Ionis Pharmaceuticals Q3 2023 Earnings Call Transcript

Quartr
Provided by Quartr
November 2, 2023

There are 18 speakers on the call.

Operator

Morning, and welcome to the Ionis Third Quarter 2023 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Mr. Wade Wach, Senior Vice President of Investor Relations to lead off the call. Please begin, sir.

Speaker 1

Thank you, Chuck. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be and recorded. Today, including a reconciliation of GAAP to non GAAP financials. We believe non GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call.

Speaker 1

With me this morning are Brett Monia, Chief Executive Officer Moneta Katare, Chief Global Product Strategy and Operations Officer Richard Geary, Chief Development Officer and Ben Haugen, Chief Financial Officer. Eric Swayze, Executive Vice President of Research and Eugene Schneider, Chief Clinical Development Officer will also join us for the Q and A portion of the call. I would like to draw your attention to slide 3, which contains our forward looking statement. During this call, we will be making forward looking language statements that are based on and will provide further details on our financial results. These statements are subject to certain risks and uncertainties and our actual results may differ materially.

Speaker 1

I encourage you to consult the risk factors contained in our SEC filings for additional detail. With that, I'll turn the call over to Brett.

Speaker 2

Thanks, Wade. Good morning, everyone, and thanks for joining us on today's call. Since taking the helm at Ionis nearly 4 years ago, We have executed on a strategy to deliver next level value and we have done so with a clear vision and laser focus on our strategic objectives to bring our medicines directly to patients, build our wholly owned pipeline and to extend our leadership in oleganucleotide therapeutics. Our successes this year, which are a direct result of our efforts in these key areas, move us closer To achieving our ultimate goal to deliver a steady cadence of new transformational medicines to patients and to generate next level value for all with Iona's stakeholders. We are on the cusp of delivering our near term commercial medicines to patients starting with We and our co commercialization partner AstraZeneca are prepared to launch eplentercen following U.

Speaker 2

S. Approval. We're also executing on a global regulatory strategy with potential approvals in the EU and Canada next year. Additional filings are also planned, positioning us for a steady cadence of approvals around the world. We recently achieved another of our key objectives for eplentirsen with the publication of a comprehensive review of Phase 3 Neurotransformed Study Results in JAMA.

Speaker 2

Publishing our results in a highly respected journal like Chalmers reflects the importance of our Phase 3 Neuro Transformed study for the treatment of ATTR polyneuropathy and showcase Based on its strong overall profile, including highly positive Phase 3 data together with Freedom of a simple at home monthly self administration profile, we believe eblontercent is well positioned to become the therapy of choice for ATTR patients Following closely behind eplentirsen are olyzarsen and Donnie Doloresen, our wholly owned near term commercial opportunities. We were very pleased with the positive top line data we reported last month from our Ozarks Phase 3 BALANCE study in patients with FCS. Olasarsen showed significant triglyceride reductions, which was the study's primary efficacy endpoint along with a favorable safety and tolerability profile. But most importantly for patients, Olizarsen demonstrated substantial reductions in acute pancreatitis events, Making Olazarsen the 1st lipid lowering therapy to achieve this result in the clinical setting. With these highly positive results, we are on track to file for marketing approval in the U.

Speaker 2

S. And EU early next year, positioning olsarsen for its first potential approval as early at the end of next year assuming priority review in the U. S. We also continue to be encouraged by the performance of Donadourcin, Our medicine for the prophylactic treatment of HAE. We recently reported 2 year open label extension data, which demonstrated Favorable safety and tolerability along with durable and sustained protection against HAE attacks, consistent with the previously reported 1 year OLE results and our Phase 2 results.

Speaker 2

We are getting closer and are looking forward to our Phase 3 readout with data expected in the first half of next year for Don and Doloresen. We also made significant progress recently in further strengthening our wholly owned neurology pipeline by advancing zilganersen, Our treatment for Alexander disease into Phase 3 development. Advancing ZILGA NURSEN further expanded our rich Phase 3 pipeline to a total of 9 drugs in development for 11 separate indications. And importantly, we remain on track to accomplish our other key strategic goals across the business, including achieving our 2023 financial guidance. With that, I'll turn the call over to Onaza to discuss our expectations for the epontercin launch and to briefly review the status of our go to market activities for ologirsin and Donnie Galoressen.

Speaker 2

After our NASDAQ, Richard will discuss our recent pipeline progress. And after that, Beth will review our Q3 financial results. And then I'll wrap things up before taking your questions. And with that, over to Inesim.

Speaker 3

Thank you, Brett. As Brett outlined and as you will hear from in more detail in a moment. Ionis' pipeline holds tremendous promise. And today, we are ready to begin delivering our medicines to patients. With an estimated 40,000 patients worldwide and fewer than 20% of patients on an approved treatment, hereditary ATTR polyneuropathy Remain significantly under diagnosed and largely underserved disease.

Speaker 3

In large parts, the low rate of diagnosis is driven by the While peripheral neuropathy may be the most important symptom in many patients, Others may present with cardiomyopathy and still others with symptoms like GI disease leading to muscle wasting. By leveraging Ionis' deep knowledge of ATTR and AstraZeneca's significant commercial reach, we are uniquely to recognize ATTR in undiagnosed patients and get them on treatment early in their disease progress. And in doing so, we are well positioned to grow this largely untapped market. Our field team is built and deployed and already executing on our strategy to drive eclonteracin growth through disease education and brand awareness. Additionally, we recently launched our unbranded disease education campaign called See the patterns aimed at accelerating diagnosis by helping HCP spot We also recently launched our healthcare professional Web With its potential approval in about 6 weeks, we and AstraZeneca are ready to deliver eplongirsen to patients with ATTR polyneuropathy.

