Alnylam Pharmaceuticals announced new findings from several clinical trials that continue to demonstrate the effectiveness of givosiran, the company’s investigational therapy for the treatment of acute hepatic porphyria (AHP).
The findings were presented at the 2019 International Congress on Porphyrins and Porphyrias (ICPP), held Sept. 8-11 in Milan, Italy.
“The new results that we and our collaborators presented this week at ICPP reinforce our belief in the potential of givosiran to reduce the disease burden associated with AHP and to improve quality of life for patients,” Akin Akinc, PhD, vice president and general manager of the givosiran program at Alnylam, said in a press release.
“Of note, patients in our open-label extension studies have continued to experience sustained reduction of both porphyria attacks and levels of toxic intermediates known to be causative of disease manifestations. Accordingly, we are hopeful that givosiran will continue to provide the potential for long term benefit for AHP patients,” Akinc added.
Also known as ALN-AS1, Givosiran is an investigational RNA-based therapy. RNA is a molecule generated from DNA that is used as the template for the production of proteins. Givosiran is designed to block the activity of the aminolevulinic acid synthase 1 (ALAS1) enzyme, preventing the accumulation of toxic molecules that cause AHP.
The therapy’s effectiveness at reducing the rates of porphyria attacks now is being tested in the ongoing, multicenter, randomized, double-blind, placebo-controlled Phase 3 trial (NCT03338816), called ENVISION.
The study enrolled a total of 94 AHP patients, including 89 with acute intermittent porphyria (AIP). Participants were randomly assigned to receive either givosiran at a dose of 2.5 mg/kg, or placebo, administered by a subcutaneous (under-the-skin) injection once a month.
Latest data from the trial showed that patients treated with givosiran had a 74% lower annual rate of porphyria attacks than those treated with placebo. In addition, givosiran lowered the levels of aminolevulinic acid (ALA), a key biomarker of AHP, in the patients’ urine by 92%. This was in agreement with previous interim findings.
After completing the six-month treatment period, all 93 eligible patients participating in ENVISION chose to continue treatment with givosiran for an additional 30 months in an open-label extension (OLE) study.
Updated findings from the OLE study showed the reduction in the annual rates of porphyria attacks, and in ALA urine levels, that were seen during ENVISION in patients receiving givosiran continued over the course of the extension study.
Moreover, participants who switched from placebo in ENVISION to givosiran during the OLE study also experienced a rapid and sustained reduction of both attack rates and ALA levels.
Givosiran’s safety profile in the extension study also was consistent with previous findings reported during the six-month ENVISION trial.
At the congress, Alnylam presented a series of patient-reported outcomes that had been gathered as part of several secondary and exploratory endpoints in ENVISION.
Post-hoc analyses revealed that givosiran significantly reduced daily worst pain. Exploratory analyses showed the reductions in patients’ perceived pain were accompanied by a drop in the use of opioids and non-opioid analgesics.
In addition, givosiran led to improvements in patients’ quality of life compared with placebo, with more than half of the participants (59%) reporting their health status had “very much improved” or “much improved” since the beginning of the study.
“AHP is a tremendously burdensome condition accompanied by disabling symptoms that have a profound impact on quality of life. To that end, the patient reported outcomes in response to givosiran treatment are highly encouraging, with patients reporting significantly less pain — a primary manifestation of this condition — less reliance on analgesic medication, improvements in their daily functioning, and ability to lead a more normal life,” said Laurent Gouya, MD, PhD, an investigator in ENVISION Phase 3.
“With patients reporting a positive treatment experience and data suggesting an improved quality of life based on exploratory endpoints, I am hopeful for the AHP patient community and look forward to the continued evaluation of givosiran,” added Gouya, also a researcher at Paris Diderot University and head of Centre Français des Porphyries.
Alnylam also presented updated findings from 16 people with AIP who participated in a previous randomized Phase 1 trial (NCT02452372) of givosiran. The participants were eligible to continue treatment in a Phase 1/2 (NCT02949830) open-label extension study for up to 30 months.
New findings showed that treatment with givosiran led to a sustained reduction in the mean annual rate of porphyria attacks, which decreased by more than 90% compared with the study’s baseline.
The company also presented additional results on givosiran’s drug interactions and new findings from the natural history study EXPLORE (NCT02240784), which is still recruiting participants. Alnylam also released real-world data analyses of disease burden and management. Details from all posters and oral presentations are available at Alnylam’s webpage.
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