When an in individual resorts to posting blatant lies in this forum such as the following -
"Arikace ..... will not be approved for TB, severe forms of pneumonia or other exaggerated medical uses because those diseases are not even considered amikacin sensitive (former) and there are a lot of complicating factors that must be treated in conjunction with any infectious process (latter)."
- it's worth contemplating his motivation.
The blatant lie - that Arikace will not be approved for TB because TB is not considered amikacin-sensitive - is easily exposed with a search for the term "amikacin resistance tuberculosis". Here's an extract from the first article I found -
Discordant Resistance to Kanamycin and Amikacin in Drug-Resistant Mycobacterium tuberculosis
"Since the recognition of the remarkable activity of streptomycin (SM) against Mycobacterium tuberculosis in 1944 (2), aminoglycosides have been a major component of therapy for tuberculosis. Kanamycin (KM) and the closely related amikacin (AK) are commonly used for treatment of multidrug-resistant tuberculosis (MDR-TB) (11). Resistance to SM in M. tuberculosis is complex. High-level resistance is associated with point mutations involving the ribosomal protein S12 (rpsL gene) and the S12-interacting regions of the 16S rRNA gene (rrs), i.e., in the proximity of positions 530 and 915 (3, 7, 17, 19). In Escherichia coli, ribosomal binding of KM is affected by mutations in the position 1400 region of the rrs gene (15).
Several investigations over 3 decades have shown that no cross-resistance occurs between SM and either AK or KM (10, 13, 23), but a general cross-resistance between AK and KM has repeatedly been demonstrated (1, 9, 18, 20, 26).
In Estonia, the incidence of primary resistance to any first-line drug among isolates from new pulmonary TB patients is more than 30% (5) and 13% of all culture-verified TB cases involve MDR disease. A majority of MDR M. tuberculosis isolates are resistant not only to rifampin and isoniazid but also to SM and ethambutol (6). Due to the high prevalence of drug resistance, there is a pronounced need for alternative agents and the deoxystreptamine aminoglycosides KM and AK are generally used in MDR-TB treatment. Even though it is generally believed that there is full cross-resistance in M. tuberculosis between these two drugs, we found susceptibility to AK in 43 of 79 (54%) KM-resistant clinical MDR-TB isolates from Estonian patients routinely tested in 2001 (12). The testing of these isolates for susceptibility to KM (4 ?g/ml) and AK (1 ?g/ml) was performed with the radiometric Bactec system at the Estonian National Reference Laboratory."
The article is nearly ten years old now, and it's not a safe assumption that the degree of amikacin resistance at that time is the same today. But it may well be that the argument for using amikacin is even more compelling today than it was then, when one factors in the likelihood that amikacin has been used less frequently than the alternative aminoglycosides streptomycin and kanamycin.
Tobramycin was not mentioned for the simple reason that TB is (and this is the truth) not considered to be sensitive to that particular aminoglycoside. But as most longs know, tobramycin IS used to treat pseudomonas infection in Cystic Fibrosis. And it is the emergence of strains of pseudomonas which are not sensitive to tobramycin (following prolonged use of tobramycin as a monotherapy) which suggests that the ongoing EU CF Phase III study comparing Arikace against TOBI is very likely to deliver a favourable outcome for Insmed.
The most important implication in the long term of EMEA or FDA approval of Arikace will not be the approval of the specific antibiotic (amikacin) - it will be the approval of a liposomal inhalation therapy for a pulmonary bacterial infection.
The advantages of liposomal inhalation delivery -
... less antibiotic is needed to build an effective concentration in the lungs than is needed to overload the body's continuous elimination of unused antibiotic from the bloodstream for as long as it takes to build an effective concentration in the lungs
... less toxicity of other organs in the body occurs (the main reason injected aminoglycosides are currently used only as a last resort) = less side effects = better compliance = shorter time on the antibiotic and less antibiotic resistance
... the bacteria in the lungs are exposed to an effective concentration of the antibiotic far sooner (often the difference between life and death when an individual is critically ill)
- would all apply to any antibiotic currently used to treat pulmonary infection.
Regulatory approval of Arikace will pave the way for a portfolio of liposomal inhalation versions of drugs currently administered by tablet or injection to treat pulmonary disease - including a liposomal inhalation therapy for the two billion people worldwide estimated to be carrying latent TB infection.
Would anybody here care to hazard a guess as to what our shares are likely to be worth if we remain independent and own that therapy?
