Alnylam Pharmaceuticals Q1 2023 Earnings Call Transcript

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Provided by Quartr
May 4, 2023

There are 11 speakers on the call.

Operator

You for standing by, and welcome to the Anilum Pharmaceuticals First Quarter 2023 Financial Results Conference Call. As a reminder, today's conference call is being recorded. I would now like to turn the conference over to the company. Please go ahead.

Speaker 1

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer Tilda Tangler, Chief Commercial Officer Akhir Basenov, President and Jeff Fulton, Chief Financial Officer. Also in the room and available for Q and A is Pritha Vulkar, our Chief Medical For those of you participating via conference call, the slides can be accessed by going to the Events section of the Investors page of our website, investors. Almilum.com/ Thanks, Yvonne.

Speaker 1

During today's call, as outlined in Slide 2, Yvonne will offer some introductory remarks and provide general context. Ova will provide an update on our global commercial progress Akshay will review pipeline updates and clinical progress and Jeff will review our financials and guidance followed by a summary of I'd like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward looking statements for the purposes of the Safe Harbor provision of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in our most Recent periodic report on file with the SEC. In addition, any forward looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

Speaker 1

With that, I will turn the

Speaker 2

call over to Yvonne. Yvonne? Thanks, Christine, and thank you, everyone, for joining the call today. 2023 is off to a great start With the Ambutra launch continuing its strong growth, with Q1 delivering 48% growth in total product sales compared to the Q1 of 2022. We've also made great strides with our pipeline, including the recent Citing announcement of positive interim results from the Phase 1 study of ALMAP, our investigational RNAi therapeutic in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy.

Speaker 2

These results mark a significant milestone for Alnylam As we believe they establish human proof of concept for RNAi therapeutics in the CNS and potentially unlock many additional opportunities where we may be able to address significant unmet medical needs. We also have a number of exciting upcoming milestones that highlight the depth and breadth of our pipeline, which includes a presentation of 18 month results from the APOLLO B Phase 3 study of patisiran at ESZHF later this month and top line results And the CARDIO-one Phase 2 study of zalbusiran in patients with hypertension expected in mid-twenty 23. This execution is in line with our focus on the following key drivers for Alnylam's growth over the next several years. First is the potential near term expansion of our TTR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicines for patients. 2nd is our expansion beyond rare diseases to also address more common disease areas.

Speaker 2

And the 3rd growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements, Opportunities with extrahepatic delivery and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond. We believe all of this puts us on track with our Nylem PISA fit by 25 goals, Making on Nylem a top tier biotech, developing and commercializing transformative medicines for rare diseases and beyond for patients around the world, driven by a high yielding pipeline of 1st and or best in class product candidates from our organic product engine, all while delivering exceptional financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Speaker 3

Thanks, Ivan, and good morning, everyone. Q1 was a strong quarter for our commercial portfolio, driven by our TTR franchise and the strength of our ongoing launch of Amutra as we delivered 48% total product sales growth or 52% on a constant exchange rate basis compared with the Q1 of 2022. Let me now turn to a summary of our Q1 TTR performance. Our TTR franchise achieved $204,000,000 in global net product revenues for Onpatro and Kombutra representing a 7% increase compared with the 4th quarter and a solid 49% growth compared with the Q1 of 2022. With the U.

Speaker 3

S. Market year over year growth standing out at a robust 75% driven by the ongoing launch of AMUTRA. At the end of the Q1, over 3,160 patients We're on commercial ONPATTRO or AMUTRA treatment worldwide, up from over 2,975 patients at the end of the 4th quarter, representing 6% quarterly patient growth. In the U. S, combined sales of ONPATTRO and AMUTRO increased 5% versus the 4th quarter and were primarily impacted by the following: a 7% increase in demand, which was driven by the strength of ongoing Albutra patient uptake more than offsetting the decrease in patients on ONPATTRO that switched to Albutra.

Speaker 3

Inventory dynamics decreased reported growth by approximately 3% as OIBDA inventory in the channel continues to decrease with ongoing patients switching to Amutra. Overall in the U. S, we continue to be very pleased with the impact we're seeing from Amutra in expanding the opportunity for our TTR franchise is reflected by the robust 75% Year over year quarterly growth that we achieved in Q1, representing the 3rd consecutive quarter of achieving TTR growth in excess of 70% on a year over year basis in the U. S. Following Amutra's launch in the Q3 of 2022.

Speaker 3

Additionally, key operating metrics continue to trend favorably, including growth in new patient start forms, The switch rate from ONPATTRO, patient compliance rates and the expansion of our prescriber base. In our international markets, total TTR Q1 product sales increased 9% versus the Q4 driven by strong demand in Japan following the Q4 launch of Almutra offset by inventory destocking in Japan. The ARMUTRA demand growth in Japan is particularly encouraging with the new patient growth being driven by a mix of switches from tafamidis, as well as patients naive to therapy. Additionally and importantly, ONPATTRO continues to deliver steady growth in markets where Almutra is not yet launched, positioning these markets for the upcoming Almutra launch. Opatro also benefited from the timing of orders In our distributor markets, our global results continue to be challenged by foreign exchange headwinds with total TTR year over year reported growth of 49% held back 5 percentage points due to changes in FX rates.

