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VIENNA -- Investigational givosiran met the primary endpoint of reduction in the annualized rate of composite porphyria attacks versus placebo in patients with acute hepatic porphyria (AHP), researchers said here.

In the interim analysis of the phase III ENVISION trial, patients treated with givosiran experienced a mean composite annualized rate of 3.2 attacks versus 12.5 attacks in patients on placebo (P<0.0001), for a mean reduction of 74%, said Manisha Balwani, MD, of the Mount Sinai School of Medicine in New York City, and colleagues.

"We saw a robust treatment effect," said Balwani at a press conference at the European Association for the Study of the Liver (EASL) annual meeting.

"Currently, there are no approved therapies aimed at preventing the painful, often incapacitating attacks, and chronic symptoms associated with acute hepatic porphyria," she added. "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."

Givosiran is a subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of AHP, according to Alnylam Pharmaceuticals of Cambridge, Massachusetts. The company released in March 2019 and, based on the findings, said it would complete its rolling submission of a New Drug Application (NDA) with the FDA, and file a Marketing Authorisation Application (MAA) with the European Medicines Agency, in mid-2019.

AHPs are rare genetic diseases due to enzyme deficiencies involved in heme biosynthesis, the authors explained.

"This was a really sick patient population," Balwani explained. "At baseline, these patients were having four attacks in the previous 6 months. Forty percent of the patients were receiving , and yet were continuing to have breakthrough attack. About 30% of the patients were taking opioids on a regular basis, and half the patients were experiencing chronic daily pain between attacks."

is a multicenter, randomized, double-blind, placebo-controlled trial in AHP patients evaluating the effect of givosiran (2.5 mg/kg given subcutaneously once-monthly) versus placebo on attack rate over 6 months. The estimated study completion date is September 2021.

Eligible patients (about 90% women) were ages ≥12 years (median age 38) with an AHP diagnosis, and a history of at least two attacks in the 6 months prior to enrollment.

Patients could not be on hemin prophylaxis during the study. The on-going trial's primary endpoint is annualized rate of attacks requiring hospitalization, urgent care, or home IV hemin. Secondary endpoints include safety/tolerability, ALA and PBG levels, symptoms, and quality of life (QoL) measures.

While study enrollment has been completed with 94 patients in 18 countries and at 36 sites, the interim analysis by Balwani's group of safety and urinary ALA, a biomarker likely to predict clinical benefit, was conducted in 43 patients. Of those, 41 had acute intermittent porphyria, one had variegate porphyria, and one had hereditary coproporphyria; 23 were randomized to givosiran and 20 to placebo. They had to be on-study for at least 3 months.

Balwani reported that half of the patients treated with givosiran had no porphyria attacks during the study time frame compared with 16.3% of patients on placebo who were attack-free.

In addition, treatment with givosiran was associated with a 92% reduction in ALAS1 and and 89% reduction in ALAS1 and prophobilinogen (PBG), which are believed to be the causative agents that trigger porphyria attacks.

"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," she stated.

However, patients with prior opioid use did not experience statistically significantly better outcomes with givosiran, she pointed out.

Balwani also said that adverse events did occur more often in patients receiving givosiran, including patients who had elevated liver enzymes. But six of seven patients with elevated enzymes three times the upper limit of normal were still able to continue on the agent. Five patients experienced chronic kidney disease (CKD), but four of them had been diagnosed with CKD before entering the trial.

Balwani added that none of the patients discontinued treatment due to renal adverse effects, no patients became symptomatic, and 93 of 94 eligible patients opted to continue on givosiran in an ongoing 30-month open-label extension of the trial.

Overall patients reported an improved QoL on givosiran "Greater improvements in the overall health status were reported by the givosiran-treated patients compared to the placebo-treated patients as measured by the Patients Global Impression of Change," Balwani said. "The givosiran-treated patients also reported a greater ability to handle the activities of daily living and had, overall, a higher treatment satisfaction compared to the placebo group at the 6-month time point."

EASL press conference moderator Markus Cornberg, MD, of Hannover Medical School in Germany, told 乌鸦传媒 that "I have some patients with porphyria that always come back with these attacks and, if you give hemin, you still get rebounds and more rebounds," noting that patients can build resistance to hemin.

"To be able to prevent this for some of these patients -- maybe not for all of them -- would be helpful these people really suffer from this disease. They are desperate for something. They have pain and sometimes they have neurological symptoms," he said. "I would use [givosiran] right away if it were available. Even with some elevation of liver enzymes, the risk benefit would still be in favor of using this in some of my patients."

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