Alnylam’s RNAi Therapy for Acute Hepatic Porphyria Positive in Phase III

Liver illustration with doctor's hand below it

Cambridge, Mass.-based Alnylam Pharmaceuticals indicated that its ENVISION Phase III trial of givosiran was positive for acute hepatic porphyria (AHP). The company presented the clinical data at the European Association for the Study of the Liver (EASL) International Liver Congress in Vienna, Austria over the weekend.

AHP is a family of rare, genetic diseases. They are characterized by potentially life-threatening attacks and often chronic debilitating symptoms. Common symptoms of AHP are severe, diffuse abdominal pain, weakness, nausea and fatigue.

The disease has four subtypes, each caused by a genetic defect that causes deficiency in one of the enzymes of the heme biosynthesis pathway in the liver. The four subtypes are acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD-deficiency porphyria (ADP). They all cause the accumulation of neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG).

Givosiran targets aminolevulinic acid synthase 1 (ALAS1). Alnylam’s technology silences the RNA coding for the protein that causes the disease.

Data from the ENVISION trial involved 94 patients. The results indicate givosiran reduced the odds of attacks by 74% compared to placebo. The primary endpoint was annualized composite attacks in patients relative to placebo during a six-month double-blind period. Givosiran hit statistically significant positive results for five of nine secondary endpoints.

The efficacy data indeed sounds encouraging. The company, however, also calls the therapy’s safety profile “encouraging,” which might be a little bit more difficult to sell to regulators.

Adverse events (AEs) were reported in 89.6% of patients receiving the drug and 80.4% receiving the placebo. Serious adverse events (SAEs) were seen in 20.8% of patients receiving givosiran compared to 8.7% of patients receiving placebo. Despite that, 93 out of 94 patients (99%) enrolled in the open-label extension (OLE) period of the trial.

As a result, the company plans to complete its rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) and file a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the middle of this year.

“Given the high unmet need in this disease setting, we are very pleased for the patients and families living with acute hepatic porphyria for whom these results signal hope for a potential new therapeutic option,” stated Akshay Vaishnaw, president of R&D at Alnylam. “Givosiran substantially reduced the frequency of attacks, providing strong support for a treatment benefit, with a consistent effect across all components of the primary endpoint and all subgroups analyzed.”

He went on to note, “In this disease with high burden and associated comorbidities, we’re encouraged by the overall tolerability profile. We firmly believe givosiran has the potential to be a transformative medicine for patients living with AHP.”

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The SAEs were two cases of chronic kidney disease (CKD) and one case each of asthma, device-related infection, gastroenteritis, hypoglycemia, abnormal liver function test, major depression, pain management, and pyrexia.

Three of the SAEs in patients receiving givosiran were related to the drug, pyrexia, abnormal liver function test and CKD. The two cases of CKD were cited as serious because of elective hospitalization for diagnostic evaluation.

The most common adverse events were nausea (27% on givosiran compared to 11% on placebo), and reactions at the injection site (16.7% on the drug and 0% on placebo). One patient receiving the drug quit treatment because of an increase in alanine aminotransferase (ALT) level greater than eight times the upper normal limits.

“Currently, there are no approved therapies aimed at preventing the painful, often incapacitating attacks and chronic symptoms associated with AHP,” stated Manisha Balwani, associate professor of the Department of Genetics and Genomic Sciences and Department of Medicine at the Icahn School of Medicine at Mount Sinai. She is also the principal investigator of the ENVISION trial.

Balwani continued, “The results from ENVISION are promising and demonstrate a strong treatment effect for givosiran, with reduction of attacks and improvement in patient-reported measures of overall health status and quality of life. Thus, givosiran represents a novel and targeted treatment approach that has the potential to make a significant impact on the lives of patients who are struggling with the disabling symptoms of this disease.”

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