Good day, everyone, and welcome to today's Neurocrine Biosciences Reports Fourth Quarter and Year End 2020 Results. At this time, all participants are in a listen-only mode. Later, you'll have the opportunity to ask questions during the question-and-answer session.

[Operator Instructions] Please note, this call may be recorded and I will be standing by if you need any assistance. It is now my pleasure to turn the conference over to Vice President of Investor Relations, Todd Tushla. Please go ahead..

Thank you, Chloe. Good afternoon everyone and thank you for joining us on our fourth quarter and full year 2020 earnings call.

On the call today is Kevin Gorman, our Chief Executive Officer; Matt Abernethy, our Chief Financial Officer; Eiry Roberts, our Chief Medical Officer; Eric Benevich, our Chief Commercial Officer; and Kyle Gano, our Chief Business Development and Strategy Officer.

I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties and our actual results may differ materially. I encourage you to review the risk factors discussed in our latest SEC filings. Following our prepared remarks, we will then head into Q&A.

So, with that, I'll turn it over to Kevin Gorman..

Thanks Todd. Good afternoon. It's good to talk to everyone again. It's only been about three and a half weeks, I think. That's a short period of time. We were able to touch base with many of you. And at that time, we announced our topline earnings.

And also, we announced those topline earnings; we told you how encouraged we were that the brand grew during a much worsening pandemic. We also talked about how we view Q1 of 2021, which now we're about a month into. Our message and our view hasn't changed from then. This Q1 was rolling out like all the other first quarters.

The first half of Q1 is being dominated by reauthorizations of our existing patients and then prior authorizations of both new patients and those who have changed insurance plans.

And again, as always this is a tale of two quarters, where the second half of the quarter is where we expect the normal pace of business to return, but obviously, as stated before, with the impact of COVID still weighing in. Now, Matt and Eric will go into more detail on the 2020 performance and our plans for 2021.

But as I look back on 2020, we performed well in all facets of the business, attaining just shy of $1 billion in sales with INGREZZA, launching a new brand ONGENTYS, effectively managing the stop and start of several of our clinical programs and then significantly expanding our pipeline.

Now, with regard to that last point, with just a robust pipeline and our continuing commitment to manage responsibly our financial and human resources, we recently made the decision to terminate the Parkinson's program with Voyager. Those resources are being redeployed to fully exploit the near and medium term opportunities our pipeline holds.

And the details of our pipeline with be addressed by Eiry. Looking ahead, we are continuing to focus on our mission of becoming the leading neuroscience company in all three disciplines and that means neurology, neuroendocrinology, and neuropsychiatry.

Our current commercial medicines, along with our pipeline, gives us a great foundation to achieve this goal. So, with that, I'd like to turn the call over to the rest of the team, starting with Matt..

Thanks Kevin. Good afternoon everyone. I'll make a few brief comments on our Q4 INGREZZA performance, expectations for Q1, and also capital allocation. During the fourth quarter, INGREZZA sales were $240 million and $258 million on an inventory adjusted basis.

We were encouraged by the Q4 new patient additions and strong compliance rates, driving inventory adjusted sequential growth, reflecting the great need that remains for patients with tardive dyskinesia.

Although encouraged, we acknowledge COVID has an impact on the growth trajectory of the TD market, given around 50% of patient visits to psychiatrists are still being done virtually. Our goal is to be well-positioned to accelerate growth as the impact of COVID on in-person patient visits lessens.

As we enter 2021, this will mark our fourth year handling the Q1 payer-related seasonal dynamics specific to a specialty product like INGREZZA, including beginning of the year reauthorizations and also elevated gross to net discounts. Similar to prior years, we expect the gross to net discount to increase from Q4 to Q1 by around 5%.

In addition, we expect net revenue per script for all of 2021 to be very similar to 2020, with strong access for patients. We remain excited about the compelling medium and long-term potential of INGREZZA and will continue to adapt in the current environment. Turning to the balance sheet.

We reduced our convertible debt exposure by repurchasing about 25% of debt outstanding for approximately $190 million. Given our ability to generate free cash flow, we exited 2020 with over $1 billion in cash, enabling us to continue to invest in long-term growth.

Our 2021 operating expense guidance reflects our capital allocation priorities focusing on maximizing the opportunity with INGREZZA as well as advancing our pipeline with the planned initiation of eight mid to late stage programs, positioning us to be a leading neuroscience company.

As you saw in the release, we reversed our tax valuation allowance this quarter and will begin recording a full tax expense in our P&L for 2021 and going forward, with federal cash tax payments expected to occur sometime in 2022 based upon the around $500 million of net operating losses that we entered the year with.

With that, I hand the call over to Eiry Roberts, our Chief Medical Officer.

Eiry?.

Thank you, Matt, and good afternoon, everyone. I'm happy to provide a brief update on our clinical programs.

But before I begin, I must once again thank our Neurocrine teams and partners for their passion and hard work in advancing the many clinical development programs already underway and for all their ongoing diligence and investment to ensure the successful initiation of the eight new mid- to late-stage clinical programs planned for this year.

