Q4 2022 Agios Pharmaceuticals Inc Earnings Call

February 23, 2023

The conference will begin shortly to raise and lower Johan during Q&A, you can dial star one.

Good morning, and welcome to Rga's fourth quarter and year end 2022 conference call. At this time, all participants are in a listen only mode.

Will be a question and answer session at the end. Please be advised that this call is being recorded at Rgs request I would now like to turn the call over to Jessie Brenda Kamp Senior director of corporate Communications. Please go ahead.

Thank you operator, good morning, everyone and welcome to <unk> fourth quarter and year end 2022 conference call you can access slides for today's call by going to the investors section of our website at <unk> Dot com.

With me on the call today with prepared remarks are Brian Goff, our Chief Executive Officer, Dr. Arguing our chief Medical Officer, and head of research and development. That's a melanoma, our chief commercial officer is the theory of Jones, our Chief Financial Officer.

Before we get started I would like to remind everyone, but some of the statements. We make on this call will include forward looking statements.

Actual events and results could differ materially from those expressed or implied by any forward looking statements as a result of various risks uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC with that I will turn the call over to Brian .

Good morning, everyone and thank you for joining us.

<unk> is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases.

Driven by the cross functional commitment of the <unk> team, we made tremendous progress over the past year toward our goal of building a PK activation franchise focused on hematologic diseases that share a common underlying pathophysiology limited treatment options and profound unmet need.

In particular, I would like to highlight the excellence in execution displayed across our research and development team to bring forward pirate kind of first in class PK activator as the first and only approved disease modifying therapy for adults living with PK deficiency.

<unk> was approved in the U S EU and Great Britain in 2022 and represents the cornerstone of our growing PK activation franchise with the potential for two additional indications by 2026.

In parallel with these approvals, we made significant advances across our broader clinical stage pipeline, including our five ongoing pivotal studies and met the ambitious clinical development targets, we outlined at the beginning of last year.

Notably, we continued to generate consistent and compelling data with our PK activators across multiple disease areas highlighting the potential of this differentiated mechanism of action to transform patient function quality of life and long term outcomes in not only PK deficiency, but also thalassemia.

Sickle cell disease, and lower risk Mds.

In 2022 data across our clinical portfolio were presented at major medical meetings, including the annual meetings of the European Hematology Association and the American Society of Hematology and were published in top tier medical journals, including the lancet and the New England Journal of Medicine.

Following the third full quarter of the launch of <unk> in PK deficiency, we continue to be encouraged by the positive reception from patients physicians and payers and the impact <unk> is having for a community that previously had no treatment options as.

As we've said in the past we continue to believe that this launch will be slow and steady and will provide a capability building platform to support potential expansion in meaningfully larger patient populations.

That said our ambition is to improve the launch trajectory and realize the full potential of the opportunity we have in front of us.

To that end in December of last year, we appointed set of melanoma as Chief Commercial officer, Scott is a seasoned commercial leader, who brings deep expertise in launching and commercializing medicines in rare diseases in hematology with a particular focus on global market access and operations.

Her experience and leadership will be critical as we continue to strengthen our commercial capabilities in order to both maximize the potential of the current launch in PK deficiency and prepare for potential future launches in thalassemia and sickle cell disease over the next few years.

We ended 2022 in an enviable cash position with approximately $1 1 billion on the balance sheet.

This includes the onetime payment we received in the fourth quarter of 2022, following the sale of our royalty rights on U S. Net sales of silver to cigars we.

We expect our cash position to support the completion of our ongoing programs as well as enable us to expand our portfolio beyond PK activation through disciplined business development and the advancement of our earlier stage pipeline.

We anticipate significant progress on each of these objectives in 2023 spin.

Specifically in the middle of this year, we expect to complete enrollment of the phase III energized and energized T studies of pirate kind in thalassemia and announce the data readout of the phase two rise up study of <unk> in sickle cell disease and the no go. The go no go decision to phase III.

And by the end of the year, we expect to enroll more than half of the patients in the phase III activate kids and activate <unk> T studies of pirate kind in pediatric PK deficiency complete enrollment of the phase Iia study of our novel PK Activator AG 946 in lower risk Mds.

And file the IND for our <unk> stabilizer for the treatment of PKU.

Throughout the year, we aim to continue to strengthen our commercial capabilities through our ongoing launch in PK deficiency and continue to evaluate BD opportunities to expand the pipeline.

Looking forward to 2024 to 2026, we anticipate a catalyst rich period with the potential for two additional <unk> indications in this timeframe.

Specifically in 2024, we're expecting the readout of the phase III studies of <unk> in thalassemia as well as the readout of the Phase Iia study of AG 946 in lower risk Mds in.

In 2025 were expecting the potential approval of <unk> in Dallas, EMEA as well as the phase III readouts of pirate kind in sickle cell disease in pediatric PK deficiency and in 2026, we're expecting the potential approvals of pirate kind in sickle cell disease and in pediatric PK deficiency.

With this slate of potential near term catalyst I look forward to a productive year as we work toward our 2026 vision of our Geos and established hematology franchise with approvals spanning three hemolytic anemias and expanded portfolio fueled by business development and advancement of our.

Internal pipeline that is aligned with our core expertise in rare disease and cash flow positivity.

With that I'll now turn the call over to Sarah.

Thanks, Brian .

2022, our research and development organization made significant progress advancing our PK activator development programs across multiple disease areas, United by the shares underlying pathophysiology of Red blood cell metabolic stress.

Representing the largest data set generated for any PK activator, the consistent and compelling data we have generated to date with <unk>.

K deficiency, thalassemia and sickle cell disease highlights the potential for peak Activations to correct red blood cell metabolism, and transform patient function quality of life and long term outcomes in each of these disease areas.

The most recent data updates across our clinical portfolio were presented at Ash in December .

<unk> and our external collaborators were pleased to present, a total of 22 abstracts.

These included long term data from the phase II study of buyer and seller senior demonstrating durable improvements in hemoglobin, and hemolysis and stabilized or improved erythropoiesis and iron homeostasis over 72 weeks in patients with alpha or better non transfusion dependent thalassemia.

In PK deficiency, we presented updated long term extension data demonstrating that adults treated with <unk> exhibited sustained improvements in hemoglobin iron overload transfusion burden and patient reported outcomes, regardless of transfusion status.

And we presented new data from the Phase one study of our novel PK Activator AG nine six in healthy volunteers, which showed a favorable safety profile at pharmacologically active doses and a PK profile supportive of once a day dosing.

Taken together the clinical data we have generated to date suggests that prioritize differentiated mechanism of action is correcting red blood cell metabolism, and leading to consistent improvements in hemoglobin hemolysis and Eric Zhou Please.

With that context, let me now provide a brief update on the powertrain development program at the beginning with thalassemia.

As a reminder, the phase III program aspire timing thalassemia comprises two randomized placebo controlled trials each of which are enrolling patients with both alpha and beta thalassemia.

Energizes enrolling patients who are not regularly transfused with a primary endpoint of hemoglobin response, and energize D is enrolling patients who are regularly transfused with the primary endpoint of transfusion reduction response.

More than half of patients in each of these studies have now been enrolled and we aim to complete enrollment of both studies in the middle of this year.

Based on the data we have generated in this program to date, we believe strongly in the potential for <unk> to become the first therapy to improve hemolytic anemia, and ineffective erythropoiesis in all subtypes of thalassemia and become a foundational therapy in the treatment of this devastating disease. We look forward to the Readouts from these phase III studies.

Yes.

I'll now turn to sickle cell disease, where we aim to deliver a novel oral therapy that both improves <unk> and reduces taper occlusive crises or voc's too.

And we are advancing the operationally seamless phase III <unk> study of pirate tanked in adults with sickle cell disease, and I am pleased to announce that the phase two portion of this study is now fully enrolled.

The primary endpoints of the phase II portion of the study or hemoglobin response, and safety and we expect to announce the phase II data readout in the go no go decision to phase III in the middle of this year.

This decision will be informed by the protocol defined go no go criteria in the phase II portion of rides up as well as any additional data from the phase two secondary endpoints and longer term data from the ongoing extension studies of investigator sponsored trials at the NIH and the University of today.