Speaker 3

Now moving to our ultra rare products and the performance of Givlar and OXLUVO, which delivered $72,000,000 in combined product sales during the Q1, representing a 2% increase compared with the 4th quarter and a more robust 45% growth compared with the Q1 of 2022. We ended the quarter with more than 550 patients on GIVLARI commercial therapy and more than 300 patients on OBSOVO commercial therapy, representing 6% and 7% quarterly growth compared with the year end 2022 for Givlari and OXOOMA respectively. For Givlari, global growth of 2% in Q1 compared with the 4th quarter was impacted by the following: A decline in U. S. Growth of 3% primarily due to reduced patient compliance associated with the seasonal impact from the annual Pre authorization required by payers during the Q1 that we expect will recover in subsequent quarters.

Speaker 3

Growth in our international markets increased 11% as demand increased in European markets and also benefited from the timing of orders in our distributor markets. For OXNOVO, global growth of 1% in Q1 compared with the Q4 was impacted by the following. U. S. Reported growth increased 3%, driven by an increase in patient demand.

Speaker 3

Growth in international markets was flat with a demand increase in European markets offset by the timing of orders in our distributor markets. Additionally, changes in year over year foreign exchange rates negatively impacted Q1, Yvela and OXXOBA reported growth by 3 percentage points and 4 percentage points respectively. In conclusion, we are pleased with the growth in revenues, Particularly with the ongoing signs of strong performance associated with the Albuterol launch, which we believe represents an important therapy option for hATTR amyloidosis patients with polyneuropathy and accelerated growth opportunity for our TTR franchise. With that, I will now turn it over to Akshay to review our recent R and D and pipeline progress. Akshay?

Speaker 4

Thanks, Tolga, and good morning, everyone. I'd like to start today with a recap of recent news that marks a very important milestone for Alnylam And the broader field of RNAi therapeutics, which is our progress with ALN APP and investigational RNAi therapeutics in development for the treatment of Alzheimer's disease And Cerebral Amyloid Angiotomy. As announced last week, we reported the first ever clinical results with an RNAi therapeutic directed to the CNS. Given the importance of the positive data and the intense interest in the study from all parties concerned, not least patients and physicians, I think it's worthwhile to further discuss the interim findings from our ALN APP program. ALN APP targets Amyloid Precursor Protein or APP, which we're investigating as a potential treatment for Alzheimer's disease and cerebral amyloid angiopathy or CAA.

Speaker 4

Human genetics has shown that certain mutations or duplications in the APP gene can cause early onset Alzheimer's disease Grammoid plaques form in brain tissue and are associated with neurodegeneration. Other mutations in the same gene can cause CAA, where A beta fragments distinct from those that aggregate to form Alzheimer's plaque deposit within the warts of blood vessels in the brain and results bleed. CAA is in fact the 2nd leading cause of intracerebral hemorrhage. So this one parent protein, APP, can be harmful in 2 distinct pathophysiological processes. In animal studies, we've shown that targeting APP with an sRNA showed great promise With broad CNS biodistribution after single intrathecal injection as shown on the left here.

Speaker 4

With knockdown in all major CNS cell types Fecal dose in non human primates resulted in significant and sustained target knockdown, the durability after 6 months at which time the experiment was terminated, but APP suppression was still ongoing. These pharmacologic findings, which were reliable, reproducible and appeared safe, Increased our excitement around the therapeutic hypothesis, specifically that by lowering APP protein production in the CNS via RNAi mechanism, We could reduce the downstream fragments that aggregate and deposit tissues and therefore hopefully fall to the disease course. To support advancement to clinical testing, we conducted short term IND enabling GLP toxicology studies in the rat and non human primate, where 2 low, medium and high doses were given a month apart, I. E, where we greatly exaggerated dose and regimen relative to that These studies demonstrated a supportive safety profile and no significant CNS histopathology and thereby enabled the ALN APP Phase 1 The Phase 1 trial is designed as a 2 part study, a single ascending dose Part A followed by a multiple dose Part B. Part A was enabled by the GLP toxicology studies I've just mentioned.

Speaker 4

The Phase 1 is being conducted in patients with early onset Alzheimer's disease. The primary endpoint of this study is safety and tolerability of ALN APP. Secondary objectives are focused on characterizing the pharmacology of ALN APP. The study also includes a variety of exploratory biomarkers, which will allow us to assess whether lN APP is showing any impact on other biomarkers of disease progression. Interim data shared are from the initial single ascending dose cohorts and we continue enrolling in Part A as we explore further doses.

Speaker 4

Excuse me. At the time of this interim look, 20 patients with early onset Alzheimer's disease have been enrolled in 3 single dose cohorts in Part A of the ongoing Phase 1 Today, ALN APP has been well tolerated with no study dropouts and all adverse events being mild or moderate in severity. Available CSF data from white blood cells and protein appears similar to placebo. Neurofilament light chain or NfL, which is a mark of neuronal damage and which may be elevated in drug induced neurotoxicity was also monitored. Reassuringly, early data for NfL, which are currently available from 2 out of the 3 cohorts study to date also looked comparable to placebo.

Speaker 4

Now let's look at the pharmacodynamic results after single intrathecal doses. To date, we've studied 3 dose levels, 25, 50 and 75 milligrams. All available data to All available data to the 3 month time point are shown. Excitingly, we observed that unlike placebo, lnAPP treatment resulted in rapid dose dependent and sustained reductions of both SAPP alpha and soluble APP beta, both biomarkers of target engagement in the CSS. We saw rapid knockdown as early as day 15 And the maximum knockdown of up to 84% 90% respectively for APP alpha and APP beta.