2020 presented us with a broad set of unprecedented challenges, and I'm proud of the progress we made across research and development, even in the face of the pandemic.

Our resilience and commitment to help patients carried the day and positions us well for a foundational year in clinical development at Neurocrine as we advance and deliver on our diverse and well-balanced neuroscience-focused pipeline in the areas of neurology, psychiatry and neuroendocrinology.

Our lead pipeline asset, crinecerfont, for the treatment of congenital adrenal hyperplasia continues to progress through clinical development with the single Phase III registrational study in adults currently enrolling patients globally.

In addition, the single parallel pediatric registration trial remains on track to initiate in the first half of this year.

We are confident based on our interaction with regulatory agencies, key opinion leaders, payers and patient advocates that if successful with the current clinical trials, we can deliver a much needed treatment alternative for patients with CAH, many of whom currently struggle to manage in the face of inadequate and outdated treatment.

Looking across our pipeline, an important product attribute shared by many of our clinical candidates is the potential to benefit patients across a number of indications.

This concept of a pipeline within a product is commonly displayed in the immuno-oncology setting and is perhaps best exemplified in our pipeline by valbenazine, our internally discovered VMAT2 inhibitor, currently marketed under the brand name INGREZZA in the U.S. for the treatment of tardive dyskinesia.

The most advanced additional indication under evaluation within our pipeline for valbenazine is Korea in Huntington's disease. Top line data from the Phase III KINECT-HD registration study is anticipated in Q4 this year.

Furthermore, we plan to initiate trials with valbenazine this year in two new areas of interest, with registration phase studies in both the neurological and psychiatric indication. In addition to potentially benefiting three new patient populations, we are also looking forward to expanding the geographic reach for INGREZZA in tardive dyskinesia.

Yesterday, our partner, the Mitsubishi Tanabe Pharma Corporation, reported successful top line results from the Asia-based J-KINECT Phase 3 study designed to evaluate the efficacy and safety of valbenazine in TD.

Mitsubishi Tanabe Pharma plans to submit an application for marketing authorization of valbenazine with the Japanese Ministry of Health and Welfare this year and has already submitted filings for marketing authorization in South Korea, Thailand, Singapore, Indonesia and Malaysia.

Valbenazine serves as a great example of a pipeline within a product, with approval in one indication already and the potential for approval in three additional patient populations. Shifting gears, but on a related note, our two precision medicine epilepsy programs also have the potential to add value for patients across multiple disease states.

I'll begin with NBI-827104 or 104 for short. 104, a potent and highly selective T-type calcium channel antagonist, is currently enrolling patients in a Phase II study for epileptic encephalopathy with Continuous Spike and Wave during Sleep. 104 has the potential to expand into a range of other central nervous system disease areas.

And we are moving forward with the initiation of a Phase II study in the first of these additional neurological indications this year. Turning now to NBI-921352, or simply 352, our potent and highly selective Nav1.6 sodium channel inhibitor.

In response to FDA feedback on our Investigational New Drug application in support of a Phase II clinical trial in SCN8A-DEE patients, we are amending the study to initiate enrollment in adolescent patients with SCN8A-DEE in the third quarter of 2021.

It is our expectation that the trial population will be expanded to include younger pediatric patients as soon as the FDA has reviewed and approved additional nonclinical information. We also plan to initiate a Phase II study of 352 for the treatment of adult focal epilepsy this year.

As a result, with our two precision medicine candidates, 104 and 352, we'll have trials underway in four distinct neurological disorders this year. Now turning to our lead psychiatry asset, NBI-1065844.

The clinical portion of the Phase II INTERACT study evaluating 844 as a potential treatment for the negative symptoms of schizophrenia is complete, and we look forward to sharing initial top line data from this study later in Q1.

Our partner, Takeda, did an outstanding job in advancing this molecule and completing the INTERACT study on schedule in the face of the pandemic.

With no current FDA-approved treatments available for the negative symptoms of schizophrenia, we hope that the INTERACT data can inform a path forward for the further evaluation of NBI-844 as a potential treatment for patients suffering from the devastating impact of schizophrenia.

Looking back, it is remarkable, given all the uncertainty and potential roadblocks that we've doubled our pipeline in just two years. In summary, 2021 marks a foundational year in clinical development for Neurocrine with two significant data readouts and the initiation of eight mid to late-stage clinical programs.

With that, I'll hand back to you, Kevin. .

Thank you very much, Eiry.

So why don't we open up for questions now?.

[Operator Instructions] And we'll take our first question from Biren Amin with Jefferies. Please go ahead..

Hi guys. Thanks for taking my question. Maybe just to start on INGREZZA, clearly, last year, scripts grew about 30% year-over-year.

What should we anticipate the growth rate to be for this year?.

Well, Biren, we don't give guidance. However, I think is – what we said is that we're not tightly linked to COVID. Certainly, COVID has an impact on our business, as we've said before, but it's not a one-to-one impact.