Speaker 3

And as our launch gets underway, a key measure of our success will be in achieving our goal of eplentirsen becoming the preferred choice for newly diagnosed patients with ATTR polyneuropathy. We expect olefarsen to be the 1st medicine we launch independently. We are developing olefarsen in 2 indications, the rare FCS indication and the broader and we will be conducting a Phase 2 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of

Speaker 4

the Phase 3 test of

Speaker 3

the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of the Phase 3 test of and together with the extremely positive results we reported from the Phase 3 BALANCE study in patients with FCS In hand, we are moving forward with our launch preparations with even greater pace. With the capabilities established for the eplentirsen launch, we are in strong And as we prepare for the follow on At HTG indication, we plan to further scale these capabilities to realize the full potential of the product pending Phase 3 trial results and FDA approval. We expect our next independent launch to be with Donna Doloresen for the prophylactic treatment of HAE. This is an attractive market for us because it involves a fairly concentrated set of prescribers, allowing us to deliver With the compelling Phase 2 and OLE data we have seen to date, Together with the once monthly self administration profile, we believe Donna Doloresen is positioned to be an important new prophylactic treatment for HAE patients once approved.

Speaker 3

I'm pleased to say that we are right where we should be in preparing for our 1st independent launches of olsarsen and donutylarsen. Our commercial infrastructure is in place and we are ready to begin delivering our medicines to people in need as they come to the market. This is a very exciting time for Ionis. I'm proud to be part of it and I look forward to keeping you up to date as our next important steps unfold. Now over to Richard.

Speaker 5

Thank you, Onaza. We could not be more pleased with the performance of our pipeline Eflomtirsen has continued to perform exceptionally well, demonstrating durable and sustained efficacy and safety through 85 weeks of treatment in patients with ATTR polyneuropathy. Just this morning, we presented new data at the European ATTR amyloidosis meeting and further reinforces these results, demonstrating improvements in measures of neuropathy impairment and quality of life that we're seeing in a substantial number of patients at 3566 weeks and were sustained through the 85 week analysis. And benefit across secondary endpoints at 85 weeks showed improved neuropathy specific and physical health Related patient quality of life, stabilized or improved ambulatory status and stabilized nutritional status with eflontersen treatment. And last month at HFSA, we showed data demonstrating improvement in cardiac function and structure in a predefined cardiac subpopulation of polyneuropathy patients from the Neuro T Transform study.

Speaker 5

The positive results from NeuroT Transform also support our confidence in the potential for eplontersen to benefit patients in the larger ATTR cardiomyopathy indication. With CardioX Transformed fully enrolled, we remain on track for data as early as the first half of 2025. As a reminder, with over 1400 patients, Cardio Ttransform is the largest study in this patient to date designed to generate the data physicians and payers want and need to understand the value that plinthirsen offers for patients and to enable the best possible treatment decisions for patients. Following eplentirsen, olisarsen is the next drug We expect to bring to the market and is the first we expect to commercialize independently. In the VALENCE study, the 80 milligram dose of olosarsen demonstrated statistically significant reductions in triglycerides, Robust target engagement and a favorable safety and tolerability profile consistent with the profile seen with our other like medicines.

Speaker 5

In addition, olosarsen demonstrated unprecedented substantial and clinically meaningful reductions in acute pancreatitis attacks. This is remarkable because it's the first time a lipid lowering therapy has ever achieved this result in a clinical trial setting. Based on the positive data we reported from the Phase 3 BALANCE study, we believe that olicarsen is poised to become the standard of care for patients with FCS. Our next step will be to file for marketing approval in the U. S.

Speaker 5

And EU in the first half of next year, positioning olosarsen for its first potential approval in late 2024, assuming priority review in the U. S. In addition to our clinical development program for FCS, we also have an ongoing program for patients with severe hypertriglyceridemia for SHTG. Phase 3 studies in SHTG patients are ongoing and we expect those studies to read out in late 2024 or early 2025 depending on enrollment. Following closely behind olsarsen is our To treat patients with hereditary angioedema.

Speaker 5

Despite several treatments already on the market, of over 500 patients with HAE, only 13% of these patients reported having good control of their disease with more than 85% reporting 2 or more attacks per year. Data reported from the ongoing Phase 2 open label extension study of Donna De Larson show sustained and durable reductions in HAE attacks and favorable safety and tolerability over 2 years and support Dada Larson's potential to address the unmet need. We look forward to presenting a comprehensive look at the 2 year OLE data next week at the ACAAI conference. With enrollment complete in the Phase 3 OASIS HAE study, we remain on track for data in the first half of next year. And from our robust late stage pipeline, We look forward to updates from epiravirsen and Ionis FBLRx.

Speaker 5

Next week at AASLD, the GSK plans to present new data from the Phase 2b, B2CETHER study of the pair ofersen in combination with pegylated immunocele. And this weekend at Kidney Week, we plan to present new interim results from our ongoing Phase 2 study of our Roche partnered medicine Ionis BLRx in patients with IgA nephropathy. We also made significant advances with our industry leading neurology franchise this year. Today, we have 2 approved breakthrough medicines for neurological disease on the market SPINRAZA and CALSAIDI and we have another 12 in clinical development and more than 10 new programs in preclinical development or lead optimization. Among our partner neurology programs, we recently completed enrollment in the Phase III study of ION-five eighty two in patients with Angelman syndrome, putting us on track for data around the middle of next year.

Speaker 5

And we were encouraged by the positive data our partner, Biogen, We reported from the Phase 1b and long term extension studies of IonisMapTRx in patients with early Alzheimer's disease. Data presented at the Clinical Trials on Alzheimer's Disease Conference showed numerical improvements on multiple cognitive and functional scales and continued favorable safety and tolerability in this small early stage study. The data published in JAMA Neurology Showed a rapid substantial and sustained reduction in tau and phosphorylated tau in CSF as well as reduced tau pathology on PET And we're particularly excited with the progress we're making in building and advancing our wholly owned neurology pipeline, which represents one of our highest priorities. As Brett mentioned, We advanced Silganersen into Phase 3 development in patients with Alexander disease, a rare debilitating pediatric leukodystrophy with no approved treatments. We're on track to advance ION-seven seventeen into Phase onetwo first in human study in patients with Prion disease before the end of the year.