Speaker 4

At the highest dose tested, 75 milligrams, the median knockdown was greater than 70% for both biomarkers and sustained for at least 3 months. Initially, per protocol, we intended to dose escalate from 75 milligrams to 225 milligrams. However, Given that the knockdown observed at 75 milligrams substantially exceeded our initial target of 50% biomarker knockdown, we chose to deescalate to 50 milligrams. As you can see at 50 milligrams, while we have more limited data set, it appears equally promising and similar to the 75 milligram dose with substantial knockdowns for both APP Alpha and Beta. Now notably, the durability we see in humans reflects what we saw in non human primate studies, where single doses gave similar profound durable knockdown extending to 6 months or beyond.

Speaker 4

Accordingly, we anticipate that the responses we see here in Part A will continue. Indeed, for the data available beyond 3 months in the student study, we see continued target suppression. This durability of effect is important for ALN APP as well as our overall CNSFAs as it suggests the potential for infrequent dosing. We look forward to seeing with longer follow-up indeed how long this knockdown effect is sustained. We believe these data suggest that the drug will be able to Those quarterly at most and based on animal data and the translation of our platform in humans, we believe there's the potential to even dose every 6 months or less frequently.

Speaker 4

Enrollment in the single ascending dose portion of the Phase 1 study is ongoing in Canada, the Netherlands, the UK and United States. Additionally, enrollment in Part A will allow us to continue to explore single dose PKM PD and characterize the durability and effect and long term safety. Results from Part A will also inform the doses and regimens to be put forward into Part B, the multiple dose portion of the study, which will include patients from Part A. In parallel to Part A of the Phase 1 study, we conducted chronic GLP toxicology studies in animals to support the multidose Part B for Phase 1. These chronic GLP tox studies were conducted without knowledge of the impressive knockdown and durability we see today at low doses of ALN APT we see in this Phase 1 study.

Speaker 4

So for standard practice, we exaggerated dosing and dosing frequency relative to any dose and regimen that would ultimately be used in clinical testing. Specifically, We administered low, medium and high intracequal doses monthly for 6 months in the RAD and every other month for 9 months in the non human primates. The data from the chronic study should be shared with regulatory authorities. We have already received regulatory approval to begin Part D in Canada, In fact, the majority of the Part A patients have been enrolled to date and approval is pending in the U. K.

Speaker 4

And Netherlands. In the U. S, The FDA has currently placed partial clinical hold on the multi dose Part B of the Phase 1 study due to findings observed chronic toxicology studies. Of course, given the high exposure that we achieved with frequent administration of high doses, it's still not expected that we would observe findings in these chronic toxicology studies. However, it's important to contextualize exposures by relative CSF volumes between toxicology species and humans.

Speaker 4

For example, relative to a potential clinical dosing regimen of 75 milligrams given every 6 months, there's a more than tenfold greater annualized exposure At all doses tested in the rat and non human primate and at the top doses evaluated in those chronic tox studies, There's a 75 and 50 fold greater annualized exposure in rat and nonhuman primates respectively relative to the same potential human dose. And if we scale based on organ weight, then these annualized exposures would be even greater in the chronic tox studies. I want to nevertheless acknowledge that the FDA will be the ultimate arbiter of the data and we look forward to getting further guidance from them. Accordingly, we plan to engage with them to discuss all preclinical information as well as these new interim Phase 1 clinical data, which provides important context to support potential initiation of Part B in the U. S.

Speaker 4

To close this part of the discussion, I'm absolutely thrilled about these incredible human data that provide the first ever evidence that we may be able to use RNAi disease causing transcript in the CNS. In animal studies, we've already demonstrated the reproducible and modular nature of our CNS platform With the knockdown against the diverse range of targets and hope that we can address disease causing genes not just for Alzheimer's, CAA, ALS and Huntington's, but also many other disorders. We look forward to presenting these interim dates from Part A of the Phase 1 ALNA study at an upcoming medical congress. With that, let me turn to our efforts in ATTR amyloidosis, where we're advancing 3 clinical stage product candidates, Thank you, Patisiran and ALM TTRF CO4. As you know, ONPATTRO is currently approved in multiple markets around the world To treat hereditary AT triamyloidosis with polyneuropathy and we're committed to expanding the product's label for the treatment of cardiomyopathy in both the hereditary and wild type AT amyloidosis patients.

Speaker 4

As announced in February, we're delighted that our supplemental new drug application, tisiran for cardiomyopathy of AT amyloidosis Been accepted by the FDA with a standard review and a PDUFA date of October 8. In their file acceptance letter, the FDA stated that they've not identified any review issues. The agency also noted that they're planning to hold an advisory committee meeting to discuss the application. Currently, we have no further details from the FDA regarding the timing of the ad or the specific topics they wish to discuss. When we learn more, we will communicate that information in due course.

Speaker 4

If the sNDA is approved, this will allow us to extend the potential benefits of patisiran to many patients with wild type and hereditary AT amyloidosis with cardiomyopathy. This filing is based on the pivotal APOLLO B study, which demonstrated improved functional status and quality of life in patients with ATramyloid doses with cardiomyopathy given patisiran for 12 months without placebo. The clinical profile of patisiran is supported by an encouraging safety profile and exploratory data that favored patisiran treatment relative to placebo on various biomarkers of disease progression at month 12. We've announced this morning that 18 month data from the APOLLO B study have been submitted to the EA is part of the sNDA review and we'll be presenting these results at the ESC Heart Failure Meet at the end of May. Now similar to ONPATTRO, we're also committed to expanding the label for Ambuetra to include the treatment of cardiomyopathy in both hereditary and wild type AT amyloidosis.

