Rare Daily Staff

Alnylam Pharmaceuticals said it initiated a late-stage study of givosiran, a subcutaneously administered, experimental RNAi therapeutic for the treatment of acute hepatic porphyrias, a group of ultra-rare, genetic diseases characterized by acute, debilitating, and potentially life-threatening attacks.

Porphyrias are a group of rarely diagnosed diseases caused by a genetic mutation that leads to an enzyme deficiency that causes an accumulation of the building blocks of porphyrins. Porphyrins are essential to the functioning of hemoglobin, which transports oxygen to organs and tissues.

Acute hepatic porphyrias constitute a subset of porphyrias where the enzyme deficiency occurs within the liver. They are often misdiagnosed and characterized by acute, potentially life-threatening attacks and debilitating multi-system symptoms. Nearly 65 percent of patients suffer from chronic symptoms and they can suffer from severe abdominal pain, neuropsychiatric symptoms, weakness, and require frequent hospitalizations.

Accumulation of ALAS1, an enzyme in the heme biosynthesis pathway, can lead to accumulation of neurotoxic heme intermediates that can cause a range of symptoms. Givosiran targets ALAS1.

Current treatment options do not prevent attacks, control chronic symptoms, or decrease the burden of disease. The only approved treatment for attacks is hemin, a preparation of heme derived from human blood. Hemin is used on demand for attacks and off-label as prophylactic therapy. It does not control chronic symptoms nor effectively and consistently prevent attacks and can cause complications.

“A once-monthly, subcutaneous injection with acceptable tolerability and the potential to prevent porphyria attacks could be transformational for patients,” said Jeff Miller, general manager of the givosiran program. “Based on our Phase 1 and Phase 2 open-label extension study results, we believe that givosiran could meaningfully reduce the frequency of attacks requiring hospitalizations and the need for hemin, with an encouraging tolerability profile.”

The late-stage study is a randomized, double-blind, placebo-controlled, global, multicenter study in more than 20 countries to evaluate the efficacy and safety of givosiran in approximately 75 patients with a documented diagnosis of AHPs.

The primary endpoint is the annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit or hemin administration at home over a 6-month treatment period. 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 will be eligible to continue an open-label extension study in which they will receive treatment with givosiran for up to 30 months.

The company reiterated its previous guidance that it expects to report interim analysis data in mid-2018. It said assuming positive results and pending U.S. Food and Drug Administration review of the program at the time of the interim analysis, it intends to file an application to market givosiran around the end 2018.

November 7, 2017

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