Results Demonstrate Potential for Givosiran as a Treatment for Acute Hepatic Porphyria

Givosiran, an investigational RNA interference (RNAi) therapy, significantly reduced urinary aminolevulinic acid (ALA), a disease biomarker reasonably likely to predict clinical benefit for the treatment of acute hepatic porphyria (AHP), according to a recent announcement from Alnylam Pharmaceuticals, Inc. Currently, there are no treatments to treat the disease’s ongoing symptoms.

“The AHPs are devastating diseases in which patients suffer from both debilitating neurovisceral attacks as well as chronic pain and fatigue,” Alnylam’s president of research and development Akshay Vaishnaw, MD, PhD said in the statement.

The rare, genetic disease has 4 subtypes and each is caused by a genetic defect leading to a lack of enzymes of the heme biosynthesis pathway in the liver. Symptoms can include abdominal pain, weakness, nausea, and fatigue, and can even resemble more common conditions like irritable bowel syndrome, appendicitis, fibromyalgia, or endometriosis. Because of this, AHP patients are often misdiagnosed—for an average of 15 years, according to Alnylam—and remain untreated for their true underlying disease.

Their announcement is based on an interim analysis report, which included 43 AHP patients who were involved for at least 3 months. The types of AHP in the study varied, as there were 41 patients with acute intermittent porphyria, 1 with variegate porphyria, and 1 with hereditary coproporphyria.

Patients were randomized to receive either 2.5 mg/kg of givosiran or placebo subcutaneously administered monthly over a 6-month treatment period, according to the report. The investigators were primarily concerned with the rate of porphyria attacks that required hospitalization, urgent health care visits, or hemin administration at home during that time.

The cutoff date was mid-August 2018. By that point, the investigators said there were no deaths, and serious adverse events were reported in 5 of the 23 givosiran patients and 2 out of 20 placebo patients. One of the givosiran patients was forced to withdraw from the study due to a liver problem, which was resolved.

Givosiran is designed to target aminolevulinic acid synthase 1 (ALAS1) to treat AHP and reduce urinary ALA levels. In the study, givosiran significantly lowered ALA, which is the biomarker the investigators described as “reasonably likely to predict clinical benefit.”

Alnylam next plans to discuss their data and the way forward with the US Food and Drug Administration (FDA) and plans to file a New Drug Application, Dr. Vaishnaw said.

“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 New Drug Application submission at or around year-end in support of an Accelerated Approval,” he added. “In the meantime, with enrollment in ENVISION completed ahead of schedule, we look forward to reporting topline results for the full study early next year. If clinical efficacy and acceptable safety are confirmed in the full study, we believe givosiran has the potential to transform the lives of patients living with an AHP.”

This study, as Dr. Vaishnaw mentioned, has enrolled 94 AHP patients. After 6 months of treatment, Alnylam believes they can report their findings on givosiran in early 2019. Secondary endpoints for the investigators include reducing the hallmark symptoms of AHP as well as the patients’ quality of life, they said.