Speaker 4

This is being done with the HELIOS B Phase 3 study of investigational bukrisiran. HELIOS B, which is fully enrolled, has an endpoint All cause mortality and CV events assessed after at least 30 and up to 36 months and we remain on track to share top line results in early 2024. Wrapping up with TTR L and TTR SCO4 is an investigational RNAi therapeutic based on our Ikaria platform It offers the potential for more durable and potent TTR silencing with the possibility for annual dosing, a potentially transformative profile. TTRS-four has entered the clinic and have become empty on dosing of the Phase 1 study and we expect top line results in late 2023. In addition to our late stage clinical programs, we believe we've also been making great progress with our early and mid stage programs.

Speaker 4

A notable highlight includes zalbiziran, our investigational REMI therapeutic for hypertension, which we believe could transform the treatment of the disease and offer a highly differentiated profile from all existing antihypertensives including oral RAS inhibitors. We look forward to the important upcoming milestones from the Phase program and remain on track to deliver top line results from KARDIA 1 in mid-twenty 20 3 and top line results from KARDIA 2 at or around year end 2023.

Speaker 3

These are just a few of

Speaker 4

the highlights from our broad and innovative pipeline, driven by our underlying organic product engine And that we where we expect to deliver sustainable innovation, representing a key growth driver for Alnylam in the years to come. To wrap up these highlights, we're excited to have initiated dosing in the Phase 1 study of ALN KHK for the potential treatment of Type 2 diabetes, whilst Regeneron as announced initiation of Phase 2 study of LN HSD in patients with NASH. Now with that, let me now turn it over to Jeff to review our financials and upcoming milestones. Jeff?

Speaker 5

Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q1 2023 financial results and discussing our full year guidance. Starting with a summary of our P and L results for the Q1. Total product revenues for the quarter were $276,000,000 or 48% growth versus Q1 2022. As Folga previously indicated, the increase is primarily related to growth in TTR product revenues, driven by the launch of Ambutra in the U.

Speaker 5

S. In the Q3 of 2022, as well as increased patients on GIVARI and OXLUMO therapies. It's also worth noting that year over year growth in combined product revenues was held back by approximately 4 percentage points due to impact of changes in foreign exchange rates. Net revenue from collaborations for the Q1 was approximately $36,000,000 representing a 41% increase compared with Q1 2022, primarily due to an increase in revenue from our collaboration arrangements with Regeneron attributed to an increase in reimbursable activities under our research services arrangement in addition to an increase in revenue recognized associated with licensed programs within the collaboration. Royalty revenue during the quarter was $7,000,000 which was driven by Novartis' sales of Lectpio, which launched in the U.

Speaker 5

S. In the Q1 of 2022. Gross margin on product sales was 85% in Q1, representing a 2% decrease compared with the Q1 of 2022. The decrease was primarily driven by increased royalties due to Sanofi on sales of Ambutra, which was partially offset by lower manufacturing costs for bambutro compared with ONPATTRO. Our non GAAP R and D expenses increased 35% in the Q1 compared to the same period in 2022, Primarily due to increases in headcount to support our R and D pipeline, development expenses associated with the APOLLO B, HELIOS B in Cardio 1, Cardio 2 clinical studies and manufacturing related expenses with our preclinical activities.

Speaker 5

Q1 2022 non GAAP R and D OpEx was disproportionately lower than all other quarters during 2022. Thus, we expect lower year over year quarterly growth rates for R and D in the remaining quarters of 2023. Our non GAAP SG and A expenses increased 17% in the Q1 compared to the same period in 2022, primarily due to increased headcount and other investments supporting our strategic growth, including the global launch of IMVE TRAC. Non GAAP operating loss for Q1 2023 was $110,000,000 representing a $7,000,000 improvement compared with Q1 2022, driven by strong top line growth offset by more moderate growth in operating expenses. Finally, we ended the quarter with cash, Cash equivalents and marketable securities of $2,100,000,000 compared to $2,200,000,000 at the end of 2022, with the decrease primarily due to our operating loss

Speaker 3

in the quarter. We continue

Speaker 5

to believe our current cash balance is sufficient to bridge us to a self sustainable financial profile. Now I'd like to turn to our full year 2023 financial guidance. We are reiterating the financial guidance we provided on our year end results call in February. Starting with net product revenues, we continue to anticipate combined net product revenues for our 4 commercialized products will be between $1,200,000,000 $1,285,000,000 Our guidance for net revenue from collaborations and royalties remains a range between $100,000,000 $175,000,000 And our guidance for combined non GAAP R and D and SG and A expenses remains unchanged and is a range between $1,575,000,000 and 1,650,000,000 Let me now turn from financials and discuss some key goals and upcoming milestones slated for early and mid-twenty 23. We will of course be executing on global commercialization of our products, ONPATTRO, IMVUTRA, GIVLARI and X LUMO.

Speaker 5

From our TTR programs, we have a couple of upcoming data presentations. 18 month results from APOLLO B will be presented at the ESC Will be presented at ASMP also at the end of May. We expect to report top line results from the CARDIA-one Phase study of zolbusiran and also intend to complete enrollment in the CARDIA-two Phase 2 study. With our partner program, SPEAR expects additional results Let me now turn it back to Christine to coordinate our Q and A session. Christine?

Speaker 1

Thank you, Jeff. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to 1 question each,

Operator

And our first question comes from Ritu Baral from TD Cowen. Your line is open. Good morning, guys. Thanks for taking the question. I know I'm a lonely loud one, so I'm going to try and stick to it as much as I can.

