are adopting the new guidance using the modified retrospective approach and will give guidance through the year on revenue recognition for the Sanofi and AbbVie collaborations. Therefore, announced recognized as revenue in prior periods will not necessarily be indicative of future announced to be recognized.

Research and development expenses were $13.3 million for the fourth quarter ended December 31, '17, compared to $12.7 million for the same period in 2016. For the year ended 2017, R&D expenses were $62.3 million compared to $42.2 million for the same period in '16. The increase in R&D expenses related primarily to the development of our pipeline, including the ongoing Phase I trial for VY-AADC and increased personnel and facility costs to support the advancement of our programs.

G&A expenses were $5.4 million for the fourth quarter of '17 compared to $3.5 million for '16 and $19.7 million for the year ended '17 compared to $13.3 million for the year ended '16. The increase in G&A expenses was primarily due to personnel and facility cost to support our pipeline programs.

Total cash, cash equivalents and marketable debt securities as of December 31, 2017 were $169.1 million.

Now turning towards guidance. As we enter 2018, with the exciting progress of the Parkinson's program advancing into the planned pivotal stage, with the preclinical pipeline advancements including the AbbVie collaboration and with the ongoing investments in manufacturing and to the vector product engine and platform, we expect to end 2018 with total cash of approximately $125 million to $135 million. This amount includes the $69 million upfront cash payment recently received from AbbVie. We project that our existing total cash will be sufficient to fund operating expenses and capital expenditure requirements into early 2020.

The cash runway into 2020 is based on our current operating plan and does not include potential new PD transactions. We remain committed to pursuing business development opportunities around some of our unpartnered programs as well as our platform capabilities.

With that, we'd now like to open the call up for questions. Operator?

(Operator Instructions) Our first question comes from Charles Duncan with Piper Jaffray.

This is Sarah on for Charles. So can you just remind me for further posterior trajectory, the dosing that you are using and how long the procedure is taking at this point in development? And then beyond procedure time, what kind of patient-reported or other outcomes, for example, a pain medicine use will help characterize that procedure as a success?

Sarah, thanks for the question. So just a reminder, the whole goal of that trial was really to develop an infusion approach that would be more scalable and efficient for the pivotal program and for commercial. So what we've been able to accomplish in that trial is take 2 to 3 hours of the overall procedure time. We're now in the 6 to 7-hour range which is, given that it's a onetime and not staged like DBS, puts it probably well under the overall procedure time compared to DBS. So we're very pleased with that, and we've gotten very good infusions that we think will be more repeatable consistent going into the Phase II and III than the transfrontal approach that we used before. In terms of outcomes, we have basically all the same measures that we had in the initial trial and have been reporting on. And we'll be updating all of you on 6-month data that are available for subjects who have made it to that point near the end of the second quarter.

Our next question comes from Jim Birchenough with Wells Fargo Securities.

This is Yanan dialing in for Jim. So first off, could you talk about the baseline characteristics of the patients in the posterior trajectory trial, in particular I'm interested in the severity of dyskinesia at baseline, and whether it's more similar to Cohort 1 and 2, or it's more similar to Cohort 3?

Yes. Thanks for the question, Yanan. So we'll unpack that more for you as we report those results. But overall, if you look at the first trial, the range of patients in there is quite representative of what you typically get. And the second trial, we should have that range as well with patients with more or less severe dyskinesias. We are using the Cohort 3 concentration in that study. So we'll see if it unfolds like Cohort 3 and will link that, again, as we have to our understanding of those baseline characteristics.

Got it. And in terms of the AADC enzyme activity, I forgot whether you are also mirroring it beyond 6 months from treatment. If you do, could you share whether in Cohort 1 at 3 years, do you see the same amount of enzyme? Or is there any change in enzyme levels?

So we will be repeating the fluorodopa PET scans, which are our measure of enzyme activity. Nobody has had their follow-up yet. That's going to occur in their -- in the long-term extension study, which is just starting up at UCSF, that has the longest term follow-up patients. So it'll be a few months yet. Reminder, Cohort 1 had very modest changes in enzyme activity, which is why we refer to them as minimally clinically active dose. And so looking for durability of enzyme activity, there may not be that informative versus Cohort 2, which has good measurable changes, and we'll be able to tell about their stability.