Speaker 5

And following ION-seven seventeen, we expect to advance 3 more wholly owned neurological on the call to call disease medicines into the clinic next year. This has been an eventful year so far and we're looking forward to several additional key events in the coming months, including the U. S. Eflontersten approval, launch and additional regulatory filings and approvals outside the U. S, allosarsen regulatory filings in FCS and Donadivolosin Phase 3 data.

Speaker 5

We will keep you updated on our progress on these events and more throughout the coming year. And with that, over to Beth.

Speaker 3

Thank you, Richard. Our year to date financial results Keep us on track to achieve our 2023 financial guidance, while we continue to execute on our strategy to unlock next level value. Revenue continued to be substantial and sustained with revenues of $144,000,000 and $463,000,000 in the 3 9 months ended September 30, 2023, reflecting a 10% decrease and a 6% increase, respectively, compared to the same periods last year and driven by the timing of certain partner payments. As anticipated, our operating expenses and operating loss for the Q3 year to date. This increase increased over the same period last year as we advanced our commercial readiness activities and our pipeline, especially our late stage program.

Speaker 3

We remain well capitalized with $2,200,000,000 in cash and investments at the end of in September, enabling us to continue investing in our strategic goals. Our commercial revenue from SPINRAZA royalties with $67,000,000 $179,000,000 in the 3rd quarter year to date, respectively. Reflecting SPINRAZA's resilience against emerging competition in the U. S. And abroad, SPINRAZA's global sales in the 3rd quarter demonstrated a low single digit increase compared to last quarter and compared to the same quarter last year.

Speaker 3

As a result, our revenue from SPINRAZA royalties increased by 9% compared to last quarter and 8% compared to the same quarter last year. We earned R and D revenue of $60,000,000 in the 3rd quarter and $233,000,000 year to date. The significant R and D revenue we continue to generate reflects the value that Ionis' technology is creating as numerous partner programs advance, in line with our goal to invest for revenue growth. Our non GAAP operating expenses increased in the Q3 year to date compared to last this year. With most of our ongoing Phase 3 studies fully enrolled, our study costs increased as expected, which resulted in higher R and D expenses.

Speaker 3

And as we prepare to launch aplantirsen, olsarsen and dominadelorsen, Our SG and A expenses also increased modestly year over year. Our year to date results keep us on track to meet our 2023 financial guidance. We continue to project revenues of more than $575,000,000 We expect our 4th quarter R and D revenue to be driven by the potential $50,000,000 milestone payment from with Astenica for the U. S. Approval of aplontersen.

Speaker 3

R and D revenue from continued development of aplontersen and additional revenue from Biogen and from our recently expanded collaborations with Novartis and Roche. We project our 2023 non GAAP operating expenses to come in at the higher end of our guidance, which is between $970,000,000 and $995,000,000 And looking ahead, we expect to generate a substantial and sustained base of R and D revenue from multiple sources in 2024 as our partnered programs advance. And we expect eplentirsen will continue to be an and is an important source of revenue in 2024. We have the potential to earn a milestone payment for an additional eplentirsen approval outside the U. S.

Speaker 3

We also expect to begin generating modest royalty revenue next year with growth expected as the launch ramps up. We project our expenses to grow modestly next year with our R and D expenses approaching steady state as our late stage programs are fully enrolled and our SG and A expenses to ramp up in line with the planned launches of by Arsen Oluzarsen and Donita Larsen. We have a strong financial foundation, substantial recurring R and D revenues, Plus substantial and sustainable royalty revenue that can continue to grow, and we expect to add new product revenue from our advancing and

Speaker 4

and we are now in a position to expand wholly

Speaker 3

owned pipeline. Together with our prolific technology, we believe we are on a path to successfully bring our medicines to patients and to unlock next level value. With that, I'll turn the call back over to Brett.

Speaker 2

Thanks, Beth. We are very proud of the remarkable progress we've made this year. We believe that the successes we've achieved so far this year position us to drive substantial value Our shareholders and all Iona stakeholders. Strategically, we have arrived where we are today by being focused on the clear vision and by being focused on all our supporting strategic objectives necessary to achieve our vision. We've now established all of the functional capabilities we need to deliver a steady cadence of new and potentially transformational medicines to the market.

Speaker 2

We are advancing and growing our wholly owned pipeline and have established Ionis as a leader in cardiovascular and neurology drug development. We continue to extend our leadership position in oligonucleotide therapeutics by expanding and diversifying our technology, further optimizing our capabilities for existing therapeutic areas and opening up new areas for drug discovery. And we continue to strengthen our financial foundation, providing the means to support all Our strategic objectives. Today, with one of the most robust late stage pipelines in the industry with 9 medicines in development for 11 indications, Returning that promise into new medicines for patients in need and not just 1 or 2, but a steady and growing cadence of new transformational medicines over the mid and long term. And in achieving this goal, we are positioned to drive great value for all with Iona's stakeholders.

Speaker 2

With that, I'll now open the call up for questions. Operator?

Operator

Thank you. We will now begin the question and answer session. And the first question will come from Gary Nachman with Raymond James. Please go ahead.

Speaker 6

Hi. Thanks for taking the question. So on eflontericine for ATTRPN, any additional updates Regarding your interactions with the FDA, and how everything is progressing in front of the PDUFA. Have they requested any additional data and are labeled discussions Progressing in the way you would like them to. And then just on the commercial plans, given the competitive dynamics in the space with Ambutra and Patro, how will payers be viewing eponterstin?