And what we look forward to and being able to get back to that kind of growth rate and probably even beyond is an opening up of all the clinics that we go to. And I think a big step forward there has been the rollout of vaccines and as those become much more available.

Eric, do you have anything to add?.

The only other thing I would add, and I think Kevin touched on this a little bit, is that over the course of the year and over the course of this launch, we've seen variability in terms of growth from quarter-to-quarter. We're still in the thick of things in terms of Q1 and dealing with the seasonal payer issues.

But certainly, we expect, as we go through the course of the year that we're going to see similar patterns in terms of growth rates from quarter-to-quarter..

Okay. And then, maybe if I could have one follow-up.

Given the negative schizophrenia data this quarter, what read-throughs, if any, should we make on this data set for 844 from the recent Concert failure with their deuterated D-serine in their negative symptom study?.

Hi, I can take that. So, we obviously saw the data from the deuterated D-serine Concert study, and just a couple of comments around that study.

Obviously, a few features that were interesting, potentially leading to the outcome that was achieved there, first of all, obviously, the dosing in that study was extremely high in terms of the dose required of the deuterated D-serine, and we don't really have any idea of central bioavailability even from that higher dose.

And so, understanding how much was really getting to the target to test the hypothesis is a big question. Also, a study conducted entirely in the US and had a very -- from what we saw in the top line data, a very high placebo response, which is not unusual in US centers in this type of environment.

So, we remain very confident and committed to the NMDA hypofunction hypothesis within schizophrenia. I mean I think there are several supportive elements to that, the first being, obviously, that NMDA antagonists themselves can produce psychotic symptomatology.

And the second of which is that there are small studies with sodium benzoate and D-serine itself that have shown positive incline of activity in the negative symptom treatment.

We're also very confident in 844 as a molecule and that -- we know we're testing that hypothesis well given the nature of the molecule, the quality of the molecule and the translational work that was done to demonstrate target occupancy and downstream pharmacodynamic effect.

So, we're very focused on understanding and getting hold of the data from the INTERACT study. And as a result of that, we'll be able to see -- the only other comment I'd make is obviously the INTERACT study is a global study, and that's, I think, important in this area..

And we'll take our next question from Paul Matteis with Stifel. Please go ahead..

Great, thanks so much. I was wondering if you could give us a little bit more color on what you're seeing on NRx to start this year and maybe kind of getting back to December. And where you are right now relative to where you were in terms of pre-pandemic levels last year? And then I just have one follow-up. Thanks..

Yeah. Hi, Paul. The way I would describe it is that we're in the thick of things from a Q1 perspective. We had a great Q1 last year. But as Kevin said, it was a tale of two half quarters.

First half of the quarter was a lot of activity in terms of focusing on continuing patients and really minimizing the impact of reauthorization requirements and prior authorization requirements for patients changing plans and so on. And then in the second half of the quarter, things really picked up in terms of new patient starts and so on.

It's the same kind of pattern that's happening this year. It's very early. We're just a few weeks into the quarter. So it'd be premature for me to comment on what the trends look like. But obviously, we expect to have the same kind of dynamic this year as we've seen in past years, with the added element of COVID-19..

And the only aspect, Paul, that I'd add is that, as we've described, we are at record NRx levels entering into the pandemic. And then we saw a pretty steep fall when patients stopped flowing into the psychiatrists' office. And then we saw a bit of recovery exiting Q3 and then through Q4.

But I would say that there is still a notable gap fall between where we were pre-pandemic and where we are now. And as Kevin said in the last question, we're doing a lot to try to minimize the impact of COVID.

But likely, the biggest indicator of return to growth will be patients returning back into offices, which likely looks like it will start occurring second half of the year in a more prominent way. .

And we'll take our next question from Tazeen Ahmad with Bank of America. Please go ahead..

Thank you very much. Good afternoon and thanks for taking my questions. Maybe a follow-up for Eiry as it relates to 844. Can you give us a little bit more detail on why it's important in these types of schizophrenia studies to have global sites as opposed to sites just limited in the US? And then I have a follow-up on INGREZZA. Thank you..

Yes. I think -- thanks for the question. There's quite a lot of public data in the recent years that shows that at least at certain sites within the US, the placebo response has been quite challenging.

And I think having that geographic spread early in the program and then being able to replicate that into Phase 3 becomes important in this type of development program. I think, there's lots of different reasons behind that, that hypothesize. Some is around the quality of the patient pool.

Some is around the relationship between the investigator and the patient being somewhat different in some US sites than elsewhere in the world. And -- but I don't think we really fully understand that. I think it's just -- we believe it's very important to have that geographic diversity from the outset in these programs. .

We'll take our next question from Josh Schimmer with Evercore. Please go ahead..

Thanks for taking the question. So you've previously indicated around 20% of tardive dyskinesia patients are diagnosed, half of those are treated.

What impact do you expect the new APA guidelines to have in terms of increasing the treatment rate of diagnosed patients? When do you expect that to occur? And then for the 80% of undiagnosed tardive dyskinesia patients, where do you see the greatest opportunity to identify them? Thanks..