But let me underscore that. In the academic study that preceded our study, this was done by Professor Bankowitz, he literally PET scan patients every year for 4 years and saw no diminution to dose levels in AADC enzyme activity. In the monkey data, the nonhuman primate data, both by Bankowitz, but also by a group in Japan, have shown really stable expression out, in the case of the Japanese group, to 15 years in monkey. So we think given where we're placing the vector in these very stable neurons, these medians binding neurons in the putamen that the expression is going to be very durable.

Great. And lastly, trying to understand a bit more about the dose adjustment in the pivotal trial design. I think the dose adjustment may be up to the discretion of the patient, according to their feeling of their motor function. So my question is, is that true that it's entirely up to the patient? And also, once the patient dose reduce, is there a way to prevent them from overshoot? And also, could they step back the dose and -- in case they did overshoot?

Thanks for the question. So this will -- the management of the substrate levodopa and related medications is going to be important part of the pivotal program. And just take a step back, these dose reductions, this is not something that people are accustomed to doing and it's a testament to the fact that we're getting real pharmacology here, especially seeing people go down 900 milligrams or even more, that doesn't happen as part of the natural course. So we've learned a tremendous amount in the Phase I, exactly what you want to do in terms of how to do it and how quickly to do it. The reductions are something that we will provide guidance on for the neurologists, who will then work with the subjects in the study. I think, what we've learned is not to reduce too quickly. We did see that in the third Cohort some over reductions. That was an important lesson that I think we're able to take forward. And yes, you're absolutely able to titrate the dose back up. And importantly, titration of medication is something that neurologists, Parkinson's experts and patients with advanced PD are accustomed to doing, but it's almost always on the way up. They're increasing the titrate to optimal motor function, and this is just now doing it on the way down. So we're confident in our ability to do that, especially with all that we've learned from these 2 Phase I.

Yes. As Bernard said, there's a bit of a learning curve here. This is very unusual to go from 1.5 grams per day of LED, levodopa equivalents, to down significantly. And this was not seen normally clinically, which is one reason we really believe this is working. But there are some lessons to be learned on how best to do this and control motor function and that's what we're doing.

Our next question comes from Matthew Harrison with Morgan Stanley.

This is Vikram on for Matthew. So our question is about the upcoming Type C meeting. Just wanted to get a sense of what you're looking to get from that meeting? What kind of questions you had from the FDA? What types of issues you're looking to get clarity on? Any context you could provide there would be helpful.

Sure. So the -- we filed the IND, and we're given clearance to go ahead with this Phase II trial. So in terms of safety, the overall design of the study and the comparability around baculo compared to the triple transfection material, the agency is comfortable with those and really had no comments around those. So the Type C is going to be about the rest of the program in the Phase II/III. So really what we're going to focus on is how much evidence is needed, what kind of overall in and safety data set. The other things to focus on, of course, are the endpoints, the analysis plan. The endpoints here are very well-established in advanced Parkinson's disease. But we'll be able to understand other things like the role of fluorodopa PET given that this an enzyme replacement different than any other Parkinson's program that has progressed thus far. So we'll get an understanding of how they view those evidence, that kind of evidence and as I mentioned, the analysis plan. So I think those will be the key areas of discussion, pretty typical at this point in development.

Our next question comes from Christopher Marai with Nomura Instinet.

Maybe to shift gears here a little bit, thinking about your pipeline, obviously, there has been some great proof-of-concept work establishing. The Huntington's construct is being potentially helpful in that disease. I was wondering how you're looking at triaging the opportunity with respect to your pipeline of assets. Obviously, you talked about SOD1 as an ex-program. Help us -- or walk us through your decision-making process there and how we should think about progress going forward? And then just secondarily, remind us of the stereotype you're using there. I think it was an AAV9 as an AAV9 variant, maybe why not use AAV9 in these contexts given the great proof-of-concept to date?

