Long-term Givlaari Treatment Greatly Lowers AIP Attacks, Study Shows

People with acute intermittent porphyria (AIP) who were treated with Alnylam Pharmaceuticals’ RNA-based therapy Givlaari (givosiran) experienced a rapid and lasting reduction in porphyria attacks — and most remained attack-free for the first six months of the ENVISION trial’s extension study.

In addition, no new adverse events were reported during one year of treatment.

The data was shared by Eliane Sardh, MD, PhD, an endocrinologist at the Porphyria Centre Sweden at the Centre for Inherited Metabolic Diseases, Karolinska Institutet, and the study’s lead investigator, in a presentation titled “Twelve-month Interim Analysis of Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic for AHP, in the ENVISION Open Label Extension.” The recent webinar was hosted by Alnylam.

Givlaari is an RNA-interference therapy, or RNAi. It is designed to degrade the messenger RNA — the genetic blueprints for making proteins — generated from the ALAS1 gene. This gene codes for the aminolevulinic acid synthase 1 (ALAS1) enzyme, which is overactive in acute hepatic porphyria (AHP) patients.

The therapy works to reduce the toxic levels of compounds called aminolevulinic acid (ALA) and porphobilinogen (PBG) inside cells.

The ENVISION Phase 3 trial (NCT03338816) enrolled 94 patients (mean age 38.8), 89 of whom had AIP — the most common form of AHP in most countries. Other AHP forms included two cases of variegate porphyria (VP) and one of hereditary coproporphyria (HCP). Two of the patients had AHP without an identified mutation.

The participants were randomly assigned to receive treatment with Givlaari at 2.5 mg/kg, or a placebo, both delivered as subcutaneous (under-the-skin) injections once a month, for six months.

Previous data at six months of treatment had shown that those taking Givlaari had a 74% reduction in porphyria attacks, and sustained decreases in toxic products, compared with participants on a placebo.

These results supported regulatory approvals of Givlaari in the U.S. and the European Union.

After completing the trial, all but one of the patients started or continued treatment with Givlaari in the one-year extension study. Some participants started on a lower 1.25 mg/kg dose, but all are transitioning to the higher 2.2 mg/kg dose, due to evidence of greater efficacy, Alnylam said.

The interim analysis showed that participants treated with Givlaari for one year had a median of zero in the annualized rate of porphyria attacks (AAR).

Patients who switched from the placebo to the therapy experienced a mean reduction in AAR of 76%, similar to the benefit seen in the main part of the trial.

In addition, 61.7% of the individuals receiving Givlaari had no porphyria attacks over six months, an increase of 11.7% over the placebo-controlled phase. In the group previously on the placebo, Givlaari increased the percentage of patients with zero attacks from 17.4% to 42.2%.

Long-term treatment with Givlaari led to sustained reductions in the participants’ levels of ALS and PBG. Continued use of Givlaari also led to a marked drop in the number of days of hemin treatment, with 70% of patients requiring no further therapy. All participants switching from the placebo were able to stop hemin use.

During the extension study, treatment also led to a drop in the patients’ reports of daily worst pain. This was accompanied by improvements in quality of life and ability to function.

No new adverse events were reported during the extension study. The most common side effects, reported in at least 10% of patients, included injection-site reactions, nausea, and fatigue. Serious adverse events included chronic kidney disease (two patients during the main phase), and urinary tract infection in two participants during the extension period. A total of 16 patients reported adverse events in the liver and 10 in the kidneys throughout the trial.

Most side effects were mild or moderate. No deaths and no treatment discontinuations due to adverse events were reported.

“The improvements in daily worst pain and quality of life exploratory endpoints [goals], and consistent safety profile, help us better understand the potential of GIVLAARI to provide ongoing and long-term benefit for patients living with AHP,” Akin Akinc, PhD, general manager of givosiran at Alnylam, said in a press release.

“Less than eight months after GIVLAARI’s first regulatory approval based on the ENVISION Phase 3 study results, we are pleased to share encouraging new data from our OLE program that we believe continue to support the sustained therapeutic benefit of this RNAi therapeutic,” Akinc added. “We remain committed to bringing GIVLAARI to patients with AHP around the world as we pursue marketing authorizations in additional countries and territories.”

Paired with the results in the parent ENVISION trial, the new findings “provide further evidence that treatment with givosiran [Givlaari] has the potential to significantly reduce the high burden of disease for patients and families affected by AHP,” Sardh said.