The “attacks,” as they’re known, are debilitating and even possibly fatal. A patient with the ultra-rare genetic disease acute hepatic porphyria (AHP) is struck with excruciating abdominal pain and rushes to a doctor’s office or hospital for some type of pain relief—even a surgery—to feel better. And then another attack could come, and another, driving some patients into isolation or robbing them of their ability to work.
For the first time, a drug that might lower the frequency of these attacks is nearing FDA approval. And its developer, Alnylam Pharmaceuticals (NASDAQ: [[ticker:ALNY]]), is setting out at a major medical meeting this weekend to allay concerns about the risks of the treatment, known as givosiran, which include some potentially worrisome side effects seen in a few patients’ livers and kidneys. Alnylam president Barry Greene says the drug’s benefits outweigh the risks. “We’re giving these patients their lives back,” he says.
At the International Liver Congress in Vienna, Austria, Alnylam (NASDAQ: [[ticker:ALNY]]) is presenting the full results of a 94-patient Phase 3 study, Envision, which could lead to the first medicine specifically approved for AHP. Alnylam has already submitted parts of its approval applications in the U.S. and Europe, and intends to wrap them up by mid-2019. If approved, givosiran would be just the second marketed drug ever that harnesses RNA interference, a gene-silencing technique cells use to stop a protein from being produced. Alnylam’s patisiran (Onpattro), approved last year, is the only other RNAi drug.
AHP occurs when a genetic mutation causes a buildup of two toxic enzymes—5-aminolevulinic acid (ALA) and porphobilinogen deaminase (PBG)—that the body normally processes and excretes. The disease most commonly effects women of childbearing age and has several forms depending on its severity and frequency of attacks—which can occur every few days, monthly, or less.
When attacks occur, patients can be hospitalized anywhere from a few days to weeks, Greene says. They get painkillers—often opioids—for relief, and can prophylactically get an engineered form of an iron-carrying molecule called hemin, what’s known as heme therapy, to try to suppress the toxins. Givosiran works differently: it is meant to stop those toxins from building up in the first place. If approved, patients would take givosiran for life.
Without disclosing details, Alnylam said in March that the Envision study succeeded because givosiran, given once monthly for six months, reduced the expected rate of attacks per year in patients with acute “intermittent” porphyria (AIP), the most common form of the disease (attacks were defined as bouts of pain that required trips to the hospital or doctor’s office, or heme therapy). The company enrolled patients who had had at median of four attacks in the six months before the study. More than half of them had chronic symptoms, like nerve pain, between those attacks.
But Alnylam also reported in March that the drug didn’t hit all of its secondary goals. And some givosiran patients had chronic kidney disease, and others had spikes in certain liver enzymes, indicative of possible organ damage.
Now Alnylam has the specifics, which are being presented at a plenary session tomorrow at the conference in Vienna.
The details: The 46 givosiran patients with AIP in the trial were on track for an expected average 3.2 porphyria attacks per year after six months, compared to an expected average 12.5 attacks/year for the 43 placebo patients with AIP—a 74 percent difference. The givosiran patients were also on pace for a median 1 attack per year, compared to 10.7 for placebo patients, a 90 percent difference. Half (23) of the givosiran patients were attack-free after six months, compared to just seven placebo patients.
“I wasn’t expecting this degree of improvement,” says Manisha Balwani, an associate genetics professor at the Icahn School of Medicine at Mount Sinai in New York, and the study’s lead investigator.
Balwani added that patients’ chronic symptoms also improved, as did scores on a survey asking patients questions about their quality of life while on treatment. They reported an increased ability to go to work, for instance, or travel or attend social events. “That’s really clinically meaningful to these patients,” she says.
The drug also led to statistically significant average decreases in attacks for patients with any form of AHP. It cut average levels of the disease proteins ALA and PBG, and decreased the number of days when patients needed hemin—all secondary study goals and markers of disease severity. Alnylam missed on other secondary goals, like measures of pain and fatigue, though Greene expects better results over time, citing positive signs the company saw in a longer, earlier open-label study. “The longer you’re on the drug it appears the more benefit you accrue,” he says.
Bruce Wang, a hepatologist at UCSF Medical Center in San Francisco who wasn’t involved with the study, says “the overall results are impressive,” particularly given how difficult it can be to manage AHP patients with such frequent attacks. But Wang adds that