Operator

The 18 month data that's coming up from APOLLO B, can you talk a little bit more about what will be presented. Maybe how many patients are in continued follow-up at 18 months? Will we have key secondary endpoints like

Speaker 2

Yes. So as a reminder to everyone call, apolubiv is a double blind randomized study for 12 months. And Arthur's point, patients who are on placebo were given the option to switch to patisiran for a continuation of dosing. These data corroborates really what we saw in the 12 month portion of the study. And as we mentioned on the call, we've submitted these data

Speaker 4

to the FDA and We'll

Speaker 2

be presenting these data at EHCF in Prague in May. Priscoll, do you want to add any other comments about the data and Engagements with the agency?

Speaker 5

Yes, absolutely. Thanks, Yvonne. Thanks, Ritu, for the question. As Yvonne said, we're really excited about these data. You asked Ritu about Ongoing follow-up, right.

Speaker 5

All patients were randomized out to 12 months and then all patients were offered the opportunity to be on active drug from 12 months and beyond. And this is a cut of data out to 18 months. And we've had very high retention on the study, which is important And corroborates the profile and I think it's going to be an opportunity to look at sort of the continued profile of what we've seen on patients on active drug, which was we saw evidence Stabilization across key endpoints, particularly the 6 minute walk test, sort of what was associated with around the age related decline that's seen In that parameter, as well as stabilization in the key secondary endpoint of the Kansas City Cardiomyopathy questionnaire. So that's important. It's an opportunity to look at the placebo patients as they cross over to active drug and look at ongoing safety.

Speaker 5

Net net, as Akshay and Yvonne commented, Ritu, we really feel quite confident and good about the data that we've seen and that it corroborates Profile of patisiran and its potential role in this disease.

Speaker 2

Yes. And as a reminder, we've submitted 120 day safety update as is Routine in the submission process. Thank you. Next question please.

Operator

Our next question comes from Tazeen Ahmad from BofA. Your line is open. And maybe just one on, Mbutra sales. It looks like you're off to a good start on the ramp. Just wondering what your internal data is saying about any kind of market share being taken from AMPOTTRO and whether or not if that is the trend

Speaker 6

you would expect that to be the case going forward as well? Thanks.

Speaker 2

Okay. I think that's one

Speaker 3

that goes to you. Thank you, Yvonne. Hi, Tazeen. Look, first of all, we're incredibly excited the fact that we have been able to build a category And essentially grow our business quarter over quarter by over 70%, 3 subsequent quarters in the U. S.

Speaker 3

And what we see in terms of the dynamic with ONPATTRO is a very healthy switch rate While we're adding net naive patients in a very robust manner, so what our internal data really suggests is that There is lesser and lesser patients that are staying on Opatro as we expect those patients' numbers to remain in small double digit or

Operator

Okay.

Speaker 2

Yes, really just I think kind of emphasize how pleased we are with the Launch metrics for AMVUTRA in terms of the balance of new patients as well as switches and really the expansion of the prescriber brace, Which is very encouraging for continued growth in the trajectory of our TTR franchise. Thanks for that question, Tazeen. Next question, please.

Operator

Thank you. Our next question comes from Ellie Merle from UBS. Your line is open.

Speaker 6

Hi. Thanks so much for taking our question. This is Sarah on for Ali. On your CAA program, I guess, can you talk about some of the timelines there and maybe the prioritization of that versus Alzheimer's and How we should think about the size of the CAA market opportunity?

Speaker 2

Yes. No, thanks for that question. I guess that question has been stimulated actually by the incredible results that we've shown, the In the journey of bringing RNAi therapeutics to patients with CNS diseases in general, we're clearly starting off with early onset But Trishkal, I think cerebral amyloid angiopathy is again another very important opportunity, potentially for ALN APP Given the genetics, but could you say a few words about how we're thinking about the opportunity in CAA?

Speaker 5

Absolutely. Thanks, Yvonne. Thanks, Sarah. Look, As been highlighted by both Akshay and Yvonne, CAE is really a devastating disease. It's the 2nd leading cause of intracerebral hemorrhage only behind hypertension.

Speaker 5

And there's really no available therapies for these patients. And so it's something where the genetics and the biology really Strongly suggest that APP lowering may be a benefit to these patients. In some ways, you can think about it as very comparable to the hypothesis We've been pursuing with our TTR program, reducing amyloid and reduce downstream tissue damage in nerves and heart, in this case, in the parenchyma of the brain in Alzheimer's disease And the vasculature of the brain in CAA. So these initial data that we've shared today really give us Promise that we can advance ALN APP towards both of these diseases, frankly in parallel. We've not announced specifically what the timelines for that are.

Speaker 5

We're obviously working through and continuing the Part A of the study to do further dose exploration and really establish what we're seeing in terms of the Magnitude of knockdown, but also the durability, so that we can identify multi dose regimens, etcetera, characterize safety, And then we'll want to be pursuing Phase 2 studies in both of these indications, so in due course and we'll update.

Speaker 2

Actually anything to add? No. Okay. Good answer, Frisco.

Speaker 3

Next question please.

Speaker 7

Thank you for your questions.

Operator

Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.

Speaker 6

This is Tommi on for Salveen and congrats on the progress. So for zolbusiran, can you frame what you're hoping to see in this Coming Phase 2 monotherapy and combo data, the path to registration here, given supportive data and any updates on the Reversierra platform? Thank you.

Speaker 2

Yes. I think your question was referring to Xalvestrant. Is that correct? Just wanted to make sure. Yes.

Speaker 2

Yes. Yes. As you know, we're very excited about the opportunity for Xalvestrant in hypertension. It's You know, a condition that impacts 100,000,000 or more people, and only 70% are able to Achieves the goal in blood pressure reduction. So we think it's a really important area that we believe our platform has a real opportunity to completely transform how these patients are treated and hopefully lead to better outcomes with respect to morbidity and Mortality and we've got 2 Phase 2 studies ongoing, CARDIO-one and CARDIO-two.