In the near term, clearly there is a compelling argument for using Arikace in situations where injected amikacin is currently used. But the argument for using Arikace in the treatment not only of MDR-TB but of any advanced pneumonia caused by a pathogen sensitive to amikacin is equally compelling.
It seems the closer we get to those two key reports scheduled for Q2, the more pathetic become the attempts of the amateur shysters here to sew doubt in the minds of investors concerning the implications of regulatory approval of Arikace.
- would you care to elaborate upon your opinion, while accounting for the following facts -
1. One of the leading pulmonologists who attended the FDA-sponsored workshop last year which addressed the development of therapies for Non-CF bronchiectasis observed that around a third of these patients are infected with pseudomonas, as opposed to only seven or eight percent with NTM.
2. Insmed quotes -
... an estimated 50,000 in the US with NTM, with no approved treatments available.
... more than 250,000 in the US with non-CF bronchiectasis in 2008, with no approved antibiotics - 30% of non-CF bronchiectasis patients are infected with pseudomonas.
3. NTM is thought not to be contagious, whereas pseudomonas is one of only four multi-drug resistant gram negative pathogens named in the GAIN legislation passed last year as having "the potential to pose a serious threat to public health".
Hint: How likely is it that the FDA will ignore its new directive to expedite the availability of drugs capable of controlling those named pathogens - by approving Arikace as a therapy for pseudomonas infection in the Cystic Fibrosis population only while allowing this potential "serious threat to public health" to continue to develop multi-drug resistant strains in a Non-CF bronchiectasis population which not only is over eight times the size but also does not currently have access to a single approved inhaled antibiotic?
Bwd recently drew our attention to the following Insmed patent application -
LIPID-BASED COMPOSITIONS OF ANTIINFECTIVES FOR TREATING PULMONARY INFECTIONS AND METHODS OF USE THEREOF
United States Patent Application 20130028960
Filing Date: 06/19/2012
46. An aerosol composition for the treatment of a pulmonary infection comprising free aminoglycoside in an amount effective to provide immediate bactericidal activity against the pulmonary infection and liposomal encapsulated aminoglycoside in an amount effective to provide sustained bactericidal activity against the pulmonary infection, wherein the lipid component of the liposome consists of electrically neutral lipids.
47. The aerosol composition of claim 46, wherein the aminoglycoside is amikacin.
48. The aerosol composition of claim 46, wherein the wherein the aminoglycoside is gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin or paromomycin.
49. The aerosol composition of claim 46, wherein the liposomal encapsulated aminoglycoside comprises a mixture of unilamellar vesicles and multilamellar vesicles.
66. A method for providing prophylaxis against a pulmonary infection in a patient comprising administering the aerosolized pharmaceutical composition of claim 46 to the lungs of the patient.
67. The method of claim 66, wherein the aminoglycoside is amikacin.
68. The method of claim 66, wherein the aminoglycoside is gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin or paromomycin.
69. The method of claim 66, wherein the electrically neutral lipids comprise a phosphatidylcholine and a sterol.
70. The method of claim 66, wherein the electrically neutral lipids comprise a phosphatidylcholine and cholesterol.
71. The method of claim 66, wherein the pulmonary infection is Pseudomonas aeruginosa.
72. The method of claim 66, wherein the pulmonary infection is a mycobacterial infection.
73. The method of claim 66, wherein the pulmonary infection is a Burkholderia infection.
74. The method of claim 72, wherein the mycobacterial infection is Mycobacterium leprae, Mycobacterium africanum, Mycobacterium asiaticum, Mycobacterium avium-intracellulaire, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium chelonae abscessus, Mycobacterium fallax, Mycobacterium fortuitum, Mycobacterium kansasii, Mycobacterium leprae, Mycobacterium malmoense, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium xenopi or Mycobacterium tuberculosis.
75. The method of claim 74, wherein the mycobacterial infection is Mycobacterium abscessus or Mycobacterium avium-intracellulaire.
Fwiw - Claim 49 was news to me. I was under the impression that Insmed's IP was limited to unilamellar liposome formulations. Until I saw that I always had it in the back of my mind that we might eventually be competing against a liposomal inhalation delivery utilising multilamellar liposomes. Although that claim doesn't prevent competition from a product comprising solely of multilamellar liposomes, it does give Insmed the flexibility to effectively get there first in the event it transpires that the multilamellar route has significant advantages.