Q4 2021 ACADIA Pharmaceuticals Inc Earnings Call

Gigi: And welcome to ACADIA Pharmaceuticals' fourth quarter and full year 2021 financial results conference call. My name is Gigi, and I will be your coordinator for today. At this time, all participants are in listen only mode.

Good day, ladies and gentlemen, and welcome to Acadia Pharmaceuticals fourth quarter and full year 2021 financial results Conference call. My name is G G and I'll be your coordinator for today at this time all participants are in listen only mode. We will be facilitating a question and answer session towards the end of two.

Mark Johnson: We will be facilitating a question and answer session toward the end of today's call. If at any time during the call you require assistance, please press star followed by zero, and a coordinator will be happy to assist you. I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at ACADIA. Please proceed. Thank you. Good afternoon, and thank you for joining us on today's call to discuss ACADIA's fourth quarter and full year 2021 financial results.

This call is that any time during the call you require assistance. Please press star followed by zero.

Cornell I'll be happy to assist you I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Acadia. Please proceed.

Okay.

Thank you good afternoon, and thank you for joining us on today's call to discuss the Katy its fourth quarter and full year 2021 financial results.

Mark Johnson: Joining me on the call today from ACADIA is Steve Davis, our Chief Executive Officer, who will provide an overview of our 2021 financial performance, a review of our business, and our outlook for 2022. Following Steve, Mark Schneyer, our Chief Financial Officer, will then discuss our financial results and guidance.

Joining me on the call today from Acadia are Steve Davis.

Our Chief Executive Officer, who will provide an overview of our 2021 financial performance a review of our business and our outlook for 2022.

Mark Johnson: Also joining us today is Brendan Teehan, our Chief Operating Officer, Head of Commercial, who will provide updates on our commercial initiatives. Dr. Serge Tankovich, our President, will then discuss our two new drug applications and our pipeline progress before turning it back to Steve for final remarks and opening up the call for your questions. Thank you very much.

Following Steve Mark Schneider, our Chief Financial Officer will then discuss our financial results and guidance also joining us today is Brendan Delaney, our chief operating officer head of commercial who will provide updates on our commercial initiatives. Dr. Serge Stankovic. Our President will then discuss our two new drug applications in our pipeline progress before turning it back to Steve for final remarks, and opening up the call for your question.

Mark Johnson: I would also like to point out that we're using supplementary slides, which are available in the events and presentation section of our website. Before we proceed, I would first like to remind you that during our call today, we'll be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, or future results, are based on current information, assumptions, and expectations that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC.

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I would also like to point out that we are using supplement slides, which are available on the events and presentations section of our website.

Before we proceed I would first like to remind you that during our call today, we'll be making a number of forward looking statements within the meaning of the private Securities Litigation Reform Act of 1995. These forward looking statements, including goals expectations plans prospects growth potential timing of events or future results are based on current information assumptions and expectations that are inherently subject to.

<unk> and involve a number of risks and uncertainties that may cause actual results to differ materially.

These factors and other risks associated with our business can be found in our filings made with the SEC you are cautioned not to place undue reliance on these forward looking statements, which are made only as of today's date.

Steve Davis: You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date. I'll now turn the call over to Steve. Thank you, Mark. Good afternoon, everyone, and thank you for joining us today.

Steve Davis: Please turn to slide five. To deliver on our mission, we are focused on three strategic pillars. First, draft growth of new plies at Branch As, where we continue to perform at a high level. Second, advance our three late-stage opportunities by submitting applications for new approvals for pimivansirin in Alzheimer's disease psychosis, or ADP, and for terpenatide in Rett syndrome, and Completing Enrollment in our negative symptoms is schizophrenia program, also with PIM-EVANN. And third, develop the next wave of CNS breakthroughs with our early-stage pipeline while continuing to pursue strategic business development opportunities. Starting on slide six, for the full year 2021, we achieved net sales of $484.1 million, which represents 10% year-over-year revenue growth.

I'll now turn the call over to Steve.

Thank you Mark good afternoon, everyone and thank you for joining US today, please turn to slide five.

To deliver on our mission, we are focused on three strategic pillars.

First drive growth of NUPLAZID franchise, where we continued to perform at a high level.

Second advanced our three late stage opportunities by submitting applications for new approvals for <unk> in Alzheimer's disease, psychosis, or ADP, <unk> and ret syndrome and.

And completing enrollment in our negative symptoms of schizophrenia program also with payment of answering.

And third develop the next wave of CNS breakthroughs with our early stage pipeline, while continuing to pursue strategic business development opportunities.

Starting on slide six for the full year of 2021, we achieved net sales of 484 $1 million, which represents 10% year over year revenue growth.

Steve Davis: During 2021, we grew both total prescriptions and market share as we continue to outperform the top neurology, Parkinson's, and long-term care companies. We achieved this despite operating in a disproportionately affected Parkinson's disease market, where in-person Parkinson's patient visits remain down approximately 20% and occupancy rates in long-term care facilities remain down approximately 15% compared to pre-pandemic levels. Our strong performance during this time underscores our ability to grow the brain. As the pandemic conditions normalize and overall PD market dynamics improve, we are poised to accelerate this growth. As we look ahead to 2022, we expect to see improvement in the infection rates of COVID-19.

During 2021, we grew both total prescriptions and market share as we continued to outperform the top neurology, Parkinson's and long term care drugs.

We achieved this despite operating in a disproportionately affected Parkinson's disease market, where in person Parkinson's patient visits remain down approximately 20%.

And occupancy rates and long term care facilities remain down approximately 15% compared to pre pandemic levels.

Our strong performance during this time underscores our ability to grow the brand.

As the pandemic conditions normalize and overall P. D market dynamics improve we are poised to accelerate this growth.

As we look ahead in 2022, we expect to see improvement in the infection rates of COVID-19, but more importantly, as it relates to the Parkinson's market, we will be looking for a normalization of staffing turnover and reduction of staffing shortages in both the office space and long term care settings.

Steve Davis: But more importantly, as it relates to the Parkinson's market, we'll be looking for a normalization of staffing turnover and a reduction in staffing shortages in both the office space and the long-term care setting. We'll also be focused on the rate at which Parkinson's patients are seeing their physicians in person. As Marc will speak about in a minute, for the full year 2022, we expect net sales to be between $500 million and

I'll also be focused on the rate at which Parkinson's patients are seeing their physicians in person.

As Mark will speak to in a minute for the full year 2022, we expect net sales to be between 510 and $560 million.

Steve Davis: What we achieve within this range will be a function of read through from the pandemic conditions and our ability to continue to outperform the top neurology, Parkinson's, and long-term care. Now, let's turn to our three late stage opportunities on slide seven. We recently announced the resubmission of our SNDA for PIMVANCER for the treatment of ADP. In addition, we look forward to submitting our NDA for Trophinatide for the treatment of Rett syndrome around the middle of this year.

While we achieved within this range will be a function of read through from the pandemic conditions and our ability to continue to outperform the top neurology, Parkinson's and long term care drugs.

Now, let's turn to our three late stage opportunities on slide seven.

We recently announced the Resubmission of our S. NDA for pivot to answer for the treatment of ADP.

In addition, we look forward to submitting our NDA for troponin tied for the treatment of Ret syndrome around the middle of this year.

Steve Davis: Our Alzheimer's disease psychosis resubmission provides additional analyses from two previously conducted clinical studies, Harmony and Study 019, to support a proposed indication for the treatment of ADP and is intended to address issues raised in the FDA's complete response letter. As we previously described, this resubmission gives the FDA an opportunity to fully review our new additional analyses and, through this process, gives us an opportunity to make our case that Pemivanserin should be the first drug approved for the treatment of ADP.

Our Alzheimer's disease psychosis Resubmission provides additional analyses from two previously conducted clinical studies harmony and study <unk> nine to.

To support our proposed indication for the treatment of ADP and is intended to address issues raised in the Fda's complete response letter.

As we've previously described this resubmission gives <unk> an opportunity to fully review, our new additional analyses and through this process gives us an opportunity to make our case that <unk> should be the first drug approved for the treatment of ADP.

Steve Davis: An important contextual point is that in our studies with Pimm of Answering, we did not observe any... impairment of cognition or motor function compared to placebo, a very important consideration in this elderly and highly medically compromised population and a historical challenge in developing drugs to treat psychosis in Alzheimer's patients.

An important contextual point is that in our studies with him of answering we did not observe impair.

Impairment of cognition or motor function compared to placebo, a very important consideration in this elderly and highly medically compromised population.

Historical challenge in developing drugs to treat psychosis and alzheimers patients.

Steve Davis: We expect this to be a class two resubmission, which would mean the FDA will be targeting a six month review with an action date in the third quarter. However, having recently submitted, we are not yet at the point where the FDA would assign an action date. We should reach that point soon, and we'll update you as soon as they do. Regarding our NDA for terfenatine, at the end of last year, we announced positive top-line results from our phase three lavender study of terfenatine for the treatment of Rett syndrome.

We expect this to be a class two resubmission, which would mean the FDA will be targeting a six months review with an action date in the third quarter.

Having recently submitted we're not yet at the point, where the FDA would assigned an action date, we should reach that point soon and we'll update you as soon as they do.

Regarding our NDA for tryphena tied at the end of last year, we announced positive topline results from our phase III Lavender study of tryphena tied for the treatment of Ret syndrome.

Our NDA submission will be based on the pivotal lavender study and its co primary endpoints.

Steve Davis: Our NDA submission will be based on the Pivotal Lavender Study and its co-primary endpoint. In preparing for our NDA submission, we scheduled two meetings with the FDA. We've already met with the FDA to review the overall content and format of the clinical data to be included in our NDA submission. The second meeting scheduled for March will be dedicated to covering similar ground on the CMC aspects of this.

In preparing for our NDA submission, we scheduled two meetings with the FDA.

<unk> already met with the FDA to review the overall content and format of the clinical data to be included in R&D submission. The second meeting scheduled for March will be dedicated to covering similar ground on CMC aspects of the submission.

Steve Davis: We're planning for an NDA submission around mid-year and expect a priority review with the Bedoufa Action Date in the first quarter of 2023. Moving to our third late-stage opportunity, in our Phase 3 Negative Symptoms of Schizophrenia program, we have something that's very rare in this space. And that is a positive pivotal study, our ADVANCE I study. The negative symptoms that schizophrenia patients suffer from have proved to be the most difficult to treat.

We're planning for an NDA submission around midyear and expect a priority review with a <unk> action date in the first quarter of 2023.

Moving to our third late stage opportunity in our phase III negative symptoms of schizophrenia program, we have something thats very rare in this space.

And that is a positive pivotal study our advanced one study.

The negative symptoms of schizophrenia patients suffer from have proved to be the most difficult to treat.

Steve Davis: Symptoms, which generally revolve around the social withdrawal aspects of the disease versus the hallucinations and delusion symptoms, have been the largest unmet need in schizophrenia for multiple decades. And today, we still have no FDA-approved treatment for negative symptoms. With one positive pivotal study complete, we're in the process of running a second pivotal study. This is our ADVANCE II study. ADVANCE 2 is designed to be virtually identical to our successful ADVANCE 1 study with one important difference.

