The Insmed presentation notes that NTM lung infections are common in Asthma, COPD, CF and Bronchiectasis.
In other words the target population is individuals with a condition which has weakened their pulmonary defence mechanism - allowing a bacterial infection.
In most cases the bacteria are Gram-positive - routinely treated with beta-lactam antibiotics (penecillin, or evolutions thereof).
In some cases the bacteria are resistant to beta-lactam antibiotics -
1. Gram-positive bacteria which have evolved resistance (MRSA).
2. Gram-negative bacteria (Pseudomonas, Klebsiella).
In countries with TB epidemics the Mycobacterium is likely to be Mycobacterium Tuberculosis.
In countries where TB is under control the Mycobacterium is likely to be one of the other 125-plus species - two of which cause Leprosy, the others simply referred to as Non-Tuberculosis Mycobacteria.
Transave chose Pseudomonas infection in CF as the initial test of Arikace.
Then the NIAID intervened, and suggested a clinical trial of Arikace in the very small proportion of patients who have an NTM lung infection which has proved chronically resistant to the standard three-drug antibiotic regimen.
To put this in perspective, that NTM sub-population is so small that Insmed had trouble finding 100 patients from the 50,000 in the US diagnosed with NTM lung infection each year.
What did the NIAID expect the FDA to do with the data from this study (which was a Phase III study before the safety concerns subsequently addressed by the dog study emerged)?
To approve Arikace as a therapy for lung infections other than TB and Leprosy caused by Mycobacteria?
Proof that Arikace makes a difference when an NTM infection is chronically resistant to the standard antibiotic regimen is a long way from being proof that Arikace has a superior risk/benefit profile to whatever it takes to successfully treat the other 49,900 NTM infections in the US each year.
Part 2 ...
If the NTM study had offered a straight comparison between Arikace and the standard regimen it might have proved that Arikace is safer. But both arms were on the standard regimen, and the inhalation aspect was always going to result in more adverse effects in the Arikace arm.
Furthermore, one of the speakers at the FDA-sponsored workshop on the development of therapies for Non-CF Bronchiectasis said that he sees at least three times as much Pseudomonas infection as he does NTM infection.
What if Arikace DOES give the physician a faster and more patient-friendly treatment option for an NTM infection? The condition which weakened his patient's defences in the first place likely guarantees a pseudomonas infection before long.
I don't believe the NIAID was ever interested in the FDA using this data to support approval of a better NTM therapy.
But approval of a better amikacin therapy would be very much in the interests of the NIAID.
The proof from the EMA CF study that Arikace is at least as effective, and a far safer therapy for a Gram-negative infection than amikacin injection - together with proof from the NTM study that Arikace is at least as effective, and a far safer therapy for a Mycobacterial infection than amikacin injection - will, imo, enable the FDA to do what the NIAID has wanted all along - to approve Arikace as a therapy for amikacin-susceptible pulmonary infections.
Then a physician who needs to treat a patient with Asthma, COPD, CF, Bronchiectasis or AIDS for a serious pulmonary infection will have a broad-spectrum antibiotic which is both safe and highly effective against all bacteria - apart from those which have evolved amikacin-resistant strains.
And there will be far less opportunity for drug-resistant strains of bacteria to evolve once the inefficient use of injected antibiotics in the treatment of pulmonary infections has been phased out - the NIAID's real objective here.
From the May 13 2014 Progress report of the Transatlantic task force on urgent antimicrobial resistance -
[ There has been a steady decline in the number of new antibacterial drugs entering the market place over the last few decades on both sides of the Atlantic.
In the setting of continued development of AMR (antimicrobial resistance) and an insufficient pipeline to supply new options, the problem of AMR has become more pronounced.
Because of the time and expense required to bring a new drug from the point of discovery to the market place, we need to respond to the current situation and prepare for the future.
The goal of such efforts is to ensure that effective treatments are available to treat patients with serious infectious diseases, including patients with resistant organisms.