To date. These investigator sponsored trials have generated compelling data, suggesting that in adults with sickle cell disease biotech reduces red blood cell signaling and similar to what we have observed in PK deficiency and thalassemia also resulted in consistent improvements in hemoglobin hemolysis in the rental fleet.

Finally, we continue to advance the phase III activate and activate T studies of pirate <unk> in pediatric PK deficiency as we aim to deliver the first approved therapy for children living with this disease.

We aim to enroll at least half of the patients in each of these studies by the end of the year.

In parallel with the <unk> development program, we continue to advance the development of <unk> 96, a novel PK activator, which provides the opportunity to further strengthen our PK activator franchise and pursue multiple therapeutic paths, including lower risk Mds.

As we presented at Ash pharmacokinetic data from the healthy volunteer cohorts of the phase one single and multiple ascending dose study, we're supportive of a once daily dosing regimen and Pharmacodynamic data suggested sustained activation of the glycolytic pathway, including dose dependent increases in ADP and dose dependent decreases in <unk> <unk>.

Okay.

Taken together with a favorable safety profile, we look forward to progressing the ongoing phase two study of $89 six in lower risk Mds and expect to complete enrollment of the phase Iia portion of the study by the end of this year.

As Brian mentioned, we aim to expand our pipeline beyond <unk> activation through both disciplined business developments in the advancement of our earlier stage pipeline.

Within our earlier stage pipeline, we continue to progress our lead research program aimed to address phenylketonuria or PKU.

PKU is a rare genetic disease with limited treatment options that impacted total of approximately 35 to 40000 patients in the U S and EU five and it's caused by a deficiency of the Pheno alanine Hydroxylate FPH enzyme.

Lots of ph activity leads to the accumulation of phenylalanine and downstream sequela in patients with PKU are therefore, often aside consumer highly restrictive diets in order to minimize <unk> intake, which can further reduce patient quality of life.

To directly address the underlying cause of PKU, we are developing an oral ph stabilizer with the goal of reducing <unk> levels and we are targeting an IMD filing for this program by the end of this year.

Overall, I'm very pleased with the significant progress the team made executing across our portfolio in 2022 and look forward to the continued maturation of our five ongoing pivotal studies over the course of 2020 with that I will now turn the call over to Sam.

Thank you Sarah.

Joining Andrew last month, I've been impressed and energized by the rigor of the commercial team.

Selling data generated across our clinical program and the potential of our portfolio to transform the treatment paradigm of multiple rare muscle lodging diseases.

It is truly a privilege to have the opportunity to join the company. So clearly poised for EMEA and locked ethanol.

For the last 20 years I've led global rare disease launches at the leading biopharmaceutical companies.

While each of those launches presented unique challenges Mike Hopkins has remained the same.

To reduce the length of the basin, Jeremy and improve patient health outcomes as efficiently as possible.

So it seems that fall, particularly for an ordinary rare disease. It is critical to implement and deploy a comprehensive commercial strategy that addresses each state of the patient journey from disease awareness.

<unk>.

Specifically that strategy must be underpinned by our focus on three key areas.

Increasing awareness of the disease and educating on available treatment option.

I've said that I think access by reducing the time between diagnosis and treatment initiation.

Supporting our Trs and maintaining reimbursement over the long term.

Leveraging this strategy my top priority is to drive operational excellence in the final margin PK deficiency and deals are the capabilities, we need to fully realize the complier show potential off by a decline in anticipated future launches into leukemia in sickle cell disease.

And then if you think the launch to date have been particularly encouraged by the progress. The team has made on market access.

<unk> policies are aligned to the label or clinical trial inclusion criteria and prior authorization criteria are in line with expectations with the majority of patients initiating therapy for up to six weeks after completion of the prescription enrollment form or P. F.

To date this continuation of continue to remain low overall and the reauthorization has not been a barrier.

Progress highlights the bulk of the positive impact of final refined and the strength of our market access and patient services capabilities.

In the fourth quarter of 2020 tool, which represented the third full quarter of launch we generated $4 $3 million in net bioscience revenue.

A total of 105 patients have now completed a D E F, including 21 in the fourth quarter of 2020% to 25% increase versus the third quarter.

Given our strong conversion rates. This has translated to a net of 78 patients on therapy, a 39% increase over Q3.

Based on cell therapy, and from our growing and diverse prescriber base of 96 physicians and they represent a broad demographic and disease manifestation range that is consistent with the adult PK deficiency population.

Despite this progress we have indentified multiple opportunities for improvement.

As is common in ultra rare disease launches, we have observed a general lack of disease awareness and a corresponding lack of urgency to diagnose monitor Anthony.

This presents a clear opportunity to focus greater attention on the earliest stages of the patient journey, and thereby increase disease awareness and diagnostic efficiency.

Specifically as the ICD 10 calls for diagnosing PK deficiency was established less than two years ago, we plan to bolster our disease awareness efforts by augmenting, our AI and machine learning capabilities to identify high professional clinicians likely to treat patients with PK deficiency.

Additionally, given the breadth and diversity of the prescriber base, we aim to strengthen our capacity to engage and educate treating physicians, including on the availability of the anemia program, which provides no cost genetic testing to identify a range of hemolytic anemia, including <unk>.

This efficiency.

I'm confident that further strengthening these rare disease capabilities will help us maximize the potential of the current launch, but PK deficiency is only the beginning building our capabilities to support their education access and adherence will directly translate to future potential.

<unk> in meaningfully larger patient population and will help us unlock the full commercial potential of our PK activator kind of franchise.

With that I will now turn the call over to Cecilia.

Thanks to setup, a fourth quarter and full year 2022 financial results can be found in the press release, we issued this morning, which I will summarize.

More detail will be included in our 10-K, which will be filed later today.

Full year 2022, net <unk> revenue was 11 $7 million.

<unk> $4 $3 million in the fourth quarter, an increase of zero point $8 million compared to PCP.

As far as the first therapy for these ultra rare patient population, we continue to gather data and insights on the launch trajectory and will not be providing guidance at this time.

Consistent with other rare disease launches gross to net continues to be in that 10% to 20% range.

Sales for the quarter was $31 4 million got it.

Moving to expenses on the balance sheet R&D expenses were $70 $3 million for the fourth quarter and $279 $9 million for the full year 2022, an increase of $22 $9 million compared to the full year 2021.

This year over year increase was primarily driven by increased cost for five ongoing pilot and pivotal studies and for the $89 six studies and increased 12% across R&D.

SG&A expenses were $32 $8 million for the fourth quarter and $121 $7 million for the full year 2022, an increase of zero point something million dollar as compared to full year 2021.

Full year tips over I guess to revenue, which is recorded under royalty income from gain on sale of oncology business on our income statement with $9 $9 million as a reminder, if silver royalty income ceased after Q3 2022, given the state of our rise to 5% royalties on U S. Net sales of the silver.

So card for a one time payment of $131 $8 million in October of which we recorded a $127 $9 million and other income in Q4.

As part of the divestiture of a quality business to serve yet we retain rights to a potential 200 million dollar milestone upon approval and 15% royalties on potential U S. Net sales of RFID.

Clinical stage <unk> inhibitor Newton I D H, one and two.

We ended the year with cash cash equivalents in marketable securities of approximately $1 1 billion.

We expect our cash cash equivalents and marketable securities together with anticipated product revenue and interest income will enable us to execute our operating plan, including funding. The currently planned development program for me to pivot 89 prospects in ph and commercializing makeup pivot outside of the U S through one or more.

Partnerships to cash flow positivity without the need to raise additional equity.

To maintain our strong cash position, we will remain focused on proactively managing our cost base and deploying a disciplined capital allocation approach to ensure the full development of our ongoing pivotal studies and flexibility to expand our pipeline through business development.

I will turn the call back over to Brian for his closing remarks.

Thanks, Cecilia 2022 was a year of tremendous progress at <unk> with the approval of pirate kind in adults with PK deficiency, we've taken an important first step toward our 2026 vision and we remained focused on advancing our industry, leading pipeline of PK activators to address the preferred.

The unmet needs of patients suffering from rare hematologic diseases in.

