Alnylam Highlights Significant Progress with Platform Innovation and Clinical Pipeline at R&D Day

– Company Anticipates Investigational New Drug (IND) Applications for Nine or More Programs with Targets Expressed in the Liver, Central Nervous System, Adipose Tissue, and Muscle by End of 2025 –

– Positive Initial Phase 1 Results with ALN-TTRsc04 Demonstrate Rapid Knockdown with Mean Serum TTR Reduction up to 97% with Durability Supporting Potential for Annual Dosing and an Encouraging Safety Profile –

– Positive Initial Phase 1 Results with ALN-KHK Demonstrate Robust Target Engagement and an Encouraging Safety Profile, Supporting Continued Development as a Novel Treatment for Type 2 Diabetes Mellitus –

– 2024 Product and Pipeline Goals Detail Expected Execution Across Four Commercial Brands and Robust Clinical Pipeline –

– Alnylam to Webcast its R&D Day Event Today at 8:30 am E.T. –

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 and platform innovation, as well as its product and pipeline goals for 2024, including continued commercial execution of four RNAi therapeutic products and the advancement of early-, mid-, and late-stage investigational programs.

“Alnylam continues to drive the next wave of RNAi therapeutics that is changing medicine, with a sustainable innovation engine generating a robust pipeline and a multi-product commercial portfolio setting the stage for the future. We expect our track record of strong pipeline and commercial execution to continue through the end of 2025 and beyond,” said Akshay Vaishnaw, M.D., Ph.D., Chief Innovation Officer of Alnylam. “As we look ahead to the next frontier of RNAi therapeutic innovation, we are excited to be presenting promising results that speak to our ambition to reach many new tissues, with new data on delivery to the central nervous system, adipose tissue, muscle, and tumors. We believe this progress—with nine or more Alnylam proprietary INDs planned by the end of 2025—will help build our pipeline to enable sustainable future growth and advance us toward achieving our ‘Alnylam P⁵x25’ goals of becoming a top-tier biotech company.”

Novel Extrahepatic Delivery Systems Extend Alnylam’s Leadership in RNAi Platform Innovation

Alnylam scientists will present new preclinical findings demonstrating RNAi-mediated knockdown of targets expressed in adipose and muscle. The data provide evidence for best-in-class delivery to these tissues using subcutaneous administration, with potent and sustained knockdown of specific genes. The Company is progressing candidates that employ the new delivery technology toward Development Candidate selection in 2024.

The Company will also share preclinical data demonstrating systemic delivery of an RNAi therapeutic across the blood-brain barrier to the central nervous system (CNS). The results, while early, have the potential to broaden applications of RNAi therapeutics in the CNS by eliminating the need for direct administration (i.e., intrathecally).

Next Wave of RNAi Therapeutics Fuel Robust Clinical Pipeline

Alnylam scientists will present new genetically validated targets for rare, specialty, and prevalent diseases, including for cholestatic liver diseases, a range of bleeding disorders, obesity, and type 2 diabetes mellitus (T2DM). By the end of 2025, the Company plans to file Investigational New Drug (IND) applications for at least nine new Alnylam-led RNAi programs, including five for targets expressed in the liver, two for the CNS, and one each for adipose tissue and muscle. The Company also anticipates that INDs will be filed for at least six additional programs led by partners during this timeframe.

New Positive Phase 1 Data Reinforce Strength of Organic Product Engine

Alnylam scientists will present positive initial results from Phase I clinical trials for ALN-TTRsc04, in development for the treatment of ATTR amyloidosis, and ALN-KHK, in development for the treatment of T2DM. In addition, Alnylam will share an update on delivery advances driving ALN-BCAT, which will soon begin clinical testing in patients with hepatocellular carcinoma (HCC).

ALN-TTRsc04 Phase 1 Study

ALN-TTRsc04 is an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis that utilizes Alnylam’s IKARIA technology and provides the potential for greater than 90% target gene silencing with once annual dosing. In the Phase 1 study in healthy volunteers, single 300 mg doses of ALN-TTRsc04 achieved rapid knockdown with a mean reduction of greater than 90% at Day 15. A peak mean TTR reduction of 97% was achieved at Day 29 and a mean TTR reduction of 93% was sustained at Day 180. At all dose levels evaluated to date, single doses of ALN-TTRsc04 have been well tolerated, with no adverse events deemed to be related to study drug by the investigator.

These initial results suggest the potential for ALN-TTRsc04 to offer over 90% TTR reduction with once annual dosing. The Phase 1 study is ongoing. Additional data will help inform selection of dose level and regimen for a Phase 3 study in ATTR amyloidosis with cardiomyopathy, which the Company expects to start at or around year-end 2024.

