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RNA Interference Shows Promise for Rare but Devastating Acute Intermittent Porphyria

Article In Brief


The graph shows the effect of givosiran on annualized rates of porphyria attacks and hemin use. T bars indicate standard errors.

Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo.

Subcutaneous injection of an interfering RNA is safe in patients with acute intermittent porphyria (AIP) and, in a preliminary analysis, appears to reduce clinical symptoms of the disease, according to a study published in the February 7 edition of the New England Journal of Medicine.

The interfering RNA, called givosiran, partially blocks the activity of an enzyme in the heme pathway, preventing build-up of neurotoxic intermediates presumed to be responsible for the disease's symptoms. A phase 3 trial to confirm its efficacy is currently underway.

“We think this has the potential to change the lives of the most severely affected patients,” said lead study author Eliane Sardh, MD, PhD, a researcher at the department of molecular medicine and surgery at the Karolinska Institute in Stockholm, Sweden.

AIP is the most common of the acute hepatic porphyrias. It is caused by a mutation in hydroxymethylbilane synthase, the second step in the pathway that produces heme. Lack of heme induces upregulation of the first enzyme in the pathway, ALA synthase 1 (ALAS1), in an attempt to ramp up heme production. The futile overactivity of ALAS1 leads to a buildup of two upstream intermediates, including delta-aminolevulinic acid (ALA), which is believed to be the most important neurotoxic species.

Clinical symptoms of AIP include a motor-predominant neuropathy, arrhythmia, and intense abdominal pain, likely from bowel stasis. Although an estimated one in 1,700 people in Western countries carry the autosomal dominant mutation, its penetrance is less than 10 percent, and most symptomatic patients will have only a few attacks in their lifetime. A small proportion, however, mostly young women, suffer recurrent attacks that often lead to hospitalization and liver transplantation.

While every cell makes its own heme, liver and bone marrow are the most important producers—bone marrow for hemoglobin, and liver for the cytochrome-containing enzymes that metabolize and detoxify xenobiotic compounds in the diet.

Heme in the bone marrow depends on a different ALA synthase enzyme, called ALAS2, which is not implicated in AIP. “But the regulation of heme biosynthesis in the liver, and ALA production, is all about ALAS1 activity,” Dr. Sardh said, making it the obvious target for treating the disease.

The Mechanism Behind the Interfering RNA

The givosiran interfering RNA binds to the messenger RNA of ALAS1, triggering its degradation by the cellular defense machinery, reducing enzyme production and thus ALA build-up. Givosiran includes a carbohydrate that preferentially targets it to the liver, meaning it can be delivered subcutaneously and still reach its target. It is made by the biotech company Alnylam, which sponsored the trial after preclinical work indicated it was likely to be safe and could reduce ALA levels.

“When we started to work on this project, we had a lot of concerns about shutting down ALAS1,” Dr. Sardh said, but the animal data indicated that, even at very high doses, the treatment was unable to completely turn off heme production. And givosiran doesn't target ALAS2, so hemoglobin production was unaffected.

Study Design

The study comprised three sections: a single-blind, single-dose, dose-ranging study for patients without recent attacks; a single-blind study with two treatments one month apart for patients without recent attacks; and a placebo-controlled study with two or four treatments over 12 weeks for patients with recurrent attacks. A total of 40 patients were enrolled across the three sections.


“Patients develop terrible pain and weakness, their thinking can be altered, and they can be almost somnolent or comatose. So if one can develop a drug that reduces or even eliminates attacks, that is a huge deal. The numbers are small, but for those with this disease, it may be a major breakthrough.”—DR. P. JAMES DYCK

Injection-site reactions were more common among those receiving active treatment. Beyond that, adverse events were common but similar between active-treatment and placebo-treated patients, and largely similar to the common symptoms of porphyria, including nausea, diarrhea, and abdominal pain. Three serious adverse events—bacteremia, hallucinations, and fatal hemorrhagic pancreatitis—occurred in one patient with a history of significant medical problems, including quadriparesis from AIP, heart failure, and bacteremia.

Urinary levels of ALAS1 mRNA indicated a dose-dependent reduction in mRNA for the target enzyme, falling to levels close to that of unaffected individuals. Levels of ALA in the urine similarly fell after treatment by up to 90 percent of baseline and remained low for at least 40 days after a single treatment.

While the study was not powered to assess the effect of treatment on frequency of attacks, Dr. Sardh found that in the third section of the study, patients who received active treatment had a mean annualized attack rate of 7.2, compared with 16.7 for those receiving placebo.

In an interim analysis of data from the ongoing phase 3 study, the company has announced that active treatment is associated with a lowering of ALA levels, a secondary endpoint, but it has not yet presented data on the primary endpoint, attack rates requiring hospitalization.

While those results are still pending, Dr. Sardh is optimistic. “We believe that with this treatment, we have the possibility of preventing acute porphyria attacks,” she said. While the number of patients who may require the treatment is small, “it is a nightmare for them, as well as for the doctor and the health care system,” with frequent hospitalizations and no definitive treatment except for liver transplantation.

Expert Commentary

“Having an alternative to the current treatments will be extremely valuable,” said Michael Badminton, MBChB, PhD, honorary consultant and clinical lead at the National Acute Porphyria Service and School of Medicine at Cardiff University in Wales. Hemin, which is used to treat AIP, “is useful, but has limitations, including requiring an in-dwelling venous catheter, and it becomes less effective over time, Dr. Badminton said. “If this is successful it could be very meaningful for our patients.”

The number of patients who will be candidates for treatment is very small, he noted, with perhaps 30 in all of the United Kingdom. “But they are expensive to treat, since they are in and out of hospital so often. This could make their management more straightforward.”

P. James Dyck, MD, FAAN, professor of neurology at Mayo Clinic in Rochester, MN, agreed. “I think this is potentially a very important discovery for AIP treatment,” he said. The side-effect profile looks benign, given that most of the adverse events reported were likely attributable to the disease, not the treatment.

He cautioned, however, that while the objective decrease in urinary ALA levels was “very encouraging,” clinical results from the full phase 3 trial will be needed to determine the actual utility of treatment.

Dr. Dyck also noted that the low number of patients who are likely candidates—he has only a handful of recurrent AIP patients—may belie the value of the treatment. “For those patients who develop attacks of AIP, they are devastating. Patients develop terrible pain and weakness, their thinking can be altered, and they can be almost somnolent or comatose. So if one can develop a drug that reduces or even eliminates attacks, that is a huge deal. The numbers are small, but for those with this disease, it may be a major breakthrough.”

“We think this has the potential to change the lives of the most severely affected patients.”


Link Up for More Information

•. Sardh E, Harper P, Balwani M, et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria N Engl J Med 2019;380(6):549–558.
    •. “The Science Explained: RNA Interference,”