November 26, 2012 9:27 pm
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
Theravance (NASDAQ:THRX) faces an uphill battle in convincing the US Food and Drug Administration (FDA) to approve its antibiotic Vibativ (telavancin) for nosocomial pneumonia (NP), infectious disease experts told BioPharm Insight.
An FDA advisory committee will discuss the company’s marketing application on 29 November.
NP, otherwise known as hospital-acquired pneumonia (HAP), is caught by a patient in hospital at least 48 hours after admission. It is a lung infection usually caused by bacteria. The Centers for Disease Control and Prevention has estimated that HAP accounts for nearly 15% of all hospital-acquired infections and is associated with the highest mortality rates (20% to 33%).
Theravance did not return a request for comment.
Vibativ’s approval attempts, which began in 2008, have been fraught with setbacks. Theravance’s initial NP application hinged on combined data from two Phase III human-based trials. The FDA determined in April 2009, however, that a reduction in patient deaths (from all causes, not just pneumonia) was the most important way of measuring an antibiotic’s success in NP.
Deep uncertainty, thus, hangs over whether the FDA advisory panel will advise the agency to approve the antibiotic based on the submitted Phase III data, which measured clinical cure rather than reduction in death, the experts agreed.
In November 2009, FDA requested additional data, and Theravance’s reply was found to be inadequate. While additional data on the number of patient deaths was provided, the FDA ruled since the data was combined from two studies, it would equate to only one adequate and well-controlled trial and would not constitute substantial evidence of the drug’s effectiveness. The FDA wanted to see evidence from what it considered to be two distinct Phase III trials.
Theravance has likely been working with the FDA to consider data on patient deaths that demonstrates Vibativ is not inferior compared to vancomycin, said Dr David Shlaes, founder, Anti-Infectives Consulting, Connecticut.
Indeed, in December 2010, BioPharm Inisght, citing a person familiar, reported that upon the FDA’s request, Theravance went back and collected additional data including death from all causes for up to three or six months; it initially collected 30-day data. Theravance’s re-analysis showed the results were within an acceptable noninferiority range as well as demonstrated similar death rates between the two trials, the person said at the time.
This issue aside, the person said, it is uncertain whether Vibativ will pass the kidney toxicity side-effect hurdle it also faces. Other experts agreed with this sentiment. Vibativ is approved for skin infections in the US and for NP in Europe.
Still caught in regulatory flux
To add to the confusion, in November 2011, the FDA held a meeting to discuss revising clinical trial guidelines for NP. While an outcome remains inconclusive, there was a consensus that death reduction has to be the accepted endpoint, it was reported at the time.
On 24 September 2012, the agency announced the creation of an internal Antibacterial Drug Development Task Force to assist in revising guidance related to antibacterial drug development. It also partnered with the Brookings Institution in Washington, DC, to offer input on how it can reboot its approach, said Dr Brad Spelberg, assistant professor of medicine, David Geffen School of Medicine at University of California, Los Angeles.
While the agency has done a 180-degree turn from last year in being more open to alternative clinical trial designs, whether it will accept clinical cure versus death reduction as a measure of effectiveness is still undecided, Spelberg said.
However, a Phase III trial investigator said he is optimistic about the FDA rescinding the death reduction requirement. Draft FDA guidance on NP represented an older line of thought, and the agency has not issued a final version, he noted.
Under the FDA’s guidelines on death as an endpoint, Vibativ did not demonstrate superiority but in subgroups of Staphylococcus pneumonia patients including those with the superbug methicillin-resistant Staphylococcus aureus (MRSA) the drug did demonstrate superiority, the investigator added.
Yet, one anti-infectives consultant said, refiling with a new analysis of old data is “fraught with peril,” adding, “I’m not interested in seeing statistical manipulation.”
The FDA will still likely want to see data comparisons on death from all causes, the consultant noted. While many experts agree this endpoint is a mistake because of the mixed patient population involved in NP trials, “I don’t think FDA will change their mind on this,” as a clinical outcomes endpoint on its own “is not good enough either,” the consultant added.
A second consultant was surprised at Theravance trying a comeback and questioned its chances for winning final approval. It is unlikely that providing some extra data on patient deaths from its existing studies to the FDA would be sufficient, the consultant added.
While politically, the FDA does not want to be publicly perceived as always blocking new anti-infective drug progress, this drug “is not progress,” noted the first consultant.
Kidney toxicity under watch
Commitments to monitor Vibativ after approval once it is on the market are unlikely to convince the agency to approve the drug, Spelberg said. It may be possible to convince the agency of its merit, he added, but Vibativ’s risk-to-benefit “does not look favorable.”
There is not a pressing need to approve another MRSA drug, Spelberg said. The agency could point to the known potential of kidney injury and lower platelet count to choose to not allow Vibativ.
Postmarket commitments could support approval, the investigator said, but declined to specify what kind of commitments the company would have to make. He agreed kidney toxicity is an issue but countered a third drug beside vancomycin and Pfizer’s (NYSE:PFE) Zyvox (linezolid) is needed.
Vibativ’s outcome will depend on whether the company can show the toxicity profile is acceptable, the second consultant and a third stressed. More case reports are coming out about the drug’s kidney toxicity, which is a problem, the second consultant said.
If approved, the drug would have similar warnings, restrictions and monitoring requirements as it does in the FDA-approved skin indication, the second consultant noted.
Yet, the first consultant said, toxicity may be less concerning in serious infections such as NP, noting that kidney- or neurotoxic drugs are given if a life is at stake. Efficacy is much more important in NP, and on that, the consultant is unconvinced.
Meanwhile, the consensus among experts interviewed by BioPharm Insight was that even if approved for NP in the US, Vibativ is not expected to have meaningful market traction, as the drug has not been proven superior to vancomycin and Zyvox. Also, it adds a kidney toxicity risk and will be more expensive.
Theravance’s current market cap is USD 2.1bn.
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