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While the road to a diagnosis of acute hepatic porphyria can be long, preventive treatment now available to patients has been "transformative."

Acute attacks of the inherited disorder occur due to overproduction of neurotoxic porphyrin molecules in the liver during heme production. Then, symptoms strike suddenly, characterized by severe pain that responds poorly to analgesics, along with a constellation of accompanying nausea, vomiting, constipation, tachycardia, seizures, peripheral neuropathy, and severe muscle weakness that can even lead to respiratory failure or death.

Initial management of such attacks calls for giving fluids, antiemetics, analgesics, and antiseizure medication for the some 20% of patients who have seizures, as a review in the pointed out. However, a number of anticonvulsants are considered unsafe in acute porphyria, and patients' medication lists should also be reviewed for oral contraceptives, progestins, spironolactone, carisoprodol, and others that are likewise risky.

The only specific treatment that can speed up resolution of acute attacks is intravenous hemin (Panhematin) treatment in the hospital, which typically takes effect within 3 to 4 days.

Hemin has been sometimes used off-label as monthly prophylaxis, but long-term use leads to iron accumulation that .

So when FDA approved the RNA interference drug givosiran as the first-ever treatment for acute hepatic porphyria in late 2019, there was excitement in the field.

"Prior to today's approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence, in the agency's of the approval.

Givosiran was a "much needed therapeutic option for patients," said Manisha Balwani, MD, interim chief of medical genetics and genomics at the Icahn School of Medicine at Mount Sinai in New York City, who was a lead investigator on both its phase II and phase III trials.

"In my experience as a physician treating patients with this disorder since 2007 and as investigator on all of these early-stage studies, I've seen a remarkable transformation," she told 名媛直播.

Some of her patients started the drug in the phase II trial in 2016 and since then have gone "from being completely unsure of being able to predict what the next week would look like, they can actually make life plans and not be constantly afraid of being in acute pain."

Even with prophylactic hemin for patients with recurrent attacks, "many of them would still be hospitalized. They were unable to hold jobs. My patients couldn't make it to class if they were in college," Balwani recounted. "Getting this drug [givosiran] and actually not having attacks really transformed their lives and their ability to hold a job ... or graduate or get married. All of these are actual personal stories from my own patients."

The drug inhibits delta-aminolevulinic acid synthase 1 (ALAS1), the upregulation of which leads to accumulation of delta-aminolevulinic acid and porphobilinogen that are behind both acute attacks and the chronic symptoms of acute hepatic porphyria that often occur as well.

The drug's approval was based on the in which 94 patients with acute hepatic porphyria were randomized to placebo or givosiran (2.5 mg/kg subcutaneously once a month). Women made up 90% of the study population; median age was 38 (minimum 12 years), and all had at least two attacks in the 6 months prior to enrollment. While 40% had been on hemin prophylaxis prior to enrollment, its use was not allowed during the trial period.

Primary endpoint results showed a mean annualized attack rate of 3.2 on givosiran versus 12.5 in the placebo group -- a 74% relative reduction (P<0.001). Secondary results also showed a reduction of urinary markers, fewer days of hemin use, and lower daily pain scores.

Other chronic symptoms that were reported by some 65% of acute hepatic porphyria patients with recurrent attacks in the prospective were reduced on givosiran as well, Balwani said.

She noted that some of her patients have decreased opioid usage and stopped needing drugs they had been taking for neuropathy and other symptoms.

"With any rare disease, we obviously need a lot more time to monitor patients," Balwani said. "One of the ways we're going to do it is with a rare disease registry developed by Alnylam Pharma," which will collect long-term data both for givosiran-treated patients and others.

With the relative newness of RNA interference therapy, it's good to be vigilant for adverse events, she pointed out. Givosiran's pivotal clinical trial showed more frequent elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions compared with placebo.

Homocysteine levels have also more recently been shown to be elevated in some treated patients, and a label change is coming in that regard, although this is of unclear clinical implication, Balwani noted. The disease registry may help answer that question, she added.

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