In 2023, we're anticipating a number of key clinical and regulatory milestones that will lay the foundation for potential phase III data readouts in thalassemia sickle cell disease in pediatric PK deficiency over the next few years.

As always we will strive to be responsible stewards of our balance sheet, and we'll continue to evaluate meaningful opportunities for value creation.

Finally, I'd like to thank all of our employees for their hard work and dedication to our mission of transforming the lives of patients living with rare diseases, and all of our partners, including physicians caregivers patients and participants in our clinical development programs with that we'll now open the call for questions.

As a reminder to ask a question. Please press star one one on your telephone.

For your name to be announced to withdraw your question. Please press star one one again, please standby, while we compile the Q&A roster.

Yeah.

Our first question comes from Chris Raymond with Piper Sandler Your line is now open.

Hey, Thanks, guys for taking the question just.

I guess a couple questions first on the phase III sickle cell.

The phase two portion of your trial reading out this year.

You guys have talked about the primary endpoint being hemoglobin response, but is there.

The option to show a POC signal at least in this portion of the trial can you just clarify that.

And then I have a follow up.

Sure. So hi, this is Sarah.

<unk>.

So for the phase II portion of the trial. Indeed, we have a primary endpoint of hemoglobin response and safety at the first half, but then in our secondary endpoints, we RMB capturing.

The rate of Vlccs as well that being said it is indeed, a 12 week period for the randomized controlled trials. So the data coming from that is.

It's going to be limited by the time that patients have been exposed to the drug.

<unk>.

As always we've always been saying this as well that we will be looking at the totality of the data generated in this trial specifically in the rise of trial and we will also be looking at our investigator sponsored trials in which patients have been exposed for a longer duration.

Okay, great. Thanks, and then just on <unk> in Europe , I know you have marketing authorization in Europe , and the U K.

And you've talked about not wanting to build really uninteresting infrastructure there, Brian I guess until you get a larger indication. So maybe any update on that strategy for launch there, especially given that you now have.

Marketing authorization.

Yes, good morning, Chris Great question. So as you noted we have mentioned that we have interest in a partner or partners as we think about commercialization outside the U S.

Alright, thank you.

You bet.

Please stand by for our next question.

Our next question comes from Mark from with Colin Your line is now open.

Hi, Thanks for taking my questions.

Maybe just to follow up on Christmas question on your son thinking about the the phase two data as we get it.

And making the decision for phase three.

<unk> you just needing to see more robust, but very similar data to what you've already seen in terms of hemoglobin things like that or they're really new input and points that need to be revealed in this data to make you want to go forward.

<unk>.

The N Y C E R E N.

Relatively similar to what we have in our other trials. However, this is the first placebo controlled data sets in our face too. So we are actually very excited about that and yeah. We are very easily looking forward to mcnair.

And I think Mark I would just add to I mean, you know one of the themes that we've been talking about this so appealing a power kindness the consistency of the data that we've seen across hemolytic anemia as P. K D.

All the way through launch of course, and then thalassemia, which is already through phase two and we have the phase three underway.

And as you know rise up where we're at.

Waiting the phase two data, we're not expecting per se surprises, but it'll be confirmatory, if we see compelling data coming out of the phase to rise up stuff.

Study and we have the endpoints of course identified and then we will look at the totality of data is Sir just noted.

Okay. Thanks.

And then maybe you just to the to the launching <unk> N P. K D keyboards kind of first full quarter of pump patient the flowing through reauthorizations and things like that and and you continue to have that experience. This this quarter cause what are you seeing in terms of the reauthorization standards that are being applied.

10% of patients do you think you should we expect to continue on therapy for the long term.

Thanks, a lot for the question, it's better here as I said, we have 78 minutes based on some therapy at the end of March quarter of 2022, and this really that's based on the number is included take up all of the patients will have started on Saturday and all of the patients will have discontinued.

We have not reported any specific numbers discontinuation. That's as we can all take the reauthorization race probation instead of releasing that six months as men has been updated a barrier. So far oh, the discontinuations continued to remain low low overall.

For the product and for me that's totally reinforces the politics, if reception than we get from <unk> physician and.

On the profile of final factor in the U S.

Okay. Thank you.

Please stand by for our next question.

Our next question comes from Greg Harrison with Bank of America. Your line is now open.

Good morning. This is Mary Kate on for Greg. Thanks for taking our questions I guess as we hit one year since you provoke T K.

Katie you've mentioned that you have about 96 physicians prescribing, maybe how do you expect to use it and update it to change as physicians become more aware of an experienced with iron.

So we were actually very pleased with the progress we've made off made on by the prescribing Uhm as you mentioned already we have 96 unique position will have generated 105 calculation enrolment forums.

Egypt unfolds romare disease and from that perspective, expanding the bride of Christ gardening is going to be our core focus of data and moving forward. We have to keep in line that it does take time because each of the unique prescribed first we'll need to basically go on.

Their own journey of disease awareness I as in all of this prescription as well and this is one of the main reasons actually will with a greater emphasis on the first part of the patient Jeremy from the really short of the main aside from that nowadays after treatment and.

Invest a great the rest rising in the data and analytics to help diagnostic efficiency and very importantly, help us improve our targeting efforts with munitions as well.

I'll just add that the kinetics of an ultra rare disease launches got a noted really will be about breath of prescribing. It's we describe it often is inch deep mile wide because it would be unusual for P. K D for a physician to have more than one or two or maybe three patients at the most so this these efforts that's federer.

One two about first of all education, which is critically important.

Secondly, she alluded to this in the prior comments the machine learning capabilities that we're working on using claims database analysis is critically important it's a modern state capability for rare disease launches that we will look to master because the more that we can be efficient in guiding our call plan targa.

Sting towards high potential providers, who are likely to have a P. K D patients the more effective or breath proliferation will be and that really is one of the key areas of focus.

Great. Thanks, and then if I could one more for those on treatment already prescribing how ya.

What kind of feedback have you been receiving from patients and physicians you either use a prescribed the drug thank you.

We're very pleased with the feedback and we are getting across the board from patient physician and and if they are as well I think the success of our happen access efforts definitely speaks to the.

Positive reception of parents, followed for patients for initiating therapy, but also the great that.

First we see lately has been able to organization right. We get a lot of positive anecdotal feedback part of our patients Survey C 10, which is fantastic just here and I actually had the opportunity to hear some of the direct feedback from our customers when I actually went out on the field and mentally some of them are in my prayers.

My last month on the job and it's really a reinforces the positive not only for a section of the product that's already experienced that early in the launch wait how five guys performing for those patients L. We are excited at least that is gonna take some time, but I believe we're put things about the the right.

M as in place to say no to that.

Prescribing and that's for PK date, which is really encouraging.

Or do you want to comment on the clinical trial experience sure. So it's it's very similar in a way the clinical trial continues to gather data in the long term for patients with B K D who has been on <unk> for now a long time it will be C. As our data is getting stronger as it matures even because the.

Women are effective maintained the impact on him all to just maintain very importantly, we see patients reported outcomes that are also maintained and really reached its clinical significant threshold for feeling better and functioning better and then on top of them. When we are very excited about it or iron overload data is.

Well, we're restarts I'm seeing more and more of an impact on iron overload. That's also I think we're we're very excited about the apparent kinds has already delivered and is continuing to delivering for patients with dignity.

Great. Thank you.

Please stand by for our next question.

Our next question comes from tests Romero with J P. Morgan to your line is now open.

<unk>. Thank you for taking my question.

So just one for me I think I'll stop disease program, if I could so thinking a little bit about the fees to rise up data in your account now about education here, specifically is there <unk> hemoglobin responds street that you view as differentiated here and I know in the past, we've talked a little bit about.

Data cruise have crises has also been important to monetary so could you help us understand a little bit better what I'm, an encouraging trend might look like <unk> as well.

So far our primary and <unk>, it's the the hemoglobin response right. So we do have the bar sex, they're asking one gram per deciliter to be qualified as a hemoglobin response between specific time points in the clinical trial.

We have pre specified in our protocol, what we consider you know statistical significant results for our primary endpoints and then how we move forward into our secondary endpoints 60. So it's a very sort of classical setup for updates to now for phase two of course, what we're looking for in the secondary endpoints. It's Ah trends are voc's.