<unk>, which generally revolve around the social withdrawal aspects of the disease versus the hallucinations and delusions symptoms.

It had been the largest unmet need in schizophrenia for multiple decades.

And today, we still have no FDA approved treatment for negative symptoms.

With one positive pivotal study complete we're in the process of running a second pivotal study. This is our advance two study.

Advanced two is designed to be virtually identical to our successful advanced one study with an important difference.

Steve Davis: In Advance 1, we observed that at the highest dose tested, 34 mg, the drug effect was markedly higher than the statistically significant and clinically meaningful results of the overall drug-treated group, which included lower doses as well. Therefore, in our advanced two study, all patients are receiving the optimal 34 milligram dose. Please turn to our pipeline chart on sliding.

In advanced one we observed at the highest dose tested 34 milligrams.

The drug effect was markedly higher than the statistically significant and clinically meaningful results of the overall drug treated group, which included lower doses as well.

Therefore in our advance two study all patients are receiving the optimal 34 milligram dose.

Please turn to our pipeline chart on slide eight.

Steve Davis: Our third strategic pillar to grow our business is to develop the next wave of breakthroughs in our early stage program. Our early stage pipeline is highlighted by our ongoing phase two pain program, evaluating ACP O44 in two studies, one in the cute and one in chronic models of pain, with data coming from both studies this year. And we have additional earlier stage programs highlighted by collaborations with Vanderbilt University and Stoke Therapeutics, as well as early stage internal programs designed to leverage the learnings of them to further our franchise and take advantage of indications we might never get to.

Our third strategic pillar to grow our business is to develop the next wave of breakthroughs in our early stage programs.

Our early stage pipeline is highlighted by our ongoing phase II pain program evaluating ACP hopeful for in two studies one in acute and one in chronic models of pain with data coming from both studies this year.

And we have additional earlier stage programs highlighted by collaborations with Vanderbilt University, and Stoke Therapeutics as well as early stage internal programs designed to leverage the learnings with him a answer too.

To further our franchise and take advantage of indications, we might never get to a joint venture.

Steve Davis: Finally, we look forward to continuing to evaluate and execute business development to grow our opportunity set in CNS, further leveraging our strong R&D and commercial capability. With that, I will now turn the mic over to Marc to discuss our financial performance and guidance. Thank you, Steve. Today I'll discuss our fourth quarter and full year 2021 results and our 2022 financial financial outlook. Please turn to slide 10.

Finally, we look forward to continuing to evaluate and execute business development to grow our opportunity set and CNS further leveraging our strong R&D and commercial capabilities.

Marc Schneyer: In the quarter, we recorded $130.8 million in net sales, an increase of approximately 8% compared to $121 million in net sales in Q4 of 2020. This was driven by strong performance of New Plaza across channels with year-over-year volume growth. As part of net sales, we observed a gross to net adjustment of 20.7%, which is up from 18.3% in the fourth quarter of last year.

With that I will now turn the back over to Mark to discuss our financial performance and guidance.

Marc Schneyer: Moving down the P&L, GAAP R&D expenses increased to $67.1 million in the quarter compared to $62.1 million in the fourth quarter of 2020. GAAP SG&A expenses decreased to $105.8 million in the quarter from $120.8 million in the fourth quarter of 2020, which included sales and marketing expenses related to the potential DRP launch. Please turn to slide 11.

Thank you Steve today, I'll discuss our fourth quarter and full year 2021 results and our 2022 financial outlook. Please turn to slide 10 in.

In the quarter, we recorded $138 million in net sales an increase of approximately 8% compared to $121 billion of net sales in Q4 of 2020. This was driven by strong performance of NUPLAZID across channels with year over year volume growth.

As part of net sales we observed the gross to net adjustment of 27%, which is up from 18, 3% in the fourth quarter of last year.

Moving down the P&L GAAP R&D expenses increased to $67 1 million in the quarter compared to $62 1 million in the fourth quarter of 2020 GAAP.

GAAP SG&A expenses decreased to $105 $8 million in the quarter from $128 million in the fourth quarter of 2020, which included sales and marketing expenses related to the potential DRP launch please turn to slide 11.

Marc Schneyer: In the full year 2021, we recorded $484.1 million in net sales, an increase of 10% compared to $441.8 million in net sales in 2020. This was driven by 3% year over year volume growth. The gross to net adjustment for the full year was 19.1%.

Full year 2021, we recorded $484 $1 million in net sales an increase of 10% compared to $441 8 million of net sales in 2020. This.

This was driven by 3% year over year volume growth.

Marc Schneyer: As a reminder, gross to net was higher in 2021, as we observed a higher percentage of 340p volume, though this remains a mid single-digit percentage of our overall Gap R&D expenses decreased to $239.4 million in 2021 from $319.1 million in 2020. This was primarily due to the typical ebbs and flows of clinical development and BD activity. For example, in 2020, we expensed in R&D a total of $62.8 million in upfront expenses related to the SurSci acquisition and Vanderbilt collaboration. Gap SG&A expenses increased slightly to $396 million in 2021 from $388.7 million in 2020.

The gross to net adjustment for the full year was 19, 1%.

As a reminder, gross to net was higher in 2021, as we observed a higher percentage of $3 40, B volume, though this remains a mid single digit percentage of our overall volume.

GAAP R&D expenses decreased to $239 $4 million in 2021 from $319 $1 million. In 2020. This was primarily due to the typical ebbs and flows of clinical development in BD activities.

For example in 2020, we expensed in R&D, a total of $62 $8 million in upfront expenses related to the <unk> acquisition and Vanderbilt collaboration.

GAAP SG&A expenses increased slightly to $396 million in 2021 from $388 $7 million in 2020.

Marc Schneyer: We ended the year with $520.7 million in cash and investments on our balance sheet compared to $632 million at year-end 2020. Please turn to slide 12 for our 2022 Financial Guide. For the full year 2022, we are providing net sales guidance for Plasid and Parkinson's disease psychosis of $510 to $560 million. The midpoint of this range represents a similar level of demand for Neuplazid as last year. The high end reflects an improvement in PD market dynamics with subsequent increased demand, and the low end represents lower demand, similar to levels we experienced in the second half of 2021.

We ended the year with $527 million in cash and investments on our balance sheet compared to $632 million at year end 2020.

Please turn to slide 12 for 2022 financial guidance.

For the full year 2022, we are providing net sales guidance for NUPLAZID in Parkinson's disease, psychosis, a $510 million to $560 million.

The midpoint of this range represents a similar level of demand for NUPLAZID as last year.

The high end reflects an improvement in PD market dynamics with subsequent increased demand.

And the low end represent slower demand similar to levels, we experienced in the second half of 2021.

Marc Schneyer: Regarding gross net, we are anticipating an increase to a range of 20 to 22% in 2022 as a result of higher 340 B volume. At the midpoint of the range, this would be an additional $13 million reduction in net sales year over year.

Regarding gross to net we are anticipating an increase to a range of 20% to 22% in 2022 as a result of higher <unk> volume mix.

At the midpoint of the range this would be an additional $13 million reduction to net sales year over year.

Marc Schneyer: As your reminder, we expect gross net to be the highest in the first quarter to the annual reset of the donut home manufacturer obligation for Medicare Part D patient. Note, if PIMA's answering is approved for the treatment of ADP this year, both our revenue and expense guidance ranges will need to be updated. On the expense side for 2022, we expect GAAP R&D expenses to be between $355 and $375 million, including approximately $25 million in stock-based compensation expenses.

As a reminder, we expect gross to net to be the highest in the first quarter due to the annual reset of the donut hole manufacturer obligation for Medicare part D patients.

Noticed Timothy answering is approved for the treatment of ADP. This year, both our revenue and expense guidance ranges will need to be updated.

On the expense side for 2022.

GAAP R&D expenses to be between $355 million to $375 million, including approximately $25 million in stock based compensation expense.

Marc Schneyer: While our R&D range does not guide for incremental spend for business development transactions, it does include the $60 million related to the upfront expenses associated with the Stoke collaboration that we executed in January. In addition, this year, we will have additional costs associated with Trophinitide, including manufacturing costs for commercial supply and a regulatory filing milestone payment to North. We expect GAAP SGA expense to be between 360 and $380 million for the full year, including approximately $45 million in stock-based compensation. The midpoint of this range represents an approximate 7% reduction in spend as compared to 2021.

While our R&D range does not guide for incremental spend for business development transactions. It does include the $60 million related to the upfront expenses associated with the still collaboration that we executed in January .

In addition, this year, we will have additional costs associated with <unk>, including manufacturing costs for commercial supply and a regulatory filing milestone payments in there.

We expect GAAP SG&A expense to be between 360 and $380 million for the full year, including approximately $45 million of stock based compensation.

The midpoint of this range represents an approximate 7% reduction in spend as compared to 2020.

Marc Schneyer: There are a few puts and takes encompassed within the range that I'd like to provide further color on. First, we are making investments in preparing for the potential launch of trufinitide in Rett syndrome. Second, we are focused on continuing our relative commercial outperformance in 2022 for Nikolazan and PDP while efficiently managing our spend as a function of the PD market conditions related to the pain. And third, as it relates to the potential launch of New Closet for ADP, most of the pre-launch work was already completed in connection with DRP, so we don't need to make a lot of additional investments prior to the ADP action date.

There are a few puts and takes encompassed within the range that I'd like to provide further color on.

First we are making investments in preparing for the potential launch of <unk> and Ret syndrome.

Second we are focused on continuing our relative commercial outperformance in 2022 for NUPLAZID in PDP, while efficiently managing our spend is a function of the PD market conditions related to the pandemic.

And third as it relates to the potential launch of NUPLAZID for PDP. Most of the prelaunch work was already completed in connection with ERP. So we don't need to make a lot of additional investments prior to the ADP action date.

Marc Schneyer: We expect our 2022 year-end cash balance to be approximately $355 to $405 million based upon our expected range of operational cash. As we look ahead, under our current business plan, we expect to turn cash flow positive during 2023.

We expect our 2022 year end cash balance to be approximately $355 million to $405 million based upon our expected range of operational cash flows.

As we look ahead under our current business plan, we expect to turn cash flow positive during 2023.

Brendan Teehan: This holds true whether or not Pimivansirin for ADP and or Trophinatide for Rett Syndrome are approved, but is subject to our standard caveats of future business development or if our pipeline experiences less than standard rates of attrition. I'll now turn it over to Brendan, who will discuss our PDP commercial performance and outlook for 2022. Thank you, Mark. Please turn to slide 14.

This holds true whether or not <unk> PDP indoor tryphena type of Ret syndrome are approved but is subject to our standard caveat to future business development or if our pipeline experiences less than standard rates of attrition.

I'll now turn it over to Brendan who will discuss our PDP commercial performance and outlook for 2022.

Thank you Mark.

Brendan Teehan: I am extremely proud of our team's performance in 2021, where we delivered another year of double-digit revenue growth. Our results underscore our team's ability to adapt and find new ways to grow the brand, including our HCP and patient caregiver campaigns, which supported growth in the second half of the year and have positioned us well for continued growth in 2022. In 2021, we continue to outperform branded drugs in the space as New Plazid grows both total prescriptions and market share.

