Most investors awaiting the CF study results due mid-year will only really be interested in the primary outcome measure - change in FEV-1.
But I believe the Federal Task Force will primarily be interested in one of the secondary outcome measures - change in density of Pseudomonas aeruginosa in sputum.
From the 10-K -
"At a public workshop discussion in September 2012, the FDA agreed that the microbiological end-point is an appropriate primary end-point for NTM lung disease."
The various Phase II studies of Arikace in Cystic Fibrosis and Non-CF bronchiectasis all evidenced a statistically significant reduction of pseudomonas density.
Around the end of this year Insmed should also be able to supply the FDA with proof of reduction in bacterial density from an additional 250-plus Cystic Fibrosis patients treated with Arikace (four weeks on / four weeks off) for a minimum of twelve months (some for eighteen months), and an additional 100-plus NTM patients treated with Arikace continuously for a minimum of twelve weeks (some for twenty-four weeks).
Confirmation that the FDA views such a low-bar surrogate end-point of reduction in bacterial density as an appropriate PRIMARY end-point for predicting a clinical benefit from a therapy for a pulmonary bacterial infection is extremely encouraging. It offers the prospect of the FDA deeming the totality of Arikace data on reduction of bacterial density as adequate to support approval not only for CF and NTM, but also for the use for which it was originally designed.
This latest guidance from the CDC that there are currently only seven new drugs in development targeting multidrug-resistant gram-negative bacteria echoes a recent observation by Lewis -
"There's just a real need for anti-infectives generally - and any arrow in the quiver is going to be welcomed by the regulatory authorities, we believe, both here and in Europe."
Arikace was originally designed as a safer and more effective method of delivery of amikacin to a pulmonary infection caused by amikacin-susceptible bacteria.
Transave's original target was FDA approval of Arikace via the 505(b)(2) pathway, based primarily upon the data already available from the historical studies on injected amikacin. The FDA denied that pathway, one assumes due to the lack of visibility on the risks associated with prolonged inhalation of liposomes.
Had the FDA allowed the 505(b)(2) pathway, Arikace would have been approved for the treatment of pulmonary conditions for which injected amikacin is already approved - "serious infections due to susceptible strains of Gram-negative bacteria".
However, if the data Insmed is able to supply around the end of this year both on the safety aspect and on efficacy in reduction of bacterial density in sputum from a variety of studies is sufficiently compelling .....
Sec. 314.500 Scope.
This subpart applies to certain new drug products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy).
Sec. 314.510 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.
But coincidentally (?) Arikace HAS been handed the two toughest tests -
1. pseudomonas - protected against many antibiotics by virtue of having both a cytoplasmic membrane and an outer cell membrane, enjoying the further protection of a biofilm, which itself is protected by the accumulated gunk in the lungs of an individual with Cystic Fibrosis.
2. mycobacteria - protected against many antibiotics by virtue of having a waxy cell wall thicker than in many other bacteria, enjoying the further protection of the macrophages which shelter it instead of killing it.
If data from both studies does indeed evidence a substantial reduction in bacterial density, it will present a compelling argument for the approval of Arikace for the treatment of pneumonia caused by any amikacin-susceptible pathogen (including mycobacterium tuberculosis).
Lewis is not allowed to say anything which could be construed as promoting an unapproved use. But one suspects he would be loath to make any comment which could be construed as an attempt to put pressure on the FDA. We must look elsewhere for clues -
""The danger posed by the growing resistance to antibiotics should be ranked alongside terrorism on the list of threats to Britain, the government's chief medical officer has claimed.
Professor Dame Sally Davies described the issues as a "ticking time-bomb" and said it should be added to the National Risk Register.
The chief medical officer warned that routine operations such as hip replacements could become deadly in a couple of decades if the ability to fight infection is lost.""
"NIH currently supports clinical trials aimed at identifying ways to reduce the use of licensed antibacterials in both community and healthcare settings. These trials focus on areas of greatest antimicrobial drug exposure, such as pneumonia ..."
Insmed's liposomal delivery would allow far less time for resistant strains to develop.