Despite safety, efficacy concerns, FDA AdCom narrowly recommends Mallinckrodt drug
A day after the FDA detailed significant concerns about just how effective or safe an experimental Mallinckrodt liver drug was, an advisory committee decided by a single vote to recommend it for approval.
“I voted yes to approve, but I also wrote in, ‘but barely,’” Paul Ridker, a cardiologist at Brigham and Women’s Hospital and one of the panelists, said at the meeting, according to FierceBiotech. The vote was 8-7.
The FDA does not have to follow the committee’s recommendation, but generally does.
The debate centered in part on what Mallinckrodt’s primary endpoint meant. The drug, known as terlipressin, had been tested for hepatorenal syndrome type 1 (HRS-1), a rapidly progressing disease where patients with cirrhosis can develop life-threatening kidney failure within days. The only current treatment is liver transplant. Between 40% and 70% of patients who don’t receive a transplant will die within a month.
Terlipressin, through, did not improve overall survival; more patients, in fact, died in the drug arm than in the treatment arm. Rather, Mallinckrodt measured “verified HRS reversal” — a measure that looks at whether a biological marker of kidney function, serum creatinine levels, declined to less than 1.5 mg/dl by day 14. For 29% of patients on the drug-arm it did, compared to 16% on the placebo arm.
The FDA agreed to that primary endpoint, acknowledging that it was difficult to design trials for HRS and that some evidence suggested creatine reversal leads to better outcomes post-transplant. But they said Mallinckrodt would also need to show that patients also saw their clinical outcomes trended in the right direction. The agency asked the panel to determine if Mallinckrodt showed that.
On top of the efficacy debates, there were also significant questions about safety. In the Phase III trial, the FDA noted, 9% of drug-arm patients died of respiratory failure, compared with 1% of placebo. More drug-arm patients also died of sepsis and septic shock than in the control group.
The three main clinical outcomes Mallinckrodt measured were length of ICU visit, post-transplant survival and length of time without resorting to renal replacement therapy. The advisors agreed that the company didn’t show improvement on the first two, but did on the latter. For 8 of the 15 members, that was enough to warrant approval in a disease that leaves patients with few other options.
Watching the meeting, though, SVB Leerink’s Ami Fadia saw at least one hurdle before approval. A majority said the drug was worth it, but like the FDA, they still had questions on how Mallinckrodt would manage the safety concerns, including that increased risk of death.
“It appears that for Mallinckrodt to obtain regulatory and/or commercial success with terlipressin this will require a much more thorough risk mitigation plan, significant patient and physician education and potentially some sort of post-approval requirement,” Fadia wrote in a note to investors.
The PDUFA date is September 12. The drug was already rejected once, in 2009.