ALN-KHK Phase 1 Study

In the Phase 1 study in overweight to obese healthy volunteers, single doses of investigational ALN-KHK at the highest dose cohort available resulted in a mean increase in fructose area under the curve to 3-fold relative to baseline levels measured at Day 85, providing clear evidence of target engagement. Decreases in circulating FGF21 levels were also observed, consistent with the known biology of KHK.

ALN-KHK was shown to be safe and well tolerated, with an encouraging safety profile supporting continued clinical development, and target engagement that suggests the potential for quarterly or less frequent dosing. The study is ongoing, and additional data from the two highest dose levels will enable dose selection for Part B, which will evaluate multiple doses of ALN-KHK in obese patients with T2DM.

ALN-BCAT Phase 1 Study

Alnylam scientists will also present promising preclinical data with ALN-BCAT, an investigational RNAi therapeutic targeting β-catenin for the treatment of HCC. The Wnt/β-catenin pathway is implicated in many human cancers, including HCC, a leading cause of cancer death worldwide.¹ Alnylam announces today that it recently filed an IND application with ALN-BCAT and plans to initiate a Phase 1 study in early 2024. The study will evaluate the investigational drug’s potential both as a monotherapy and in combination with immunotherapy in patients with advanced disease. ALN-BCAT employs Alnylam’s advanced lipid nanoparticle (LNP) delivery technology termed “reLNP,” which provides improved tolerability due to enhanced biodegradability.

2024 Product and Pipeline Goals

Alnylam plans to provide guidance on 2024 combined net product revenue for ONPATTRO®, AMVUTTRA®, GIVLAARI®, and OXLUMO® with its fourth quarter and full year 2023 results.

Vutrisiran, a commercial-stage RNAi therapeutic for the treatment of polyneuropathy in patients with hATTR amyloidosis, and in development for the treatment of the cardiomyopathy of ATTR amyloidosis (including both hATTR and wtATTR amyloidosis). Alnylam plans to:

• Report topline results from the HELIOS-B Phase 3 study in early 2024.
• Submit a Supplemental New Drug Application (sNDA) for the cardiomyopathy of ATTR amyloidosis in mid-2024, assuming positive HELIOS-B results.

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

• Initiate a Phase 3 study in patients with ATTR amyloidosis with cardiomyopathy at or around year-end 2024.

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

• Report topline results from the KARDIA-2 Phase 2 study in early 2024.
• Initiate the KARDIA-3 Phase 2 study in early 2024.

ALN-APP,^* an investigational RNAi therapeutic in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA). Alnylam plans to:

• Initiate a Phase 2 study in CAA in early 2024.
• Report initial Part B multi-dose data from the Phase 1 study in Alzheimer’s disease in late 2024.
• Initiate a Phase 2 study in Alzheimer’s disease at or around year-end 2024.

ALN-KHK, an investigational RNAi therapeutic in development for the treatment of type 2 diabetes mellitus. Alnylam plans to:

• Initiate Part B of the Phase 1 study in early 2024.

ALN-BCAT, an investigational RNAi therapeutic in development for the treatment of hepatocellular carcinoma. Alnylam plans to:

• Initiate a Phase 1 study in early 2024.

In addition, the Company plans to file INDs for three new Alnylam-led programs by the end of 2024.

Partner-Led Program Highlights

Alnylam also plans to support its partners in advancing multiple mid- and late-stage programs, including:

• Fitusiran, an investigational RNAi therapeutic partnered with Sanofi in late-stage development for the treatment of hemophilia A and B, with or without inhibitors. Sanofi plans to file a New Drug Application for fitusiran in 2024.
• ALN-HBV02 (VIR-2218), an investigational RNAi therapeutic partnered with Vir Biotechnology in development for the treatment of chronic hepatitis B and D virus infection. Vir expects to report clinical data from multiple Phase 2 studies throughout 2024.

R&D Day Webcast Information

The Company’s R&D Day event will be held today, Wednesday, Dec. 13, from 8:30 a.m. to 12:45 p.m. ET and will include a video stream on the Investors section of the Company’s website, investors.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.

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 Pharmaceuticals (Nasdaq: ALNY) has led 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 and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple 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 X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or Instagram.

Alnylam Forward Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a top tier biotech company, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, Alnylam’s projected commercial and financial performance and the planned achievement of its “Alnylam P⁵x25” strategy, should be considered forward-looking statements. 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: Alnylam’s ability 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 Alnylam’s product candidates, including vutrisiran, zilebesiran, ALN-APP, ALN-TTRsc04 and ALN-KHK; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; delays or interruptions in the supply of resources needed to advance Alnylam’s research and development programs; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the approved indications for AMVUTTRA in the future; 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; 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; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products, including Roche, Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the risks of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q 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.

*ALN-APP is an Alnylam-led program partnered with Regeneron. Zilebesiran is an Alnylam-led program partnered with Roche.

Reference

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Alnylam Highlights Significant Progress with Platform Innovation and Clinical Pipeline at R&D Day