Please turn to slide 14.

I am extremely proud of our team's performance in 2021, where we delivered another year of double digit percent revenue growth.

Our results underscore our team's ability to adapt and find new ways to grow the brand, including our HCP and patient caregiver campaigns, which supported growth in the second half of the year and have positioned us well for continued growth in 2022.

In 2021, we continue to outperform branded drugs in the space as NUPLAZID group, both total prescriptions and market share.

Brendan Teehan: In the office setting, New Plazid current script levels are up 30% when compared to pre-pandemic levels. This continues to be nearly double the neurology segment branded average growth rate of 17%. During the same time frame, the top 10 Parkinson's brands were down 7%, and Carbidopa-Levodopa scripts were down 3%.

Any office space setting NUPLAZID current script levels are up 30% when compared to pre pandemic levels. This continues to be nearly doubled the neurology segment branded average growth rate of 17%.

During the same timeframe the top 10, Parkinson's brands were down 7% and carpet Opel levodopa scripts were down 3% went under normal circumstances, we would expect them to be up 3% to 4%.

Brendan Teehan: When, under normal circumstances, we would expect them to be up 3 to 4%. This is particularly relevant because carbidopa and levodopa are essential motor medications for PD. Let's turn to the long-term care setting. Here, Carbidopa and Levodopa remain even further down at 11%, a reflection of a significantly lower LTC occupancy rate. The top 15 LCC brands were even further suppressed, down an average of 24%.

This is particularly relevant because carboplatin and levodopa or essential PD motor medications.

Let's turn to the long term care setting.

Here Carboplatin and levodopa remain even further down at 11% a reflection of a significantly lower LTC occupancy rate.

The top 15, LTC brands, where even further suppressed down an average of 24% at the same time.

Brendan Teehan: At the same time, New Plazid was actually up 4%. Most importantly, we continue to drive share growth in both the community and LTC settings for New Plus. This tells us that while patient dynamics may be temporarily suppressed, our messaging is resonating with our customers, leading to Nuplazid being selected as the therapy of choice more often in appropriate PDP patients. We outperformed despite significantly fewer in-person PD patient visits with their physicians and significantly lower occupancy rates in long-term care facilities.

It was actually up 4%.

Most importantly, we continued to drive share growth in both the community and LTC settings for NUPLAZID. This tells us that while patient dynamics may be temporarily suppressed our messaging is resonating with our customers leading to NUPLAZID being selected as the therapy of choice more often inappropriate PDP patients.

We outperformed despite significantly fewer in person PD patient visits with their physicians and significantly lower occupancy rates in long term care facilities.

Brendan Teehan: As the graphs at the bottom of the slide indicate, these market dynamics continue to persist. In addition, throughout the pandemic, New Plaza has maintained very high refill rates, which point to a strong user experience and the fact that refills are not impacted by the same market dynamics.

As the graphs at the bottom of the slide indicate these market dynamics continue to persist.

In addition throughout the pandemic NUPLAZID has maintained very high refill rates, which point to a strong user experience and the fact that refills are not impacted by the same market dynamics to.

Brendan Teehan: To grow meaningfully, we will need to continue to drive new patient starts, and those are most often diagnosed when patients have in-person physician visits or are admitted to a long-term care facility. Most importantly, based on our market research and forecasts, we continue to see a significant opportunity to grow our brand for years to come. Beyond PDP, we have two near-term potential commercial opportunities. Let's start with Neuplazid for the treatment of ADP on slide 15. As you know, we were previously preparing our commercial teams for a potential Neuplazid label expansion for the treatment of dementia-related psychosis, of which 70% are ADP patients. And the market dynamics are very similar.

To grow meaningfully we will need to continue to drive new patient starts and those are most often diagnosed when patients have in person physician visits or are admitted to a long term care facility.

Most importantly, based on our market research and forecasts, we continue to see a significant opportunity to grow our brand for years to come.

Beyond PDP, we have two near term potential commercial opportunities, let's start with NUPLAZID for the treatment of ADP on slide 15.

As you know we were previously preparing our commercial teams for a potential NUPLAZID label expansion for the treatment of dementia related psychosis of which 70% are ADP patients and the market dynamics are very similar.

Brendan Teehan: While the ADP indication is much larger than PD psychosis, this indication will be a line extension of an established brand already on the market since 2016. For New Plaza, this means we will leverage and build upon our current commercial foundation and established infrastructure. For example, since its launch, New Plaza has generated significant brand awareness.

While the ADP indication is much larger than PD psychosis. This indication will be a line extension of an established brand already on the market since 2016 for NUPLAZID. This means we will leverage and build upon our current commercial foundation and established infrastructure.

For example, <unk>.

Since its launch NUPLAZID has generated significant brand awareness.

Brendan Teehan: We have a well-established patient support service to help patients and caregivers start and stay on the plazid, and we'll expand that capability for 80s. New Placid enjoys broad formulary access in PDP with a well-recognized value proposition, and we anticipate similar access dynamics for this Linux. And finally, we have strong and experienced field teams in both the community and the LTC market sector. Now, let's discuss the opportunity with triphenatide for the treatment of Rett syndrome.

We have a well established patient support service to help patients and caregivers start and stay on NUPLAZID and we'll expand that capability for ADP.

NUPLAZID enjoys broad formulary access and PDP with a well recognized value proposition and we anticipate similar access dynamics for this line extension and finally, we have strong and experienced field teams in both the community and LTC market segments.

Now, let's discuss the opportunity with tryphena tied for the treatment of Ret syndrome.

Brendan Teehan: With strong positive phase three results in hand, we are now focused on preparing for a highly successful commercial launch. Today, we have developed partnerships with engaged and motivated patient advocacy groups within the Rett community and are working with the Rett Syndrome Centers of Excellence as we work to identify patients who can benefit from trophinatide at launch. We are evaluating opportunities to increase education and genetic testing to further support patient identification, and we will leverage our existing sales force and infrastructure while investing appropriately in further dedicated customer-facing roles for Trufenetide where necessary.

With strong positive phase III results in hand, we are now focused on preparing for a highly successful commercial launch today.

Today, we have developed partnerships with engaged and motivated patient advocacy groups within the <unk> community and are working with the Ret syndrome centers of excellence as we work to identify patients who can benefit from tryphena tied at launch.

We are evaluating opportunities to increase education and genetic testing to further support patient identification.

And we will leverage our existing sales force and infrastructure, while investing appropriately in further dedicated customer facing roles for tryphena tide where necessary.

Dr. Serge Tankovich: In summary, we are executing on pre-launch preparedness for both opportunities and look forward to helping patients and caregivers alike. I would now like to turn it over to Serge to provide an R&D update. Thank you, Brandon. And good afternoon, everyone.

In summary, we are executing on prelaunch preparedness for both opportunities and look forward to helping patients and caregivers alike.

I would now like to turn it over to Serge to provide an R&D update.

Thank you Brandon.

Dr. Serge Tankovich: I would like to begin by taking a deeper dive on our two U.S. regulatory submissions this year. Please turn to slide 17 to discuss the recent resubmission of our SNDA for the treatment of Alzheimer's disease psychosis. We estimate that there are approximately 900,000 ADP patients currently being treated in the United States, the vast majority of whom are using off-label, multi-receptor antipsychotics, which offer little to no proven efficacy and can accelerate cognitive decline and impact motor function.

Good afternoon, everyone.

I would like to begin by taking a deeper dive on our two U S regulatory submissions this year.

Please turn to slide 17 to discuss the recent resubmission of our NDA for the treatment of Alzheimer's disease psychosis.

We estimate there are approximately 900000 ADP patients currently treated in the United States.

The vast majority of which are we off label multi receptor antipsychotic, which offer little to no proven efficacy and can accelerate cognitive decline and impact motor function.

Dr. Serge Tankovich: Today, there are no FDA-approved treatments for FDA. [inaudible] Our resubmission package focuses on additional efficacy analysis from two separate, previously conducted placebo-controlled studies of pimavansirin that included ADP patients. In the Harmony Study, where we observed highly statistically significant and clinically meaningful results in the overall DRP population, we also observed meaningful benefits in ADP, a pre-specified dementia shock.

Today, there are no FDA approved treatments for ADP.

Our Resubmission package focuses on additional efficacy analysis from two separate previously conducted placebo controlled studies of people of answering that included.

B patients.

In the Harmony study, where we observed highly statistically significant and clinically meaningful results in the overall DRP population. We also observed a meaningful benefit in ADP, a prespecified dementia sufferers.

As previously reported the subgroups were not powered to show statistical significance. However, the additional analysis, we've conducted show consistency of effect that strongly support the meaningful benefits observed.

Dr. Serge Tankovich: However, the additional analysis we've conducted shows a consistency of effect that strongly supports the meaningful benefit observed. The study, conducted on 19, was designed and powered to evaluate Mimovansirin in ADP patients and showed both statistically significant and clinically meaningful results demonstrating the benefit of Pima Vansarin in ADP.

Studied all 19 was designed and powered to evaluate answering in ADP patients and showed both statistically significant and clinically meaningful results demonstrating the benefit of the Melbourne, Sydney and ADP.

Dr. Serge Tankovich: [inaudible] In our weeks of mission, we will include additional analysis that supports the benefit observed and specifically address the issues the FDA laid out in the complete response lab. Given the high unmet need, The Demonstration of Benefit, and the lack of negative impact on cognition and motor function observed with pimavenserine compared to placebo, we strongly believe that pimavenserine should be approved for the treatment of ADP.

In our Resubmission. We will include additional analyses, which supported the benefit observed and specifically address the issues. The FDA laid out in the complete response letter.

Given the high unmet need.

A demonstration of benefit and the lack of negative impact on cognition and motor function observed with game of arms compared to placebo. We strongly believe that <unk> should be approved for the treatment of ADP.

Dr. Serge Tankovich: We would expect the FDA to notify us soon that this will be a Class II resubmission, and as such, we expect an action date target in the third quarter. Now, let's turn to our Trufinetide NDA, starting on Slide 18. Rett syndrome is a very serious and rare disorder for which we estimate there are between 6 and 9,000 patients in the United States and for which there is no FDA-approved treatment. The core symptoms of rat that significantly impact the daily life of patients include loss of ability to communicate, both verbally and non-verbally, gate abnormalities, and repetitive and relentless hand movements, moderate and autonomic impact, and serious GI issues, especially constipation.

We would expect the FDA to notify us soon.

We'll be a class two resubmission and as such we expect an action date target in the third quarter.

Let's turn to our total phenotype NDA starting on slide 18.

Red syndrome is a very serious and rare disorder for which we estimate there are between six and 9000 patients in the United States and for which there is no FDA approved treatment.

The core symptoms of that that significantly impact the daily life of patients include lots of ability to communicate both where body of Nomura.

Gates abnormalities, and repetitive and relentless tens movements motor Nuomi, kiehn pad and serious Gi issues, especially constipation.