Speaker 6

What's your work telling you there? Will all these drugs be covered on most formularies? And where is AstraZeneca on the hiring of the sales force? Just give us a sense of how big you think that will be? Thanks.

Speaker 2

Thank you, Gary. I'll take the first one and briefly give you an update on regulatory and then I'll ask Onaza to cover The second part of your question on competitive dynamics. So it's we don't comment on ongoing regulatory discussions for Drugs under review for potential approval. But what I can say with high confidence is that we're very pleased with the progress we're making with the FDA, and bringing up on Tercen to an on time Potential approval either PDUFA date on December 22nd. So there's been really everything is moving on track And I also want to remind you everybody that we are now under review with our filings accepted in Canada And in Europe with potential approvals for those markets as well for next year for eponterstin and TTR polyneuropathy.

Speaker 2

Monaiza?

Speaker 3

Hi, Gary. Yes, launch plans are really underway. I would say they're actually in place. We have As you know, being led by AstraZeneca are hired and deployed in market. They are in the field.

Speaker 3

They are working on on disease and brand awareness. Really given that this is a very growth market, identifying with different physician sets The types of symptoms that ATTRPN patients present with is very much underway. You've seen some of the campaigns and see the patterns. So they're out there really since the last month in field. And we are just awaiting approval.

Speaker 3

PDUFA is December 22nd and all things are in motion. Our nurse case managers on the IONIS side are hired And since they're mostly post approval, we would deploy them right after. And as you know, the field medical team has been in place for the last 18 months to 2 years. So All signals are ready to go. From a payer perspective, I think we have a very strong payer strategy.

Speaker 3

We've done a lot of research with the majority of the payers in the U. S. We don't expect anything different than Other kind of PN agents that have been priced on the analogs of rare disease pricing, again, we believe this is a really active rare disease. We do not expect tons of beyond the normal prior authorization for rare disease to get through. We haven't seen

Operator

The next question will come from Luca Issey with RBC Capital. Please go ahead.

Speaker 4

Great. Thanks so much Sure. Taking my questions. Maybe 2 quick ones. One on hepatitis B, what was your reaction to GSK in licensing the siRNA from Airohead and J and J, given that they already had a silencing agent, will you why do you think they need a second one?

Speaker 4

And then maybe circling back on the prior questions on TCR, polyneuropathy and the PDUFA. Any color on manufacturing? Has the tech Transfer to AstraZeneca has been successfully completed. Has the FDA inspected the facility that will provide the commercial supply? Just trying to understand if there's anything that keeps you up at night ahead of the PDUFA?

Speaker 4

Thanks so much.

Speaker 7

Thanks, Luca.

Speaker 2

We have a very good relationship with GSK. So we're aware of what was coming and what was announced this The way to think about it is that the acquisition of the RNAi RNAi molecule from Janssen really represents a double down, a triple down if you will on bepivirsen. Dopaviracin is the only treatment that has produced a Meaningful percentage of patients receiving achieving a functional cure, patients with HBV, chronic HBV. And in the Phase 2b in the CLEAR study, what we demonstrated with GSK was about a 10% functional However, in patients with a lower HPV burden like below 1,000 IUs per milliliter, That functional cure rate was well into the 20% plus range, which is really impressive. And so the strategy that GSK has stated for bringing in the RNAi molecule, Which has not shown functional cures, but what it has shown is reductions in HBV antigen levels.

Speaker 2

Two levels that And which is substantial percentage of patients could get below that 1,000 IU level is to do a sequential treatment to reach even more patients to achieve even greater And your functional cures by bringing patients down to a level maybe below 1,000 more patients below 1,000 IUs per milliliter and then coming in with bepivirsen. So this is an added dimension to a very comprehensive And it's also consistent with everything that GSK has been saying in which they will be exploring Different combinations for bepivirsen to maximize success on this market, which as you know is 100 of millions of people suffering from Chronic HBV. So we're very pleased about this new outcome for GSK for Beth Paperson. And Beth, maybe you could talk a little bit about the where we are with the on our launch preparations for commercial supply?

Speaker 3

Sure. Absolutely. We are all ready to go just as we are on the commercial side and the medical affairs side. All of the products Needed for launch has been manufactured. It was manufactured through the registration process regulatory process, has been reviewed, and is ready to go.

Speaker 3

We just are waiting for a final label to do label and packaging and get product into channel shortly after approval. And all of the tech transfer necessary from Ionis to AstraZeneca with the commercial manufacturer, the contract manufacturer is done, and all of that has gone extremely well. So we are all systems ready to

Speaker 4

go. Great. Thanks so much.

Operator

The next question will come from Yale Jen with Laidlaw and Company. Please go ahead.

Speaker 8

Good morning and thanks for taking the questions. I've got 2 quick ones here. The first one is for the SPINRAZA Sales, I believe that will be ultimately announced by Biogen. But nevertheless, as you indicated that the growth, Small growth quarter over quarter. Should we anticipate that this is again consistent with the stabilization Of the franchise in the larger SME space?

Speaker 8

Then I have a quick follow-up.

Speaker 3

So, what I would say is, we're very pleased with the low single digit Growth in against last quarter and against the previous quarter same quarter last year, we believe that demonstrates SPINRAZA's continued resiliency even in the face of emerging competition. Beyond that, Yale, I really need to respect by Biogen's earnings call next week, and I really can't go any further.

Speaker 8

Okay, great. That's helpful. And in In terms of JAMA publication regarding the blantarizant sustained benefits, How should we think about that to incorporate into the marketing strategy, particularly for Untreated newly treated or untreated patients? And thanks.

Speaker 2

The publication specifically, I mean That's going to be a really effective tool to take Bryonathan.

