Alnylam Presents Positive Phase 3 Results from ILLUMINATE-A Study of Lumasiran, an Investigational RNAi Therapeutic for Treatment of Primary Hyperoxaluria Type 1

- Lumasiran Achieved Primary Endpoint with 53.5 Percent Mean Reduction in Urinary Oxalate Relative to Placebo and Showed a 65.4 Percent Reduction Relative to Baseline -

- 84 Percent of Patients on Lumasiran Achieved Normal or Near-Normal Levels of Urinary Oxalate and More than Half of Patients Reached Normalization, Compared with Zero Percent in the Placebo Group -

- Lumasiran Demonstrated an Encouraging Safety and Tolerability Profile -

- Alnylam to Host Conference Call Today at 8:30 am ET -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today positive Phase 3 results from the ILLUMINATE-A study of lumasiran, an investigational RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) - the gene encoding glycolate oxidase (GO) - in development for the treatment of primary hyperoxaluria type 1 (PH1). The clinical data were presented at a late-breaking session at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress being held as a virtual event on June 6-9.

Lumasiran achieved the ILLUMINATE-A primary endpoint with a 53.5 percent mean reduction in urinary oxalate relative to placebo (p=1.7x10-14) and showed a 65.4 percent mean reduction in urinary oxalate relative to baseline. All tested study secondary endpoints were met, including the proportion of patients achieving near-normalization (84 percent) or normalization (52 percent) of urinary oxalate, compared with zero percent in the placebo group. Lumasiran administration was associated with an encouraging safety and tolerability profile, with no serious or severe adverse events (AEs) and with mild injection site reactions (ISRs) as the most common drug-related AE.

PH1 is an ultra-rare orphan disease caused by excessive oxalate production, and elevated urinary oxalate levels are associated with progression to end-stage kidney disease and other systemic complications.1,2

Based on the ILLUMINATE-A results, Alnylam filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA). The FDA has granted a Priority Review for the NDA and has set an action date of December 3, 2020 under the Prescription Drug User Fee Act (PDUFA). In addition, the Marketing Authorisation Application (MAA) for lumasiran has been submitted to and validated by the European Medicines Agency (EMA), and has received Accelerated Assessment designation.

"We are very pleased to report positive Phase 3 results from the ILLUMINATE-A study of lumasiran. The substantial and sustained reductions in urinary and plasma oxalate reported demonstrate that lumasiran addresses the underlying pathophysiology of PH1 by reducing the production of the toxic metabolite responsible for the clinical manifestations of this serious and progressive disease. Thus, we believe lumasiran has the potential to have a favorable impact on disease manifestations, including nephrocalcinosis and renal stones, and overall disease progression, which we are continuing to evaluate in the ongoing ILLUMINATE program," said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. "The ILLUMINATE-A study represents the sixth positive Phase 3 study for an investigational RNAi therapeutic, and we believe it further highlights the transformational potential of this modality as a whole new class of medicines. Assuming favorable regulatory reviews, we look forward to bringing lumasiran to patients with PH1 around the world."

"For those living with PH1, the continuous overproduction of oxalate can have a devastating impact on the kidneys and other organs. Current disease management strategies aim to lessen the damage to the kidneys, with liver transplantation as the only means to correct the metabolic deficiency and normalize the high oxalate production. As patients approach end-stage kidney disease, they may require intensive dialysis as a bridge to a dual liver/kidney transplant," said Professor Jaap Groothoff, M.D., Ph.D., Head of the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, The Netherlands. "Based on results from the ILLUMINATE-A study, lumasiran shows potential to substantially curb oxalate overproduction - the cause of progressive kidney failure in PH1. Reduction in hepatic oxalate production is expected to confer clinical benefit in PH1 patients and has the potential to change the course of disease."

Efficacy Results

In the ILLUMINATE-A study (N=39), lumasiran met the primary efficacy endpoint of 24-hour urinary oxalate reduction from Month 3 to Month 6 (averaged across timepoints) relative to placebo and all tested secondary endpoints. Specifically, lumasiran treatment (N=26) in PH1 patients, aged six years and older with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73m2, resulted in 65.4 percent mean reduction in urinary oxalate relative to baseline, with a mean treatment difference of 53.5 percent relative to placebo (N=13) (p=1.7 x 10-14). The mean maximal reduction with lumasiran was 76 percent, similar to results (75-76 percent) reported in Phase 1/2 and Phase 2 open-label extension (OLE) studies using a different assay method. Lumasiran also demonstrated a 62.5 percent mean reduction in 24-hour urinary oxalate:creatinine ratio - an alternative measure of urinary oxalate excretion - relative to baseline, with a mean treatment difference of 51.8 percent relative to placebo (p=5.0 x 10-10). At Month 6, the majority (21/25 or 84 percent) of patients randomized to lumasiran achieved urinary oxalate levels at or below 1.5 times the upper limit of normal (1.5 x ULN = 0.77 mmol/24hr/1.73m2) (p=8.3x10-7). Approximately half (13/25 or 52 percent) of the lumasiran-treated patients achieved urinary oxalate levels within the normal range (less than or equal to 0.514 mmol/24hr/1.73m2) (p=0.001). In contrast, none of the patients on the placebo arm achieved normal or near-normal levels of oxalate. Lumasiran led to a rapid and sustained reduction in plasma oxalate levels in patients whose baseline plasma oxalate was at or above 1.5 times the lower limit of quantification, with patients on lumasiran (N=23) experiencing plasma oxalate reduction of 39.8 percent versus 0.3 percent for patients on placebo (N=10) (p=2.9 x 10-8).