Dr. Serge Tankovich: Ultimately, red syndrome patients lose their ability to maintain independent functioning on a daily basis and require around the clock support. Our positive results from the Pivotal Lavender Study demonstrated efficacy across multiple core symptoms of Rett syndrome. Trophinatide demonstrated statistically significant separation from placebo and meaningful benefit on the co-primary endpoint, the Rett Syndrome Behavioral Questionnaire, a Caregiver Assessment Tool, as well as the Clinical Global Impression of Improvement, a Physician Assessment Tool. Importantly, trophinatide showed improvement across all eight domains of the RSVQ.

Ultimately ret syndrome patients lose their ability to maintain independent functioning on a daily basis and required around the clock support.

Our positive results from the people to Lavandera study demonstrated efficacy across multiple core symptoms over at syndrome.

Throw phenotype demonstrated statistically significant separation from placebo and meaningful benefits on the co primary endpoints.

The Ret syndrome, Behavioural questionnaire, a caregiver assessment tool as well as the clinical global impression of improvement.

<unk> assessment tool.

Importantly, <unk> phenotype.

Phenotypes showed improvement across all domains of the auditors be cute.

Dr. Serge Tankovich: In addition, the study achieved statistical significance versus placebo on its key secondary efficacy outcome, another caregiver assessment focused on the patient's ability to communicate. This has the potential to address a significant challenge for parents and their children whose lack of ability to communicate fully interferes with many aspects of their daily lives. Importantly, the efficacy results were consistent across all age groups and severity of disease.

In addition, the study achieved statistical significance versus placebo and its key secondary efficacy outcome.

Either caregiver assessment focused on the patient's ability to communicate.

This has the potential to address a significant challenge for parents and their children, whose lack of ability to communicate fully interferes with many aspects of their daily lives.

Importantly, the efficacy results were consistent across all age groups and severity of disease.

Dr. Serge Tankovich: Trafinitized has been granted fast-track status, orphan drug designation, and rare pediatric disease designation, which means it's eligible for priority review, and if approved, could be awarded a rare pediatric disease priority review. We recently met with the FDA to review the overall content and format of the clinical data to be included in our NDA submission. We have a dedicated CMC review meeting in March and plan to submit our NDA around media.

So phenotype has been granted fast track status orphan drug designation and rare pediatric disease designation, which means it is eligible for priority review and if approved could be awarded a rare pediatric disease priority review voucher.

We recently met with the FDA to review the overall content and format of the clinical data to be included in our NDA submission.

We have a dedicated CMC review meeting in March and plan to submit our NDA around mid year.

Dr. Serge Tankovich: Now, let's discuss our Negative Symptoms of Schizophrenia program on slide 19. There are over 700,000 patients in the United States who are currently treated for schizophrenia but still have persistent and potentially debilitating negative symptoms, such as social withdrawal, lack of emotion, and blunted affect, among others, for which there is no FDA-approved treatment, as part of our advanced program.

Now, let's discuss our negative symptoms of schizophrenia program on slide 19.

There are over 700000 patients in the United States, who are currently three dates for schizophrenia, but still have persistence and potentially debilitating negative symptoms such as social withdrawal lack of emotion and <unk> among others and four weeks.

There is no FDA approved treatment.

As part of our advanced program.

Dr. Serge Tankovich: We have one positive pivotal study already, Advance One, results for which were published last year in the Lancet Psychiatry. ADVANCE served as a dose-finding study where we clearly observed the most robust results on the primary endpoint in patients receiving 34 milligrams of Pimavansin. Please recall, this is the dose commercially available and recommended for PDP and shows the most robust results in ADP. We are now evaluating only the 34 milligram dose of pimavansirin in our second pivotal study, ADVANCE II.

We have one positive people at those probably already advanced one results, which were published last year in the lancet psychiatry.

Advanced server as a dose finding.

How do you, where we clearly observed the most robust results on.

On the primary endpoint in patients receiving 34 milligram of Puma vans.

Please recall this is the dose commercially available and recommended for PDP and showed the most robust results in AVP.

We are now evaluating only the 34 milligram dose of <unk>.

In our second pivotal study advance two.

Dr. Serge Tankovich: In addition, building on the learnings of our two previous studies in schizophrenia, ADVANCE II is being conducted in non-US clinical trial sites. Enrollment is going well and is expected to complete by the end of this year, with top-line results available in 2023. It's like 20 highlights our early stage pipeline opportunities. For acute pain, we have an ongoing Phase 2 study evaluating ACPO44 for the treatment of post-operative pain following bionectomy surgery, and we expect results around the end of this quarter or early next year.

In addition building on the learnings of our two previous studies in schizophrenia.

Still he is being conducted in non U S clinical trial sites.

Enrollment is going well and expected to complete by the end of this year with top line results available in 2023.

Slide 20 highlights our early stage pipeline opportunities.

For acute pain, we have an ongoing phase two study evaluating HCP all 44 for the treatment of postoperative pain following bunionectomy surgery.

We expect the results around the end of this quarter.

Dr. Serge Tankovich: And for chronic pain, we have an ongoing Phase 2 study evaluating ACP-044 for the treatment of pain associated with osteoarthritis that is expected to complete by the end of 2022. Additionally, our M1 PAM program, that we licensed from Vanderbilt University, has a lead compound, ACP319, that is currently in phase 1 multiple ascending dose. Another exciting opportunity is our recently executed collaboration with stoke therapeutics to pursue multiple RNA-based treatments for severe and rare genetic neurodevelopmental diseases, including Cingat-1 and Red Cingat-1.

Early next quarter.

And for chronic pain.

Have an ongoing phase two study evaluating <unk> T O 44 for the treatment of pain associated with all starts rises that is expected to complete by the end of 'twenty to 'twenty two.

Our M. One Pam program that we licensed from Wonder builds University has a lead compound HCP 319 that is currently in phase one multiple ascending dose trial.

Another exciting opportunities, our recently executed collaboration which stope therapeutics to pursue multiple RNA based treatments for severe and rare genetic neurodevelopmental diseases, including she got one and ret syndrome.

Dr. Serge Tankovich: And finally, we have multiple early stage molecules that are focused on different targets, such as analog compounds, which build upon the learnings of Pimavani. With that, I'll turn it back to Steve for closing remarks. Thank you, Serge. Please turn to slide 22.

Thank you Serge please turn to slide 22.

Steve Davis: Today, we are executing on our promise to deliver new clients to patients with PDP while preparing for a potential second indication in ADP. In addition, in the middle of the year, we expect to submit a new drug application for Trofinetide for the treatment of Rett syndrome. We continue to advance our third late-stage opportunity with expected enrollment completion of our Pivotal Phase III study in the negative symptoms of schizophrenia, with results expected in 2020.

Today, we are executing on our promise to deliver NUPLAZID to patients with PDP.

Preparing for a potential second indication in ADP.

In addition in the middle of the year, we expect to submit a new drug application for tryphena tied for the treatment of <unk> syndrome.

And we continue to advance our third late stage opportunity with expected enrollment completion of our pivotal phase III study in the negative symptoms of schizophrenia with results expected in 2023.

Steve Davis: And from our early stage pipeline, we have two ongoing Phase II studies for ACP 044 with results expected this year. In closing, I would like to thank our employees for their accomplishments and their continued commitment and passion as we continue our mission to elevate life. I'll now open up the call for questions. Operator? Ladies and gentlemen, if you wish to ask a question, please press star followed by one on your touchtone telephone. If your question has been answered or you wish to withdraw your question, press the pound key.

And from our early stage pipeline with two ongoing phase III studies for ACP O four hor with results expected this year.

In closing I would like to thank our employees for their accomplishments and their continued commitment and passion as we continue our mission to elevate life.

I will now open up the call for questions operator.

Ladies and gentlemen, if you wish to ask a question. Please press star followed by one on your Touchtone telephone. If your question has been answered or you wish to withdraw your question press the pound key.

Operator: Please limit yourself to one question. I repeat, please limit yourself to one question. Press star one to begin.

Please limit yourself to one question I repeat please limit yourselves to one question press Star one to begin please standby for your first question.

Operator: Please stand by for your first question. Your first question comes from the line of Nina Betrito-Garg from Citi. Your line is now open.

Your first question comes from the line of Neena <unk> Garg from Citi. Your line is now open.

Nina Betrito-Garg: Hey guys, thanks for taking the question. I was just wondering if you could elaborate a little bit more on the SG&A guidance and what specifically you're kind of cutting back on there. I know you did have some commentary around kind of reprioritizing spend, but if you could talk a little bit more about that and then how we should assume the SG&A spend could ramp if FEMA is approved in ADP. I know previously you were talking about maybe adding 250 reps; if that number has changed at all.

Hey, guys. Thanks for taking my question I was just wondering if you could elaborate a little bit more on the SG&A guidance and what specifically you're kind of cutting back on there I know you did have some commentary around kind of re prioritizing spend but if you could talk a little bit more about that and then how we should assume the SG&A spend could ramp if pima.

Is approved in ADP I know previously you were talking about maybe adding 250 reps.

That number has changed at all particularly.

To note two things.

Nina Betrito-Garg: It'd be great to know that too. Thanks. Yeah, thanks much for the question, Nina. Mark, you want to take these? Sure. On the.

Yes. Thanks, so much for the question isn't it mark.

Mark you want to take these.

Mark Schneyer: You know, on the SBA range, as we mentioned, we have a number of puts and takes where the investment is propenitized. I know you asked a question about the kind of PDP. I mean, we have a mixture of activities that support, you know, we don't disclose exactly what we're spending on, but we are evaluating and focusing on the highest return investments. And yes, kind of within this range, you know, depending on. How the market dynamics progress over the year, that could be a reduction in overall PDP commercial spend. And as I mentioned in prepared remarks, from an ADP standpoint, there is, you know, limited investment needed prior to our action date.

Sure on the.

On the SG&A range as you mentioned.

We have a number of puts and takes right.

Investment in <unk> I know you asked a question about kind of PDP I mean, we have a mixture of activities that support it.

Don't disclose exactly what were spending on but.

But we are we.

We are evaluating and focusing on the highest return investments.

And yes kind of within this range, depending upon how the market dynamics, our progress over the year that could be a reduction in overall PDP commercial spend.

As I mentioned in the prepared remarks.

We from ADP standpoint, there is.

Limited investment needed prior to our action date I.

I think we'll we'll.

We will reserve kind of guidance for potential increases in expenses and revenue for ADP.

Mark Schneyer: I think we'll, we'll reserve kind of guidance for potential increases and expenses and revenue for ADP. You know, if we get a positive approval, and it will reflect kind of later in the year, how to give guidance as appropriate at that. Got it.

If we get a positive approval.

And we will reflect kind of later in the year.

How do you give guidance.

As appropriate at that time.

Got it thank you.

Mark Schneyer: Thank you. Thank you. Our next question comes from the line of Tazeen Ahmad from Bank of America. Your line is now open.

Thank you. Our next question comes from the line of Devine Ahmed from Bank of America. Your line is now open.

Tazeen Ahmad: Hi guys, good afternoon, and thanks for taking my question. Can I just ask about the levels of guidance that you've provided for 2022 sales? What would you need to see in terms of the major driver to hit the operands of guidance? Is it the ability to see more doctors in person, therefore leading to additional prescriptions? Let's go ahead. Or is it that, you know, for doctors already prescribing, you need them to prescribe to more patients than they do? Thanks. Steve, I think you're on mute.

