Rare Daily Staff

Alnylam Pharmaceuticals reported positive topline results from an interim analysis of a late-stage study of givosiran, an experimental RNAi therapeutic in development to treat acute hepatic porphyria (AHP), a family of rare, genetic disease that cause potentially life-threatening attacks.

The interim analysis of the data showed that givosiran was associated with a statistically significant reduction in urinary ALA levels in acute intermittent porphyria (AIP) patients, relative to placebo. AIP is a subtype of AHP. The Company plans to discuss these data and the regulatory path forward with the FDA and is hoping to file for approvals around year-end 2018 in support of a potential Accelerated Approval.

AHPs can cause abdominal pain, weakness, nausea, and fatigue. Because symptoms of AHPs can often resemble that of other more common conditions, 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.

AHPs result from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver. These defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), with ALA believed to be the primary neurotoxic intermediate responsible for causing both attacks and ongoing symptoms between attacks.

Givosiran is an experimental, subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1). The effect is to lower levels of ALA and PBG. By reducing accumulation of these intermediates, the company said 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.

The interim analysis had a data cut-off date of August 22, 2018 and included 43 patients with AHPs (41 patients of who had AIP), 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 percent (5/23) of givosiran patients and 10 percent (2/20) of placebo patients. One patient (4 percent) 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.

“The AHPs are devastating diseases in which patients suffer from both debilitating neurovisceral attacks as well as chronic pain and fatigue,” said Akshay Vaishnaw, president of research and development at Alnylam. “With these interim results in hand, we plan to meet with the FDA to discuss the results and the overall benefit-risk profile for a potential NDA submission at or around year-end in support of an Accelerated Approval.”

Givosiran has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration and PRIME designation by the European Medicines Agency. Givosiran has also been granted orphan drug designations in both the United States and European Union.

September 27, 2018
Photo: Akshay Vaishnaw, president of research and development at Alnylam

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