23 August 2018 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has achieved full patient accrual in its ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias, the company said.

Enrollment was completed with 94 AHP patients randomized across 36 sites in 18 countries, surpassing the initial target of approximately 75 patients due to high patient demand.

The company reiterated its previous guidance that it expects to report topline results of the interim analysis by the end of September in support of a potential accelerated approval, and topline results on the primary endpoint of annualized attack rate after six months of treatment in early 2019.

The interim analysis is based on lowering of urinary aminolevulinic acid levels from approximately 30 patients at three months of treatment as a surrogate biomarker that is reasonably likely to predict clinical benefit.

Pending company and FDA review of the program at the time of interim analysis and assuming positive results and acceptable safety, the company continues to expect to submit an NDA at or around year-end 2018, seeking an accelerated approval.

The ENVISION Phase 3 trial is a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of AHPs.

Patients were randomized on a 1: 1 basis to receive 2.5 mg/kg of givosiran or placebo subcutaneously administered monthly, over a 6-month treatment period.

The primary endpoint is the annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit or hemin administration at home over the 6-month treatment period.

The planned interim analysis will evaluate reduction of a urinary biomarker ALA in approximately 30 patients after three months of dosing, as a surrogate endpoint reasonably likely to predict clinical benefit.

Key secondary and exploratory endpoints will evaluate reductions in the hallmark symptoms of AHPs, such as pain, nausea, and fatigue, as well as impact on quality of life.

All patients completing the 6-month treatment period are eligible to continue on an open-label extension study in which they will receive treatment with givosiran for up to 30 months.

In April, Alnylam presented new results from the Phase 1 and Phase 1/2 open-label extension studies of givosiran for the treatment of AHPs during the European Association for the Study of the Liver Annual International Liver Congress in Paris, France.

Acute hepatic porphyrias are a family of rare, genetic diseases characterized by potentially life-threatening attacks and for many patients chronic debilitating symptoms that negatively impact daily functioning and quality of life.

AHPs are 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 AHPs include severe, diffuse abdominal pain, weakness, nausea, and fatigue.

The symptoms of AHPs can often resemble that of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia, and endometriosis and consequently, patients afflicted with AHPs are often misdiagnosed or remain undiagnosed for up to 15 years.

Currently, there are no treatments approved to prevent debilitating attacks and treat the chronic symptoms of the disease.

Givosiran is an investigational, subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyrias.

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 to near normal levels.

By reducing accumulation of these intermediates, givosiran has the potential to prevent or significantly 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.

Givosiran has been granted Breakthrough Therapy designation by the US Food and Drug Administration and PRIME designation by the European Medicines Agency.

Givosiran has also been granted orphan drug designations in both the US and the EU for the treatment of AHPs.

The safety and efficacy of givosiran are currently being investigated in the ENVISION Phase 3 clinical trial and ongoing Phase 1/2 OLE study and have not been evaluated by the FDA, the EMA or any other health authority.

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.

RNAi therapeutics are a new class of medicines that harness the natural biological process of RNAi. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of 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 in developing medicines to improve 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 improve the lives of people afflicted with rare genetic, cardio-metabolic, and hepatic infectious 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.

Onpattro, available in the US for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults, is Alnylam's first US FDA-approved RNAi therapeutic.

Alnylam has a deep pipeline of investigational medicines, including three 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 800 people worldwide and is headquartered in Cambridge, MA.