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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.