Now we're capturing over time, you know, we will accrue a crew that data.

We're not looking there for something hugely impactful are meaningful because that's ultimately what the C. Three will deliver them and say three is setup to truly delivered towards our.

Targets product profile in which we're hoping to be able to treat the totality of sickle cell disease by impacting both hemolytic anemia sickle cell Big crisis and then there is the also the opportunity to then further hits. They should report. This outcome. So really are providing a drug that can be meaningful across the.

Single cell.

Please stand by for our next question.

Our next question comes from Greg <unk> with our a B C. Your line is now open.

Great. Thanks, Good morning, Brian and Tim Congrats on the progress and thanks for taking my question.

Brian just maybe turning two 2026 and just the the remarks on cash flow positivity I just wanted to give you an opportunity to perhaps.

Provide some color on some of those assumptions and while you're thinking about the inputs to to get there certainly keeping in mind.

The launch the lemonade.

Many programs and development and of course, you're you're mentioned on I'm looking at.

External assets in the pipeline. Thank you very much.

Sure. Thanks, Good morning, Greg I'm going to have Cecilia start yep. Thanks. That's my question. So as we mentioned our cash cash equivalents in my favour securities will and in doing. So in addition to anticipate into the product revenue interest income will enable us to execute the plan current plan includes on the dividend <unk> described.

<unk> pediatric and Asemia Enseco Sad also 80, 946, and yeah area programming P. H and part of the plan is friend described earlier about commercializing appeared outside the U S.

Got it and just any color on even on top line I know, we're not asking for guidance as you think about pirate time, certainly as as as backbones therapy and the potential across all these indications.

<unk> indications.

See sort of the velocity of that potential layering as you March through this development and potential criminals in the mid 20th Thank you so much.

Greg So.

With P. K D. We certainly have an ambition to maximize the P. J D launch opportunity and.

The bigger picture of course for us is to strengthen our commercial capabilities for these meaningfully larger sequential launches potentially become namely thalassemia sickle cell disease in the case of Peaky D. It's it's ultra rare by name and by nature. So it will take some time to for us to refine the.

The prevalence as well as the peak sales estimates as we learn more than.

I would say peak sales depends on a whole lot of factors, including the times of peak sales the approval timelines the distribution partnerships as we talked about outside the U S from where we are today you know this discussion reflects only the third full quarter of launches so far it's clear to us that the.

<unk> will be slow and steady and if it gets reflected in the numbers that we continue to report out.

I will say it I'm just going to take the opportunity to reiterate that I am Super pleased that set of Illinois has joined doses CCL, because feta as deep expertise and experience in rare disease launches and I think that's not a moment too soon for us as we look at continuing the momentum of the P. K D launch.

And more importantly, getting ready for these bigger launches potentially to come.

Great. Thanks, again and congrats on the progress.

Thanks, Greg.

Please stand by for next question.

Our next question comes from Mark Breidenbach puts Oppenheimer. Your line is now open.

Good morning, most of my questions have been answered, but let me, let me dip down into a kind of a early stage pipeline maybe.

Maybe you could just remind us how the ph stabilizer for PKU differentiated from preparing an unrelated drugs, but are already approved or in late development for <unk>. Thanks.

Sure.

Sarah So our program is really invasive it's has a different mechanism of action then the other that are currently in development or.

Being Ah are have been approved and haven't been on the market for awhile.

Six indeed, a ph stabilizer, which is different.

Where we see an opportunity with this product is because the two that are currently available do have their own.

Own limitations in the in the treatment of advocate you in the sense that either there is a lot of drugs to take or it's you know subcutaneous Ah administration for Arizona.

That goes along with that that's where we are looking to does it developed an oral therapy that would treat the majority of.

Of course, the whole place for us to provide some things that can be meaningfully different in the sense that it is providing.

Providing all of the benefits as measured handle alanine reductions, but also easier to use easier to tolerate and then we will disclose more details on our cdp's as we progressed the program.

And Mark I'll, just add that the so the addressable market is significant we're talking here about another step function change in prevalence from where we are today with P. J D. This would be 35 to 40000 patients across the U S. You five maybe other point about this one is this comes from our Accio his expertise and seller metabolism. So.

It's pretty early right now we talked about a potential pathway towards an int at the end of this year, but we are excited to have this is a potential.

Continued diversification of our pipeline.

Got it thank you.

You bet.

Please stand by for our next question.

Our next question comes from Danielle Brill with Raymond James Your line is now open.

Hi, guys. Good morning. Thanks, so much for the questions I have a couple at first online for six just a clarification can you remind us.

Plans for the Saint <unk> cohort the ear enrolling habit, that's tracking Emily <unk> for data.

And then <unk> I just wanted to clarify does the 78 patients that are on drugs factor in discontinuation.

Or is that the total number of patients that have received pirate kind and then I have a follow up to that.

Sure. It's a Sarah can start with the first one.

Yeah. So thanks for the question is 946 and sickle cell disease. Indeed, it sounds so we have a complete it then disclose all of the results of our faith wanting healthy volunteers and within that trial. There is indeed, a cohort that is ongoing for sickle cell disease in which it said it's in multiple ascending go skiing within the phase one.

For sickle cell disease, specifically in which we are looking to generate data in the context of hemolytic any Netflix a short duration trial, we have not disclosed when we are I'm going to release those results at trial is ongoing and is on track right. Now we are very excited to always 946, Afghans just I know you didn't.

But I just want to face because we are very excited about our Mds program.

Which is currently interface to a portion of that specific trial.

And then spent a few I think that's going to be leaving him on the on the patients, but I'm glad you asked Daniel it's good to clarify clarify yeah. So 78 patients on therapy at the end of Q4, it's really an X number of patients. So that includes the patients will have started therapy. These.

<unk> the patients will have discontinued the all of the sign up to eight patients who are actually actively saving files times at the end of the quarter and the only thing I'll add is again the discontinuation rates launched two days have been low which is super encouraging because it shows us that power kindness, performing very well as a patient.

And provider level and as we look beyond P. J D. That's a very important data point as we think about bigger launches to come.

Okay. Thanks, that's very helpful. And then I guess my follow up with for the enrollment form.

Just curious what proportion of those actually <unk>.

Translate the patient on drug.

When it comes to the <unk> actually we had a very city sweet perfectly made on on my access as well as patient services, because we do see the majority of the B F. Two actually progressed if any initiation.

There is a time delay between the completion of a P. D F N treatment initiation at the moment, it's about four to six weeks, we do not expect for that time frame supervisor significantly and that is really primarily driven by the fact that a lot of that they are policies in a prior authorization criteria.

Required genetics type thing and if a patient has not completed the genetic fast or they don't have the results that we need to go through the process and the pure timing of genetic testing is the driving force of the four to six weeks.

Balance really in an ultra rare disease launch is the generation of the Pel the demand because it's so rare there's so much heavy lifting required in terms of educational components I think to pull through PDF. The patient on therapy will take time, but that's not per se the real challenger the launch.

[noise] great. Thank you so much you're.

You're welcome.

Police standby for our next question.

Our next question comes from South being richer with Goldman Sachs. Your line is now open.

Good morning. This is <unk> first I guess into the mid twenty-three sickle cell update which is leaping most focused on and then.

In your opinion, what would be considered success in the phase two portion and.

And then just couldn't parsley, what would lead you to make a note go decision. Thank you.

So far the face to we have our pre specified criteria for our primary endpoints, which the primary influence are the hemoglobin response and safety in the secondary endpoints. We have you know hemolytic markers.

Inefficient report the outcome and C O C. As our secondary endpoints. We are first of all looking to have our primary endpoint bars b and it's two doses tested against placebo. So we will be looking for both.

The office to see which one is the better dose to move forward into phase three so those are all.

Things that are pre specified within the protocol then of course in the context of an overall go no go decision.

For the program there other data that we will take into account, including our investigator sponsored trials and and we are of course as always for any program that we have when we take a step towards the next part of development, we make sure that we.

Truly believe that we're going to get on our target product profile and so that is the discipline. We you know after this program for all of our programs and we are very excited to reach mid here. So we can actually talk about data.