Yes. Christopher, great question or questions. So for us, the key is adequate delivery and in the case of both the SOD1 program and the Huntington's program, adequate knockdown in relevant cells and the relevant tissues. So for SOD1, we need to see knockdown of SOD1 up and down the spinal cord in motor neurons and in the brainstem, ideally. And frankly, we don't see a lot of that having been done already out in the literature and out in the world today. So we're intent on making sure we can do that before we get into the clinic. Similarly for Huntington's, there is a bit more of a challenge and that Huntington's not only affects the basal ganglia, putamen, the caudate nucleus, the globus pallidus, but also, the whole cerebral cortex. And if you look at a late-stage patient, that's very, very evident on a simple MRI scan. So we need to see silencing of Huntington's or knocking down of Huntington's to a sufficient degree. Now the antisense oligonucleotide data that you're aware has shown in CSF knockdown of Huntington's in CSF. Now that's encouraging, I agree. But only insofar as it reflects what's happening in the brain and in the cortex, in particular. So in our monkey work, we now are using, for example, for Huntington's, AAV1 and we're using sites of administration that we believe will give us a very good knockdown of Huntington's throughout the brain and in those relevant brain regions. We're not, obviously, talking too much about exactly where what the sites are, but with that capsid, we're reasonably confident we can achieve those goals. And we're going to do that, make sure we do that in a monkey before advancing it to the clinic because if we can't do it in a monkey brain, which is larger than a mouse brain, obviously, but still much less -- much smaller than a human brain, the chances of achieving that in humans is low, but we're cautiously optimistic we can get there. And I would advise anyone who is evaluating any of these programs to make sure you've ascertain whether that kind of silencing or knockdown can be achieved.

Okay. And then when might we see some of the monkey brain data, if you will?

We're hoping later this year, we'll have some data for you that will convince you of the route of administration and the capsid that we're using.

Our next question comes from Brian Skorney with Robert Baird.

Yes, also, looking at the pipeline, I was just hoping maybe you could kind of comment a little bit when we look at SOD1, Huntington, Friedreich's ataxia. In terms of where you think you're going to have the doses? Where do think you can get away with local injection? Is Friedreich's ataxia, are you thinking that's going to require systemic AAV dosing? And then, Steve, maybe just kind of a high level off of that, any thoughts on Jim Wilson's recent publications and the risks that he's highlighting around systemic high-dose AAV? And any concerns on that, number one.

Yes. Great question. For -- just to remind everybody, for Parkinson's disease, we're going directly into the brain, intraparenchymal injections, that avoids very significant systemic exposure. We get great transduction in neurons, and as you know, it looks to be relatively safe, at least based on many subjects that have been dosed with AAV2, which is the capsid we're using there. It also obviates the concern about preexisting immunity antibodies that could neutralize the vector before it absolute -- actually transduces itself. So that one we feel very good about. Huntington's will be the same approach. Different capsid and different route, exact sites of administration will be different. But again, we feel the same way about that program. It's kind of derisked from some of that systemic exposure data that Jim Wilson has reported. Now for Friedreich's, on the other hand, we are looking at systemic exposure because there we want to get DRGs, which are technically neurons -- sensory neurons outside the blood-brain barrier. And also, we have a capsid that transduces the heart, which we're very excited about. And to be blunt, there's still a lot of work that needs to be done there, but using our capsids, which are AAV9 derivatives, we do not see the same kind of robust toxicity that Jim Wilson has reported in his monkey studies. Now we're using different monkeys. He is using rhesus monkeys, we're using cynos. There are differences in the transgene we're expressing. There are slight differences in the capsid. So they're not direct head-to-head comparisons. But all I can say is going up to doses very similar to the ones he use, one time either the 14th vector genomes per kilogram, we have not seen a fatality yet in any of our monkeys. So we will be reporting on that later this year in a peer-reviewed article and also presenting work at the upcoming ASCGT meeting in May.

Our next question comes from Reni Benjamin with Raymond James.

