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Alnylam Announces 2022 Product and Pipeline Goals and Provides Program Updates at R&D Day

ALNY | November 19, 2021

− Introduces New Near-Term Opportunity for Vutrisiran in Stargardt Disease, Expected to Enter Phase 3 Development in Late 2022 –

– Adds New Preclinical Cardiovascular Disease Programs, GEMINI-CVR and “Gene X,” with Highly Transformative Potential –

– Highlights Strong Progress in Extrahepatic Delivery of RNAi Therapeutics, Including Delivery in Muscle, Heart, and Adipose Tissue, and New CNS and Ocular Programs Including ALN-SOD in SOD-1-Specific Amyotrophic Lateral Sclerosis (ALS) –

– Alnylam to Webcast its R&D Day Event Today at 8:30 a.m. ET –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, is hosting a virtual R&D Day today. During the event, the Company plans to showcase its R&D progress, including its product and pipeline goals for 2022, focused on continued commercial execution of four RNAi therapeutic products, the potential launch of its fifth product, as well as advancement of early-, mid- and late-stage investigational programs.

“At Alnylam, we are excited about the opportunity for RNAi therapeutics in rare and common diseases utilizing liver and extrahepatic delivery to realize the greatest potential for this new class of medicines in human health,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “Our annual R&D Day will feature updates across our pipeline, including deep dive discussions on RNAi therapeutic opportunities in ATTR amyloidosis and hypertension. In addition, we’ll highlight an exciting new program opportunity for vutrisiran in an inherited retinopathy, Stargardt Disease, and will describe additional new programs that have the potential to provide a foundation for sustainable innovation. Finally, we’ll highlight the strong progress we have made in extrahepatic delivery of RNAi therapeutics that we believe could have broad applicability across human disease. These new advances are all a part of building Alnylam for the future and will play a critical role in helping us achieve our ‘Alnylam P5x25’ goals.”

2022 Product and Pipeline Goals

Alnylam intends to provide guidance on 2022 combined net product revenue for ONPATTRO®, GIVLAARI®, and OXLUMO® in association with its fourth quarter and full year 2021 financial results.

Patisiran, a commercial-stage RNAi therapeutic targeting transthyretin (TTR) for the treatment of polyneuropathy in patients with hATTR amyloidosis. Alnylam plans to:

Report topline results from the APOLLO-B Phase 3 study in patients with ATTR amyloidosis with cardiomyopathy in mid-2022
File a supplementary New Drug Application (sNDA) in late 2022, assuming positive results from the APOLLO-B Phase 3 study

Vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis and Stargardt Disease. Alnylam plans to:

Achieve approval from the U.S. Food and Drug Administration (FDA) in early 2022 (PDUFA date is April 14, 2022) for the treatment of the polyneuropathy of hATTR amyloidosis in adults
Launch vutrisiran in the U.S. in early 2022
Achieve approval from the European Medicines Agency (EMA) in mid-2022
Report data from evaluation of the biannual dosing regimen in late 2022
Initiate a Phase 3 Stargardt Disease study in late 2022

ALN-TTRsc04, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. Alnylam plans to:

File an Investigational New Drug (IND) application in late 2022
Initiate a Phase 1 study in late 2022

Lumasiran, a commercial-stage RNAi therapeutic for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels in pediatric and adult patients. Alnylam plans to:

Complete enrollment in a Phase 2 study in patients with recurrent renal stones in late 2022

Leqvio® (inclisiran), a commercial-stage RNAi therapeutic for the treatment of hypercholesterolemia and mixed dyslipidemia. Alnylam’s partner Novartis has stated:

The FDA action date is January 1, 2022

Cemdisiran, an investigational RNAi therapeutic in development for the treatment of complement-mediated diseases as monotherapy and in combination with anti-C5 monoclonal antibody pozelimab. Alnylam and its partner Regeneron plan to:

Report results from the Phase 2 monotherapy study in patients with IgA nephropathy in early 2022
Regeneron plans to initiate a Phase 3 combination study in PNH

Zilebesiran, an investigational RNAi therapeutic in development for the treatment of hypertension. Alnylam plans to:

Complete enrollment in the KARDIA-1 Phase 2 study in mid-2022
Complete enrollment in the KARDIA-2 Phase 2 study in late 2022
Report topline results from the KARDIA-1 Phase 2 study in late 2022

ALN-HBV02 (also known as VIR-2218), an investigational RNAi therapeutic in development for the treatment of chronic hepatitis B virus (HBV) infection. Alnylam’s partner Vir Biotechnology plans to:

Report additional results from the Phase 2 program in early and late 2022

ALN-HSD, an investigational RNAi therapeutic in development for the treatment of nonalcoholic steatohepatitis (NASH). Alnylam and its partner Regeneron plan to:

Report topline results from Part B of the Phase 1 study in NASH patients in mid-2022

ALN-APP, an investigational RNAi therapeutic in development for the treatment of Alzheimer’s Disease. Alnylam plans to:

Initiate a Phase 1 study in patients with early onset Alzheimer’s Disease (EOAD) in early 2022
Report topline Phase 1 results in late 2022

ALN-XDH, an investigational RNAi therapeutic in development for the treatment of gout. Alnylam plans to:

Initiate a Phase 1 study in early 2022
Report topline Phase 1 results in late 2022

In addition, the Company plans to continue advancement of its preclinical portfolio of investigational RNAi therapeutics targeting genes expressed in multiple tissue types, and plans to advance between 2-4 new IND applications from its organic product engine in 2022.