Hi, guys. Good afternoon, and thanks for taking my question can I just ask about the upper ends of guidance that you provided for 2022 sales what would you need to see in terms of the major driver to hit the upper end of guidance is it.

The ability to see more doctors in person therefore, leading to additional scripts or is it that you know for doctors already prescribing you need them to prescribe some more patients than they do thanks.

Yeah.

Yes.

Steve I think you're on mute.

Steve Davis: Sorry about that; thank you. Let me answer at a very high level and then I'll turn over to Mark. So, as we mentioned in our prepared remarks, the range of revenues that you see is really driven by two things. One is the pandemic conditions and how they normalize as we move through the year.

Sorry about that thank you.

Let me answer it a very high level, and then I'll turn it over to Mark.

Steve Davis: And the second is our ability to continue to outperform other drugs in the sector. So we're very confident in the latter and our ability to do that in the investments that we're making in SGNA, and the revenues that we have in our forecast reflect that. But the level of normalization and the rate of normalization and the pandemic, or what I mean by that is, our ability to subside as it relates to the medical community and the Parkinson's community, is something that we'll just have to continue to assess as we go forward.

As we mentioned in our prepared remarks, the range of revenues that you see really driven by two undercurrents are one is the pandemic conditions and how they normalize as we move through the year.

And then the second is our ability to continue to outperform other drugs in this sector.

We're very confident in the in the water and our ability to do that and the investments that we're making on SG&A.

And the revenues that.

And that we are that we have in our forecast reflects that.

But the but the.

Level of normalization in the rate of normalization independently of what my what I mean, but that is because he is our ability as a society and particularly as it relates to the medical community and the Parkinson's community.

Is it something that you will just have to continue to assess as we go forward and the precise timing it is a those things as well.

Steve Davis: And the precise timing of those things is less clear. So, Mark, I think Tazeen's specific questions were about things in particular that may drive the upper end of the pandemic that, or excuse me, the upper end of our guidance, that would reflect an improvement in pandemic conditions. I'll let you add additional detail on color.

What's clear so mark I think.

The disease specific questions or about things in particular that may drive that upper end of the pandemic that or excuse me the upper end of our guidance.

Guidance that that would reflect an improvement in pandemic conditions I'll, let you add additional detail and color.

Mark Schneyer: I think, you know, while we have, as always, a variety of assumptions that comprise our range, really the principle, assumption underlying the range is what Steve reflected is really the underlying market dynamics. So I think Steve explained it well. And it, you know, just at the higher end of the range, as I mentioned earlier, would reflect an improvement in market conditions from what we've seen, you know, last year and recently. Okay, but by market conditions, are you saying more interactions?

I think you know, while we have a I was always a variety of assumptions.

That comprise our range really the principal.

Assumption underlying the range is what's the reflected as really the.

Hi.

Market dynamics, so I think Steve explained it well.

As you know we're just at the higher end of the range as I mentioned earlier.

Would reflect an improvement in market conditions from what we've seen.

You know last year in recent months.

Okay, but the market conditions are you, saying more interactions with physicians.

Mark Schneyer: I think it's staffing, right, at both long-term care facilities and in office settings, more in-person patient visits with their doctors, and it's just a continuation because we've seen improvement recently in our ability to visit physicians in person. Brendan, do you have anything else to add to that? I think you're on. Sorry, thanks.

But I think it's it staffing right at both.

Long term care facilities and in office settings.

More in patient in person patient visits with their doctors and it.

Asian, because we've seen improvement recently and our ability to.

Visit physicians in person.

Brendan do you have anything else to add.

Okay.

And I think you're on mute.

Brendan Teehan: Yes. Tazeen, thanks for the question. I just wanted to add to that. Yeah, the biggest driver is patients returning for face-to-face visits and an increase in the LTC census. Both of those are important market dynamics that will emerge as the pandemic abates.

Alright, Thanks, Yes, Susan Thanks for the question I just wanted to add to that the biggest driver is patients returning for face to face visits increase and L. T. C census, both of those are important market dynamics that as dependent.

Brendan Teehan: We have grown market share throughout 2021, which suggests that our message is absolutely resonating. We are gaining more and more share of first-line setting patients. So it's really the opportunity for those patients to show up in the office or for new residents to enter long-term care. Okay, that's helpful.

Debates.

We'll have a better opportunity for for new patient starts than we have today.

With that said as Steve pointed out we have grown market share throughout 2021, which suggests that our message is absolutely resonating we are.

Gaining more and more share of first line setting patients. So it's really the opportunity for those patients to show up in the office or for new residents to enter long term care facilities.

Okay. That's helpful. Thank you.

Brendan Teehan: Thank you. Thank you. Our next question comes from the line of Corey Casimo from JP Morgan. Your line is now open.

Thank you. Our next question comes from the lineup Cory <unk> from J P. Morgan. Your line is now open.

Corey Casimo: Hey, good afternoon, guys. Thanks for taking the question. I wonder if you have any insight from the agency yet as to whether or not you should expect an adcom for Neuplazid and ADP. Is that something you would have been communicating with them already?

Hey, good afternoon, guys. Thanks for taking the question I Wonder if you have any insight from the agency yet as to whether or not you should expect an AD comm for NUPLAZID. In ADP is that is that something you would have been communicated to already or would you expect to learn about that when you get the F. D. A response to your Resubmission. After I think 30 days and just kind of taking a step.

[noise] back would you look at the opportunity to go in front of a an FDA Advisory Committee is a favorable development for you. Thank you.

Corey Casimo: Or would you expect to learn about that when you get the FDA response to your resubmission after, I think, 30 days? And just kind of taking a step back, would you look at the opportunity to go in front of an FDA advisory committee as a favorable development for you? Thank you.

Yeah. Thanks, so much for the question Corey Serge I'm going to take that.

Dr. Serge Tankovich: Surgery on, Yes, Corey, thanks for the question. In respect to the advisory committee, this is a decision for the FDA. And, you know, at this time, it's really difficult for us to speculate on whether or not they would request it. It is very unlikely, and I would say that we will learn about that in the 30 day communication when the FDA returns following our submission. But we would anticipate, considering the six month review cycle, that fairly soon we should learn about that.

Serge you on mute.

Yes.

Yes Carter thanks for the question in respect to the Advisory Committee.

This is a decision for the a D a M.

This time, it's really difficult for us to speculate on whether or not they would go with requested.

It is a very unlikely it it's unlikely I would say the we will learn about it.

30 day communication when the FDA return following our our submission so but.

We would anticipate considering a six month review cycle that.

Hum fairly soon wish or we should learn about that.

Dr. Serge Tankovich: All I can say is that in regard to the advisory committee. We will be ready to make our case to the FDA advisors as well. We look for every opportunity to make the case for the efficacy and safety of primavansirine in the treatment of Alzheimer's disease psychosis, but we'll just wait for the ultimate decision of the FDA in regard to whether or not they will move toward the advisory committee. Okay, thank you. Thank you. Our next question comes from the line of Ritu Baral from Cowan. Your line is now open.

You know all I can say is in regard to advisory Committee, we will be ready to make our case to the F. D. A advisers as well we look for every opportunity to go make the case, all the efficacy and safety of Primavera and asserting in treatment of Alzheimers disease.

If it closes.

But you know, we'll just wait for the ultimately the decision of the FDA in regard to whether or not they will.

<unk> covered the Advisory Committee.

Okay. Thank you.

Thank you. Our next question comes from the line of Richard morale from Cowen. Your line is now open.

Ritu Baral: Hi guys. Thanks for taking the question. It's on trithenatide for RET.

Hi, guys. Thanks for thanks for taking the question.

Oh.

Ritu Baral: Have you guys discussed functional unblinding analyses as part of the FDA meeting that you had on the data, or was it submitted as part of the statistical analysis plan? And then further, can you just go through what the gating items are, aside from that CMC meeting, for that submission? Thanks. Thanks for the questions, Ritu, and Serge. Thanks, Ritu. As part of our briefing documents for the meetings, we submitted detailed information on the results from our pivotal trial and from the trial results, so complete and full efficacy and safety information was available to the FDA in preparation for the meeting. To your question whether this potential functional unblinding has been discussed, the answer is no.

It's it's entre phenotype for Rex.

Discussed.

Discuss functional and blinding analyses.

Part of the FDA meeting that.

But you had on the data or was it submitted as part of the statistical analysis plan and then further can you just go through what the gating items are aside from that fancy name for that submission. Thanks.

Thanks for the questions Ritu Serge.

Okay.

Oh, yes, thanks Ritu.

As a part of our briefing documents for the meetings. We are we have submitted.

Detailed information on the results from the our pivotal trial and from the results of the trials. So.

A complete Oh.

For both efficacy and safety information is a base that was available to the FDA in preparation for the meeting to your question whether this there's a potential functional on blinding was discussed the answer is no that question did not was not raised in the in the meeting.

Dr. Serge Tankovich: That question was not raised in the meetings and contacts that we had with the FDA, so we did not discuss that at all. Do you want to just recap the analyses that we've done on that point? Sorry, Ritu. Go ahead. I'm sorry you were both.

The contracts that we had with the FDA. So we did not.

Discuss that at all.

What's it going to just recap the analyses that we've done on that one sorry Richard.

Alright.

Dr. Serge Tankovich: Yeah, maybe you could just give a very high-level recap of the analysis that we've done on. Oh, yes. We did a very detailed analysis, both evaluating the efficacy data for patients with and without the area on either of the co-primary outcome measures. We also looked at the scatter plots. We looked at the responder analysis. So we did look. We did look.

I'm sorry, you were both yes sure.

Maybe you could just give a very high level recap of the analysis that we've done on that point.

Oh, Yes, I mean, you know we did the.

A very detailed analysis boat.

Evaluating the efficacy data for patients with and without diarrhea bone either of the <unk>.

Co primary outcome measures, we also looked at and Ah Ah Ah scatter plots, we looked at the responder analysis. So we did look we we did perform a very detail.

Dr. Serge Tankovich: We did a very detailed analysis, and all of them point to the same consistent conclusion that there is no indication of any bias in terms of the assessment of efficacy in regard to the area as, as, I'm not at all mercy, that event, but as I said, that question was not raised, and there was not discussion at all on that question at all in the, Got it. Without the analysis, search with those analyses pre-specified and submitted as part of this statistical analysis plan.

Analyses and and all of them point and the same consistent conclusion that there is no indication of any bias in terms of the assessment.

Efficacy in regard to diarrhea is as of a month.

Got to pay back, but as I said that the question was not raised but there was no discussion on that question at all in the meetings.

Got it where does analysis of search where those analysis pre specified in and submitted as part of its lifestyle analysis plan.

Dr. Serge Tankovich: Those analyses will be part of our MDA submission, but obviously, the statistical analysis plan is always submitted prior to unblinding the data, so these analyses were not part of the statistical analysis plan because there wasn't any information based on which you could anticipate those analyses. Got it. Thank you. Thank you. Our next question comes from the line of Jeff Hung from Morgan Stanley. Your line is now open.