I guess, I'm interested in the comparability test. Could you provide a little bit more color on those tests? Are you looking at both enzyme levels and function? And can you remind us if any patients have been dosed with the new process? And kind of as we're waiting for the Type C meeting and the start of the pivotal study, do you plan on exploring more patients at the relevant cohort?

Thanks for the question. So as you know, baculovirus material has been used in clinic and other programs. So there is a precedent clinically and agency, of course, is well aware of that. In our discussions with them and as part of the IND we submitted, we had clear criteria in terms of comparing baculo to the triple transfection material that is currently used in clinic. Criteria were very straightforward, involve the identity, right. It's AAV2 with the same transgene, the same flanking elements. The purity, of course, as you would have with any release specs, and then -- I think the key of what you're asking about was the potency, right. Does this make AADC? Does it express AADC at the same levels and have the same kind of infectivity? So the answers to those are, yes. So that puts us in a good position to really move forward with that material. And we're comfortable with our understanding of how those match up on those characteristics.

Yes, in addition, for the IND submission, we did a complete toxicology study with the new prep and that was, obviously, compared with the old prep and the older data that was done many, many years ago. But to achieve and be successful in that tox study, we had to achieve exposures that were comparable and produced enough enzyme activity. These were primarily lab studies, but nonetheless showed very nice comparability.

And I'll add one other point, which is our -- clinically, our measure of expression is those fluorodopa PET scans. We have actually 3 fluorodopa PET scans in that Phase II trial, baseline, around 45 days and then at the primary endpoint 1 year. So we'll have an early look to make sure that we're getting good expression in patients.

Got it. And maybe just as a follow-up regarding the AbbVie collaboration, can you provide us an idea as to how we should be thinking about the time lines associated with this program? Is this something that could be seeing an IND in 2019? Or is this something that's quite early, and we should really be thinking about 2020 and beyond?

Yes. It's early. It's a discovery research collaboration initially. Stage 1 will be for 2 or 3 years, and then after that, hopefully, we'll be able to select the clinical candidate. Let me though underscore how excited we are about the collaboration. AbbVie is a terrific company. They have a lot of expertise in monoclonal antibodies, a terrific neuroscience group. And we like this for several reasons. Obviously, we're focused initially on antibodies to tau, which we believe will and could be disease-modifying in a number of neurodegenerative disorders, tauopathies and Alzheimer's perhaps. But also this gets us into an area -- a new area for us, which we're very excited about and that is the delivery of monoclonal antibodies with AV vectors broadly speaking for whole host of CNS diseases and conceivably non-CNS diseases. So it really does allow us to segue into a brand-new platform we believe for the company.

Got it. And I'm sorry. The previous question I had asked about kind of while you're this waiting period before dosing the pivotal study, does it -- would it make sense to continue to enroll in the ongoing Phase I at a given cohort with either the new prep or any of the other changes you're thinking about?

So no. We've really learned what we needed to learn from that posterior delivery study about dosing. And you can't readily switch material within a protocol. They're under different INDs. So we'll do what we said we're going to, start the Phase II. We'll have that PET scan as assurance on enzyme expression, and we'll move forward from there.

Yes. And we'll continue to follow the 22 patients that we've already dosed, and it'll be very interesting to see what happens in Cohort 3 over time, as we make dosage adjustments and the like. So we're going to continue to update you periodically on the activity, the benefits in these patients over time.

Our next question comes from Dane Leone with BTIG.

Two from me. One on the PK efforts and then one on the pipeline. Starting with the PK efforts, I want to ask, in terms of your design of the Phase II/III study, how are you thinking about analyses and prespecified endpoints that could give you some level of -- additional level of differentiation clinically on outcomes versus the DBS methods? I appreciate that, obviously, the differences and the procedure and the calibration, et cetera. But just in terms of clinical outcomes, how do you think you can design the study to make it more compelling from an outcomes point of view?

