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


oxluma (Lumasiran)


CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jun. 7, 2020 -- 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


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.

Source: Alnylam Pharmaceuticals, Inc.

Posted: June 2020

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