Speaker 2

Clearly, we need to wait for those results before we speak more specifically about Plans beyond that, but Priscilla, do you want to talk a little bit maybe around the current Status of our studies and how we're thinking about future development?

Speaker 5

Sure. Yes. So, look, albesiran has the potential be incredibly transformative medicine for high blood pressure. What we saw in the Phase 1 study that we've already reported was Opportunity to realize almost 20 millimeters of systolic blood pressure lowering with 24 hour ABPM lasting and durability lasting up to 6 months with a single injection. We think as Yvonne highlighted that that can actually address a multitude of the issues that lead to Hypertension being the number one addressable cause of cardiovascular morbidity and mortality around the world.

Speaker 5

We've got 2 studies. The CARDIATE-one study is a monotherapy study. I think that was the first study you asked about. And that study completed enrollment at the end of last year. And so we're looking forward to data in the middle of this year.

Speaker 5

And that's really going to allow us to establish the dose and the regimen for ongoing pivotal studies. So we're looking at a range of doses 150 to 600 milligrams in Q3 and Q6 month dosing. And so coming out of that study, we'll hopefully be able to establish What that pivotal dose and regimen is. The second study that we're doing is CARDIA-two. As you're probably familiar in hypertension combination therapy is sort of Standard of care.

Speaker 5

And so what we're doing in CAR T2 is looking at combining zalvisiran with 3 common classes of medicines, diuretics, calcium channel blockers and angiotensin And what we want to be seeing there is the additive efficacy and safety, and that will help us design ongoing studies for I'm really excited that their enrollment has really been picking up in that study and we are on track to complete enrollment early this year and report out data towards the at or around year end. So with those data together, We think we'll be able to provide more guidance on what the pivotal registrational program will look like.

Speaker 2

Yes, perhaps important to add that actually from a regulatory perspective To achieve an approval in a medicine for hypertension, I have to demonstrate a 5 millimeter of mercury lowering of systolic blood pressure. And of course, You've actually already demonstrated more than that in our Phase 1 studies as it's highlighted. So as we deliver the Phase 2 days and hopefully move to larger numbers in the Phase 3 and deliver similar efficacy and also robust safety. We feel that it's a fairly straightforward

Operator

Our next question comes from Paul Matteis from Stifel. Your line is open.

Speaker 8

Hey, thanks so much for taking the question. Congrats on the quarter and the recent CNS data. I wanted to ask just a commercial question. It looks like you saw this really nice jump in the sequential net patient add rate when Ambuccher became available. It looks like that's kind of stepped back down to more than normal rate we were observing throughout 2022.

Speaker 8

Is that kind of how you're thinking about the likely cadence going forward that maybe there was this bolus of patients that were interested in a much more convenient product and now The growth rate from here is probably steadier.

Speaker 3

Okay. Yes. Thank you, Paul. I mean, look, first of all, I just want to reiterate the fact that we're incredibly pleased with how our OVITRA performance is Taking shape in the U. S.

Speaker 3

And in Japan and other European markets. What's really important to highlight is The product profile is very compelling that this category growth not only Address the pent up demand that we were anticipating, but it's also continuing to actually help us expand this franchise, Mostly noted by the fact that we have we are seeing an expanding prescriber base. Our start form rates are continuing to go up and what we see is also our ability to get The naive patients, not just on PETRA switches, are continuing to be at the stated rate. The result that you see in Q1, Paul, It's mostly it's a bit diluted because given the insurance renewals that we see in this Q1, That's the impact, the net sales impact in the U. S.

Speaker 3

We're actually very encouraged with some of those internal metrics that I just shared with you, making us quite confident that in subsequent quarters we see the uptake continue to be at the similar rates that we see in the prior quarters.

Speaker 2

Thank you so much, Silke. Next question please.

Operator

Thank you for your question. Our next question, excuse me, comes from Jessica Fye from JPMorgan. Jessica, your line is open.

Speaker 9

Good morning. Thank you for taking our questions. This is Jayeo for Jess. So we have questions on reimbursement around in which so from a cost benefit perspective for payers and recognizing, right, The Helios B data has yet to come out. How would you compare Ambuccia to tafamidis for cardiomyopathy?

Speaker 9

And also curious how you're thinking about this for ONPATTRO where you already have your positive pivotal data? And then Moving to Medicare patients specifically, can you remind us what the out of pocket cost is like Again, for the Medicare patients and with the upcoming RA changes to Medicare, how do you see this change potentially How do you see the difference can change potentially? Thank you.

Speaker 2

So there's a lot of questions here. We'll try and remember them and pass them out. I mean, Tulk, I'd maybe start with the last

Speaker 4

Actually, talk a little

Speaker 2

bit about how we're seeing out of occupation costs, right,

Speaker 3

the sort of Medicare context. So let's also kind of let the straighten the record. So we have about 70% of our patients on Medicare and Medicaid. And those are patients that are on our Part B. And right now, if you look at our current Cost burden on those patients, about 70% of our patients pay 0 co pay In the Part B program and it's consistent with both ONPATTRO as well as Albutra.

Speaker 3

As you all know, we have Very innovative value based agreements that actually really unburdens the patients to be able to have access. And what we really see, that's probably the most important marker If you look at are these patients that are put on therapy with a start form, do they actually end up Getting the therapy and are they staying on therapy? And what's really encouraging is both and we can say that now with our Muttra 3 quarters in the market, we see very similar exceptionally high compliance rates, which also suggests that those patients that They have stopped copay burden, are continue to be able to access thanks to our value based agreements And other ways that we support those patients. And what was the other question?

