Therapy Areas: Infectious Diseases
Alnylam Touts Positive Topline Results from Interim Analysis of ENVISION Phase 3 Study of Givosiran in Patients with Acute Hepatic Porphyria
1 October 2018 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has announced positive topline results from the interim analysis 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.

The pre-specified interim analysis was based on lowering of urinary ALA levels as a surrogate biomarker that is reasonably likely to predict clinical benefit.

Results of the interim analysis showed that givosiran treatment was associated with a statistically significant reduction in urinary ALA levels in acute intermittent porphyria patients, relative to placebo (p less than 0.001).

Alnylam plans to discuss these data and the regulatory path forward with the FDA, and, pending the outcome of those discussions, intends to file a New Drug Application at or around year-end 2018 in support of a potential Accelerated Approval.

The interim analysis had a data cut-off date of August 22, 2018 and included 43 patients with AHPs (41 patients with AIP, one with variegate porphyria [VP], and one with hereditary coproporphyria [HCP]) who were on study for at least three months.

As of the data cut-off date, there were no deaths, and serious adverse events were reported in 22% of givosiran patients and 10% of placebo patients.

One patient (4%) on givosiran discontinued treatment due to an increase in liver transaminase which resolved that was greater than eight times the upper limit of normal, a protocol-defined stopping rule.

There were no treatment discontinuations in the placebo group.

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.

The ENVISION Phase 3 trial is a randomised, 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 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 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 new class of innovative medicines with the potential to improve the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system diseases.

Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a 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 (patisiran) lipid complex injection, 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.

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 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.
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