Those are now this is will be part of our submission.

Oh, NDA submission, but obviously sophistical analysis plan as always submitted prior to unblinded. The data. So there wasn't these analyses were not a part of the statistical analysis plan, because there where there wasn't any informational.

Based on which you could.

Our anticipated those analysis.

Got it thank you.

Right.

Thank you. Our next question comes from the line of Jeff Hung from Morgan Stanley . Your line is now open.

Jeff Hung: Hey, thanks for taking the question. For your collaboration with Stoke and Rett, can you just remind us of how that may be differentiated from triphenatides and how different the patient population might be than those that you could treat with triphenatides? Sure. Serge, do you want to take that question? Yes. The... The...

Hey, Thanks for taking the question for your collaboration with spoken Red can you just remind us of how that may be differentiated from <unk> and how different my patient population b and those that you can treat with defense side.

Sure Terry do you want to take that question.

Yes.

Uh huh.

Dr. Serge Tankovich: Stoke technology addresses about one-third of the patients that display genetic hypomorphism. So that's not the entirety of the population, but rather, as I said, about 35 to potentially 40% of the overall population of the patients. And the difference in technology is that, based on these inter-ransions, the... The increase in the protein is actually on the gene that is performing sub-optimally. So from that perspective, it's a completely different approach than what is generally approached with terfinitide.

Uh huh.

Stoke technology addresses about one third of the patients.

That.

Have a bed display a generic type of more morphism. So that's a that's not the entirety of the all the population but rather.

As I said about <unk>.

35 to potentially 40% of the overall population of the all of the patients and the differentiated technologies that are.

Based on these intervention.

<unk>.

Doug.

The increase in the protein and he's actually.

One on the gene that is not our debt is performing.

Sub optimally so from that perspective, it's a completely different approach than what was in general these approach with the thrift phenotype.

Steve Davis: I think I just want to maybe just add a couple of annotations there. One is, with Trophinitide Wave Rites to North America and under the Stoke Collaboration, our rights are worldwide in that program. And then the short version is that with the approach that we're taking in collaboration with Stoke, there's a greater potential for disease modification, so potential for an even greater or more profound effect with that type of approach. So we think that that program is a very, very nice complement to the franchise that we're building around Trophinitide. Thank you. Thank you. Our next question comes from the line of Mark Goodman from SVB Larynx. Your line is now open.

Yeah.

I think just to maybe just to add a couple of indications one is.

With tryphena tied wave rights to North America, and indeed stroke Cloudberry stope collaboration our rights are more wide.

And that program.

And then in the short version is with the approach that we're taking in collaboration with Stoke there's a greater potential for disease modification.

So a potential for an even greater or.

A more profound effect.

With that type of approach so over.

We think that their programs are very very nice complement to the franchise that we're building retrofit.

Okay. Thank you.

Thank you. Our next question comes from the line of Marc Goodman from SBB Leerink. Your line is now open.

Marc Goodman: Yes, Serge, I was wondering if you could talk about 044 and the upcoming data on acute pain. What are we going to see? Kind of what's the bar for you to move forward and get excited about the product? And then just talk about whether the mechanism works both in acute and chronic conditions in the same way, such that the first study would give us a good sense of, you know, how the second study is going to report out later this year. Thanks. Yes.

Yes, Serge I was wondering if you could talk about all four four in the upcoming data in acute pain, what are we going to see.

Kind of what's the bar for you to move forward and get excited about the product and then just talk about whether the mechanism works both.

In acute and chronic in the same way such that the first study would give us a good sense of how.

The second study is going to report out later this year.

Yes.

Dr. Serge Tankovich: Thanks, Mark. This is a, you know, the bunionectomy study is the first phase two study evaluating ACPO 44 for treatment of post-operative pain following bunionectomy. So it's an acute model. Um, The study, just as a reminder, is a randomized, double-blind, placebo-controlled study that enrolled about 240 patients, so it's appropriately, appropriately powered. But, the objective of this study is really to evaluate safety and efficacy of ACP-044 in the targeted patient population and to evaluate efficacy compared to placebo in pain control in analgesia.

Yeah.

Yes, okay. Thanks Mark.

Dr. Serge Tankovich: And from that perspective, we would consider the success of the study if we had statistically significant separation from placebo in terms of pain control and had an acceptable safety and tolerability profile for the drug. Related to your question, we are doing a chronic model of osteoarthritis study. That study will take a little longer to complete, so results will be sometime next year. But, you know, obviously, the mechanism per se, theoretically, but also on the basis of preclinical animal models, the drug was active, the molecule was active, both in the control of acute and chronic models of pain.

This is.

Bunionectomy study is the first phase two study.

Evaluating ACP O 44 for treatment of postoperative pain. Following bunionectomy. So it's in a pure acute model.

Dr. Serge Tankovich: And from that perspective, our anticipation would be that success in one model should indicate potential success in the other model. However, I will remind everybody that pain studies are notoriously sensitive to placebo response. They are difficult to conduct, and from that perspective, I think that read-through is not automatic, and we should always be very careful in interpreting and translating the results of one model into another model.

Hmm.

The study just as a reminder is a randomized double blind placebo controlled enrolled about 240 patients. So it's it's.

Appropriately.

Appropriately powered but.

Objective of this study is really to evaluate safety and efficacy of ACP, Oh 44 in the targeted patient population and to evaluate efficacy compared to placebo in control pain control and that'll GCI and from there.

Perspective.

We would consider a success of this study if we have.

I have a statistically significant separation from placebo in terms of pain control and.

Have hum.

Acceptable.

Safety and Tolerability profile for the drug.

Related to your question, we are doing the chronic model the osteoarthritis study.

That study will take a little longer to complete so our results won't be sometimes sometimes next year.

But.

You know obviously are the mechanism per se theoretically, but also on the basis of the preclinical animal.

Models.

The drug was October the molecule was octave boat in control of acute.

And chronic models of pain and from that perspective, our anticipation would be that.

Success in one model.

Should should.

Indicate potential success in the other model, however, I will remind everybody of the pain studies are notoriously.

Sensitive to placebo response, there are difficult to conduct them from that perspective, I think that a.

It reads through is not automatic and we should be always very carefully and in third party income.

Translating the results of one model and took them right not our model.

Dr. Serge Tankovich: Thank you. Our next question comes from the line of Jay Olson from Oppenheimer. Your line is now open. Oh, hey, this is Matt on behalf of Jay.

Thank you. Our next question comes from the line of Jay Olson from Oppenheimer. Your line is now open.

Jay Olson: Thanks for taking our questions. The first question we had was just on your M1-PAM program, just in terms of data timelines. And as a corollary, if you would ever plan or imagine doing a combination trial of your M1-PAM with Pima-Vanceren, if you could imagine any combination synergies there, that would be interesting to hear about, and also in terms of what indications could make sense. And then separately, we were just curious about any physician feedback you might have gotten so far after the Phase 3 lavender results for trofenit That would be really helpful.

Yeah.

Oh, Hey, this is Matt on for Jay Thanks for taking our questions.

The first question we had was just.

On your M. One Pam program I'm, just in terms of data timelines and as a corollary, if you would ever a plan or imagine doing a combination trial.

Of your M. When Pam with team events are in if you could imagine any combination synergies there that would be interesting to hear about and also in terms of what indications could make sense and then separately. We were just curious about any physician feedback you might have gotten so far after the phase III lavender results for trucking to tide them and how you're currently thinking about.

The market opportunity in terms of driving diagnosis rates that would be really helpful. Thank you.

Steve Davis: Okay, a few questions in there. I'm going to start with an answer on the, sorry, my watch is talking to me, start with an answer on the combination, and then I'll turn it over to Serge for further color on the M1 Pan Program, and then Brendan on Trufenetide.

Okay, a few questions in there.

I'm just I'll I'll.

Start with an answer on the sorry, I was talking to me Jordan answer on the on the combination and then I'll turn it over to search for a further.

Color on that.

They wont paint program and then Brendan on a trip at a time.

Steve Davis: So, in relation to the combination, I'll just simply say, for competitive reasons, we don't talk a lot about opportunities that we're interested in, in terms of additional things we're doing that are early in the pipeline, or things that we might have an interest in pursuing. So, I'll just simply say that, you know, the potential applications for 319 are very interesting, and they're things that we've learned through the development and commercialization of Pimivanserin that we think give us insights to further leverage with new molecules, including combinations going forward. Surge, you want to speak more to 319, and then Brendan, do you want to take the Trifinitac? Yeah, just as a reminder.

So as it.

Released the combination I'll, just simply say for competitive reasons, we don't talk a lot about all producer we're interested in in terms of.

Additional things we're doing there early in the pipeline.

Or things that we that we might have an interest in pursuing so I'll just simply say that.

You know the the potential applications for 319.

We found very interesting and they're things that we've learned.

Through the development and commercialization of him of answering that we think of us in.

Insights to further leverage.

With our new molecules, including combinations going forward.

So did you Wanna speak more to three long island and printing you won't take the triplet attack yeah.

Dr. Serge Tankovich: We've met, our ACP319M1 pain program is for the potential treatment of cognition, cognitive impairment in Alzheimer's disease, and negative symptoms of cognitive impairment in schizophrenia. As we announced, we initiated a multiple ascending dose Phase 1 study last year, and it's currently ongoing.

And just as a reminder.

Matt.

Our ACP $3 19, and one probe pain program is for the potential treatment of cognition cognitive impairment and how alzheimer disease and negative symptoms and cognitive impairment schizophrenia.

As we announced we initiated multiple ascending dose phase one study last year, it's a currently ongoing.

Dr. Serge Tankovich: It's a multi-phase study, and we look forward to providing additional updates later this year on the study. Even in these early development Phase 1 studies, we will be evaluating target engagement to try to better understand where the benefits are and what may be the potential for our further development. But as I said, we look forward to updating you later this year on the progress with TIRIN-19. And I will not forget to address your question on the feedback that we are receiving on the results of the Lavender study.

Multi phased study and we look forward to providing additional updates later this year on the study even in these early development of Phase one studies, we will be evaluating our target engagement to try to better understand whether what are the benefits and what may.

The potential for our further development, but as I said, we will look forward to updating you later this year on progressing with our 2019.

And it doesn't have to forget to address your question on.

The feedback that we're receiving on the results of the lava in them from the alarming there Ah study Ah I can say that we are oh quite pleased with the level of enthusiasm and excitement that we are seeing with the.

Dr. Serge Tankovich: I can say that we are quite pleased with the level of enthusiasm and excitement that we are seeing with treating physicians and experts out there in regard to the data. I mean, you know, it's to some extent understandable considering that, so far, there haven't been any successful late-stage programs in Rett syndrome for the treatment of symptoms of Rett syndrome.

Treating physicians and experts out there in regard to the to the data I mean, you know it's to some extent understandable considering that so far there hasn't been a successful late stage programs with.

Oh in dry eye syndrome for treatment of symptoms over that syndrome, so from that perspective.