Yes. So first of all, I'll say that it's a welcome development to have the APA put out their updated guidelines last fall.

Certainly, there are some important components there such as the recommendation of VMAT2 inhibitors as first-line treatment, but also putting into context the lack of evidence to support antipsychotic adjustment as a treatment strategy for TD and the fact that Cogentin, for example, and anticholinergic agents can actually do more harm than good in these patients and that it's been a widespread treatment approach in the past.

In terms of when do we expect those new guidelines to start benefiting patients with TD, well, we're already attempting to do that. We've incorporated the new guidelines into educational programming. We've rolled them out to our field sales team. Our field medical team has access to those guidelines.

And certainly, they've been incorporated into discussions that we're having with thought leaders as well as with community providers. So that's an important dynamic. And we're going to continue to make sure that in the psychiatry community, everyone that we talk to and work with is aware of the new recommendations from the APA.

Then with regard to the second half of your question in terms of the majority of patients that still remain undiagnosed with TD and what can be done to address that situation. Obviously, we've invested a lot in education, especially on the health care provider side.

We're coming up on four years now since the launch of INGREZZA, and we feel like we've made an awful lot of progress. However, there are still a large amount of information that we can share in terms of helping providers, especially in psychiatry, to be more confident and capable in terms of their ability to recognize and diagnose TD.

We're also continuing to invest in patients and care partners directly, for example, in our educational efforts with the talk about TD DTC campaign, but also indirectly working through patient advocacy groups and other venues.

So we're going to continue to educate all the stakeholders, whether it's the providers, whether it's the patients, working with advocacy organizations, professional medical associations and so on. And we'll continue to make progress there.

But I feel really good about the progress that we've made so far, but we recognize that there's still a lot of people suffering from TD that could benefit from treatment..

And we'll take our next question from Laura Christianson with Cowen. Please go ahead..

Hi, thanks for taking my question. Congrats on another great quarter. So I'm just curious on the ONGENTYS launch. What you're seeing so far from physician prescribing? And then also, we've heard from KOLs that patients with Parkinson's like to avoid adjunctive treatment.

And I'm just curious if you have any sense of what might help any inroads there that you're seeing thus far?.

Sure. I'll take a crack at that, and then maybe Eiry has some comments she'd like to share. With regards to the early response to ONGENTYS, the feedback has been very favorable, frankly. I mean, we've been in launch -- in this launch mode for about a quarter, and we're still conducting what I would describe as introductory product presentations.

We've been sampling quite a bit. And we've been educating the neurology community, not just about the product, but also about the reimbursement process, since this is essentially a non-formulary product everywhere.

But the feedback has been very positive in terms of physicians putting patients on initial trial and getting strong reviews from the patients in terms of the benefit that they're getting with ONGENTYS. So this is one of those products where the clinical experience actually lives up to the clinical data.

With regards to the second half of your question, with patients maybe not wanting to go on adjunctive treatment, the reality is that the majority of patients that are out there with Parkinson's on levodopa therapy are on one or more adjunctive treatments already.

About two-thirds, frankly, of the 900,000 people that are on levodopa are on an adjunctive. And so our approach has been to really position ONGENTYS as the go-to adjunctive treatment and a product, frankly, that is ideally suited to optimize levodopa therapy.

There are two enzymes in the periphery that break down levodopa before it can reach the brain and do its job. And COMT is one of them. And so we've been busy reminding neurologists about the important role of the comp enzyme, as well as the clinical profile of ONGENTYS.

And so ideally, a provider would consider adding ONGENTYS before escalating the dose of levodopa or adding an adjunctive treatment from another class that doesn't directly boost levodopa levels. So like I said, it's early in the launch.

The feedback has been favorable, and we're continuing to position ONGENTYS as the go-to early option for optimizing levodopa therapy.

Anything to add?.

Yeah. I mean, I would just add to what Eric said that we know that patients and clinicians view levodopa as the gold standard treatment for Parkinson's disease and that there's a lot of commitment and loyalty to levodopa treatment.

And levodopa is always used with an adjunct carbidopa, because of the fact that that's necessary to optimize levodopa treatment and exposure. And so we really believe that ONGENTYS can continue to optimize that levodopa treatment.

And I think sometimes patients get nervous about some of the other adjunctive agents in terms of side effect profile, drug-drug interaction issues and things of that sort.

And so I think the labeling around ONGENTYS as a single once-a-day treatment and the ability to be used very efficiently and effectively with levodopa and potentially reduce the number of doses of levodopa required by individuals as a result, I think that's -- we've heard that that's very promising to clinicians.

And we're, obviously, hoping that that will add a lot of value for patients..

We'll take our next question from Brian Skorney with Baird. Please go ahead..

Hey. Good afternoon, guys. Thanks for taking my question. Todd, I love the smooth jazz hold music, on the prelude to the call, but you did promise me from GNR/Metallica. So one of these days, I really do want to hear that. And my question is on, 352 and the plans in SCN8A-DEE disorders.

