Alnylam Pharmaceuticals, Inc.

pleased with the impact we're seeing from Amutra in expanding the opportunity for our TTR franchise as reflected by the robust 75% year-over-year quarterly growth that we achieved in Q1. Representing the third 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 third quarter of 2022. Additionally, key operating metrics continue to trend favorably, including growth in new patient start forms, the switch rate from Ampetro, patient compliance rates, and the expansion of our prescriber base. In our international markets, Total TTR Q1 product sales increased 9% versus the fourth quarter, driven by strong demand in Japan following the fourth quarter launch of Amutra, offset by inventory destocking in Japan. The Amutra demand growth in Japan is particularly encouraging, with the new patient growth being driven by a mix of switches from tefamidus as well as patients naive to therapy. Additionally and importantly, Amutra continues to deliver steady growth in markets where Amutra is not yet launched, positioning these markets for the upcoming Amutra launch. Amutra 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. Now, moving to our ultra-rare products. and the performance of Givlari and Oxlumo, which delivered $72 million in combined product sales during the first quarter, representing a 2% increase compared with the fourth quarter and a more robust 45% growth compared with the first quarter of 2022. We ended the quarter with more than 550 patients on Givlari commercial therapy and more than 300 patients on Okslova commercial therapy, representing 6% and 7% quarterly growth compared with the year-end 2022 for Givlari and Okslova, respectively. For Givlari, global growth of 2% in Q1 compared with the fourth 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 first quarter that we expect will recover in subsequent quarters. 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 Oxlumo, global growth of 1% in Q1 compared with the fourth quarter was impacted by the following. U.S. reported growth increased 3%, driven by an increase in patient demand. 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, GIVLAR, and OXLUMA reported growth by 3 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 Albuter launch, which we believe represents an important therapy option for HATTR amlidiosis 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&D and pipeline progress. Akshay? 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 Alnydum and the broader field of RNAi therapeutics, which is our progress with LNAPP, an investigational RNAi therapeutic in development for the treatment of Alzheimer's disease, and cerebral amyloid angiotopy. 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 ALNAPP 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. Human genetics has shown that certain mutations or duplications in the APP gene can cause early onset Alzheimer's disease, where amyloid 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 plot deposit within the walls of blood vessels in the brain and result in bleeds. CAA is in fact the second leading cause of intracerebral hemorrhage. So this one-parent protein, APP, can be harmful in two distinct pathophysiological processes. In animal studies, we've shown that targeting APP with an sRNA showed great promise with broad CNS biodistribution after a single intrathecal injection, as shown on the left here, with knockdown in all major CNS cell types, such as the neuron, oligodendrocyte, microglia, and astrocytes. On the right, we can see that a single 60-milligram intrathecal dose in non-human primates resulted in significant and sustained target knockdown with durability out to six 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 an RNAi mechanism, we could reduce the downstream fragments that aggregate and deposit in tissues, and therefore hopefully alter the disease course. To support advancement to clinical testing, we conducted short-term IND-enabling GLP toxicology studies in the rat and nonhuman primate, where two low, medium, and high doses were given a month apart. i.e., where we greatly exaggerated dose and regimen relative to that expected in the clinic. These studies demonstrated a supportive safety profile and no significant CNS histopathology and thereby enabled the ALN-APP Phase I study. The Phase I trial is designed as a two-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. Phase one is being conducted in patients with early onset Alzheimer's disease. The primary endpoint of this study is safety and tolerability of LNAPP. Secondary objectives are focused on characterizing the pharmacology of LNAPP. The study also includes a variety of exploratory biomarkers, which will allow us to assess whether LNAPP 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. Excuse me. At the time of this interim look, 20 patients with early onset Alzheimer's disease have been enrolled in three single-dose cohorts in Part A of the ongoing Phase I study. To date, L and 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 appeared similar to placebo. Neurofilament light chain, or NSL, which is a mark of neuronal damage and which may be elevated in drug-induced neurotoxicity, was also monitored. Reassuringly, early data for NSL, which are currently available from two out of the three cohorts studied to date, also looked comparable to placebo. Now let's look at the pharmacodynamic results after single intrathecal doses. To date, we've studied three dose levels, 25, 50, and 75 milligrams. All available data to the three-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. At the highest dose tested, 75 milligrams, the median knockdown was greater than 70% for both biomarkers and sustained for at least three months. Initially, per protocol, we intended to dose escalate from 75 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 a more limited data set, it appears equally promising and similar to the 75 milligram dose with substantial knockdown of both ABP 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 six months or beyond. Accordingly, we anticipate that the responses we see here in part A will continue. Indeed, for the data available beyond three months in this human study, we see continued target suppression. This durability of effect is important for ALN-APP as well as our overall CNS effort 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 be dosed 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 six months or less frequently. Enrollment in the single ascending dose portion of the Phase I study is ongoing in Canada, the Netherlands, the UK, and the United States. Additional enrollment in Part A will allow us to continue to explore single-dose PK and 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 I study, we conducted chronic GLP toxicology studies in animals to support the multi-dose Part B for Phase I. These chronic GLP tox studies were conducted without knowledge of the impressive knockdown in durability we see today at low doses of ALN and APT we see in this Phase I study. 