In a pre-specified subgroup analysis of the primary endpoint, lumasiran demonstrated a consistent treatment effect relative to placebo across all subgroups, including baseline kidney function. As expected, given the 6-month duration of the study, eGFR levels and renal stone eventsa were comparable between the two treatment arms. Three of 22 evaluable lumasiran patients demonstrated early signs of unilateral and bilateral improvements in nephrocalcinosis at six months, in a pre-specified analysis of this exploratory endpoint, including one patient in the lumasiran arm demonstrating a 2-grade improvement in one kidney and 1-grade improvement in the other kidney. In contrast, no improvement in nephrocalcinosis was reported for evaluable placebo patients (N=12) and one placebo patient experienced a unilateral, 1-grade worsening. As anticipated and consistent with the lumasiran mechanism of action, levels of plasma glycolate - a pharmacodynamic marker - initially increased and then reached a plateau in the lumasiran group. A total of 38b of 39 patients completed the 6-month primary analysis period and all eligible patients transitioned to the ILLUMINATE-A OLE study.

Safety and Tolerability

There were no deaths and no severe or serious AEs reported. AEs were reported in 22/26 (84.6 percent) of lumasiran patients and 9/13 (69.2 percent) of placebo patients. All AEs were mild to moderate in severity. AEs reported in greater than or equal to 10 percent of patients in both groups were ISRs, headache, rhinitis, and upper respiratory tract infection. The most common AEs related to lumasiran were ISRs reported in 9/26 (34.6 percent) of patients. All ISRs were mild in severity, transient, and did not result in treatment interruption or discontinuation. Most common ISR-related symptoms were erythema, pain, pruritus, or discomfort at the injection site. AEs leading to discontinuationc of study treatment were reported in 1/26 (3.8 percent) of lumasiran patients. No clinically relevant changes in laboratory parameters (including liver function tests), vital signs, and electrocardiograms related to lumasiran were observed.

To view the results presented at ERA-EDTA, please visit

Conference Call

Alnylam Management will discuss the ILLUMINATE-A results via conference call on Sunday, June 7, 2020 at 8:30 am ET. A webcast presentation will also be available on the Investors section of the Company's website at To access the call, please dial 800-239-9838 (domestic) or +1 323-794-2551 (international) five minutes prior to the start time and refer to conference ID 6976021. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 888-203-1112 (domestic) or +1 719-457-0820 (international) and refer to conference ID 6976021.

aRenal stone event was a pre-specified exploratory endpoint during the 6-month placebo-controlled treatment period and defined as an event which includes at least one of the following: visit to healthcare provider because of a renal stone, medication for renal colic, stone passage, or macroscopic hematuria due to a renal stone.

b One patient discontinued study drug after receiving a single dose and withdrew from the study after Month 3. Parent/guardian stopped participation due to patient's inability to comply with protocol-specific testing.

c Discontinuation of study treatment was attributed to AEs of fatigue and disturbance in attention.


  1. Cochat & Rumsby. N Engl J Med 2013;369:649-58.
  2. Milliner et al. GeneReviews® [updated November 30, 2017]. Available from:

About ILLUMINATE-A Phase 3 Study

ILLUMINATE-A (NCT03681184) is a six-month randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study (with a 54-month extension period) to evaluate the efficacy and safety of lumasiran in 39 patients with a documented diagnosis of PH1. Patients were randomized 2:1 to receive three monthly doses of lumasiran or placebo followed by quarterly maintenance doses at 3 mg/kg. The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to the average of months 3 to 6 in the patients treated with lumasiran as compared to placebo. Treatment arms were stratified at randomization based upon mean 24-hour urinary oxalate during screening (≤ 1.7 or > 1.7 mmol/24hr/1.73m2). Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate (eGFR), nephrocalcinosis, renal stone events, safety and tolerability.

About Lumasiran

Lumasiran is an investigational, 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 both U.S. and EU Orphan Drug Designations, Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA), and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA). The safety and efficacy of lumasiran are under evaluation by the FDA and EMA.

About Primary Hyperoxaluria Type 1 (PH1)

PH1 is an ultra-rare disease in which excessive oxalate production 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. Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Current treatment options are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability. Although a small minority of patients respond to vitamin B6 therapy, there are no approved pharmaceutical therapies for PH1.

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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam is headquartered in Cambridge, MA.

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-A Phase 3 study and the potential for lumasiran to have a favorable impact on PH1 disease manifestations and overall disease progression, Alnylam's expectations with respect to the review timelines for the lumasiran NDA and MAA by the FDA and EMA, respectively, Alnylam's plans, assuming favorabale regulatory reviews, to bring lumasiran to patients with PH1 around the world, and expectations regarding the continued execution on its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics, 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 a future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam's business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam's ability to execute business continuity plans to address disruptions caused by the COVID-19 or a future pandemic; 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, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; Alnylam's ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's ability to manage its growth and operating expenses within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, including completing an agreement for funding by Blackstone of certain R&D activities for vutrisiran and ALN-AGT; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; the outcome of litigation; the risk of 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 other filings that Alnylam makes with the SEC. 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.


Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom
(Investors and Media)

Josh Brodsky


Source: Alnylam Pharmaceuticals, Inc.

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