I guess -- I know maybe it's a little premature, but can you kind of talk -- walk us through, sort of this patient population.

And how you kind of think of trial design? Is this going to be put -- it's like a 28-day, looking primarily at reduction, in seizures type endpoint? And what are sort of like the baseline characteristics in terms of seizure frequency in these patients.

So you could sort of start gauging, what would be successful here?.

Yeah. We haven't really talked a great deal about the trial design, up to this point. And in fact, I think our usual intent is to do that, when the trial is posted on clinicaltrials.gov, which will be later this year.

What I would say, though, is that, given that this is a very rare pediatric epilepsy and actually has quite heterogeneous phenotype in terms of its -- how it expresses itself in terms of seizure type, seizure frequency. But actually, it can be very devastating, as you may know, for patients from a very young age.

The important thing for us was to ensure in our interactions with the agencies that every single patient, that we enrolled in this program would count, towards the ability for us to bring this to patients and register the medication.

And so the way in which the trial will be designed is to enable us to have the best opportunity of it being a registration-quality trial. And we're working through that even in the context of starting in the older adolescent population. And then, moving ultimately into pediatrics, where obviously a large amount of the value will be derived..

And we'll take our next question from Anupam Rama with JPMorgan. Please go ahead..

Hey, guys. This is Tessa on, for Anupam. Thanks for taking my question. On the schizophrenia program, maybe one for Eiry, are you able to quantify [Technical Difficulty].

Hey, Tessa, you -- we only heard the first part of asking about the schizophrenia program, then, we lost you..

Can you hear me now?.

Yeah, can hear you now..

Okay.

Wondering, if you can quantify what placebo-adjusted decline, on a point basis or a percent basis, in the negative subscale of the PANSS, is viewed as clinically meaningful? So embedded in the question is, how we should be thinking about placebo performance? And then, is there any color you can provide on, what the anticipated baseline range might be, given the inclusion-exclusion criteria? Thanks so much..

Yeah. We haven't really commented to any great extent on the actual baseline characteristics that we anticipate. I think we're going to wait to see the data. And then, we'll be obviously very happy to talk through, what we are seeing there.

In terms of kind of just guiding you around placebo-adjusted changes and levels of clinical significance, I think we are -- this is a very well powered trial, in order for us to determine a clinically significant difference if it exists.

And also, I would look to other positive programs in this field, to kind of guide in terms of what the nature of that change might be. The one point I do want to make, though, is that although the primary endpoint here, is the negative factor symptom score.

We have a significant number of other endpoints in this study that are focused both on the negative symptoms, the total PANSS score and on functional and other cognitive endpoints. And this is a Phase II dose-finding study.

So, we will be looking at the totality of the data, rather than just at the primary endpoint itself, in order to help inform us in the next steps in development..

We'll take our next question from Paul Choi with Goldman Sachs. Please go ahead..

Thank you and good afternoon. And thank you for taking my questions. Another one for Eiry, please, on 844 in the schizophrenia trial.

As we think about the dosing ranges that you are using in this trial, how do you think about the sort of magnitude and therapeutic window here, given the wide range of doses you're doing? And just how do you think about a potential dose response here? And then as a follow-up – thanks for the OpEx guidance, but I want to ask either Kevin or Matt.

As you think about the rate of reinvestment in the business here, is this sort of the – as you think about the longer term the rate of reinvestment in the business you'd want to continue at, or how do you think about thinking about generating leverage and reallocating an increasing portion of your cash flow to business development?.

On the first question around dose response, and I think I've mentioned this before, but in the context of this molecule 844, one of the things that was really appealing to us was the really great translational medicine network that Takeda had done.

And as part of that, they had taken a really good look at exposure response in terms of target engagement and downstream pharmacodynamic activity. And so we know that the dose range that we're testing in the INTERACT study is one which encompasses a broad range of different levels of DAAO inhibition.

And that's really important, we believe, in order for us to be able to determine from a – as we look at the overall benefit/risk profile from the INTERACT study, which dose or doses to progress forward with if we're successful..

Matt, do you want to talk about allocation of capital?.

Yes, sure. So from a rate of reinvestment perspective, Paul, I would say we're more focused on what do we have in hand and how are we going to invest behind that to maximize the opportunity. We've long said, we're not going to just spend money to avoid probability.

But where we have conviction, we're going to reinvest back into the business, INGREZZA first and then our pipeline. So what I would say, Paul, is this is just a reflection of where we're at today. But Kyle has $1 billion of cash to work with as well as our balance sheet and equity value.

And as we see the right kinds of opportunities, we'll continue to be aggressive. We want to build a leading neuroscience company. And I think it's going to take internal development, and then it's also going to continue to reach in on the external side. So I wouldn't say our OpEx guidance this year is a reflection.

But we do know, over the long run, reinvestment of 25% to 35% of revenue back into R&D seems to be the right level of reinvestment for companies to have sort of sustainable staying power within biotech. And that's more of a mature base. So hopefully, that answers your question. .