Speaker 3

Yes. I think with the promotional and regulatory kind of You know, guidance, looking at the JAMA publication and where our promotional messages Our head is going to be highly supportive. The JAMA publication is also very consistent with the label that we expect.

Speaker 2

Yes. So in other words, Yale, although our package that's Under review at the FDA is based on the week 35 interim data that we reported last year. Having this publication for week 66 week 85 is very, very helpful from a marketing standpoint and we expect to utilize that publication very effectively. I think that was the basis of your question.

Speaker 8

Okay, great. Thanks a lot and congrats.

Operator

The next question will come from Paul Matteis with Stifel. Please go ahead.

Speaker 9

Hi, this is James on for Paul. Thanks for taking our question. Just one on Olazarsen quickly. I guess, as we get ready for the FCS launch, I guess, how are you thinking about pricing just given that The higher trigs opportunity may be coming behind it and assuming there will be different price points there. And I guess just as you've kind of put some of this commercial infrastructure in How much I guess leverage either from like sales force or spend perspective do you anticipate getting from This FCS infrastructure as you think about launching the higher TRIGS opportunity?

Speaker 9

Thanks so much.

Speaker 3

Sure. So we've done some extensive work with payers to understand kind of this dual indication that we're going Sure. In prevalent and rare disease, does that actually really make a shift in your pricing strategy? Do we know that once we have The more prevalent price prevalent indication, the pricing will obviously be in line with good kind of cardiovascular premium priced products. We see really no indication in terms of thinking about this differently as a result of the 2 indications.

Speaker 3

If they were 2 single indications in different molecules, we So you should think about it that way. I would say that the FCS account sales team We'll be calling on obviously a much smaller portion than the total universe of physicians you would call on for PG, it will be more focused on the lipidologists, but extend out a bit beyond that as well for where we believe the FCS patient population is. We're doing a lot of work from our integrated data analysis and qualifying where those physicians are that And then as we get into the broader indication, those sales teams will obviously Stay on board and we will extend the size of the sales team for the broader SHTG market to incorporate some of the other physician specialties that we believe will be very

Operator

The next question will come from Allison Bradshaw with Piper Sandler. Please go ahead.

Speaker 10

Hi. Thanks for taking the question. So first, I guess, I just wanted to ask on the anti tau update, last week, for BIIB080. I know Biogen is responsible for development of the asset, but I'd still be curious just to get your thoughts on how that approach could fit into the Alzheimer's treatment paradigm, be it in combo or monotherapy or what have you. And then hoping you could also just describe how that data maybe influences your confidence in the wholly owned neurology assets.

Speaker 10

And then on a second front, just on the complement Factor B program, Looking at that interim Phase 2 data being presented at ASN in a couple of days, is there any update just on your view of the IgA nephropathy market, and potential opportunity in IgAN, just given the in context of an evolving competitive landscape there. Thank you.

Speaker 2

Thank you, Allison. So The Phase 2 study evaluating tau in patients with Alzheimer's disease is underway and enrolling and it's a very it's a really quite an extensive study with more than 700 patients to

Speaker 7

be treated for well over

Speaker 2

a year with the primary endpoint really being efficacy, improvement in cognition. And the purpose of that Phase 2 study is to really make a decision to set up and support A path forward to go to Phase 3 development for a pivotal study. And in this study, we are exploring different dose levels as well as for dose regimens, including twice a year dosing and that's based on the data that you're referring to, which is the Phase III study That is now published in JAMA Neurology and was presented at CTAD last week and is incredibly supportive of that Phase 2 study in the tau program overall. We and our partner Biogen could not be more thrilled The data that was generated from the long term extension of the Phase onetwo study in patients with Alzheimer's disease. Tau is considered by essentially all the experts in the field as being the most important target for Alzheimer's disease based on the neurofibrillary tangles that appear just before cognition impairment occurs.

Speaker 2

It's downstream of beta amyloid, which can be present long before Cognition deficits occur, but it's a difficult to drug target because what matters most is intracellular tau And that causes the neurofibrillary tangerine, the neurodegeneration. What we have shown for the first time is not only can we substantially lower All forms of tau and CSF, we can actually reverse tau pathology in that long term in the long term extension data in patients by PET imaging. But now we also have from the long term extension data actually signs, Trends that patients are actually improving in cognition. So we couldn't be more thrilled about the data and this has built on our confidence From the CELIA Phase 2 study that's underway that I referred to earlier. As far as combination, monotherapy, that kind of thing, that's this is the start of a development program for a drug that's leading the way to target tau.

Speaker 2

The Phase 2 study is intended to assess the benefits of tau and cognition as a mono In combination with the TAO drug and so on, that will require further development and but it can make sense. We can see how those two mechanisms can actually complement each other, maybe even synergize with each other. So all that is on the table. But right now, Biogen and Ionis are focused And as far as confidence in neuro, this is just another piece of Data, evidence, validation of our leading neurology platform. I would start with SPINRAZA and CALSAIDI to approve breakthrough treatments for neurodegenerative diseases, using the same platform as Tau, using the same platform as our Angelman's program, using the same platform as all of our 12 drugs that are currently in clinical development for all kinds of for neurodegenerative neurodevelopmental disorders.

Speaker 2

And as Richard highlighted in his earlier remarks, we expect to start a PRION program, only on program by the end of this year and 3 more next year that are wholly on neurology programs for diseases that have a high unmet medical need for both rare and large indications. So it just adds to our confidence in our leading neurology platform. As far as IGAN, Epi LRx to be presented at Kidney Week coming up. This will be an additional data cut that was presented at Kidney Week last year In patients with IgA nephropathy, just showing more data, more patients, longer treatment, showing reductions in proteinuria In that study, as far as the competitive landscape, it's crowded. There's no question.