Stargardt Disease: Promising New Opportunity for Vutrisiran
Alnylam will discuss a new near-term opportunity for vutrisiran as an investigational RNAi therapeutic for the potential treatment of Stargardt Disease. Stargardt Disease is a rare, inherited form of blindness caused by accumulation of toxic vitamin A metabolites in the retina which leads to central vision loss. It is a leading cause of blindness from inherited retinal diseases in children, and almost all people affected by this disease become legally blind as adults. Stargardt Disease is estimated to affect about 65,000 people in the U.S. and EU (incidence of approximately 1 in 8,000-10,000), with high unmet medical need and no approved treatments.

Transthyretin (TTR) functions as a transporter of vitamin A in the blood. It forms a complex with retinol binding protein (RBP4) to deliver vitamin A to extrahepatic tissues, including the eye. In healthy individuals, the protein ABCA4 acts as a transporter for vitamin A in the eye, ensuring that toxic vitamin A metabolites do not accumulate in the retina. In contrast, patients with Stargardt Disease have an inherited defect in ABCA4. As a result, toxic vitamin A metabolites accumulate in the retina as lipofuscin, triggering degeneration of macular rods and cones, leading to central vision loss and eventually blindness in most patients.

The Company believes that RNAi-mediated serum TTR reduction with vutrisiran has the potential to reduce RBP4-mediated delivery of vitamin A to the eye and could prevent lipofuscin accumulation and resulting macular damage. Data from the HELIOS-A Phase 3 study of vutrisiran have demonstrated a high correlation between serum TTR reduction and vitamin A reduction, supporting the therapeutic hypothesis.

Alnylam plans to initiate a Phase 3 study in patients with Stargardt Disease in late 2022, following regulatory alignment.

Sustainable Innovation Driven by Platform Advances and Human Genetics
Alnylam’s continued investment in scientific innovation has yielded a new technology with the potential to simultaneously silence two unique gene transcripts using a single chemical entity. The Company believes that this platform, called GEMINI (formerly referred to as BIS technology), could have potential applications in cardiometabolic, CNS, oncologic, and viral diseases. The first investigational compound from this platform, GEMINI-CVR, targets two genes implicated in cardiovascular disease: Angiopoietin-like protein 3 (ANGPTL3) – a genetically validated target involved in lipid metabolism – and angiotensinogen, a pharmacologically validated target involved in blood pressure regulation. Reducing these two highly validated risk factors could reduce cardiovascular morbidity and mortality in at-risk populations with tonic control of both risk factors providing the potential for high adherence with a vaccine-like medicine administered by subcutaneous injection biannually or annually. The Company plans to identify a Development Candidate for the GEMINI-CVR program in 2023.

In addition, the Company will present new human genetics data from the UK BioBank (UKBB) that led to the identification of a liver-expressed target, referred to as “Gene X,” shown to be highly associated with metabolic syndrome and visceral adiposity. RNAi-mediated knockdown of Gene X is predicted to have broad beneficial effects on all facets of metabolic syndrome with potential reductions in the risk of Type 2 diabetes and coronary artery disease. IND-enabling work is ongoing to potentially allow for a biannual or annual subcutaneous dose regimen with an IND filing possible in 2023.

Opportunities with RNAi Therapeutics Beyond the Liver
Finally, Alnylam will present an update on its programs involving extrahepatic delivery of investigational RNAi therapeutics, including opportunities for CNS and ocular diseases. The disclosed CNS and ocular programs include:

ALN-APP, targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s Disease;
ALN-HTT, targeting huntingtin protein, including exon 1, in development for the treatment of Huntington’s Disease (HD);
A new program, ALN-SOD targeting SOD-1, in development for the treatment of SOD-1-Specific Amyotrophic Lateral Sclerosis (ALS); and,
A new program in glaucoma.

Alnylam is advancing its CNS and ocular disease programs in a 50-50 collaboration with Regeneron.

Alnylam will also present new data on delivery of RNAi therapeutics to additional tissues, including muscle, heart, and adipose, and an initial oncology program targeting hepatocellular carcinoma.

R&D Day Webcast Information
The Company’s R&D Day event will be held today, Friday, November 19th, from 8:30 am to 1:00 pm ET and will include a live video stream on the Investors section of the Company’s website, www.alnylam.com/events. A replay will be available on the Alnylam website within 48 hours after the event. Presentations showcased during the event will be featured on Capella (www.alnylam.com/capella).

About RNAi
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

About Alnylam Pharmaceuticals
Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), and OXLUMO® (lumasiran), as well as Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam’s expectations, plans and prospects, including, without limitation, its aspiration to become a leading biotech company, and the planned achievement of its “Alnylam P5x25” strategy through continued platform, pipeline and commercial product advances, the potential of its platform to yield RNAi therapeutics for rare and prevalent diseases and to address multiple disease targets and tissue types, the potential of product candidates emerging from its IKARIA and GEMINI platforms, the anticipated timing of potential regulatory approvals for vutrisiran and Leqvio and additional regulatory filings for patisiran, new product opportunities for patisiran, vutrisiran and lumasiran, the achievement of additional pipeline milestones and data, including relating to ongoing clinical studies of patisiran, vutrisiran, lumasiran, zilebesiran, ALN-HBV02 (Vir 2218), ALN-HSD and cemdisiran, the initiation of additional clinical studies for zilebesiran, lumasiran and the combination of cemdisiran and pozelimab, the anticipated initiation of Phase 1 studies for ALN-TTRsc04, ALN-APP and ALN-XDH, the multiple development opportunities within its preclinical portfolio and its plans to advance potential treatments for oncology indications constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition and the effectiveness or timeliness of Alnylam’s efforts to mitigate the impact of the pandemic; the potential impact of the planned leadership transition at year end on Alnylam’s ability to attract and retain talent and to successfully execute on its “Alnylam P5x25” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO (and vutrisiran in the future, if approved); Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.