Thank you I guess just to follow up on that link would be the ideal target profile for pirate kind and sickle cell.

So our ideals targeted product profile is truly something like a product that can deliver benefits for the pathologist sickle cell disease, meaning that we are programs designed to entries hemolytic anemia and have a reduction on sickle cell sale prices. But then we are also hoping to be able to.

Strange benefit <unk>.

If you don't see I'm, sorry, and just one more question I guess, if you don't see an improvement on the V O C right with that.

Influence your decision to not go forward with the trial.

So the data that we have in our face too long Voc's will be very limited just because of the duration of the trial. It's a 12 weeks 12 week randomized controlled trial portion. So that that's not how the trial is designed to show a huge benefits on C. O C. So we continued to <unk>.

Collect the data <unk> are open label extension in the Phase two and then we of course have much longer exposure of yarn instigators sponsored to trials.

Thank you.

I am showing no further questions I would now like to turn the conference back to Brian for closing remarks.

Alright, well, thanks, a lot everybody for participating in today's call and of course for your continued interest in arduous as you heard this morning, we're generating significant momentum towards our long term vision and we are confident in our potential to deliver significant value for both patients and shareholders. So thanks again and look forward to speaking with all of your real soon.

This concludes today's conference call. Thank you for participating you may now disconnect.

The conference will begin to to.

To raise and lower Yohan doing Q&A, you can dial 911.

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The conference will begin to Pee.

And lower Yohan during Q&A, you can dial 911.

[music].

Good morning, and welcome to <unk> fourth quarter and year end 2022 conference call. At this time all participants are in a listen only mode. There will be a question and answer session. At the end. Please be advised that this call is being recorded at <unk> request.

I would now like to turn the call over to Jessie Brenda Kamp Senior director of corporate Communications. Please go ahead.

Thank you operator, good morning, everyone and welcome to ideas fourth quarter and year end 2022 conference call you can access slides for today's call by going to the investors section of our website Ikea Dot com with.

With me on the call today with prepared remarks are Brian Goff, our Chief Executive Officer, Dr. Kristi, arguing our chief Medical Officer, and head of research and development, that's a melanoma, our chief commercial officer, and Cecilia Jones, our Chief Financial Officer.

Before we get started I would like to remind everyone, but some of the statements. We make on this call will include forward looking statements.

Good morning, everyone and thank you for joining us.

<unk> is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases.

In particular I'd like to highlight the excellence in execution displayed across our research and development team to bring forward pirate kind our first in class PK activator as the first and only approved disease modifying therapy for adults living with PK deficiency.

<unk> was approved in the U S EU and Great Britain in 2022 and represents the cornerstone of our growing PK activation franchise with the potential for two additional indications by 2026.

Sickle cell disease, and lower risk Mds.

As we've said in the past we continue to believe that this launch will be slow and steady and we will provide a capability building platform to support potential expansion in meaningfully larger patient populations.

That said our ambition is to improve the launch trajectory and realize the full potential of the opportunity we have in front of us.

To that end in December of last year, we appointed set of melanoma as Chief Commercial Officer said it is a seasoned commercial leader who brings deep expertise in launching and commercializing medicines in rare diseases in hematology with a particular focus on global market access and operations.

We ended 2022 in an enviable cash position with approximately $1 $1 billion on the balance sheet. This includes the onetime payment we received in the fourth quarter of 2022, following the sale of our royalty rights on U S. Net sales of silver to cigars we.

We anticipate significant progress on each of these objectives in 2023 spin.

Specifically in the middle of this year, we expect to complete enrollment of the phase III energized and energized T studies of <unk> in Dallas EMEA.

<unk> announced the data readout of the phase two rise up study of <unk> in sickle cell disease and the <unk> is the go no go decision to phase III.

And by the end of the year, we expect to enroll more than half of the patients in the phase III activate kids and activate <unk> T studies of <unk> in pediatric PK deficiency complete enrollment of the phase Iia study of our novel PK Activator AG 946 in lower risk Mds.

File the IND for our <unk> stabilizer for the treatment of PKU.

Throughout the year, we aim to continue to strengthen our commercial capabilities through our ongoing launch in PK deficiency and continue to evaluate BD opportunities to expand the pipeline.

Looking forward to 2024 to 2026, we anticipate a catalyst rich period with the potential for two additional <unk> indications in this timeframe.

Specifically in 2024, we're expecting the readouts of the phase III studies of <unk> in Dallas, EMEA as well as the readout of the Phase Iia study of AG 946 in lower risk Mds.

In 2025 were expecting the potential approval of <unk> in Dallas, EMEA as well as the phase III readouts of pirate kind in sickle cell disease in pediatric PK deficiency and in 2026, we're expecting the potential approvals of <unk> in sickle cell disease and in pediatric PK deficiency.

Internal pipeline that is aligned with our core expertise in rare disease and cash flow positivity.

With that I'll now turn the call over to Sarah.

Thanks, Brian .

2020 to our research and development organization made significant progress advancing our PK activator development programs across multiple disease areas, United by the shares underlying pathophysiology of Red blood cell metabolic stress.

Representing the largest data set generated for any PK activator, the consistent and compelling data we have generated to date with pilot PK deficiency, thalassemia and sickle cell disease highlights the potential for peak Activations to correct red blood cell metabolism, and transform patient function quality of life and long term.

Outcomes in each of these disease areas.

The most recent data updates across our clinical portfolio were presented at Ash in December .

Yields in our external collaborators were pleased to present, a total of 22 abstracts.

These included long term data from the phase two study of buyer and seller senior demonstrating durable improvements in hemoglobin and hemolysis and stabilize our improved erythropoiesis and iron homeostasis over 72 weeks in patients with alpha or better non transfusion dependent senior.

And we presented new data from the Phase one study of our novel <unk> Activator AG nine six in healthy volunteers, which showed a favorable safety profile at pharmacologically active doses and a PK profile supportive of once a day dosing.

Taken together the clinical data we have generated to date suggests that paradigm differentiated mechanism of action is correcting red blood cell metabolism, and leading to consistent improvements in hemoglobin hemolysis and Eric Zhou Please.

With that context, let me now provide a brief update on the powertrain development programs beginning with thalassemia.

As a reminder, the phase III program of prioritizing policy now comprises two randomized placebo controlled trials each of which are enrolling patients with both alpha and beta thalassemia.

Energizes enrolling patients who are not regularly transfused with a primary endpoint of hemoglobin response and interchange is enrolling patients who are regularly transfused with the primary endpoint of transfusion reduction response.

More than half of patients in each of these studies have now been enrolled and we aim to complete enrollment of both studies in the middle of this year.

Yes.

Ill now turn to sickle cell disease, where we aim to deliver a novel oral therapy that both improve the anemia and reduce sustained occlusive crises or POC.

And we are advancing the operationally seamless phase III study of <unk> in adults with sickle cell disease, and I am pleased to announce at the phase two portion of this study is now fully enrolled.

This decision will be informed by the protocol defined go no go criteria in the phase two portion of rides up as well as any additional data from the phase two secondary endpoints and longer term data from the ongoing extension studies of the investigator sponsored trial at the NIH and the University of it today.

To date. These investigator sponsored trials have generated compelling data, suggesting that in adults with sickle cell disease, viracon reduces red blood cell signaling and similar to what we have observed in PK deficiency and thalassemia also resulting consistent improvements in hemoglobin hemolysis in your rental fleet.

Finally, we continue to advance the phase III activate and activate T studies of <unk> in pediatric PK deficiency as we aim to deliver the first approved therapy for children living with this disease.

We aim to enroll at least half of the patients in each of these studies by the end of the year.

In parallel with the <unk> development program, we continue to advance the development of $89 six a novel PK activator, which provides the opportunity to further strengthen our PK activator franchise and pursue multiple therapeutic paths, including lower risk Mds.

As we presented at Ash pharmacokinetic data from the healthy volunteer cohorts of the phase one single and multiple ascending dose study, we're supportive of a once daily dosing regimen and Pharmacodynamic data suggests the sustained activation of the glycolytic pathway, including dose dependent increases in AEP and dose dependent decreases into <unk>.

Okay.

