Target knockdown and safety results support continued clinical development

Alnylam and Regeneron intend to initiate a Phase 2 study in late 2022

Detailed results to be presented at an upcoming medical congress

CAMBRIDGE, MA & TARRYTOWN, NY, USA I September 15, 2022 I Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) and Regeneron Pharmaceuticals (Nasdaq: REGN) announced today preliminary Phase 1 data supporting the clinical advancement of ALN-HSD, an investigational RNAi therapeutic targeting HSD17B13 in development for the treatment of nonalcoholic steatohepatitis (NASH).

“We are excited to share these initial results, indicating what we believe to be a favorable profile for ALN-HSD and supporting continued clinical development of this investigational medicine, particularly given the significant prevalence and unmet need in NASH – a progressive liver disease and a leading cause of liver transplant”

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After single-dose evaluation in healthy adult volunteers (Part A), multiple doses of ALN-HSD are being studied in adult patients with NASH (Part B). Patients in the first two Part B cohorts (200 and 400 mg quarterly) have completed at least 6 months on the study; remaining cohorts are exploring a lower dose or a later biopsy time point. In the first two Part B cohorts, ALN-HSD was associated with robust target knockdown and numerically lower liver enzymes and biopsy-derived nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS)* over six months in patients receiving ALN-HSD (N=20) relative to placebo (N=4). The study was not powered to achieve statistical significance on these endpoints, and the primary outcome measure is frequency of adverse events. ALN-HSD has exhibited an encouraging safety and tolerability profile to date; the most common treatment-emergent adverse event in healthy subjects treated with ALN-HSD (N=44) was injection site reaction in five patients; all injection site reactions were mild in severity. No treatment-related serious adverse events have been reported in either healthy volunteers or patients with NASH to date. Based on these results, the companies plan to initiate a Phase 2 study in adult patients with NASH in late 2022.

“We are excited to share these initial results, indicating what we believe to be a favorable profile for ALN-HSD and supporting continued clinical development of this investigational medicine, particularly given the significant prevalence and unmet need in NASH – a progressive liver disease and a leading cause of liver transplant,” said Kevin Sloan, Ph.D., Vice President, Development Programs and Program Leader for the ALN-HSD program at Alnylam. “Our RNAi platform is ideally suited for this genetic target. We look forward to reporting detailed results from this study at an upcoming medical congress and to share details of the Phase 2 study design in partnership with our colleagues at Regeneron.”

“The Regeneron and Alnylam collaboration continues to produce compelling clinical and pre-clinical stage therapeutic candidates targeting notoriously hard-to-treat diseases such as NASH and Alzheimer’s,” said Aris Baras, M.D., Senior Vice President and Head of the Regeneron Genetics Center. “By building on each company’s deep expertise in human genetics as well as drug technology and development capabilities, we are progressing ALN-HSD to Phase 2 assessment and are rapidly moving PNPLA3– and CIDEB-targeting therapeutics towards first-in-human studies, resulting in an exciting portfolio of potential future genetic medicines for NASH.”

* The NAFLD Activity Score (NAS) is a widely accepted scoring system developed by the NASH Clinical Research Network for use in clinical trials. The score is based on histological assessment of liver biopsies and is comprised of a sum of steatosis, ballooning, and lobular inflammation component scores.

About the Phase 1 Study Design
The Phase 1 trial is a randomized, double-blind, placebo-controlled, multi-center, single-ascending dose (SAD) and multiple-dose (MD) study designed to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of ALN-HSD in healthy adult subjects and adult patients with NASH. The primary endpoint of the study is the frequency of adverse events. The study was conducted in two parts. Part A enrolled 58 healthy adult subjects randomized 3:1 to receive a single ascending dose of 25, 100, 200, 400, or 800 mg of ALN-HSD or placebo; Part A of the study is complete. Part B enrolled 45 patients with NASH randomized 4:1 to receive two doses of 25, 200, or 400 mg of ALN-HSD or placebo, quarterly. Patients in the first two cohorts (200 and 400 mg) have completed at least 6 months on the study; remaining cohorts are exploring a lower dose or a later biopsy time point. Secondary and exploratory endpoints of the study include the characterization of plasma and urine PK of ALN-HSD and the evaluation of the drug PD effect.

ALN-HSD is an investigational, subcutaneously administered RNAi therapeutic targeting HSD17B13 for the treatment of NASH. It is being developed in collaboration with Regeneron following their identification of a loss-of-function variant in HSD17B13 that is associated with a reduced risk of chronic liver disease and progression from steatosis to steatohepatitis1. ALN-HSD utilizes Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index. The safety and efficacy of ALN-HSD have not been evaluated by the FDA, EMA or any other health authority.

About NASH
Nonalcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease in which inflammation and liver cell injury are caused by accumulation of hepatic fat. NASH is a subset of a group of conditions called nonalcoholic fatty liver disease (NAFLD) that can lead to progressive fibrosis, cirrhosis, and hepatocellular carcinoma. Comorbidities include obesity, metabolic syndrome, and type 2 diabetes. Approximately 16 million people in the US live with NASH, with prevalence of the disease increasing due to rising rates of obesity. NASH is projected to be the leading indication for liver transplants in developed countries within the next 10 years. There are currently no approved medical therapies for NASH.

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) 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 20 years ago, 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), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and AMVUTTRA® (vutrisiran), 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 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 and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

About Regeneron
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for nearly 35 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to nine FDA-approved treatments and numerous product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, hematologic conditions, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune®, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.

For more information, please visit or follow @Regeneron on Twitter.

SOURCE: Regeneron Pharmaceuticals