Dr. Serge Tankovich: So, from that perspective, there is quite a bit of excitement not only in the medical community, in the scientific community, but also in the parents and caregivers and community. So, bottom line, we are very enthusiastic to see the level of excitement and enthusiasm across and look forward to the NDA and approval. Thanks, Serge.

There's quite a bit of excitement not only in the medical community in the scientific community, but also in and parents and caregivers and community. So Bottomline are we are very enthusiastic to see the leather.

A lot of excitement and enthusiasm across and look forward to D. M D E and and approve them.

Brendan Teehan: And I just want to echo Serge's comments. The RET treatment community has given us very encouraging feedback on what they've seen of the lavender results. But to address your question specifically, Matt, around RET diagnoses, as with a number of rare pediatric diseases, the pursuit of a diagnosis has increased pretty dramatically over time. There is already a high diagnosis rate for RET, so we have access to databases that will show us physicians and the numbers of patients that they have that are already diagnosed with RET.

Yeah. Thanks, Serge, it's and I just want to Echo <unk> comments, the the ret treatment community has given us very encouraging feedback on what they've seen of 11 to results.

To address your question, specifically met around Red diagnoses as with a number of rare pediatric diseases. The the pursuit of a diagnosis has increased pretty dramatically over time.

There is already a high diagnosis rate for rent. So we have access to databases that will will show us physicians and numbers of patients that they have that are already diagnosed with red.

Brendan Teehan: There's also been a significant increase in genetic testing in recent years, and we as an organization will work diligently and are pursuing a number of avenues to educate people on MEK-P2 testing and then looking at potential partnerships to have confirmatory MEK-P2 testing for suspected RET patients post launch. Okay, got it. Extremely helpful. Appreciate all the info.

There's also been a significant increase in genetic testing in recent years.

And we as an organization will work diligently and are pursuing a number of avenues to educate on Mcafee to testing and then looking at potential partnerships to have confirmatory met a messy to testing.

For suspected red patients post launch.

Okay got it extremely helpful. I appreciate all the input.

Brendan Teehan: Thank you. Our next question comes from the line of Ami Fadia from Meetham. Your line is now open. Hi, thanks for taking my question. I have two questions.

Sure. Thanks. Thank you. Our next question comes from the line of Amit <unk> from Needham. Your line is now open.

Ami Fadia: Firstly, just with regard to the PDP indication for nucleic acid, Has something changed structurally with regard to the market? Because of which, you know, we may not see. I'm here to talk to you about recovery in patient inflow or patients being admitted to long-term care for quite some time. Can you sort of comment on that?

Hi, Thanks for taking my question I have to be two questions. Firstly just.

With regards to the PDP indication for NUPLAZID.

Has something changed structurally with regards to the market.

Because as you.

You know we may not see it.

Recovery in patient inflow or patients being admitted to long term care.

For quite some time can you kind of comment on that and then just separately on the ADP indication should you get approval.

Brendan Teehan: And then just separately on the ADP indication, should you get approval, can you talk about the market opportunity there? Your expectation for, you know, being able to tap into that market, relative to PDP. Thank you. Brendan, you want to start? I'll add color. EconUber.

Can you talk to the market opportunity there.

Your expectation for you know being able to tap into that market.

Relative to PDP.

Brendan you're going to start I'll add color.

You got me Brendan.

Brendan Teehan: My apologies. Ami, thank you so much for both questions. In PDP, no, I don't think that there's anything fundamentally restructured around PDP as a market. With the abating Omicron trends, we would expect that in-person PDP patient visits will improve. We've already seen from some of our top physicians that type of dynamic has taken place. Patients that we're not seeing in December, they are beginning to see more readily in the first quarter. So I think there are pandemic-related headwinds that, as those abate, will improve for us. Similarly, in long-term care, as you suggested, the census rate has been suppressed.

My apologies.

Thank you so much for both questions and PDP no I don't think that there's anything fundamentally restructured around PDP as a market.

With the abating.

On the Crown trends, we would expect that in person PDP patient visits will improve we've already seen from some of our top positions that type of dynamic is taking place patients. They were not seeing in December they are beginning to see more readily in the first quarter. So I think there are.

Our pandemic related headwinds that as those abate will improve for us. Similarly in long term care as you had suggested the census rate has been suppressed.

Brendan Teehan: Steve spoke to staffing challenges in long-term care facilities. Again, in this environment, we're seeing selective improvements where staffing is improving. When staffing improves, new residents become potentially available to us. So, again, I would call these temporal types of changes for us to adapt to in the near term, but we are hopeful that as the pandemic abates, these will begin to return as well.

Steve spoke to staffing challenges in long term care facilities again in this environment, we're seeing selective improvements where staffing is improving when staffing improves new residents become potentially available to us and so again I would call. These temporal types of.

Changes for us to to adapt to in the near term, but we are hopeful that as pandemic conditions abate. So will this begin to return as well.

Brendan Teehan: Your second question was about ADP. This is a tremendous opportunity for us. It has about seven times the number of addressable patients that we have in PDP. We've quoted a number of about 900,000 patients treated today. This is a line extension for an already existing and very well-known brand and new plasid launched back in 2016. The core reasons to treat ADP are very similar as they are for PDP, and there's an overlap in the types of treaters that are addressing ADP that also have treated PD.

Your second question was around ADP.

And this is a tremendous opportunity for us it is about seven times the number of addressable patients that we have in PDP.

Quoted a number of about 900000 patients treated today. This is a line extension for an already existing and very well known brand in NUPLAZID launch back in 2016.

The court reasons to treat are very similar as they are for PDP and there are there's an overlap in the types of treaters that are addressing ADP that also have treated PDP, we will expand obviously to address a broader audience of psychiatrists and <unk>.

Brendan Teehan: We will expand, obviously, to address a broader audience of psychiatrists and psych-like PCPs that will also address ADP, but this is an opportunity for us to be first to market by a significant margin with a product that would be the first to treat ADP. I'll just add one quick thought to Brendan's point about PDP. So, the question was, is there, do we see any evidence of a structural change in the market? As Brendan mentioned, the impact that we're seeing, the principal leading indicator, it's multi-faceted, but the principal leading indicator is not infection. But it's the staffing.

Like like P C piece.

It will also address our ADP, but this is an opportunity for us to be first to market by a significant margin.

With a product that would be the first to treat ADP.

I would just add.

One quick thought too.

To Brendan's point on PDP.

So.

The question was is there do we see any evidence of a structural change in the market as Brendan mentioned.

The impact that we're seeing it at that.

The principal leading indicators, it's multifaceted, but the principle, leading indicators not infection rates are but it staffing it staffing both in long term care as well as an office based setting both shortage in staffing as well as significant staffing turnover.

Steve Davis: It's staffing both in long-term care as well as in an office-based setting. There are both shortages of staff as well as significant staffing turnover. And so in addition to, particularly in long term care where occupancy rates are just down, the staffing turnover has both had an impact on new patient starts. In all other aspects of the franchise, we continue to see very, very solid results. Our refill rates have not wavered, so we continue to see very high refill rates.

And so in addition to particularly in long term care, where occupancy rates are or are just down.

The staffing turnover.

Both have an impact on new patient starts in all other aspects of the franchise, we're seeing continuing to see very very solid results.

Our results our refill rates have not wavered. So we continue to see very high.

Steve Davis: Our conversion rates when scripts are written, quite frankly, climbed during this time frame, but the impact of the pandemic, particularly as it relates to staffing rates and as it relates to Parkinson's patients seeing their physician in person, had more of an impact on starting new patients. And so as we, that's why we say, as we see conditions normalize and those dynamics shift, we will see an increased opportunity to start new patients.

So rates are conversion rates when scripts are written.

Quite frankly.

Klein during this timeframe, so so but the impact of the pandemic, particularly as it relates to staffing rates and as it relates to Parkinson's patients seen their position in person have more of an impact on starting new patients.

So as we that's why we say, we see conditions normalize and those.

Hum.

Dynamics shift we will.

We will see a increased opportunity to start new patients and as Brendan mentioned, we've continued to grow share.

Steve Davis: And as Brendan mentioned, we continue to grow share during this timeframe. So as these conditions normalize, we expect that they'll get to do that. So, if I could just sort of follow up, I mean, it seems that you've assumed... The incomparable volume to last in your guidance or the midpoint of your guidance, [inaudible] Um, is that sort of conservative, and as you see the trends evolve. You know, you would sort of review that. Is that how I should think about it? Or is it something else you've seen?

This time frame. So so as soon as these conditions normalize we expect that they will get significant winter.

Thanks.

So if I could just kind of follow up I mean, it seems that he was the film Hum.

Comparable volume to locked in your guidance at the midpoint of your guidance.

Is that sort of.

And as evidenced and as you'll see the trends evolve.

You know you would send them to view that is that how I should think about it or is there something else you're seeing.

Instead of Syn <unk>.

Did you have to think about it or are you now because it makes you instead of giving our guidance range, but it's sort of a flat.

Ami Fadia: you know, which is sort of guiding you to think about a, or, you know, because of issues that are giving a guidance range where it's sort of a flat, Thank you for joining us. Mark, do you want to respond to that? Yeah, so just to clarify, the midpoint of the gauge is similar volume growth to last year, not. Thank you, everyone, for joining us today, and we hope to see you again next week.

While you're on western blot.

Yeah.

Mark you want to respond to that.

Yeah, So just to clarify I guess.

The midpoint of the gauge it as similar volume growth for last year not.

<unk> volume over last year. So there is underlying growth just not you know as high as we've seen in the past and that is you know as we live through.

No it's still living through the pandemic.

Operator: Thank you, everyone, for joining us today. Thank you, everyone, for joining us today. Thank you, everyone, for joining us today. And Mark spoke to the midpoint of the range and the upper end, just for the sake of completeness. Of course, when we provide a guidance range, we model a number of scenarios.

And then the higher end of the range is coming out of the pandemic and getting back towards higher growth and hopefully over the long term that that trajectory and above.

So I think that's that's kind of where we stand now I wouldn't you know I have you.

Just say listen work.

Third year of the pandemic I think we're getting better at forecasting I wouldn't use the word conservative or just say we have confidence in the range. We still are living in the pandemic. So that is influencing this range, but we are.

We hope and expect to exit that.

In the near term and then continue on with investment and growth in Nebraska.

And Mark spoke to the.

Midpoint of the range in the upper end just for the sake of completeness of course, when we provided guidance range, we modeled a number of scenarios, but the low end of the range, we're reflecting the recognition that it is possible that we're going to have another variant besides all across the world or walk towards the home of gone too are there other things that we just can't predict today that that could impact us in at the low end.

Steve Davis: At the lower end of the range, we're reflecting the recognition that it's possible that we're going to have another variant besides Omicron, or it'll be Omicron 2. But there are other things that we just can't predict today that could impact us. And at the lower end of the range, you do see flat volume there.

Steve Davis: That's not our expectation. Our expectation is for Infection rates subside, most importantly, as staffing stabilizes, as Parkinson's patients get more comfortable coming to see their physicians in person, that will get a lift from that. The timing of those changes and the magnitude of them directly correlate to the scenarios that we think are most helpful. Thank you. Ladies and gentlemen, if you wish to ask a question, please press star followed by one on your touchtone telephone. If your question has been answered or you wish to withdraw your question, press the pound key. Please limit yourself to one question.