Move next to Jeff Hung with Morgan Stanley. Please go ahead..

Thanks for taking the question. For the time being, you've decided to maintain the partnership with Voyager on the Friedreich's ataxia gene replacement program.

Are there differences from 1817 that gives you confidence in Friedreich's ataxia? And more broadly, does that mean that you're still open to gene therapy as a modality for neuroscience for future programs? Thanks..

Yes. Thanks for the question. We're – as we said from the beginning, we're very open to gene therapy, and we said that this is just – our collaboration with Voyager is the first that we'll be doing in gene therapies. There were four programs when we started this collaboration with Voyager. There is the Parkinson's program with VY-AADC.

There is a preclinical Friedreich's ataxia program. And then there are two genes that we brought into the collaboration to work with Voyager. And so just with all of the programs in our wholly owned pipeline within those with our collaborators, each program stands independently in that collaboration with Voyager.

And so we look at each one of them independently. And based on their merits, the data that's being derived that we will take forward, invest or not in each of those. So it's – there's nothing different within the Voyager collaboration than there is within the rest of our pipeline..

Move next to Marc Goodman with SVB Leerink. Please go ahead. And it looks like Marc withdrew his question. We move next to Vamil Divan with Mizuho Securities. Please go ahead..

Great. Thanks so much for taking my question. So maybe if I could just ask again on the first quarter sort of dynamics a little bit more, I think last year at this time, you had sort of similar commentary, kind of warning us about the dynamics.

And then you ended up sort of delivering a quarter that was up a little bit from what the fourth quarter was in 2019. And so I'm just trying to get a sense -- I'm sure we're going to get other questions over the next few weeks as we go through the quarter here.

Is that sort of performance sort of flat, maybe up a little bit from fourth quarter taking out any inventory fluctuations sort of what you think would be a reasonable sort of performance? I know you don't give guidance.

I'm just trying to get a sense of what your sort of general expectations would be or what you'd sort of be happy with, just so we can frame it appropriately [Indiscernible] last year. .

Yes, I'm not sure that I totally understand your question, but I'll take a crack at it.

I mean what we've seen really since the first full year of the launch back in 2018 was that in Q1, INGREZZA had to go through a process -- given the fact that it's a specialty product, had to go through a process for existing patients of getting them reauthorized and back on treatment.

And each year, we've gotten a little bit better as a company and as a team in terms of helping our customers to navigate that process. So this is not unique to INGREZZA. It's just a function of the fact that it's a specialty medicine.

But as our base of patients has grown each year, you've got a larger group of patients that are at risk of dropping off treatment, albeit temporarily because of insurance reasons. And so, what we've seen each year is that, Q1 is challenging in terms of navigating those payer issues.

And then we get back into more of a growth mode as we exit the quarter and go into Q2. And you've seen that in years past with a strong new patient starts going from Q1 to Q2. And that's, frankly, what we saw in 2020. We had a record number of new patient starts in Q1 of 2020, and then the pandemic hit.

And so from a sort of annual cycle basis, I would expect that 2021 is going to look similar to years past with challenging Q1, strong -- relatively stronger Q2. We've seen Q3 be a more challenging quarter in years past and then stronger growth in Q4.

So that pattern, I don't think, is going to necessarily change, but with the pandemic layered on top of everything, that's created some new challenges for us in the near term. And in the longer term, obviously, we're very optimistic about the potential for INGREZZA to help many more thousands of patients. .

So to build a bit on what Eric just commented on. If you recall, last year, as you pointed out, our overall sales were, call it, flattish from Q4 to Q1 when adjusting for inventory. So the same dynamics are still at play, as you mentioned, this year.

The only other piece would be the fact that COVID does have an impact on NRx as we've spoken about earlier in this call.

But importantly, as Eric said, we're working to get patients through the reauthorization process, and importantly, ensuring that patients don't discontinue through the first quarter, because that really sets us up nicely for a strong Q2 and beyond. .

Yatin Suneja with Guggenheim partners. Please go ahead..

This is Yatin. Thank you for taking my question. Just a question on INGREZZA in the long run, once we are through COVID. So if we look back 2018, 2019, I think in terms of quarter-over-quarter script growth, I think you were growing somewhere around 3,500 to 4,500. Obviously, COVID had a big impact in 2020, so the quarter-over-quarter growth decline.

Maybe talk about conceptually like how is 2018, 2019, a good proxy for longer term from a growth perspective?.

Hard to say. I mean, obviously, our goal in the near term is to get back onto a stronger growth trajectory. And what we've described as drivers for that, obviously, there needs to be higher foot traffic into especially psychiatry practices. We've seen that neurology is relatively less impacted by COVID than psychiatry.

We've made a concerted effort to push more into neurology, especially with the launch of ONGENTYS to benefit INGREZZA. And I think that those are going to be important drivers to help us return to a stronger growth trajectory with our INGREZZA franchise.