Taken together with a favorable safety profile, we look forward to progressing the ongoing phase II study of $89 six in lower risk Mds and expect to complete enrollment of the phase Iia portion of the study by the end of this year.

As Brian mentioned, we aim to expand our pipeline beyond <unk> activation through both disciplined business development and the advancement of our earlier stage pipeline.

Within our earlier stage pipeline, we continue to progress our lead research program aimed to address <unk> for PKU.

PKU is a rare genetic disease with limited treatment options that impacted total of approximately 35 to 40000 patients in the U S and EU five and it's caused by a deficiency of the new alanine Hydroxylate FPH enzyme <unk>.

Lack of ph activity leads to the accumulation of phenylalanine and downstream sequela in patients with PKU are therefore, often insights to consume a highly restricted diet in order to minimize <unk> intake, which can further reduce patient quality of life.

To directly address the underlying cause of PKU, we are developing an oral ph stabilizer with the goal of reducing for nuomi levels and we are targeting an IND filing for this program by the end of this year.

With that I will now turn the call over to Seth.

Thank you Sarah.

Joining Andrew last month, I've been impressed and they're done by the rigor of the commercial team.

The data generated across our clinical program and the potential of our portfolio to transform the treatment paradigm of multiple radiochemical lodging diseases.

It is truly a privilege to have the opportunity to join the company. So clearly volume for EMEA and locked ethanol.

For the last 20 years I've led global rare disease launches at leading biopharmaceutical companies.

Each of those markets presented unique challenges Mike Clark Hopkins has remained the same to reduce the length of the basin, Jeremy and improve patient health outcomes as efficiently as possible.

Specifically that strategy must be underpinned by our focus on three key areas.

Increasing awareness of the disease and educating on available treatment option.

I've said that I think accessed by reducing the time between diagnosis and treatment initiation.

Supporting our CRM and maintaining reimbursement over the long term.

Leveraging this strategy my top priority is to drive operational excellence in the foreign market and PK deficiency and deals are the capabilities, we need to fully realize the complier show potential off by a decline in anticipated future losses anti leukemia in sickle cell disease.

In reviewing the launch to date have been particularly encouraged by the progress. The team has made on market access.

To date this continuation of continue to remain low overall and re authorizations have not been a barrier.

This progress highlights the bulk of the positive impact of final refined and the strength of our market access and patient services capability.

In the fourth quarter of 2020 tool, which represented the third full quarter of launch we generated $4 3 million in net <unk> revenue.

That's helpful of 105 patients have now completed a bps, including 21 in the fourth quarter uplift in 'twenty two.

25% increase versus the third quarter.

Given our strong conversion rate. This has translated to a net of 78 patients on therapy at 39% increase over Q3.

Based on some therapy bank from our growing and diverse prescriber base of 96 physicians and they represent but also demographic and disease manifestation range that is consistent with the adult PK deficiency population.

Despite this progress we have indentified multiple opportunities for improvement.

As is common in orphan or rare disease launches, we have observed a general lack of disease awareness and a corresponding lack of urgency to diagnose monitor entity.

This presents a clear opportunity to focus greater attention on the earliest stages of the patient journey, and thereby increase disease awareness and diagnostic efficiency.

Specifically as the ICD 10, Baltimore diagnosing PK deficiency was established less than three years ago, we plan to bolster our disease awareness efforts by augmenting, our AI and machine learning capabilities to identify high potential clinician likely to treat patients with PK deficiency.

Additionally, given the breadth and diversity of the prescriber base, we aim to strengthen our capacity to engage and educate treating physicians, including on the availability of the anemia program, which provides no cost genetic testing to intensifying our range of hemolytic anemia, including <unk>.

Patiency.

I'm confident that further strengthening these rare disease capabilities will help us maximize the potential of the current launch.

PK deficiency is only the beginning building our capabilities to support the education access and adherence will directly translate to future potential launches in meaningfully larger patient population and will help us unlock the full commercial potential of our PK activator.

Franchise.

With that I will now turn the call over to <unk>.

Thanks setup, a fourth quarter and full year 2022 financial results can be found in the press release, we issued this morning, which I will summarize.

More detail will be included in our 10-K, which will be five data today.

Full year 2022, net <unk> revenue was $11 $7 million.

<unk> $4 $3 million in the fourth quarter, an increase of zero point $8 million compared to Q3.

As <unk> as the first therapy for these ultra rare patient population, we continue to gather data and insights on the launch trajectory and will not be providing guidance at this time.

Consistent with other rare disease launches gross to net continues to be in the 10% to 20% range.

Cost of sales for the quarter was $31 4 million.

Moving to expenses on the balance sheet.

<unk> expenses were $73 million for the fourth quarter and $279 $9 million for the full year 2022, an increase of $22 $9 million compared to the full year 2021.

Year over year increase was primarily driven by increased costs for our five ongoing pilot pivotal studies and for the $89 six studies and increased workforce spend across R&D.

SG&A expenses were $32 $8 million for the fourth quarter and $121 $7 million for the full year 2022, an increase of zero point something million dollar as compared to full year 2021.

Full year, two silver again fee revenue, which is recorded under royalty income from gain on sale of oncology business on our income statement was $9 $9 million as a reminder, quicksilver royalty income ceased after Q3 2022, given the state of our rights to 5% royalties on U S net sales of disk.

<unk> two <unk> for a onetime payment of $131 $8 million in October of which we recorded a $127 $9 million.

Other income in Q4.

As part of the divestiture of our quality business to Serbia, we retain rights to a potential $200 million milestone upon approval and 15% royalties on potential U S. Net sales of our site and in our clinical stage <unk> inhibitor Newton I D H, one and two.

We ended the year with cash cash equivalents in marketable securities of approximately $1 1 billion.

We expect our cash cash equivalents and marketable securities together with anticipated product revenue and interest income will enable us to execute our operating plan, including funding. The currently planned development program from at a pivot 89, six in ph and commercializing makeup pivot outside of the U S grew one four.

More partnerships to cash flow positivity without the need to raise additional equity.

I'll now turn the call back over to Brian for his closing remarks.

Thanks, Cecilia 2022 was a year of tremendous progress at <unk> with the approval of pirate kind in adults with PK deficiency, we've taken an important first step toward our 2026 vision and we remain focused on advancing our industry, leading pipeline of PK activators to address the <unk>.

Found unmet needs of patients suffering from rare hematologic diseases.

In 2023, we're anticipating a number of key clinical and regulatory milestones that will lay the foundation for potential phase III data readouts imbalance EMEA sickle cell disease in pediatric PK deficiency over the next few years.

As always we will strive to be responsible stewards of our balance sheet, and we'll continue to evaluate meaningful opportunities for value creation.

As a reminder to ask a question. Please press star one one on your telephone.

For your name to be announced to withdraw your question. Please press star one one again, please standby, while we compile the Q&A roster.

Our first question comes from Chris Raymond with Piper Sandler Your line is now open.

Hey, Thanks, guys for taking the question just.

I guess a couple questions first on the phase III sickle cell.

The phase two portion of the trial reading out mid year.

I know you guys have talked about the primary endpoint being hemoglobin response, but is there.

And to show a POC signal at least in this portion of the trial can you just clarify that.

And then I have a follow up.

Sure. So hi, this is Sarah.

So for the phase II portion of the trial. Indeed, we have a primary endpoint of hemoglobin response in.

On safety at the FERC SaaS attending our secondary endpoints, we RMB capturing.

The rate of Voc's as well that being said it is indeed, a 12 week period for the randomized controlled trials. So the data coming from that is.

It's going to be limited by the time that patients have been exposed to the drug.

<unk>.

As always we've always been saying this as well that we will be looking at the totality of the data generated in this trial specifically the rise of trial and we will also be looking at our investigator sponsored trials in which patients have been exposed for a longer duration.

Okay, great. Thanks, and then just on <unk> in Europe , I know you have marketing authorization in Europe .

K in hand, and you've talked about not wanting to build really an interest infrastructure there Brian I guess until you get a larger indication. So maybe any update on that strategy for launch there, especially given that you now have.

Marketing authorization.

Yes, good morning, Chris Great question. So as you noted we have mentioned that we have interest in a partner or partners as we think about commercialization outside the U S.

