Research & Development
Alnylam to Initiate Rolling Submission of a New Drug Application and Pursue Full Approval for Givosiran
16 October 2018 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY), in consultation with the US Food and Drug Administration, plans to pursue a full approval based on the complete results of the ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria, rather than filing based on the interim Phase 3 results, the company said.

The FDA has also agreed to a rolling submission of a New Drug Application, which will be initiated in 2018 with full clinical sections submitted in mid-2019, assuming positive study results.

Alnylam previously reported positive topline results from the interim analysis of the ENVISION Phase 3 study of givosiran demonstrating a statistically significant reduction (p less than 0.001) in urinary ALA levels, a surrogate biomarker that is reasonably likely to predict clinical benefit.

As previously reported, serious adverse events were reported in 22% of givosiran patients and 10% of placebo patients in the interim analysis cohort of 43 patients, with one patient (4%) on givosiran discontinuing treatment due to an increase in liver transaminase that resolved.

Alnylam continues to dose patients in the ongoing ENVISION study, where enrollment was completed ahead of schedule with 94 AHP patients.

The company expects to report topline full study results of the primary endpoint the annualized attack rate after six months of treatment in early 2019.

As previously guided, the company intends to file for marketing authorization in all other markets based on the complete results of the ENVISION Phase 3 study, assuming positive results.

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 six-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 six-month treatment period.

The interim analysis included 43 AHP patients who were on study for at least three months and evaluated reduction of a urinary biomarker ALA in 41 patients with AIP, 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.

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.

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 an AHP are often misdiagnosed or remain undiagnosed for an average of 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 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, to near 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 utilizes 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 AHP.

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.

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.
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