You do see flat volume there.

Not our expectation our expectation is as.

Infection rates.

Subside and most importantly, as staffing stabilizes as Parkinson's patients get more comfortable coming see their physicians in person that will get lift from that.

The the timing of those changes and the magnitude of them.

Or directly correlate to the scenarios that we model.

That's very helpful. Thank you.

Ladies and gentlemen, if you wish to ask a question. Please press star followed by one on your Touchtone telephone. If your question has been answered or you wish to withdraw your question press the pound key.

Please limit yourself to one question I repeat please limit yourself to one question.

Operator: I repeat, please limit yourself to one question. Our next question comes from the line of Paul Matias from Stiefel. Your line is now open. Hey, thanks for taking our questions, Alex. I'm on behalf of Paul.

Our next question comes from the line of Paul Martin from Stifel. Your line is now open.

Paul Matias: Just one question on the progress of the study. I was wondering if you could comment on impacts from sites in Ukraine and Russia as it relates to, you know, data integrity, as well as potential timing of the study. Thanks. Sure. Sir, do you want to take that?

Hey, Thanks for taking our questions Alex on for Paul Just one question on the advance two study I'm wondering if you could comment on.

Impacts from sites and in Ukraine, and Russia as it relates to you know data integrity as well as potential timing of the study. Thanks.

Sure Serge when you take that.

Dr. Serge Tankovich: Yeah, let me just remind you first that ADVANCE II is a multinational study and is being conducted in 12 countries across multiple regions, Western Europe, Eastern Europe, and South America. So from the perspective of the impact of the current geopolitical situation in Russia and Ukraine, I think that although there will be some impact locally, we certainly expect, considering the setup of the study, that no single country or geography would have a prevailing impact on the overall recruitment or conduct of the study.

Yeah.

Let me just remind you first that advanced SKU is a multinational study is being conducted in 12 countries across multiple regions Western Europe , Eastern Europe , and South America.

So from the perspective of impact of the current Uh huh.

The geopolitical situation in.

Russia and Oh, yeah.

Ukraine, I think that our although there will be some impact luckily.

We certainly expect that to.

Considering the setup of the started that no single country or geography.

It would have a prevailing the impact on the overall recruitment or conduct of the study.

Dr. Serge Tankovich: In regard to data, we have, through the COVID pandemic, made a number of adaptations in terms of remote data collection and interruptions in the programs. So we have in place mechanisms to deal with this sort of situation as well. Having said all of this, I do also want to express grave concern for the Ukrainian people and the suffering that they are going through with this unprovoked attack. I wish that the situation gets resolved as fast as possible to a constructive resolution for Ukraine, but I will say as far as our trial is going, we do not expect a dramatic impact.

You know when I'm in regard to the data.

We have through the Covid pandemic became you know made a number of our.

Adaptations to in terms of the remote data collection and interruptions in the in the programs. So we have in place mechanisms to deal with this sort of situation.

Well, having said all of this Ah Ah.

Do also want to express.

A grave concern, Florida Ukrainian people and.

You know the suffering that they're going through.

We did unprovoked attack, but you know as far as our and I wish that the situation, obviously gets resolved as fast as possible to the to the.

A constructive resolution core Ukraine, but I will say as far as our trial go.

He is going we do not expect.

Thereabouts you came back.

Okay.

Dr. Serge Tankovich: Thank you. Our next question comes from the line of Gregory Renza from RBC Capital Markets. Your line is now open.

Thank you. Our next question comes from the line of Gregory <unk> from RBC capital markets. Your line is now open.

Gregory Renza: Hey, good evening, Stephen team. Thanks for the update. And thanks for taking my question. Maybe just a quick one, Stephen, just in the event that I missed something.

Hey, good evening, Steve and team Thanks for the update and thanks for taking my question, maybe just a quick one Steven just in the event that I missed it I'm just curious if you could comment just a bit about what what youre seeing in this in this current quarter with nearly two months down just as far as that recovery is concerned and wildlife.

Certainly appreciate the the general comments on our full year I'm I'm I'm, just I'm interested in some of your thoughts on that recovery in some of those market dynamics for for NUPLAZID in PDP as we've come out of the gate not just with 2021, but and exiting January and Opex exiting February to that extent. Thank you very much.

Steve Davis: And I'm just curious if you could comment just a bit about what you're seeing in this current quarter with nearly two months down just as far as that recovery is concerned. And while I certainly appreciate the general comments on the full year, I'm just interested in some of your thoughts on that recovery and some of those market dynamics for the new plasmid in PDP. As we've come out of the gate, not just with 2021, but leaving January and also leaving February to that extent.

Steve Davis: Thank you very much. Yeah, thanks a lot, Greg. So I just need to start by saying, you know, we don't guide quarter to quarter.

Yeah. Thanks, so much Greg so.

Yeah, I'll just need to start by saying, yeah, we we don't.

Guide quarter to quarter and so the guidance we gave.

Steve Davis: And so the guidance we gave for the year today reflects very up-to-date information in terms of what we're seeing in the marketplace. And the thing that I would like to stress is the factors that we believe are responsible for the outperforming basket of top neurology, top Parkinson's, top LTC drugs continue to be very much at play. So we're continuing to see strong performance on those elements, continuing to see very strong performance in terms of our refill rates, with our conversion rates, et cetera.

For the year today reflects very up to date information in terms of what we're seeing in the marketplace and it's the thing that I would like to stress is.

The factors that that we believe are responsible rose outperforming basket of top neurology.

Top Parkinson's top LTC drugs continued to be very much.

I play so we're continuing to see strong performance on those elements, you're continuing to see very strong performance in terms of our refill rates, our conversion rates et cetera, and so so as we look for.

Steve Davis: And so, as we move. All right. So we're moving forward in the year. We're at a point right now where we're just now kind of coming out as a society, it appears, of the Omicron wave. We don't know what the impact will be from the reduction of mask requirements and just the way we behave as a society.

Afford in the year, we're at a point right now where we're just now kind of coming out of us as a society are kind of coming out. It appears of the omicron wave, we don't know what the impact will be from.

A reduction of mask requirements and and just the way we behave.

Steve Davis: But I would simply say that, as it relates to our business and specifically around PDP, we've tried to cover the range of outcomes for the year, and everything we've seen right up to today is consistent with the scenarios or reflected in the scenarios that we've run. And again, the two underlying currents, undercurrents, that will determine where we fall in this range are both our ability to continue to outperform drugs in the sector. We're highly confident of that. And then just precisely the precise timing and magnitude of the normalization of the pandemic.

As a society, but I would just simply say that that as it relates to our business and specifically around PDP. We tried to cover the range of outcomes for the.

The year and everything we've seen run right up to today is consistent with the scenarios are reflected in the scenarios that we've run and again the two under buying current undercurrents that will determine where we fall in this range are both are our ability to continue to outperform our drugs in the sector. We're highly confident of that and then.

Precisely the precise timing magnitude of normalization of pandemic and for that I think that we are as well informed as anyone can be particularly as it relates to the impacts on the Parkinson's community, but we do need a little bit of time to see this play out through the year.

Steve Davis: And for that, I think that we're as well-informed as anyone can be, particularly as it relates to the impacts on the Parkinson's community, but we do need a little bit of time to see this play out. Great, thanks for the call. Thank you. Our next question comes from the line of Jason Butler from J&P Securities. Your line is now open.

Great. Thanks for the color.

Thank you we have time for one last question.

Jason Butler: Hi, thanks for taking the question. I was just wondering if you could speak to the commercial prep work you'll be doing in RET this year. Obviously, assume the infrastructure outlay will mainly be towards the end of the year and into next, but from a medical education perspective, just can you walk us through the work you're going to be doing to get the market ready for the drug? Thanks. Sure. Brendan, do you want to start? Brendan, I think you're on mute. My humble apologies, Jason.

Our next question comes from the line of Jason Butler from JMP Securities. Your line is now open.

Hi, Thanks for taking the question I'm just wondering if you can speak to the the commercial prep work you'll be doing in rent.

This year, obviously assume they'd be infrastructure out bill will mainly be you know towards the end of the year and it's an expert from a medical education perspective, just a can you walk us through the work you're going to be doing to get the market ready for the drug. Thanks.

Sure.

Brendan you want to start.

Where do you think you're on mute.

Brendan Teehan: Thanks again for the question. Yes, obviously, we're very excited about the trophinotide opportunity, and we have been preparing, even as the lavender study was ongoing, in phase three for a favorable result.

My humble apologies, Jason Thanks again for the question, Yes, obviously, we're very excited about the tryphena tied opportunity and we have been preparing even as 11th study was was ongoing in phase III for a favorable result.

Brendan Teehan: The initial work, obviously, we want to work with the payer community to make sure that they're aware of the burden of illness, understand the unmet medical need, and the size of the patient population, roughly 6,000 to 9,000 patients. We also have developed, over time, strong relationships with the foundations that support patients, caregivers, and the health care community to help us to understand where we're going to find our representative patients and the volumes of patients that we're going to want to support.

The initial work obviously, we want to work with the payer community to make sure that they're aware of the burden of illness I understand the unmet medical need and the size of the patient population.

Roughly six to 9000 patients. We also have developed over time, a strong relationships with the foundations that support patients caregivers and the health care community, which has helped us to understand where we're going to find a ret patients.

Brendan Teehan: And then broadly, another area that we'll focus on is our white glove support services to be prepared by the time of lawn, to support families not only getting started on Trafenatide but to have a successful clinical experience, all of the support that they need from a clinical perspective, as well as prior authorization, assistance with co-pay, and so on. So those are probably the principal areas where we'll focus as they relate to the product.

And the volumes of patients that are that we're going to want to support and then broadly are another area that we'll focus on our white glove support services to be prepared by the time of launch.

To support families not only getting started on tryphena tied but to have a successful clinical experience all of the support that they need from a clinical perspective as well as prior authorization assistance with co pay and so on.

So those are probably the principal areas, where we will where we'll focus as they relate to the product.

Brendan Teehan: For the disease state, obviously, this is a tightly knit community; there's a high level of awareness of Rett Syndrome. We will work with the community to make sure that, where necessary, confirmatory MeCP2 treatment will also be available for suspected patients with R.E.D. at any of their agencies.

For the disease State. Obviously this is a tightly knit community, there's a high level of awareness of of Ret syndrome.

We will work with the community to make sure that where necessary confirmatory macphee. Two tests will also be available for suspected patients with red at any of their hcp's.

Steve Davis: Great, thank you. Thank you. Mr. Davis, please proceed to closing remarks. Thank you, Operator, and thanks to each of you for joining today. We appreciate your time and attention and support and look forward to updating you as we go forward. Thank you for your participation on today's conference call. This concludes the presentation. You may now disconnect. Good day.

Great. Thank you.

Yeah.

Thank you Mr. Davis. Please proceed to closing remarks.

Thank you operator, and thanks to each of you for joining today, we appreciate your time and attention and support and look forward to updating you as we go forward.

Thank you for your participation today's conference call. This concludes the presentation you may now disconnect good day.

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