Matthew Klein: Thanks for the question, Joe. We are very much looking forward to the HC data readout later in the second quarter. As we talked about, this will be our opportunity to share 12-month data from that initial group of patients on whom we share 12-week data last summer. And this will allow us to, for the first time, get a glimpse at CNS biomarker effect, including Huntington protein levels in the CSF, NFL levels, brain volumes and as you pointed out, clinical scales, looking at the total motor score and total functional capacity. I think from our standpoint, a home run on the data would be to be able to see continued safety and tolerability after 12 months and then be able to see some signal of CNS activity, whether that’s on biomarkers or on any of the clinical scales.
And given the small number of patients, I think we’re really looking for a signal or a trend here, given the duration of 12 months. And then, we said this is approximately 30 patients. And so that’s how we’re really looking at success here. Safety tolerability us signal either on biomarker and/or clinical scores that we’re having CNS activity, I think patients. And let me turn it over to Kylie, do you want to give some more color on AEC reimbursement and how that’s setting the stage for the U.S.
Kylie O’Keefe: Yes, absolutely. So we continue to see progress with pricing and reimbursement negotiations across Europe and we’ve continued to have favorable agreements come into place and we’ll be shortly treating patients in those additional countries. As we talked about in the quarter, we treated additional patients in France, in the U.K. and additional patients in — through cross-border health care. And so that’s continued success in this space. If you talk about learnings and how we sort of think to the U.S. market, I think one of the things that we’ve walked away with from some of these discussions is there’s a recognition of high unmet need in AADC and with the absence of standard of care from a disease-modifying point of view, there’s no treatments available.
There’s a recognition of an ultra-orphan condition and therefore, small budget impact and a recognition of the transformative results that come with the treatment of Upstaza. And so put together, this allows us to be able to move forward with favorable pricing and reimbursement negotiations. And we do expect that to carry across into the U.S. upon launch.
Operator: Our next question will come from the line of Brian Abrahams with RBC.
Unidentified Analyst: This is John [ph] on for Brian. So back on Translarna, can you talk more about the buying pattern you’re seeing for Translarna in Europe in recent weeks? If European Commission does decide to follow CHMP opinion, are you seeing anything on the ground that might suggest that withdrawal from the channels may be more gradual or on the orphan side, even more rapid than you’re expecting?
Matthew Klein: Yes. Thanks for the question, Joe. Look, we are seeing, as I said, really business as usual. Their prescriptions and numbers are really unchanged here. And it goes without saying that the patients and the physicians want to take advantage of every day that Translarna is on the market and we expect that fully to continue to be the case. Our teams, as Kylie pointed out, are focused on ensuring that happens. So we’re ensuring that patients can access to therapy. Of course, we’ve also been working in the background to put mechanisms in place to leverage mechanisms that might be available on a country-by-country basis to continue to provide Translarna in the event that the EC Commission adopts the opinion of Translarna
Unidentified Analyst: Got it. If I could squeeze one more. Are you scheduled to meet with the FDA regarding the filing anytime soon? Just wondering if you will get a visibility on whether you can file in parallel to the carcinogen study or not?
Matthew Klein: Yes. We had — Joe, we had the pre-NDA meeting last year with the agency last fall and it was very clear that every other part of the package is there and in place, that safety efficacy data would support our NDA and support approval on review. And the one outstanding matter was the completion of that carcinogenic study. We’ve mentioned that we expect that study to be done in June. We don’t expect to have a formal meeting with the agency. We did say that we plan to contact them to discuss timing of the submission relative to the completion of that study. We said that we still remain on track to submit in Q3 but we maybe bring that in a little early into Q2 based on that correspondence. But we don’t expect that will be a formal meeting.
Operator: Our next question comes from the line of Wang with Barclays.
Gena Wang: I just have very quick questions. The first one is regarding Translarna Europe status. Based on your discussion with EMA, when do you expect Translarna will be withdrawn in Europe? And then second question is regarding sepiapterin in PKU. I think you mentioned that you wanted to target initial patient population that could be one part is a classic PKU. Can you help us understand how our understanding that the sepiapterin is a precursor cofactor and across the PKU usually does not have any hydroxylase. So basically does not have an enzyme like how would the sepiapterin will be helpful in classic PKU patient population?
Matthew Klein: Thank you for the question, Gena. As we’ve discussed regarding your first question on the status of Translarna in Europe, the — following the opinion in January, typically, the European Commission would have adopted that opinion within 67 days. Clearly, we’re sitting here late in April in that adoption in the clinic has not occurred. We had to notify that the commission was planning to meet this week to discuss the matter. And I assume they’re taking into consideration the current status in Europe, the lack of alternative therapies for patients with nonsense mutation DMD, the data which supports safety and efficacy of Translarna and the outpouring of support for the authorization remaining intact from the patient and physician community across Europe.
So I think they’re looking at the matter closely. We expect to have an update in the near future. And as we said, until that time, the business as usual, using every day to continue to ensure that patients have access to Translarna. On your second question regarding classical PKU, I think there’s sometimes a misunderstanding if the definition of classical PKU is basically patients, children and adults who at some point in their life have a documented phenylalanine level of greater than 1,200 micromolar per liter. They’re that going to be at any point in time or could they be lower but they get a diet control. A very small number of those patients have what’s called homozygous no mutation. That means they have on both allele no mutation that prevents them from having phenylalanine and hydroxylase enzyme.
But that is a very small minority of patients. And therefore, the remainder of the classical PKU patients have functional enzyme, Obviously, it’s severely affected by the mutation and has no function. Sepiapterin is, as you pointed a precursor of BH4 which is the cofactor for the enzyme. It also has a second function which is a chaperone function which stabilizes the confirmation of the PAH enzyme. And therefore, we believe that’s why we’re seeing what we’ve seen in classical PKU patients in our studies which is a significant fact. In fact, in the AFFINITY trial in the subset of classical PKU patients, we had a mean phenylalanine reduction of 69%, that is actually a greater magnitude of production than was observed in the overall population.
So certainly, signifying that sepiapterin can play an important role for these patients. Similarly, as we’ve included — we’ve seen patients going to the open label extension and participate in Phe tolerance protocol, the classical PKU patients that is defined as classical PKU patients being able to mineralize their diet and maintain control of phenylalanine. So all of that really speaks to the importance of sepiapterin and a potentially really important role to have all patients with PKU, including those classical patients who tend to be the most severe.
Operator: Our next question comes from the line of Jeff Hung with Morgan Stanley.
Jeff Hung: For sepiapterin, can you just remind us of the data that’s collected in patients under 2 years old? And are there plans or time lines for starting that? And then given the meaningful effects on phenylalanine, like what would you give you confidence for results to translate into those younger patients?
Matthew Klein: Thanks, Jeff. We did include patients under 2 in the AFFINITY study. Now they went through the initial run-in phase and we had patients who had a greater than 30% reduction in the run-in phase. But the regulatory authorities wanted those patients not to be randomized but to go directly into the open-label extension study. So we have patients who started in AFFINITY who were under 2 and we’ve actually had additional patients that we’ve enrolled directly into long-term extension. So we’re getting data in a number of patients under the age of 2. And what we’re seeing is exactly what we’re seeing in patients over the age of 2. We’re seeing safety and tolerability and also efficacy in terms of reducing phenylalanine. So again, the data continues to support the potential benefit of sepiapterin in the full range of PKU patients, both classical and nonclassical and then patients of all ages.