I mean, the way that I'm thinking about this is that, we're still relatively early in the overall commercialization ramp for this product. This is a nascent market, still relatively undeveloped. In fact, in my career in this industry, I've never worked in a therapeutic area that was less developed.

And so we've got, obviously, a very strong focus on recognition and diagnosis. And diagnosis is a driver of new patient starts for INGREZZA.

So we're going to continue to do everything we can to navigate the pandemic, both in terms of our ability to get in front of providers in psychiatry, neurology in-person and also to leverage new approaches to helping our customers recognize and diagnose TD during telehealth interactions.

And as I mentioned earlier, we're going to continue to invest in direct-to-consumer efforts. And all of those things together will position us well once the pandemic starts to wane and we see a return to normalcy in the health system.

So what the quarter-over-quarter growth looks like as we go forward remains to be seen, but we're very confident in our ability to get on to a more robust growth trajectory as we move forward..

Question from Joseph Stringer with Needham & Company. Please go ahead..

Hi. Thanks for taking our questions. A couple of quick ones. Can you comment on -- of the diagnosed TD patients, what percent market's penetration you think you're currently at with INGREZZA? And a follow-up on the percentage of virtual patients. You commented around 50% now.

But can you maybe walk us through where that was sort of at the start of the pandemic and to where it is now? And then also what percent you would like to see or think it will be towards the end of this year? Thanks..

Okay. So I'm going to put on my prognosticator hat here. I'll take your first question -- or your second question first. With regards to what telehealth looked like pre-pandemic, what it looks like now and maybe where it's headed, pre-pandemic, it was relatively underutilized.

And I will say, though, that it was more broadly utilized in psychiatry than in other therapeutic areas. When we launched INGREZZA, we took a look at telehealth and the opportunity in psychiatry. And at that time, about less than 6% of all patient visits were billed as a telehealth visit. So it gives you a sort of a point of reference.

Early in the pandemic when states were issuing shelter-in-place directives, clinics were shutting down and so on, it got above 90% really across multiple different physician specialties, and that includes both psychiatry and neurology. Neurology has bounced back to a more normal cadence over the last quarter or so.

Total patient visits are similar to what they were pre-pandemic. And the percentage of telehealth is less than 10% in neurology. I'll contrast that with psychiatry. Psychiatry is only about 70% of the volume of patient visits of what it was pre-pandemic, and about half of all of those visits are billed as telehealth.

And it may be even higher in the subset of psychiatrists that we call on with -- within specially community mental health practices. So, quite a bit of difference in terms of the use of telehealth between psychiatry and neurology.

In terms of where it's going, the Biden administration recently announced that they were going to carry forward the public health emergency designation through the end of this year, which functionally means that the temporary waivers that CMS issued last year that spurred the increase in telehealth will carry forward through the balance of this year.

So our expectation is that we're going to see continued high levels of telehealth in psychiatry. And then as we get further into the year, we can reevaluate to the extent that psychiatrists are coming back into their practices and they're seeing their patients in person. That's why we've invested so heavily in telehealth.

And the first part of your question, sorry, was really around the rate of diagnosis and what we're seeing there. So obviously, we see a lot of upside potential here with the majority of patients remaining as yet undiagnosed with TD.

But another area of focus and opportunity for us is that to this day, about half of the patients that do get diagnosed with TD aren't offered a VMAT2 inhibitor. And as I mentioned earlier, the APA guidelines will help to change that paradigm or that behavior in the provider community.

So it's both a combination of increasing the rate of diagnosis and increasing that available patient pool, but also changing those practice patterns and getting physicians to recognize that VMAT2 inhibitors, and especially INGREZZA, should be considered first-line therapy..

And we'll take our next question from Charles Duncan with Cantor Fitzgerald. Please go ahead..

Okay. Thanks. Hi, Kevin and team. Thanks for taking the question. I had a question on valbenazine and its future. It's a 2-part question.

One is how to differentiate valbenazine from INGREZZA, given some of the work that you're doing in Korea and then also the neuro and psych indications you're contemplating, especially given some of the kind of debate that we had a few years ago when Auspex was public and AUSTEDO was coming to the market? And the second part is regarding Mitsubishi Tanabe collaboration, congrats on the data, recently.

I'm wondering if you could remind us of the milestones and royalty rate? And any color on the patient population in Asia relative to the States? Thanks..

Matt or Kyle, you want to talk about the MTPC financials first?.

Matt is not jumping on the line here. We do get a milestone for submission in the Japanese territory or in Japan, and upon approval, those probably are the most meaningful ones and those are about $30 million in total between now and approval.

And then in terms of the royalties, it's tiered on net sales in the mid-teens to mid-20s in terms of percentage. And we would guide on the royalty front to somewhere in the mid-teens..

Eiry, you want to take the first part of Charles question?.

Yeah, certainly, Charle. So with respect to Huntington's Korea and valbenazine program and potential differentiation from other VMAT2 inhibitors already approved in that space, if I understand your question correctly. I mean, obviously, we're very confident in the profile that we've seen and its differentiation in tardive dyskinesia.