The recent emergence and spread of Carbapenem-Resistant Enterobacteriacieae (CRE), such as gram-negative bacteria carrying the New Delhi Metallo beta-lactamase (NDM) or Klebsiella Pneumonieae Carbapenemase (KPC) resistance genes, are particularly worrisome because carbapenems are one of the last line antibiotic drugs to treat MDR infections. ]
[ The rapid spread of carbapenem-resistant bacteria is a serious threat to healthcare and patient safety worldwide ...
Given that few novel antimicrobial agents are likely to become available for clinical use in the short- to medium-term, the risks that AMR poses to public health are not difficult to fathom.
Developing new drugs alone will not be sufficient to address the growing resistance problem. Microbes will always find a way to overcome the therapeutic effect of new drugs; therefore, the efficacy of existing drugs needs to be preserved.
Promoting the appropriate use of antimicrobial agents - use that maximises therapeutic effect while minimising the development of AMR - in both human and veterinary medicine is key to reducing selective pressure that leads to the development of resistance. ]
From Insmed's 10-K -
[ In 2009 and 2012, we entered into a cooperative research and development agreement (CRADA) with the National Institute of Allergy and Infectious Diseases (NIAID) to design and conduct our phase 2 study of ARIKAYCE in patients with NTM. NIAID has also agreed to provide biostatistical advisory input in connection with the phase 2 NTM study. If we decide not to continue with the commercialization of ARIKAYCE in NTM, NIAID will have the right to complete the clinical trial. Further NIAID may elect to pursue its rights to obtain license rights to certain inventions made under the CRADA. ]
[ NTM patients average 7.6 antibiotic courses per year (SDI Healthcare Database, July 2009). ]
If Insmed had trouble in finding 100 patients with an NTM infection chronically resistant to the standard antibiotic regimen - it seems a reasonable conclusion that the vast majority of the 50,000 US patients diagnosed with an NTM pulmonary infection each year are adequately served by the "antibiotic courses" mentioned in Insmed's 10-K.
And one suspects the National Institutes of Allergy and Infectious Diseases has far more important demands upon its resources than the 100 or so US NTM patients for whom a combination of old age and a serious underlying pulmonary condition results in an NTM infection which doesn't respond to the standard antibiotic regimen.
The Generating Antibiotic Incentives Now legislation was signed into law in July 2012 - in response to the potentially catastrophic threat to public health posed by infectious strains of bacteria which have evolved resistance to first-line antibiotics.
The NIAID has those drug-resistant infectious bugs as its top priority. NTM isn't even infectious.
Why is the NIAID so interested in Arikace?
What did the NIAID expect the FDA to do if the study had delivered the results everybody was expecting - evidence that Arikace reduced the bacterial load of an NTM patient?
1. The FDA's Most Wanted list -
[ (g) Qualified Infectious Disease Product- The term 'qualified infectious disease product' means an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections, including those caused by--
..... (1) an antibacterial or antifungal resistant pathogen, including novel or emerging infectious pathogens; or
..... (2) qualifying pathogens listed by the Secretary under subsection (f). ]
[ (f) Qualifying Pathogen-
..... (1) DEFINITION- In this section, the term 'qualifying pathogen' means a pathogen ... that has the potential to pose a serious threat to public health, such as--
.......... (A) resistant gram positive pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, and vancomycin-resistant enterococcus;
.......... (B) multi-drug resistant gram negative bacteria, including Acinetobacter, Klebsiella, Pseudomonas, and E. coli species;
.......... (C) multi-drug resistant tuberculosis; and
.......... (D) Clostridium difficile. ]
2. The NTM results -
[ The Company also intends to apply for Breakthrough Therapy Designation for ARIKAYCE in the United States based upon the culture conversion results. ARIKAYCE has already received Orphan Drug, Qualified Infectious Disease Product (QIDP) and Fast Track designations from the U.S. Food and Drug Administration (FDA) ]
3. Lewis last year -
[ ... in the anti-infective space generally, what we're seeing is a real engagement on the part of regulatory authorities where there is efficacy and safety to find a pathway forward to get these drugs onto the market - whether it's through breakthrough therapy, QIDP designation or indeed, just evaluation of final data outcomes, has been seen with other products as well. 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. ]