<unk> as you know is an ultra rare indication.

Just to have the commercialization on its own for PK D would be quite a challenge. So what we're looking towards is as we make progress as Sara just mentioned with the sickle cell data and particularly solar senior.

Where we stated that we expect to be fully enrolled by mid year that puts us on a path to really.

Methodically look for partners that we believe will represent very well the footprint, we anticipate globally for those launches to come TKD of course as I mentioned is.

It is very rare astellas EMEA is meaningfully larger as an opportunity and it does just like sickle cell disease have a unique global footprint. So those are the factors that will go into our partnership.

Okay. Thank you.

Beth.

Please standby for our next question.

Our next question comes from Mark from with Cowen. Your line is now open.

Hi, Thanks for taking my questions.

Just a follow up on Chris's question on just on thinking about the.

The phase two data as we get it in terms of making the go no go decision for phase III.

Are you just needing to see kind of more robust.

But very similar data to what you've already seen in terms of hemoglobin and things like that where they're really new inputs and points that need to be revealed in this data to make you want to go forward into phase III.

So the endpoints and needs are.

Relatively similar to what we have in our other trials. However, this is the first placebo controlled datasets in our phase two so we're actually very excited about that.

And yes, we are.

Sure.

Sorry, eagerly looking forward to mid year.

And I think Mark I would just add too I mean, one of the themes that we've been talking about this so appealing a pirate kind is the consistency of the data that we've seen across hemolytic anemias TKD all.

All the way through launch of course, and then <unk>, which is already through phase II and we have the phase III underway.

And as you know rise up where we're awaiting the phase II data, we're not expecting per say surprises, but it'll be confirmatory, if we see compelling data coming out of the phase II rise up stuff.

<unk>.

And we have the endpoints of course identified and then we will look at the totality of data is Sarah just noted.

Okay. Thanks.

And then maybe you can just launching into.

P J D.

Q4 is kind of the first full quarter of some patients flowing through re authorizations and things like that.

Continued have their experiences.

This quarter.

Are you seeing in terms of the reauthorization standards that are being applied.

What percent of patients do you think you should we expect to continue on therapy for the long term.

Thanks, a lot for the question. It's further here as we said we had 78 net patients on therapy at the end of fourth quarter of 2022, and this really net basis number is inclusive of all of the patients will have started on therapy and all of the patients will have discontinued.

We have not reported any specific numbers on discontinuation, but as we now take the reauthorization rates for patients that are reaching the six months.

Assessment has not been a barrier so far.

No.

Discontinuation of continuous to remain lower low overall for the product and for me that's slowly reinforces the positive reception that we get from patients physicians and payers on the profile a final guidance in the U S.

Okay. Thank you.

Please standby for next question.

Our next question comes from Greg Harrison with Bank of America. Your line is now open.

Good morning. This is Mary Kate on for Greg. Thanks for taking our questions I guess as we hit one year since the approval of powertrain TKD, you've mentioned that you have.

96, new physicians prescribing, maybe how do you expect usage and updates to change as physicians become more aware of and experience with IRA times.

So we are actually very pleased with the progress that we have met all made umbrella prescribing as you mentioned already we have 96 <unk>.

Physicians will have generated a 105 escalation enrolment forum.

This unfolds a rare disease.

And from that perspective, expanding the breadth upfront I think you are going to be our core focus today and moving forward we have to keep in mind that it does take time, because each of the unique prescribers who needs to basically go on their own journey of disease awareness.

This.

And prescription.

As well and this is one of the main reasons actually will put a greater emphasis on this first part of the patient Jeremy.

From the really shortening the time from diagnosis to treatment.

Invest greater referencing in the data and analytics to help diagnostic efficiency and very importantly, help us improve our targeting efforts with clinicians as well, yes, and I'll just add that.

The kinetics of an ultra rare disease launches set a noted really will be about breadth of prescribing. We describe it often is inch deep mile wide because it would be unusual for TKD for a physician to have more than one or two or maybe three patients at the most so this these efforts that set of refers to about.

First of all education, which is critically important and then secondly, she alluded to this in the prior comments the machine learning capabilities that we're working on using claims database analysis is critically important it's a modern state capability for rare disease launches that we will look to master because the more that.

We can be efficient in guiding our call plan targeting towards high potential providers, who are likely to have a PK PD patients. The more effective our breath proliferation will be and that really is one of the key areas of focus.

Great. Thanks, and then if I could one more on treatment are already prescribing, how youre kind of what kind of feedback have you been receiving from patients and physicians, who either user prescribed the drug. Thank you.

We're very pleased with the feedback that we're getting across the board from patients.

<unk>.

And if they are as well.

I think the success of our market access efforts definitely speaks to the positive reception of bearings followed for patients initiating therapy.

Also the great success, we've seen with enables organization right we get.

A lot of positive anecdotal feedback from our patient services team, which is fantastic to hear and I actually have the opportunity to hear some of the direct feedback from our customers.

Actually went out on the field and met with some of them in my first.

Martha month on the job and it really reinforces the positive not only for reception of the product have already experienced that.

Early in the launch.

Passage of our farming for those patients.

We are excited that it gets done on time.

Some time, but I believe we're putting all the right elements in place to continue to drive breadth of prescribing.

And Thats for PK data, which is really encouraging.

<unk> do you want to comment on the clinical trial experience sure. So.

It's very similar in a way the clinical trials continue to gather data on the long term for patients with <unk>, who have been on archive for now a long time and what we see is our data is getting stronger as it matures, even because the hemoglobin.

<unk> has maintained the impactful hemolysis is maintained very importantly, we see patient reported outcomes that are also maintained and really reached its clinical significant thresholds for feeling better and functioning better and then on top of that we are very excited about is our iron overload data as well where we start.

<unk> seen more and more an impact on iron overload as well. So I think we're very excited about what <unk> has.

<unk> already delivered and is continuing to deliver for patients with <unk>.

Okay.

Great. Thank you.

Please stand by for our next question.

Our next question comes from Tess Romero with J P. Morgan Your line is now open.

Good morning, Brian and thank you for taking our question.

So just one from me.

Disease program, if I could so thinking a little bit about disease gene rise up data in your go no go decision here specifically is there.

Hemoglobin response rate that you view as differentiated here and I know in the past, we've talked a little bit about.

So occlusive crises has also been important to monitor so could you help us understand a little bit better what an encouraging trend might look like there.

<unk> as well.

So far our primary end point.

The hemoglobin response rate. So we do have the bar set there as one gram per deciliter to be qualified as a hemoglobin response between specific fine.

<unk> trial.

Half pre specified in our protocol will be considering a statistical significant results for our primary endpoints and then how we move forward into our secondary endpoint 60, since a very sort of classical setup for fleets to now for phase II of course of what we're looking for in the secondary endpoints is uptrend, so our POC.

Now we're capturing over time.

We will accrue accrue that data.

We're not looking there for something hugely impactful are meaningful because thats ultimately what the phase III will deliver <unk> and phase III is setup to truly deliver towards our target product profile in which we're hoping to be able to treat the totality of sickle cell disease by impacting both hemolytic anemia sickle cell pain.

Rice's and then there is also the opportunity to then further assets.

Patient reported outcomes, so really providing a drug that can be meaningful across the totality of single cell.

Okay.

Please standby for our next question.

Our next question comes from Greg <unk> with RBC. Your line is now open.

Great. Thanks, Good morning, Brian and team congrats on the progress and thanks for taking my question.

Brian just maybe turning to <unk>.

2026, and just the remarks on cash flow positivity I just wanted to give you an opportunity to perhaps provide some color on some of those assumptions and how youre thinking about the inputs to get there certainly keeping in mind.

Launch.

There are many programs in development and of course, you mentioned on looking at.

External assets in the pipeline. Thank you very much.

Sure. Thanks, Good morning, Greg I'm going to have some serious start yes. Thanks, Craig for the question. So as we mentioned our cash cash equivalence and marketable securities will do.

In addition to anticipated product revenue and interest income will enable us to execute the plan. Our current plan. While this includes the dividend <unk> described <unk> pediatric CNS, EMEA and sickle cell or so $89 six.