Speaker 2

And we're glad Roche Is taking the lead on this because they have a tremendous global might, global strength, global presence to if the drug is successful to bring it to as many patients as possible. But I really think that that's to be determined once we see the Phase 3 data and to see how this positions itself. But really we couldn't be more pleased to have when you're in competitive market like this with a high unmet need, It's great to have the global strength of a partner like Roche.

Operator

The next question will come from Yunnan Liu with Wells Fargo. Please go ahead.

Speaker 11

Great. Thanks for taking the questions. Three questions, if I may. On eplongerson, what launch metrics would you provide So we can have an understanding of how the drug is performing in the market in the early launch quarters. On the tau program, can you talk about how you see the feasibility of the intrasequal route of the administration in this very large indication.

Speaker 11

Lastly, on the Angelman syndrome program, Following the recent updated data from Ultragenyx, any insights you could share regarding how Your program could be differentiated from that program as we look forward to data in mid-twenty 24. Thank you.

Speaker 2

Thanks, Yanan. Maybe we'll start with launch metrics for 1 person.

Speaker 12

So, Yanan, I think

Speaker 3

the way to think about this market, as I said, is it's a growth market, and we have a lot of patients to get diagnosed and get treated on eflontersen. And I think the Phenomenon that you might be seeing now with switches is very temporary, and I think we will have they will have worked through that. We're squarely focused on growth and growth mindset on newly diagnosed patients. As such, our launch

Speaker 11

Got it. Thanks.

Speaker 2

So next year, we'll be providing some metrics And we'll see how with that, so stay tuned for that, Yanan. Regarding the So Alzheimer's disease, despite the really remarkable progress That's been made recently on delivering medicines to the market to patients for AD. This is still a very severe neurodegenerative disease with a very high unmet medical need. And like I touched on earlier, we think tau is the best target for treating this disease broadly. And with that comes the need for treatments and we don't we believe the intrathecal Delivery will be well accepted if the drug is efficacious and as efficacious as we expect it to be.

Speaker 2

With that said, the tau program is an example of the great progress we're making in further optimizing and advancing our Neurological disease drug discovery capabilities with through medicinal chemistry and just experience. In the tau program, we actually have a treatment arm that we expect and will be efficacious with twice a year dosing. So we've moved from monthly to every 3 months Many programs and now we're even moving some programs to twice per year dosing intrathecal. That is part of the for our program that's in Phase 2 development today. In addition, as we highlighted at Innovation Day, a few weeks ago, we're making great progress on our research organization in overcoming the blood brain barrier As an obstacle for delivery of our treatments, our drugs for using subcutaneous or intravenous administration.

Speaker 2

And obviously, programs like TAO are on our radar as our other programs. So, we also think that that could be in the future for a large population chronic disease indication like Alzheimer's disease. So, No promises there yet, but we're very pleased with the progress we're making there. Regarding Angelman syndrome, I prefer not to comment on other People's programs or the company's programs, what I will say is that we are fully enrolled And our Angelman's program, we've actually over enrolled the study a bit. We expect data mid year next year.

Speaker 2

We expect data on efficacy as well as of course safety and biomarker data from that And that the trial is designed to set up a potential Phase 3 decision based on all that. And then what I'll also say Is that and it's kind of related to the earlier question that I got, that I tried to address, which is We have a vast amount of experience with our platform in neurological diseases. 1,000 and 1,000 and 1,000 of patients have been treated for very extended periods of time with our chemical platform, with our know how, with everything. And we think that that bodes very well for the Angelman's Community because they're going to be able to take it they're going to benefit from the vast experience that we have at Ionis with delivering neuro drugs for the treatment of severe neurological diseases like Angelman syndrome. So stay tuned for all that.

Speaker 2

We're very much looking forward to the data next year.

Speaker 11

Great. Very helpful. Thank you.

Operator

The next question will come from Debjit Chattopadhyay with Guggenheim. Please go ahead.

Speaker 13

Hey, good morning team. This is Robert on for DeJet. Thanks for taking our questions. 2 from us this morning. First, could you share any pricing thoughts on Uponersen?

Speaker 13

Specifically, would you anticipate launch price in line with current PN treatments on the high end or Centimeters treatments on the low end? And for the Alexander program, what pace enrollment would you hope to see in the Phase 3? And subsequently, When would you potentially anticipate a Phase 3 readout based on those timelines? Thank you.

Speaker 2

Moneta, would you want to take the launch price PNCM?

Speaker 3

Yes. So Robert, I think that We would expect that again, the 2 indications are both rare disease indications, but They are priced differently if you looked at analogs in the marketplace. Based on all the work that we've done, we don't believe there is Any reason to kind of shift from that in terms of our pricing strategy? So I would expect that As the price is set by AZ that we would expect polyneuropathy to be priced according to the analogs and benchmarks of other

Speaker 2

in polyneuropathy products. And regarding our newest Phase 3 program, our Alexander disease Sometimes, not sometimes, most of the time, we're enrolling rare disease indications Can be challenging because they are rare and finding patients to get into your study, obviously can present challenges. But what's unique about our Phase 3 program Alexander's disease is that we designed a seamless Phase 1 through 3 Design such that, it's all the same sites, it's all the same the protocols already been baked and everything like that. And after our Phase 2 results, which was which when we reviewed it, we had 2 decisions to make Really? One was to dose escalate or to move into Phase 3 development.

Speaker 2

And during that review process, when you go through all the data, you're The data you're cleaning the data and before we actually review the data, enrollment is put on pause, right, because we don't know what the next step will be for the program. And what happened in this situation is that patients were on the sideline waiting to get into either the dose escalation phase of the next step or the Phase 3 part of the program. So with that said, we think actually enrollment will go well for the Alexander program because we have patients on the sideline waiting to qualify to enter our Phase 3 program now that we've activated it. So, enrollment is going is ongoing and we expect data in 2025.

Operator

The next question will come from Yaron Werber with Cowen. Please go ahead.

