Alnylam Presents Positive Results from ILLUMINATE-C Phase 3 Study of Lumasiran in Patients with Advanced Primary Hyperoxaluria Type 1

- Lumasiran Resulted in Substantial Reductions in Plasma Oxalate in PH1 Patients with Severe Renal Impairment -

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today positive results from the 6-month primary analysis of the ILLUMINATE-C Phase 3 open-label study of lumasiran, an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – that is being investigated for the treatment of patients of all ages with advanced primary hyperoxaluria type 1 (PH1). The clinical data were presented at a late-breaking session at the American Society of Nephrology (ASN) Kidney Week being held as a virtual event on November 4-7. Lumasiran resulted in substantial reductions in plasma oxalate (POx) in PH1 patients with chronic kidney disease (CKD) stage 3b-5, with or without dialysis. Elevated plasma oxalate is directly correlated with the pathophysiology of systemic oxalosis, a life-threatening complication of PH1. Lumasiran demonstrated an acceptable safety profile through Month 6, with mild injection site reactions (ISRs) as the most common drug-related adverse event.

“Elevated plasma oxalate levels are responsible for much of the morbidity associated with advanced PH1 and can result in oxalosis, leading to bone fractures, cardiomyopathy, vision loss, skin ulcers and other serious manifestations,” said Mini Michael, M.D., Associate Professor, Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, and Pediatric Nephrologist, Texas Children’s Hospital. “Changes in plasma oxalate of the magnitude seen in this study are encouraging and may positively impact long-term clinical outcomes, including those related to systemic oxalosis, which will be further evaluated in the extension period of this study.”

“PH1 patients progressing to or being diagnosed with end-stage kidney disease often have substantial elevations in plasma oxalate despite intensive hemodialysis. The ILLUMINATE-C results underscore the potential of lumasiran to achieve meaningful reductions in plasma oxalate in patients with impaired kidney function, including those on hemodialysis, who are at risk of systemic oxalosis and multiorgan damage,” said Jeroen Valkenburg, General Manager, Lumasiran program at Alnylam. “We look forward to submitting these results to both the U.S. and European regulatory authorities later this year to support supplemental filings for lumasiran to allow for potential label expansions.”

Results

ILLUMINATE-C enrolled 21 patients: six patients in Cohort A who did not require dialysis and 15 patients on hemodialysis in Cohort B. The primary efficacy endpoint of the study was the percent change in POx (Cohort A) and predialysis POx (Cohort B) from baseline to Month 6, averaged across Months 3 to 6. Treatment with lumasiran in Cohorts A and B, respectively, led to 33 percent and 42 percent mean reductions in POx and predialysis POx from baseline to Month 6. Reduction in POx was evident by Month 1 and persisted through the end of the 6-month primary analysis period. Lumasiran also demonstrated positive results across secondary endpoints, including patients in Cohort B achieving substantial reductions in POx area under the curve (AUC) 0-24h between dialysis sessions from baseline to Month 6, and lumasiran demonstrating consistent reductions across all measures of urinary oxalate in Cohort A. In addition, a similar magnitude of plasma glycolate increase, an exploratory endpoint in Cohorts A and B, was observed as compared to previously completed studies in patients with relatively preserved kidney function (ILLUMINATE-A and ILLUMINATE-B), suggesting similar pharmacodynamics of lumasiran regardless of kidney function. Mild and transient ISRs were the most common drug-related AE reported in 24 percent (5/21) of patients. There were no deaths and no serious or severe AEs related to lumasiran. Furthermore, there were no treatment discontinuations or study withdrawals.

Results from a separate modeling analysis were also presented at ASN Kidney Week, predicting a long-term reduction in kidney failure risk among PH1 patients treated with lumasiran, assuming prompt treatment at diagnosis.

To view the full results presented at the virtual ASN Kidney Week, please visit www.alnylam.com/capella.

OXLUMO^® (lumasiran) INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

OXLUMO is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients.

Important Safety Information

Adverse Reactions

The most common adverse reaction that occurred in patients treated with OXLUMO was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

Pregnancy and Lactation

No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.

For additional information about OXLUMO, please see the full U.S. Prescribing Information.

About Lumasiran

Lumasiran is a subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) in development for the treatment of primary hyperoxaluria type 1 (PH1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Lumasiran has received regulatory approvals from the U.S. Food and Drug Administration (FDA) for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients and from the European Medicines Agency (EMA) for the treatment of PH1 in all age groups under the brand name OXLUMO^®.

About ILLUMINATE-C Phase 3 Study

ILLUMINATE-C (NCT04152200) is a single arm, open-label, multinational Phase 3 study evaluating the safety and efficacy of lumasiran in PH1 patients of all ages with severe renal impairment (eGFR ≤ 45 mL/min/1.73m² or elevated serum creatinine for patients <12 months of age). The study is being conducted at 13 study sites across 10 countries around the world. Cohort A enrolled six patients with advanced PH1 who do not yet require dialysis, and Cohort B enrolled 15 patients who are hemodialysis-dependent. The dosing regimen is based on weight with three monthly starting doses followed by ongoing monthly or quarterly doses. The primary efficacy endpoint for Cohort A was the percent change in plasma oxalate from baseline to month six, and the primary endpoint for Cohort B was the percent change in pre-dialysis plasma oxalate from baseline to month six. Key secondary endpoints are designed to evaluate additional measures of plasma oxalate and changes in urinary oxalate. Kidney function, frequency and mode of dialysis, frequency of kidney stone events, and measures of systemic oxalosis, including clinical manifestations, will also be evaluated in the extension period of the study.

About Primary Hyperoxaluria Type 1 (PH1)

PH1 is an ultra-rare genetic disease that affects an estimated one to three individuals per million in the United States and Europe. PH1 is characterized by oxalate overproduction in the liver. The excess oxalate results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. PH1 is associated with a progressive decline in kidney function, which exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and deposition of oxalate in bones, eyes, skin, and heart, leading to severe illness and death.

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), OXLUMO^® (lumasiran), and Leqvio^® (inclisiran) 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 future expectations, plans and prospects, including, without limitation, Alnylam’s views with respect to the safety and efficacy of lumasiran as demonstrated in the ILLUMINATE-C Phase 3 study and the potential for lumasiran to be a therapeutic option for PH1 regardless of age or disease severity, including for patients on hemodialysis, the potential for changes in plasma oxalate following treatment with lumasiran to positively impact long-term clinical outcomes, including those related to systemic oxalosis, expectations regarding the timing of the presentation of full results from the ILLUMINATE-C Phase 3 study, and the timing and planned filing of supplemental applications with FDA and EMA based on the ILLUMINATE-C results, and Alnylam’s aspiration to become a leading biotech company, and the planned achievement of its “Alnylam P⁵x25” strategy, 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 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; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current 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 the use of a previously approved RNAi therapeutic in continued development and is not intended to convey conclusions about efficacy or safety as to these uses. There is no guarantee that the data described in this release will result in expanded use of this commercial product, will successfully complete clinical development or will gain health authority approval.

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