FDA raises questions about Mallinckrodt's HRS-1 drug before advisory hearing
Last August, UK drugmaker Mallinckrodt presented positive topline findings for its embattled terlipressin, illustrating the candidate met its primary endpoint in treating a life-threatening form of liver disease that causes kidney failure.
But the FDA continues to have questions about terlipressin’s safety and efficacy. After determining from the outset of the trial that the primary endpoint would only classify as a surrogate endpoint, the agency is questioning whether or not patients “trended toward clinical improvements” while on terlipressin. Regulators will convene in a hearing today and have released a document outlining their thinking ahead of the meeting.
In particular, the FDA highlighted “a significant safety concern” regarding a higher number of patients in the terlipressin arm who suffered respiratory failure than in the placebo arm. More than half of these events occurred within five days of administering treatment and 61 percent resulted in death, compared to 20 percent in the control.
The FDA did note that because of the medical complexities in most of the patients studied, it is difficult to determine to what extent, if any, the role terlipressin played in each of the individual cases. The agency is also concerned about an increased rate of sepsis and septic shock in the treatment arm.
Terlipressin has faced several challenges in its quest to win approval to treat hepatorenal syndrome type 1 in the US ever since it received a complete response letter all the way back in 2009. At the time, the FDA required Mallinckrodt to conduct an additional study to prove the efficacy and safety of terlipressin, but the follow-up again failed to reach statistical significance.
The third trial for terlipressin, which the FDA is evaluating in today’s hearing, did show a statistically significant reversal in HRS-1 compared to the placebo. Additionally, due to high mortality rates of HRS-1, patients may sometimes require renal replacement therapy, and those in the terlipressin arm showed higher rates of RRT-free survival despite terlipressin treatment in combination with RRT not showing an association with improved survival.
But because the primary endpoint of the study captured treatment effects on a laboratory parameter (serum creatinine), the agency considered it a surrogate endpoint. Whether or not the FDA approves terlipressin for use to treat HRS-1, in light of the trial meeting for that endpoint, is up for debate. It’s worth noting that terlipressin is approved for use in Europe under the brand name Glypressin.
HRS-1 is a life-threatening condition involving a rapid decline in kidney function in people with advanced liver disease. The ailment is most common in individuals with advanced cirrhosis and ascites, but can also occur in some with acute liver failure and other liver diseases. Half of those with HRS-1 die within two weeks of diagnosis and 80 percent within three months.