Speaker 2

I think you've actually answered 2, that's the 3 questions. And the third question How we're thinking about pricing in cardiomyopathy, particularly with respect to Tafamidis. I mean, given that We're still awaiting a label for ONPATTRO and we're awaiting EDSB results for vatutiran. I think it's probably too early To speak to that detail. So thank you for your questions and let's go on to the next question.

Operator

Thank you. Our next question comes from Gena Wang with Barclays. Your line is

Speaker 4

open.

Speaker 10

Thank you. Thank you for sharing your APP data. Indeed, very impressive knockdown profile. I have one question on the data, but with 3 cards that hopefully can cover all three questions. So when we look at the Nature Biotechnology Paper 60 milligram from non human primates data was only showing similar knockdown when we look at compared to the 75 milligram In human, so will it led to almost nearly tenfold better translation to human?

Speaker 10

And then my second question is that you Show the median percentage in knockdown. So what is the mean and the standard deviation look like if we're only focusing on 75 milligram profile. And then lastly, do you need to run another non human primates study in order to Satisfy FDA to remove the partial clinical hold.

Speaker 2

Okay. So three questions there. And I think I'd say, I think that they're kind of all for you. I think one was about the translation from the preclinical setting, 2nd was with respect to the percentage knockdown that we're seeing. And the 3rd, our plans to address the clinical hold.

Speaker 2

I think before I actually answered the questions on the clinical call. I think it's really important to emphasize that Part A is ongoing in a number of countries, including The U. S. And in fact, we have approval to progress with Part B from Health Canada. In fact, as I actually Said in his remarks, most of the patients actually in Part A come from Canada.

Speaker 2

So it's really important

Speaker 3

to note that we're able to progress With

Speaker 2

Part B, but clearly still a lot to learn from Part A in terms of PK, PD, durability, etcetera, the full Before we define our plans for the next possible study, actually maybe you want to talk a little bit more about how we're thinking about Addressing the clinical hold with the FDA and then

Speaker 4

the other two questions that relates to data. Yes. Thanks, Yvonne. Thanks, Gina. Let me just go in order.

Speaker 4

So I

Speaker 2

think your first question, Gina, if I got

Speaker 4

it right, was 60 milligram in the monkey expectations in man in terms of translation. I think I mean, keeping with that being a lot of calculations, if you think about the size of the monkey brain and the CSF volume and you have to administer 60 milligrams To get something like the knockdown curves we're seeing at 50 milligrams here in human and 75 milligrams, it just shows the gain in potency and we We'll also see durability in humans relative to non clinical species. Now you've watched us for a long time and if you talk That's the liver data. That's exactly what we see in the liver setting. So these human Phase 1 data are really rather exciting and I think spell a Our profile where we hope that low doses relative to the animal, we see very important clinically significant knockdown For highly durable intervals that would allow in infrequent dosing hopefully every 6 months, maybe even annually.

Speaker 4

So that was question 1. Your second question was, we showed the medians, what about the mean standard deviations of 75? Again, we haven't shown the patient by patient data. We'll of course share more data in the upcoming meeting. But I can reassure you that as you go from low to high dose, The kind of variability you see patient to patient at high dose, you now see track off the track for each patient who's following the same The data will be very tight in terms of means and standard deviations.

Speaker 4

In fact, we've looked at them at the 5075 that we haven't shared them today. So again, that conforms exactly to what we see with RNAi and other tissues, where at low doses, sub pharmacologic doses, you see the Variability between individuals, just as you see in placebo, but once you're at the operative thrombotic doses, you get very tight knockdown and little inter individual variability. Again, these are all small numbers, but very encouraging data. And finally, do we need a non human primate slate to get off hold? I mean, I think I shared today our impressions of the clinical data, the situation with the chronic tox studies, The exaggerations and exposures we have, we want to discuss all this with the FDA and get their guidance.

Speaker 4

Obviously, they have a very important voice in this. We want to benefit from their input. So let's go and do that. And from that, we'll learn whether we need to do more studies or not. But If we can administer low doses and get up to a year of lockdown, who knows, we'll see, but certainly very exciting times.

Operator

Our next question comes from David Lebowitz with Citi. Your line is open.

Speaker 7

Hi, this is Debanjana on for David. So we wanted to ask like that the ATS space appears likely to have an additional TTR silencer entry. How does the competition shake out between your offerings and eventual competitors? And maybe one more if you have time, that Assuming ONPATTRO approval for ATTR Centimeters is going to be based on functional endpoints, how do you see the therapy getting utilized Thanks.

Speaker 2

Yes. Actually, it would be really helpful if you could repeat your question and maybe just Kind of hold yourself to kind of one question. So maybe you can just repeat the one key question you'd like us to address.

Speaker 7

Sure. Okay. So my first question was that the ATTR space appears to likely have an additional TTR silencer entry. How does the competition shake out between your offerings and eventual competitors? Thank you.

Speaker 2

Okay. So Let's start off with Tolga and then Priscilla will also add some remarks. Tolga?

Speaker 3

Yes. So as you know, Avoutra has really been a game changer and it's been transforming the market and building the category growth. And frankly, the potential availability of more treatment options is really good for patients. This is a highly devastating disease. Patients are still either undiagnosed or undertreated.

