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: 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: 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 these patients are typically on hemin, so “ultimately it will be important to compare givosiran to heme therapy.” (Alnylam declined to comment on its future development plans.)
In March, Alnylam reported 10 serious side effects among givosiran patients, compared to four in those on placebo. The most alarming side effects were five cases of chronic kidney disease, or, damaged kidneys among givosiran patients and none on placebo—though four of the treated patients had a history of chronic kidney disease before the study. Alnylam now says that two of those cases were considered serious. Those patients were hospitalized for further analysis when a lab test showed that their levels of eGFR, a measure of kidney function, had dropped.
Additionally, seven patients on givosiran had a spike in liver enzymes—an indication of potential liver damage—and one of them had to stop treatment as a result.
“This is a concern,” says Wang, of UCSF, referring to the liver enzyme elevation. He noting that up to 13 percent of AHP patients already have evidence of liver inflammation.
These findings, however, never led to any serious problems, Alnylam reports today. The dip seen in eGFR in two patients was “small and transient” and resolved quickly, Greene says. And that single patient who dropped out was the only one to do so. All the others chose to stay on treatment for a 30-month extension study, he says.
Balwani adds that a tie between givosiran and kidney disease, in particular, wasn’t seen in earlier tests. What’s more, about 60 percent of AHP patients have underlying kidney and liver problems, and it may be worse for those who suffer more frequent recurrent attacks. She believes the safety findings are more indicative of the unknowns of AHP and how it impacts patients, rather than givosiran. The extension study could answer critical questions.
“I do think it’s something we need to explore a little more and see the long term effects,” she says, “but when I look at the severity of the disorder, the drug, and my own personal experience [treating AHP patients], I have no reservations using it.”
Wang says based on the data, he would put patients with frequent attacks—more than four per year—on givosiran, as well as those for whom he’d normally recommend heme therapy. But he wonders whether treated patients can have “break through attacks,” or whether the drug would work fast enough to stop an attack when it starts.
As a treatment for an ultra-rare disease, givosiran’s price will likely be high. But Alnylam estimates that each AHP patient already costs the healthcare system between $480,000 and $650,000 per year, Greene says. Though AHP can be easily diagnosed with a blood or genetic test, it is often mistaken for something else, like inflammatory bowel disease. Patients can go years before getting a proper diagnosis, get multiple unnecessary abdominal surgeries, be treated with the wrong drugs, and still suffer attacks. These issues lead to large medical bills, Greene says.
Assuming givosiran is approved, the challenge for Alnylam is twofold. It has to find these rare patients and ensure that they get properly diagnosed. The disease’s most common form, AIP, is estimated to affect just five to ten out of every 100,000 people. Greene believes at least 1,000 patients in the U.S. and Europe have “recurrent” attacks and 5,000 have less frequent, “sporadic” attacks.
The second challenge is that Alnylam will have to convince payers that the benefits are big enough—for a large enough segment of the AHP population—to cover what will likely be a high price tag for a life-long therapy (patisiran, for instance, has an average net price of $345,000 per patient, per year). The long-term extension study could go a long way in helping Alnylam’s case.
Alnylam launched patisiran, a chronic drug for a different rare disease, hereditary transthyretin amyloidosis, with ‘pay for performance’ deals in place with a handful of payers. It aims to do the same with givosiran.
“Payers don’t want misdiagnosed patients on the wrong drugs,” Greene says. “They want people the right drugs and see that they’re getting better.”