Speaker 14

Hi, guys. This is Brendan on for Yaron. Thanks so much for taking Just a couple of quick ones from us. Just another one on MAPTEE, excuse me. Sorry if I missed this, but just Wondering if there's any plan for any interim look at the Phase 2 study or any possibility of any additional data Updates there before the full Phase 2 reads out, assuming maybe 2026 for the full Phase 2.

Speaker 14

So just wondering if we can expect anything new there in the meantime? And then quickly on Donnie Delorson, obviously, you have a few different studies ongoing there, but I think you're planning to incorporate into one filing, maybe including the switching study, etcetera. So Can you just maybe give us a sense of timing for data beyond the top line readout in the first half of next year? Maybe how long thereafter do you think you'd need to collect and analyze data? And if you're thinking to maybe file in the second half of next year, is that fair to assume?

Speaker 14

So thanks very much.

Speaker 2

Sure. So There's no plan for an interim look in the Phase 2 study for the tau program at this time. So that's a short answer, quick answer. It's very important to get the study right and get the richest data set as you possibly can. And as I mentioned earlier, it's this is what we're looking for here is actually evidence to support a Phase 3 decision that we're improving cognition impairment.

Speaker 2

So that's going to take time. That study is over a year long, as I mentioned earlier, more than 700 patients. So no interim look at this time. For Don and Doloresin, I don't think we've said that we're expecting to include switch data in the filing for the NDA. Really the Phase 3 data along with all the other data that we've generated from Phase 1 and Phase 2 will be sufficient to support a filing assuming positive outcome.

Speaker 2

With that said, we expect Switch data from our Switch study, which as a reminder is to our knowledge, we're the only sponsor that has actually conducted A true switch study, in which patients that are on an existing treatment therapy, prophylactic treatment I'll switch over to our investigational medicine, Donna Galerson, who an investigational medicine, which in our case is Donna Galerson. And then we assess everything, including protection against HAE attacks and identifying demonstrating that there's no gaps between one treatment switching to another treatment, tolerability, sustained efficacy and actually be able to generate the information that prescribers are going to want to have to understand How do I do this? Okay. I want to switch to your drug. I want my patient to go on your drug, but how should I do this?

Speaker 2

And that's really the goals of the switch study. We expect that data to be out next year or at least a cut into that data next year that's going to really allow us to actually demonstrate the value of Donavilirsen in this market, which is a switch market, but we have no plans to include that at this time to my knowledge In the NDA filing, Dara.

Speaker 3

If we believe that the publication will be more than sufficient to

Speaker 4

be consistent

Speaker 3

with label to be It was labeled to be used actively by our sales teams in promotion. And to the extent, if it's all ready alongside of it. We could actually add it in, but it's really not a requirement nor do we think it's really necessary for commercial uptake. We like it in the publication. That's what we're really looking for as our strategy going forward.

Speaker 14

Great. Thanks very much.

Operator

The next question will come from Jessica Fye with JPMorgan. Please go ahead.

Speaker 12

Hey, guys. Good afternoon. Thanks for taking my questions. Can you remind me of your expectations And around whether in addition to a clear impact on triglycerides, whether you believe you could show an impact on pancreatitis for olezarsen in SHTG. And then second, forgive me if you stated this, but for I believe the follow-up is up to 140 weeks.

Speaker 12

I just wanted to clarify, is there a minimum planned follow-up for those who do not reach I noticed some of the endpoints are assessed at week, I think, 121. Is that the minimum assuming the study is not stopped early? Thanks.

Speaker 2

Eugene, you want to take those? Sure.

Speaker 7

Happy to. Maybe I'll start with the last one. So As you said, of course, there is excruciating level of detail on the statistical analysis plan, but just to summarize it, The exposure in the study is up to 140 weeks, which means that in some patients, if the study reads out early, We've defined the minimal exposure and the time points, specific time points for those early looks in our SAP. And I don't think that we've come out and included specific timelines on those other than Sort of the general statement about early opportunity for closing the study earlier based on some

Speaker 2

And then I

Speaker 3

was asking for in the event you

Speaker 12

don't stop the study early, What the minimum would be?

Speaker 7

Well, if we don't set the study early, we go all patients will be treated for 100 That's the double blind period.

Speaker 10

Okay.

Speaker 2

And then Likelihood of achieving AP in SHTG?

Speaker 7

Yes. So SHTG, again, it's, of course, a very different population from FCS in terms of risk for Having said that, again, the program that we designed, the 2 very large studies, certainly, we believe will Have an opportunity to show an effect and what we are also going to be looking at is combination of those two studies. So looking at sort of integrated analysis of efficacy, combining those 2 large studies, which together amount to about almost 1,000 patients. So we're fairly confident, of course, today. We don't know what the data will show.

Speaker 7

What we can say is that we were Extremely pleased with the effect on AP events in our FCS population. So we do I believe that the thesis is very strong, but we need to wait until the data readout. Yes.

Operator

The next question will come from Qasif Belouris with BMO Capital Markets. Please go ahead.

Speaker 15

Hi, everyone. Thanks for taking our question. One quick question from us on ATTR. This morning Intellia presented data from the literature demonstrating that in addition to the percentage of TTR reduction, The absolute serum TTR levels after treatment are also very important as they can contribute to the ongoing fibrillation and They actually have an impact on survival. That said, I'm wondering whether you have any thoughts around that given that Most of the discussions in this space focus on the percentage of TTR reduction rather than the absolute levels of TTR post treatment.

Speaker 2

Thank you. Thanks, Costas. Not a lot of thoughts on Gene editing efforts in the TTR space, I mean, the progress that they're making It's steady. Percent reductions in TTR are absolutely important For efficacy, I don't think there's a I think we've known for a long time that there's not a threshold effect, if that's your question that there's a Specific magnitude threshold by which if you lower TTR that you'll achieve benefit on neuropathy or cardiomyopathy or whatever. But that it's actually individualized per patient and percent reductions is very important.