Speaker 3

So similar to other competitive markets, it will increase disease awareness, support earlier diagnosis, Enable early treatment initiatives, which in turn supports a significant category growth that we already see and we expect to see. Now in terms of the product profiles, obviously what we see is and I'll have Pushkar comment a little bit on our clinical profile, but What we're really pleased to see is, 1st of all, the rapid offset is very important for patient outcomes. Disease reversal is important. I have confidence and we're obviously very confident of our product profile, only 4 times a year administration And also given the fact that strong uptake is a clear signal of our Watsworth's profile is and our customer facing profiles and how we're competing in the market. So with that, David, I'll turn it over to Pushpa to comment on the product profile on the clinical level.

Speaker 5

Yes. I mean, I think, Tobey, I think you hit Those are the key points. I mean, I think it's important to state that there's really no head to head studies between eflinturisin and We've just seen some early data here and we look forward to learning more about it. But there's no head to head data between eplentirsen and vatrisiran. I think as we've been in the marketplace, as we've talked to clinicians, as we've talked to patients, what we've learned about what's important to them, obviously, they're looking for strong efficacy And a good safety profile.

Speaker 5

And as you dive deeper into that, speed of onset of action is quite important. We've been very pleased by the Repidity of knockdown, TTR knockdown that we see with our agent and that seems to translate actually to patients feeling better. We've noticed that with the MVMI data And nutritional status and we get reports of patients anecdotally feeling a lot better very early on therapy. And likewise, ultimately people want to regain function as much as possible. They want to be able to live their lives Basically, it's free of this disease as humanly possible.

Speaker 5

And what's this concept of disease reversal that Tolga mentioned becomes very important. And We've been encouraged when you look across key parameters like the MNIST, when you look at the Norfolk quality of life, etcetera in the PN space That we have 50% or upwards of patients who are sort of reaching that reversal threshold. And so again, we're really excited about the profile that we have with AMBUTRA, how it's been received and Feedback that we've been hearing. And so I think we're very encouraged. And again, it's great that there'll be another agent out there as Colga said, But we're very confident about the profile of bambutar and what it offers.

Speaker 2

No, that's great. And I think having sort of 5 years of experience Marketing, TTR medicines, I think gives us the opportunity to really understood this market and extract insights that are helpful in terms of educating patients and physicians. So thank you for that question. Next question please.

Operator

Thank you. Our next question is from Mike Ulz from Morgan Stanley. Your line is open.

Speaker 5

Good morning and thanks for taking the question. For ALN TTR SC04, assuming you Get some supportive data later this year. Can you talk about the potential path forward there and if there's opportunity to maybe shorten that timeframe And would you be looking to move forward in both polyneuropathy and cardiomyopathy? Thanks.

Speaker 2

Thanks for that question. We are really I said about progressing ALN and TCR as Q4 for a number of reasons. Importantly, the potential for increased Knockdown greater than 90% and frequency perhaps annual dosing. So we think this is a real step forward for our platform In general and, Priscilla, maybe you can talk a little bit about how we're thinking about developing this program going forward?

Speaker 5

Yes, absolutely. Yes, Scl4 I think really represents sort of the next generation of innovation in the TTR space where we want to bring Best possible offering to patients and we believe that deeper knockdown and greater durability are the 2 things that will make a huge difference for patients. And obviously from a business perspective, it's also valuable to us because it doesn't it frees us some of the royalties etcetera that we have around And Butra, so we're obviously motivated and excited to bring this forward to patients as quickly as we can. So to your point, we will be looking for ways to Speed up the development program. And while it's early to speak to exactly what the details of that are, this first Phase 1 study is going to allow us to look at Both the magnitude of knockdown, the durability of knockdown, as well as safety.

Speaker 5

And with that, maybe one way to think about this to look back at what we did with the INBUTRO program where we went directly from Phase 1 studies into Phase 3 pivotal trials. And moreover, when we have patient level data across a number of studies, it allows us to pursue some very innovative development approach. For example, with HELIOS A, we did not have a placebo control group. We were able to use patient level data and do a historical control against The APOLLO placebo data. And so you can imagine that we will be moving this forward and trying to use similar approaches to speed up Development both in polyneuropathy and particularly in cardiomyopathy.

Speaker 5

So we'll have more to say about that as we advance our development plans.

Speaker 2

Thanks for squeezing. We've got time for one last question.

Operator

Yes. Our final question of the day comes from Kosta Belores from BMO Capital Markets. Your line is open.

Speaker 4

Congrats on the progress and thanks for taking my question. One quick question on the ONPATTRO filing. I'm wondering whether you have already submitted data to the FDA as part of the format safety update. And if so, whether you can elaborate on the Type of additional safety data that you have submitted? Thank you.

Speaker 5

Sure. Gus, thanks for the question. So the review of the ONPATTRO sNDA for cardiomyopathy is ongoing, and we have submitted Both the day 120 safety update, which really just corroborates with additional safety across adverse events, laboratory data, etcetera, With some extended follow-up beyond what we've submitted in the initial NDA and we also as announced today have submitted the month 2018 efficacy update across primary and secondary endpoints to the agency as well, which we also think corroborates the efficacy that we saw, the clinical importance of those data And a favorable benefit risk profile of the product in this disease population. So we look forward to the agency's ongoing review.

Speaker 2

That's great. So, look, yes, thank you for the question. And thanks to everyone for joining this call. We're really happy with the Strong start that we made in 2023. We've got strong commercial execution, significant pipeline and platform development, which really underscore the power of RNAi Therapeutics in addressing major unmet needs for patients.

Speaker 2

And we look forward to sharing more progress with you in the coming months And as we continue to deliver on both our near and long term goals. Thank you, everybody.

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Earnings Conference Call
Alnylam Pharmaceuticals Q1 2023
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