Research & Development
Alnylam Initiates ILLUMINATE-B Phase 3 Pediatric Study of Lumasiran for the Treatment of Primary Hyperoxaluria
17 April 2019 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has initiated ILLUMINATE-B, a global Phase 3 pediatric study of lumasiran, an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of primary hyperoxaluria type 1, the company said.

The study will enroll approximately eight patients with PH1 under six years of age. The primary endpoint is the percent reduction in urinary oxalate from baseline to six months. The company expects to report initial ILLUMINATE-B results in mid-2020.

Alnylam also announced new positive efficacy results from the ongoing Phase 2 open-label extension study of lumasiran. The results were presented at the International Society of Nephrology 2019 annual meeting held on April 13-16 in Melbourne, Australia.

All patients from the Phase 1/2 study of lumasiran have now transitioned to the Phase 2 OLE study designed to evaluate long-term safety and efficacy of lumasiran.

The new Phase 2 OLE results were reported with 18 patients dosed in the OLE as of the data cut-off date of February 8.

Patients were on a range of lumasiran doses and regimens (1.0 mg/kg monthly, 3.0 mg/kg monthly, and 3.0 mg/kg quarterly).

There were no discontinuations from study treatment. A single patient (1/18; 5.6%) reported two serious adverse events of traumatic brain injury and bone contusion sustained in a car accident; neither was assessed as related to study drug.

Adverse events were reported in 12/18 (66.7%) patients. Injection site reactions were reported in 3/18 (16.7%) patients; all were mild and assessed as related to study drug. There were no clinically significant laboratory changes.

Lumasiran demonstrated a 72% mean maximal reduction (range: 41-90%) in urinary oxalate excretion relative to Phase 1/2 baseline values across all dose cohorts.

The mean reduction relative to baseline at Day 85 was 69%. Lumasiran also demonstrated a mean maximal reduction in urinary 24-hour oxalate: creatinine ratio of 77% (range: 57-91%) relative to Phase 1/2 baseline values across all dose cohorts. The mean reduction relative to baseline at Day 85 was 70%.

The ILLUMINATE-B Phase 3 trial is an open-label, global, multicenter study to evaluate the efficacy and safety of lumasiran in approximately eight patients less than six years of age with a documented diagnosis of PH1. Dosing regimen will be based on patient weight.

The primary endpoint is the reduction of urinary oxalate at six months relative to baseline. Key secondary and exploratory endpoints will evaluate additional measures of urinary oxalate, estimated glomerular filtration rate, safety and tolerability, and quality of life.

Lumasiran (formerly known as ALN-GO1) is an investigational RNAi therapeutic targeting glycolate oxidase in development for the treatment of Primary Hyperoxaluria Type 1.

Lumasiran is designed to reduce hepatic levels of the GO enzyme, thereby depleting the substrate necessary for the production of oxalate the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilises Alnylam's Enhanced Stabilization Chemistry -GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.

Lumasiran has received both US and EU Orphan Drug Designations, a Breakthrough Therapy Designation from the US Food and Drug Administration (FDA), and a Priority Medicines (PRIME) designation from the European Medicines Agency.

The safety and efficacy of lumasiran have not been evaluated by the FDA, EMA or any other health authority.

PH1 is an ultra-orphan 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.

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 current medicines by potently silencing messenger RNA the genetic precursors that encode for disease-causing 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.

Alnylam (NASDAQ: ALNY) is leading the translation of RNA interference 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 /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 discovery platform.

Alnylam's first US FDA-approved RNAi therapeutic is ONPATTRO (patisiran) lipid complex injection available in the US for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. In the EU, ONPATTRO is approved for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy.

Alnylam has a deep pipeline of investigational medicines, including five product candidates that are in late-stage development.

Looking forward, Alnylam will continue to execute 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 employs over 1,000 people worldwide and is headquartered in Cambridge, MA.