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 intrathecal doses monthly for six months in the rat and every other month for nine months in the non-human primate. The data from the chronic studies have been shared with regulatory authorities. We have already received regulatory approval to begin Part D in Canada, where in fact the majority of the Part A patients have been enrolled to date, and approval is pending in the UK and Netherlands. In the US, the FDA has currently placed partial clinical hold on the multi-dose Part B of the Phase I study due to findings observed in chronic toxicology studies. Of course, given the high exposures that we achieved with frequent administration of high doses, it's not unexpected 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. For example, Relative to a potential clinical dose and regimen of 75 milligrams given every six 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 non-human 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 one clinical data, which provide important context to support potential initiation of Part B in the U.S. 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 to silence disease-causing transcripts in the CNS. In animal studies, we've already demonstrated the reproducible and modular nature of our CNS platform with the knockdown against a 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 I ALN HIV study at an upcoming medical congress. With that, let me turn to our efforts in ATTR amyloidosis, where we're advancing three clinical stage product candidates, namely Patisran, Bifisran, and ALN TTRS-C04. As you know, Onpatra is currently approved in multiple markets around the world to treat hereditary AT2 amyloidosis with polyneuropathy, and we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type AT2 amyloidosis patients. Announced in February, we're delighted that our supplemental new drug application for T-strand cardiomyopathy of AT2 amyloidosis has been accepted by the FDA with a standard review and a PDUFA date of October 8th. 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 outcome or the specific topics they wish to discuss. When we learn more, we will communicate that information in due course. If the FNDA is approved, this will allow us to extend the potential benefits of paticeram to many patients with wild-type and hereditary AT-tramyloidosis with cardiomyopathy. This filing is based on the pivotal Apollo B study, which demonstrated improved functional status and quality of life in patients with AT-tramyloidosis with cardiomyopathy given paticeram for 12 months without placebo. The clinical profile of Pertusseran is supported by an encouraging safety profile and exploratory data that favored Pertusseran 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 FDA as part of the SNDA review, and we'll be presenting these results at the ESC heart failure meeting at the end of May. Now, similar to Ampatra, we're also committed to expanding the label for Ambutra to include the treatment of cardiomyopathy in both rotary and wild-type atrial amyloidosis. This is being done with the ILEOS-B Phase III study of investigational butrysram. ILEOS-B, which is fully enrolled, has an endpoint of 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 RNA therapeutic based on our iCarrier platform and offers the potential for more durable and potent TTR silencing with the possibility for annual dosing, a potentially transformative profile. TTR-SCO4 has entered the clinic and begun dosing in the phase one 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. A notable highlight includes Zalbiceran, our investigational RNA 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 II program and remain on track to deliver top-line results from CARDIA-1 in mid-2023 and top-line results from CARDIA-2 at or around year-end 23. These are just a few of the highlights from our broad and innovative pipeline, driven by our underlying organic product engine, and 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 ALNKHK for the potential treatment of Type 2 diabetes, plus Regeneron has announced the initiation of a Phase 2 study of LNHSD in patients with NASH. Now, with that, let me now turn it over to Jeff to review our financials and upcoming models.

But it's Jeff. Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Allen Island's Q1 2023 financial results and discussing our full-year guidance. Starting with a summary of our P&L results for the first quarter. Total product revenues for the quarter were $276 million, a 48% growth versus Q1 2022. As Tolga previously indicated, the increase is primarily related to growth in TTR product revenues driven by the launch of Ambutra in the U.S. in the third quarter of 2022, as well as increased patients on Yabari and Oxaluma therapies. It's also worth noting that year-over-year growth in combined product revenues was held back by approximately four percentage points due to impact of changes in foreign exchange rates. That revenue from collaborations for the first quarter was approximately $36 million, 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 million, which was driven by Novartis' sales of Lectio, which launched in the U.S. in the first quarter of 2022. Gross margin on product sales was 85% in Q1, representing a 2% decrease compared with the first quarter 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 Ambutra compared with Ampatro. Our non-GAAP R&D expenses increased 35% in the first quarter compared to the same period in 2022, primarily due to increases in headcount to support our R&D pipeline, development expenses associated with the Apollo B, Helios B, and Cardio 1, Cardio 2 clinical studies, and manufacturing-related expenses with our preclinical activities. Q1 2022 non-GAAP R&D OpEx was disproportionately lower than all other quarters during 2022. Thus, we expect lower year-over-year quarterly growth rates for R&D in the remaining quarters of 2023. Our non-GAAP SG&A expenses increased 17% in the first quarter compared to the same period in 2022, primarily due to increased headcount and other investments supporting our strategic growth, including the global launch of Invitro. Our non-GAAP operating loss for Q1 2023 was $110 million, representing a $7 million 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 $2.1 billion, compared to $2.2 billion at the end of 2022, with a decrease primarily due to our operating loss in the quarter. continue 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 four commercialized products will be between $1.2 and $1.285 billion. Our guidance for net revenue from collaborations and royalties remains a range between $100 and $175 million. And our guidance for combined non-GAAP R&D and SG&A expenses remains unchanged and is a range between $1.575 and $1.65 billion. Let me now turn from financials and discuss some key goals and upcoming milestones slated for early and mid-2023. We will, of course, be executing on global commercialization of our products on PATRO and VUTRA, GIVLARI, and XLUMO. From our TTR programs, we have a couple of upcoming data presentations. Eighteen-month results from Apollo B will be presented at the ESC heart failure meeting later this month, and the Heliose randomized treatment extension results looking at a biannual dose regimen for GUTRISERAN will be presented at ASNP also at the end of May. We expect to report top-line results from the CARDIA-1 Phase 2 study of Zalbiceran and also intend to complete enrollment in the CARDIA-2 Phase 2 study. With our partner programs, VEER expects additional results from Phase 2 combination trials of ALN-HVV02. Let me now turn it back to Christine to coordinate our Q&A session. Christine?