Got you. And thanks. So I think I understand the core of your question there, how do we really differentiate this based on outcomes of interest from deep brain stimulation. And it is a good reminder. All of the patients in our trials were candidates for deep brain stimulation and chose to enter one of these 2 studies. Most of them because they didn't want to have indwelling hardware. In terms of differentiating it further, the motor function measures are going to be very similar across our studies and what we was seen in DBS. And so it becomes a question of magnitude of the fact and are there differences across those endpoints. But the even more important aspect we think here is that there are clear side effects to deep brain stimulation that we think we may not have. The most important one being cognitive function. So it became clear, very nice paper, published at the end of last year showing that deep brain stimulation, both the implantation of the electrodes in the electrical stimulation caused very specific cognitive deficits. And it makes sense because it's related to where the electrodes are going. So we believe we will not have those cognitive deficits, and those cognitive deficits in DBS are clinically significant, in communication and kind of attention. So we'll be measuring cognitive function and some other behavioral endpoints that might provide a very important point of differentiation.

Great. And then one on the pipeline, if I may. I want to ask since you've hit on some of the to-do list in terms of getting these IND applications. I want to ask, as you decide between the different programs or for the 2 INDs, how much is it factoring into your decision-making process, whether these programs that you decide upon may or may not be partnered and/or whether they'd be partnered before an IND is filed or after you have some clinical data? And then on the potential of an IP position, whether there might be some debate whether you owe someone royalty or something like that depending on the clade used?

Well, just to refresh everybody's memories. So the Huntington's program and the Friedreich's program kind of remain under the rubric of our Sanofi Genzyme agreement, where they have an opt-in provision once we get into the clinic. The ALS program we have worldwide rights on. At this point, I think we're optimizing for technical feasibility and probability of success. And we get good silencing in monkeys with SOD1 and Huntington's. We'll move those programs forward. We're, as I said earlier, cautiously optimistic that we're going to achieve that kind of silencing and knockdown in that case. And from the standpoint of Friedreich's, we're very excited about that program because it's a major unmet medical need, but a very large population of patients. Relatively speaking, there's some 7,000, 8,000, 9000 Friedreich's patients in the U.S. alone today. And again, given the data we generated in this mouse model of Friedreich's ataxia, which is where frataxin has been silenced in certain tissues, we see really remarkable correction of that disease phenotype. So we're excited about all programs. We're going to move them forward. And we're going to base our decision based on our data and what we think the probability of technical success will be moving them into the clinic.

Our next question comes from Sumant Kulkarni with Canaccord.

First one is a clarification. Is the pace of recruitment in the posterior trajectory trial as planned? Because it appears that there was just 1 more patient dosed relative to the last update during your R&D day.

Yes. It was exactly as planned, and we've wrapped up enrollment. So we do have 1 more patient who was screened before we cut off enrollment, who'll be having procedure soon. But no, we've wrapped up enrollment. The key there, as I mentioned before, is we've learned what we needed to learn, and the surgeons at the sites got the experience they needed to take it into the Phase II.

And something Bernard mentioned earlier, we recruited 7 patients so far in that trial, really the last half of last year. Very rapid recruitment. I think it reflects a great deal of enthusiasm on the part of patients who would otherwise have an opportunity to have DBS reelected, nonetheless, to have our treatment. So we're pretty excited about that. We think that augurs well potentially for enrollment in the pivotal trial.

And my second follow-up is, given the number of patients with advanced PD, could you remind us about what interactions you might have had with the FDA on pursuing potential orphan-drug exclusivity? And what those interactions might mean for perhaps broadening the use of your program in the wider set of PD patients?

Great question, yes.

That's great question. Thank you. So we did have several interactions with both the U.S. and European regulators around orphan designation. And yes, they agreed this is a large population, and this mechanism of action could apply not just to advanced Parkinson's disease, but to more moderate Parkinson's disease. So in this case, we're happy to say that we didn't and we will not further pursue orphan designation.

Than you. I'm showing no further questions at this time. I'd like to turn the call back over to Steve Paul for closing remarks.

Okay. Well, thank you, and that concludes our call. We want to thank all of you for attending this morning and for your thoughtful questions. We look forward to updating you on our progress in the near future. Thanks so much.

Ladies and gentlemen, this concludes today's conference. Thanks for your participation. Have a wonderful day.