Speaker 2

And we're very pleased with the mid-eighty percent mean reductions that we've achieved in the neuro TRANSFORM study for epilentirsen in polyneuropathy And as you know, we've actually a substantial number of patients actually improve in both MNIST Plus Seven and in quality of life. So I don't know what else to say about those other programs except that they have a long way to go. Cardio Myopathy indications are going to require an outcome trial in our view, to not just be approvable, but to actually compete and it's It's going to take a long time to get there. And it's a new platform that you never know what will come up. So

Speaker 7

I I don't know what

Speaker 2

else to say about it other than that, Costas, but we love our program and we're very much ahead.

Speaker 15

Thank you very much.

Operator

The next question will come from Joseph Springer with Needham and Company. Please go ahead.

Speaker 16

Hi. Thanks for taking our question. Just a quick one on Phase 2 GOLDEN trial and geographic atrophy. When can we expect top line data? And given some of the Competitor data and data, can you handicap expectations on what a successful Phase 2 outcome looks like?

Speaker 16

And If the results are sufficiently positive, what would be the next steps in the program collaboration with Roche?

Speaker 5

Don't take that Richard. Yes. I'll take a stab at it. I think, of course, we want a positive trial on geographic atrophy and comparable, if not better results than I've been presented by other competitors. So that's the goal.

Speaker 5

We have no insight into That is today, but the data will be out next year, second half.

Speaker 2

Yes. So 2nd half, as Richard said, second half next year. What I can add to that Joey is that We also had a interim look in this Phase 2 study that allowed us to select the doses to complete this study, right. We started with A number of dose and then whittle those down to 2 doses to complete the Golden Phase 2 study and bring it to the finish line. We've seen excellent tolerability.

Speaker 2

We're seeing profound reductions in Factor B and in downstream effects like split products, exactly where we expect to be. So we're getting great target engagement. We're not seeing any risk Associated with that target engagement by blocking the alternative complement pathway, it's going great. And what we expect to see is What we hope to see is slowing down of lesion, formation and improvement in visual acuity. I mean these are the outcomes that we're expecting to support a decision whether to go to Phase 3 or not.

Speaker 2

As far as competitive landscape, this is a subcu once per month Drug using which could use an auto injector once it got to the market if it gets there, simple at home auto injector like eponcirsen, Whereas the drugs that are under review or recently been approved are intravitreal and they have side effects as you well know. So I think this although there's been progress made in GA, I think patients are desperately waiting for a drug that's not so invasive and simple and convenient like a subcu at home administration.

Speaker 16

Great. Thank you for taking our questions.

Operator

The next question will come from Myles Mentor with William Blair. Please go ahead.

Speaker 17

Hey, I just had a question on ION-nine zero four. I think you've got an upcoming presentation at American Heart Association. Just Just wondering whether we should be thinking about similar AGT knockdowns to the previous LICA molecule and just more infrequent dosing or is there potential to get more than So, 75% that we're seeing with that molecule. Thanks very much.

Speaker 2

You got it, Myles. So our presentation on our AGT program at will really focus on The dose dependent reductions in AGT that We sought to achieve in the Phase 2 study. This is a molecule that is being dosed monthly. Our earlier generation molecule that you mentioned was weekly. And we expect to see greater reductions Our earlier generation molecule because it's a more advanced chemistry.

Speaker 2

So that's what we're expecting.

Speaker 17

Cool. Thanks for the question.

Operator

The last question will come from David Lebowitz with Citi. Please go ahead.

Speaker 16

Thank you very much for taking my question. With respect to olezarsen, given the recent pivotal data, As you look forward to severe hypertriglyceridemia, how I know that you achieved benefits with respect to pancreatitis, you achieved the But given dynamics and differences in that population, how easy do you think it's going to be to show a pancreatitis benefit?

Speaker 2

That's a great question, David. And it's a question that our answer today is a lot different than it would have been earlier this year. The FCS data, we in our wildest dreams, we hoped to see the AP Reductions that we saw in FCS, and those are while the streams turned into reality. So, it's And as we mentioned in our remarks earlier, we couldn't have been more pleased and this is the first time anyone has demonstrated that blowing a lipid like triglycerides can actually Result in positive outcome in AP. My point is that our confidence has grown, because the efficacy was so remarkable on reduction in AP events.

Speaker 2

And that lends confidence to the SHTG population, which although it's not a genetic in the form of severely elevated triglycerides, there is no known genetic causes. It's not a monogenic disease like SCS. These patients still suffer from highly elevated triglycerides much like FCS patients. Sure, some of those patients could be in the above 500 range to a 1,000 range, but many, many of these patients are in the multiple thousands or at least above a 1,000, which puts them at very high risk for AP. So I We're going to get AP events in the Phase III SHDG study.

Speaker 2

And based on the effect size The effect that we saw with olitarsen in FCS, our confidence has grown, but we have to see that. Even and despite the fact that the Number of AP events per patient may be less than SHTG versus FCS, it's such a bigger study. It's It's a much bigger study. So we're going to have much more data that we're going to collect. And as Eugene said, we have the ability to combine 2 Phase 3 studies, CORE and CORE II to really look at Overall, the impact of all is ours and on AT events in SHTG.

Speaker 16

Thank you,

Speaker 2

David, and thanks everybody for joining us today and Everyone who has participated in our call, we really are proud of all the progress we've made this year and we believe that the future has never been brighter here at Ionis. And we plan to continue our momentum by delivering on additional key commercial updates, pipeline updates, technology updates, objectives, as we go forward. And we very much look forward to it. But until then, Thank you again and everybody have a great day.

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Earnings Conference Call
Ionis Pharmaceuticals Q3 2023
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