And a lot of that revolves around the simple once-a-day treatment paradigm, the lack of need for complex titration and a very favorable benefit risk profile in tardive dyskinesia. And so the KINECT-HD trial is designed to replicate that as much as possible in this new population.

And so we hope to be able to deliver on a very favorable benefit/risk profile in that population, continuing with the once-a-day treatment paradigm, obviously dependent on the data package, we're able to generate. We don't have a black box currently for suicidality in the TD environment.

And we're hopeful that, that would continue, and that would potentially be an additional differentiator..

And we'll take our next question from Marc Goodman with SVB Leerink. Please go ahead..

Sorry about the technical difficulties before. Matt, two questions.

One, can you just give us a sense in the SG&A line 2020 versus 2021? Just tell us what the increases are, the decreases are kind of in the business, just so we get a sense of how the money is being spent? And second, can you just repeat your tax rate comment? And when you do exhaust all the NOLs, what is a good tax rate that we should be using as a sustainable one? Thanks..

Yeah. On the tax front, we're going to start recording a full tax expense here in 2021. What I've said historically is it's around 21% or so. And even though we will be taking a tax expense in 2021, from a federal perspective, we likely won't be a cash taxpayer until 2022, because we still do have $500 million of NOLs entering into 2021.

So hopefully that's helpful. On the SG&A front, what I would say is that you are going to see an increase in SG&A.

And it largely, going behind what Eric described earlier is positioning ourselves to be able to grow well with INGREZZA and positioning it both through the pandemic and then as we get out of the pandemic that we can have accelerated growth.

So a lot going on the telepsychiatry front, going on as it relates to engaging with patients to have them bring up and ask about their tardive dyskinesia to their physicians. On the R&D side, initiating eight trials this year is going to come with a lot of expense behind it, specific to the Takeda transaction as well as epilepsy programs.

We will have a little bit of an offset, because of our decision to terminate the Voyager Parkinson's gene therapy program. And that's all reflected in our guidance. So hopefully, that answers your question, Marc..

Question from David Amsellem with Piper Sandler. Please go ahead..

Hey, thanks. So a question on your philosophical thinking on M&A. We've seen some pretty significant M&A of late, certainly, quite a large deal in the neuro space yesterday.

So I guess with that in mind and what we're seeing with M&A activity, what's your appetite for something that I would term transformational? And to the extent you do have an appetite, where would you take pro forma leverage up to if you were entertaining something like that? Thanks..

Yeah. Thanks for the question. Throughout business development, whether it's licensing or whether it's acquisitions or whatever the structure of a licensing would be, what guides us first is that the science is very strong and it's innovative. Number two, that it is truly addressing the needs of the patients there.

We're not looking for incremental benefit. We're looking for life-changing benefits in everything. So we look at all – that's the lens that we look at in everything. And then when we find those things, then it just becomes, can the two parties agree on the value of the assets.

And past that, if we agree on the value, then actually we really will do any kind of structure that makes sense to both parties. Then we're not wed to any one structure. And I think you've seen that in the deals that Kyle has done with – throughout the last probably three years that you've seen.

Kyle, do you have anything to add to that?.

Maybe just to touch a little bit on what Matt said, I think that first and foremost, we appreciate that programs and assets are scarce. And we have a number of high-quality programs and assets in the pipeline currently. And it's our goal to make sure we maximize what we have and execute on the plans that allow us to be successful there.

So I think that's one message, I would say. And the other one would be is, if you look back at the pipeline today versus, say, when INGREZZA was approved in 2017 in the absence of M&A, but through probably more traditional biz development licensing, we've taken that pipeline from about three programs to about 10 today.

And that really speaks to the organization in terms of its ability to look at a number of different programs and bring them onboard and start working on the development there on those programs. So I think we can show – we've shown we've been active and productive through one area of business development.

I think when it comes to M&A, then, to Kevin's point, we really look at the science and make sure that the programs that we're bringing in really add value to physicians and patients' lives. And they provide that innovation that the payers would be willing to reimburse and help patients get those medicines.

And those types of profiles, if you look at the landscape, aren't readily available in our space. So we look at those very carefully in the context of also other licensing types of deals and structures that might allow us to augment our portfolio that way as well.

So opportunistic in terms of how we approach programs and assets in terms of structure, but it really goes back to the science..

There are no further questions at this time. I would now like to turn the call back to Kevin Gorman for any closing remarks..

Thank you very much. Just in close, I'd like to make two comments. One is that, as you've seen and as you -- from us over time and what you will see from us going forward is that, we continue to adapt, particularly commercially, on the fluid environment.

And I'm confident that we're going to come out -- our business will come out even stronger than what we went into this pandemic with. And then, also, I'm looking forward to the continued maturation of the pipeline. And as Eiry said, several of our compounds are pipelines in and amongst themselves. So that is a real strength that we have here.

And we're going to have a couple of very important data readouts here just this year. So having said that, I want to thank you all for participating today, and take care..

This does conclude today's program. Thank you for your participation. You may disconnect at any time..