7 June 2019 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has completed a rolling submission of a New Drug Application to the US Food and Drug Administration for givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria, the company said.
Givosiran previously received Breakthrough Therapy Designation from the FDA and Orphan Drug Designation in the US for AHP.
It has also been granted Priority Medicines (PRIME) Designation by the European Medicines Agency and Orphan Drug Designation in the EU for AHP. Alnylam intends to file a Marketing Authorisation Application in mid-2019.
Givosiran is an investigational, subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria.
Monthly administration of givosiran has the potential to significantly lower induced liver ALAS1 levels in a sustained manner and thereby decrease neurotoxic heme intermediates, aminolevulinic acid and porphobilinogen, towards normal levels.
By reducing accumulation of these intermediates, givosiran has the potential to prevent or reduce the occurrence of severe and life-threatening attacks, control chronic symptoms, and decrease the burden of the disease.
Givosiran utilises Alnylam's Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
The safety and efficacy of givosiran were evaluated in the ENVISION Phase 3 trial with positive results; these results have not been evaluated by the FDA, the EMA or any other health authority.
The ENVISION Phase 3 trial was a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of acute hepatic porphyria.
The primary endpoint was reduction relative to placebo in the annualised rate of composite porphyria attacks, defined as those requiring hospitalisation, urgent healthcare visit, or hemin administration at home, in patients with acute intermittent porphyria (AIP, the most common subtype of AHP) over six months.
Key secondary and exploratory endpoints evaluated reductions in neurotoxic heme intermediates, aminolevulinic acid and porphobilinogen, usage of hemin, symptoms of AHP, such as pain, nausea, and fatigue, as well as impact on quality of life.
The trial enrolled 94 patients with AHP, at 36 study sites in 18 countries around the world and is the largest ever interventional study conducted in AHP.
Patients were randomised 1: 1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly. Upon completion of dosing in the double-blind period, all eligible patients (99%) enrolled in the ENVISION open-label extension to receive givosiran on an ongoing basis.
Acute hepatic porphyria refers to a family of rare, genetic diseases characterized by potentially life-threatening attacks and for some patients chronic debilitating symptoms that negatively impact daily functioning and quality of life.
AHP is comprised of four subtypes, each resulting from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver: acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and ALAD-deficiency porphyria.
These defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid and porphobilinogen, with ALA believed to be the primary neurotoxic intermediate responsible for causing both attacks and ongoing symptoms between attacks.
Common symptoms of AHP include severe, diffuse abdominal pain, weakness, nausea, and fatigue.
The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia, and endometriosis, and consequently, patients afflicted by AHP often remain without a proper diagnosis for up to 15 years.
In addition, long-term complications of AHP and its treatment can include chronic neuropathic pain, hypertension, chronic kidney disease and liver disease, including iron overload, fibrosis, cirrhosis and hepatocellular carcinoma.
Currently, there are no treatments approved to prevent debilitating attacks or to treat the chronic manifestations of the disease.
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 engaged in the translation of RNA interference into a 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.