The earlier program in PAA and part of the plan as Brian described earlier about commercializing that can pivot outside the U S.

Got it and just any color on even on top line I know, we're not asking for guidance, but as you think about <unk>.

<unk> certainly.

Backbone therapy and the potential across all of these.

Indications, how do you see sort of the velocity of that potential layering as you March through this development and potential approvals in the mid twenties. Thank you so much yes.

Yeah, Greg so with PK D. We certainly have an ambition to maximize the PK day launch opportunity.

The bigger picture of course for US is to strengthen our commercial capabilities for these meaningfully larger sequential launches potentially to come, namely thalassemia and sickle cell disease in the case of PPD.

It's ultra rare by name and by nature. So.

It will take some time to for us to refine the prevalence as well as the peak sales estimates as we learn more.

And then I would say peak sales depends on a whole lot of factors, including the time to peak sales the approval timelines the distribution and partnerships as we talked about outside the U S from where we are today.

This discussion reflects only the third full quarter of launches so far it's clear to us that the <unk> launch will be slow and steady and I think that's reflected in the numbers that we continue to report out.

I will say this.

It's going to take the opportunity to reiterate that I am Super pleased that set of melanoma has joined us as CCL because further has deep expertise and experience in rare disease launches and I think thats not a moment too soon for us as we look at continuing the momentum of the <unk> launch and more importantly, getting ready for these big.

<unk> launches potentially to come.

Great. Thanks, again and congrats on the progress.

Thanks, Craig.

Please standby for our next question.

Our next question comes from Mark Breidenbach with Oppenheimer. Your line is now open.

Hey, good morning.

Both of my questions have been answered, but let me, let me dip down into kind of the early stage pipeline.

Maybe you could just remind us how the PIH stabilizer.

For PKU is differentiated from.

<unk>.

And related drugs that are already approved or in late development for behavior. Thanks.

Sure.

So.

Our program is really indeed, it has a different mechanism of action than the other that are currently in development or.

Are being or have been approved that have been on the market for a while.

So it's indeed, a ph stabilizer, which is different where we see an opportunity with this product is because of the two that are currently available do have.

Their own.

One limitations in the in the treatment of PKU in the sense that either there is a lot of drug to take or it's <unk>.

Subcutaneous administration. So there is a lot that goes along with that that's where we are looking to.

Develop an oral therapy that would treat the majority of them.

Thank you Jim.

Of course, the hope is for us to provide something that can be meaningfully different in the sense that it is.

All of the benefits as measured on fuel.

Alanine reductions, but also easier to use easier to tolerate and then we will disclose more details on our CDP as we progress the program.

Mark I'll, just add that the so the addressable market is significant we're talking here about another step function change in prevalence of where we are today with PK D. This would be 35% to 40000 patients across U S and EU five and the other point about this one is this comes from our <unk> expertise in cellular metabolism. So it's.

Pretty early right now we've talked about a potential pathway towards an IND at the end of this year, but we are excited to have this as a potential continued.

Continued diversification of our pipeline.

Got it thank you.

You bet.

Please stand by for our next question.

Our next question comes from Danielle Brill with Raymond James Your line is now open.

Hi, guys. Good morning. Thanks, so much for the questions I have a couple first on line six just a clarification can you remind us.

Plans for the phase one sickle cell cohort that you are enrolling.

Hi.

Thats tracking and what your plans are for data.

And then on <unk> I just wanted to clarify does the 78 patients that are on drug factor in discontinuation.

Or is that the total number of patients that have received prior times and then I.

I have a follow up to that.

Sure. So Sarah can start with the first one.

Yes. So thanks for the question so of $90 six in sickle cell disease and so.

So we have completed then disclose all of the results of our phase one in healthy volunteers.

Within that trial there is indeed, a cohort that is ongoing for sickle cell disease in which it's in.

It's a multiple ascending dose scheme within the phase one for sickle cell disease, specifically in which we are working to generate data in the context of hemolytic anemia. It's a short duration trial, we have not disclosed when we are.

Going to release those results of the trial is ongoing and is on track right now.

We are very excited to work with $9 six have kind of just I know you didn't ask but I just wanted space because we are very excited about our Mds program.

Which is currently at the Phase Iia.

A portion of that specific trial.

And then I think thats going to be an easy among the patients, but I'm glad you asked and it's good to clarify clarify yes, Phil 78 patients on therapy at the end of Q4 is really a net number of patients. So that includes the patients will have started therapy.

These applications will have discontinuous fill all of the benefit patients who are actually actively receiving final time at the end of the quarter and the only thing I'll add is again the discontinuation rates launch to date has been low which is super encouraging because it shows us that <unk> is performing very well as a patient.

And provider level and as we look beyond PPD, that's a very important data point as we think about bigger launches to come.

Okay. Thanks, that's very helpful. And then I guess my follow up was for the enrollment form so I'm just curious what proportion of those actually.

Translate to patients on drug.

When it comes to the <unk> actually we are very pleased with.

We've made.

Access as well as patient services, because we do see the majority of the BS to actually progressed.

So.

There is a time delay between the completion of a PDF and treatment initiation.

At the moment, it's about four to six weeks, we do not expect for that time frame as far as a significantly and that is really primarily driven by the fact that a lot of that they are policies from the prior authorization criteria required genetic testing and if a patient has not completed the genetics.

Or they don't have the results that we need to go through the process in terms of pure timing of genetic testing is the driving force of the positive yes.

The challenge really in an ultra rare disease launch is the generation of the PFS the demand because it's so rare theres. So much heavy lifting required in terms of educational components I think the pull through PDF to patient on therapy will take time, but that's not per se the real challenge of the launch.

Great. Thank you so much youre welcome.

Please standby for our next question.

Our next question comes from Sal been richer with Goldman Sachs. Your line is now open.

Good morning, this is amit on for <unk>.

First I guess into the mid 23 sickle cell update wishes, we'd be most focused on and then in.

In your opinion, what would be considered success and the phase two portion and then just Conversely, what would lead you to make a no go decision. Thank you.

So far the phase two we have our.

Pre specified criteria for our primary endpoints, which are the primary endpoints are the hemoglobin response and safety in the secondary endpoints we have.

Hemolytic markers.

Patient reported outcome and.

POC as our secondary endpoints.

We are first of all looking to pass our primary endpoint bars.

<unk>.

It's two doses tested against placebo. So we will be looking for both doses to see which one is the better dose to move forward into phase III and so those are all.

Things that are pre specified within the protocol then of course in the context of an overall go no go decision.

Org program there other data that we will take into account, including our investigator sponsored trials.

And.

And we are of course as always for any program that we have when we take a step towards the next part of development, we make sure that we.

That's it.

We believe that we're going to hit our target product profile and so that is the discipline we.

Offered this program for all of our programs.

We are very excited to reach mid year. So we can actually talk about data.

Thank you I guess, just a follow up on that like with be the ideal target profile for <unk> in sickle cell.

So our ideal target product profile is.

Truly from like a product that can deliver benefit for the pathology of sickle cell disease, meaning that we are programs designed to and treat hemolytic anemia and have a reduction on sickle cell stage prices. But then we are also hoping to be able to demonstrate a benefit on euros.

If you don't see.

Alright.

Just one more question I guess, if you don't see an improvement on the VLCC rates would that.

Influence your decision to not go forward with the trial.

So the data that we have in our phase II <unk> will be very limited just because of the duration of the trial at 12 weeks.

12 week randomized controlled trial portion.

That's not how the trial is designed to show a huge benefits on CEOC.

So we continue to collect data on Vlccs in our open label extension in the Phase two and then we of course have much longer exposure via our investigator sponsored trials.

Thank you.

I am showing no further questions I would now like to turn the conference back to Brian for closing remarks.

Well, thanks, a lot everybody for participating in today's call and of course for your continued interest in <unk> as you heard this morning, we're generating significant momentum towards our long term vision and we are confident in our potential to deliver significant value for both patients and shareholders. So thanks again, and we look forward to speaking with all of you real soon.

This concludes today's conference call. Thank you for participating you may now disconnect.

Q4 2022 Agios Pharmaceuticals Inc Earnings Call

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