Some liver concerns, but FDA mostly favorable on Durata's dalbavancin
This article was originally published in Scrip
Other than some liver concerns, which weren't drastic, and the reports of adverse hemorrhage events, the FDA gave Durata Therapeutics' experimental antibiotic a positive review, declaring the drug has an overall favorable safety profile with similar rates of mortality and non-fatal side effects as its study comparators.
Shares of Chicago-based Durata bobbled up and down during the trading day on 27 March, falling 1.8%, or a loss of 26 cents, and then rising 5.3%, or 76 cents, before closing at $14.26, up 5 cents.
Durata is seeking approval of dalbavancin, a lipoglycopeptide antibacterial, which the company intends to market as Dalvance, as a treatment for patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive microorganisms, including methicillin resistant Staphylococcus aureus (MRSA).
The drug was granted a priority review, with a Prescription Drug User Fee Act action date of 26 May, and also won the FDA's qualified infectious disease product designation – a status that could garner the experimental medicine an additional five years of market exclusivity if approved (scripintelligence.com, 27 November 2013, 10 July 2012, 19 July 2012).
In briefing documents released ahead of the 31 March meeting of the FDA's Anti-Infective Drugs Advisory Committee, agency drug reviewers said dalbavancin met its primary endpoint objectives of early clinical response defined as cessation of spread of ABSSSI and the absence of fever at 48 to 72 hours after study drug initiation in the intent-to-treat population, with a noninferiority margin of 10%.
The new drug application (NDA) for dalbavancin, which was submitted this past September, was based on the entire data set from Durata's clinical development program, including positive results from two Phase III DISCOVER 1 (DUR001-301) and DISCOVER 2 (DUR001-302) trials, which were conducted under a special protocol assessment agreement with the FDA (scripintelligence.com, 28 September 2013).
The two identical double-blind, double-dummy, randomized Phase III trials compared the efficacy and safety of dalbavancin on day 1 and day 8 to vancomycin with an optional switch to Pfizer's oral antibiotic Zyvox (linezolid) in treating patients with ABSSSI known or suspected to be caused by Gram-positive bacteria.
The duration of treatment ranged from 10 to 14 days.
Both trials demonstrated dalbavancin was noninferior to the regimen of vancomycin/linezolid.
But the FDA's drug reviewers raised concerns about the possibility of dalbavancin-associated liver injury, especially in patients with underlying liver disease.
They said that finding was based on an observation of several cases of high-degree transaminase elevations in dalbavancin-treated patients, which was not observed in the comparator group.
Although none of the dalbavancin-treated patients with liver tests abnormalities met Hy's law criteria, the degree of elevation and imbalance in liver tests abnormalities between the drug and comparator arms suggest the possibility of drug-induced liver injury (DILI) associated with Durata's antibiotic.
The majority of dalbavancin-treated patients with abnormalities in liver tests developed hepatocellular pattern of DILI, although two developed mixed injury, if categorized based on the R ratio as defined by modified definitions of the Council for International Organizations of Medical Sciences. The R ratio is a ratio of the alanine transaminase (ALT) to the alkaline phosphatase (ALP) relative to their upper limits of normal.
One study participant with a history of hepatitis C virus, who received 1000mg and 500mg of dalbavancin on day 1 and day 8, had concomitant total bilirubin elevation, although the ALT elevation resolved and bilirubin and ALP levels improved by day 27.
Another safety finding WAS a higher rate of adverse events related to hemorrhages in dalbavancin-treated patients, including gastrointestinal and soft-tissue hemorrhages.
All events of hemorrhages were non-fatal, the FDA said.
"Whether this imbalance is due to chance or indeed associated with dalbavancin is uncertain," the drug reviewers said.
Sagient Research's BioMedTracker, an affiliate of Scrip, put the likelihood of dalbavancin gaining approval in ABSSSI at 87%, which is 6% above the average probability of US approval for the same indication based on the historical performance of medicines in the same development phase.
A subsidiary of Pfizer initially submitted the NDA for dalbavancin to the FDA, but the company later withdrew the application. Durata assumed the sponsorship of the drug in 2009 and initiated a new clinical program in 2011.