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Insmed Incorporated Message Board

  • fudfighter4 fudfighter4 Dec 30, 2012 8:24 PM Flag

    The target patient population for Arikace in the US

    Pneumonia is most often a consequence of infection by gram-positive bacteria such as Streptococcus pneumoniae. Such infections usually respond to treatment by beta-lactam antibiotics such as penicillin. But even in countries with a high standard of healthcare, thousands of people nevertheless do die of pneumonia every year.

    The common problem here seems to be infection by bacteria which are resistant to beta-lactam antibiotics, e.g. -

    ..... strains of gram-positive bacteria such as staphylococcus aureus which have developed with resistance (MRSA)

    ..... gram-negative bacteria - protected against many antibiotics by virtue of having both a cytoplasmic membrane and an outer cell membrane

    ..... mycobacteria - protected against many antibiotics by virtue of having a cell wall thicker than in many other bacteria (hydrophobic, waxy, and rich in mycolic acids/mycolates) (thanks Wiki).

    During the workshop sponsored by the FDA earlier this year to address the development of antibacterial drugs for the treatment of Non-CF Bronchiectasis, one of the leading pulmonologists was asked if there was a noticeable correlation between the severity of disease and the types of bacteria involved. His response was that the more serious conditions usually involve infection by gram-negative bacteria such as pseudomonas aeruginosa and haemophilus influenzae (aka H-flu). But he made the point that one should expect co-infection by several types of bacteria, and that it is often difficult to be sure which bacteria is responsible for the development of the pneumonia.

    That idea was reinforced by the following observations -

    "In the unit, in the hospital, we frequently double coverage people with pseudomonal pneumonia, for example, or gram-negative pneumonia, or just empirically before we know what anything is. And a patient with a ventilator-associated pneumonia, or just a rip-roaring severe pseudomonal pneumonia, often gets two drugs of a different class"

    "There's a lot more adverse events when you use two drugs versus one. I think in the end, probably you should use two drugs if someone's really sick, because it improves the chances that you're going to actually have one of them working"

    The following extract from a presentation during ECCMID 2012 confirms that the concept of "double coverage" is not new -

    "The addition of a short-course of high-dose aminoglycoside to initial antipseudomonal improve the treatment of healthcare-associated pneumonia by shortening the length of hospital stay, researchers said here at the 22nd European Congress of Clinical Microbiology and Infectious Diseases.

    Limited treatment options and delays in empiric therapy for multidrug resistant gram-negative organisms (MDR-Gn) are said to be largely to blame for the unsettling rise in such infections, causing increased lengths of stay, costs, and mortality resulting with infections.

    Healthcare-associated pneumonia has been shown to be associated with particularly resistant pathogens, and a combination therapy in which aminoglycoside is added to antipseudomonal beta-lactam has been suggested to improve treatment and resolve symptoms faster than monotherapy.

    In testing the efficacy of the combination therapy, researchers evaluated a group of 227 geriatric patients with nursing home acquired pneumonia, in which 104 patients received a combination therapy of antipseudomonal beta-lactam plus aminoglycoside and 123 received beta-lactam therapy without an aminoglycoside between 2009 and 2010.

    The results showed that the combination aminoglycoside therapy group had a mean length of stay that was 1.83 days shorter than the non-combination therapy group, resulting in lower overall inpatient costs."

    By the middle of 2013 we should know the degree to which the Arikace inhaled liposomes deliver their aminoglycoside cargo safely and effectively - though one suspects that news from the key safety study (data analysis due to start in January) will leak out much sooner. But if there are no more surprises in store, one can't help but feel that it will be practically a no-brainer to use Arikace in place of an injected aminoglycoside as a therapy for pneumonia.

    One imagines that the higher cost of Arikace will severely restrict its use in underdeveloped countries. But the following statistics still promise massive adoption of Arikace as an emergency therapy alone -

    Deaths in the US during 2009:

    50,774 - Pneumonia

    122,448 - Bronchiectasis and other chronic lower respiratory diseases, excluding cystic fibrosis, bronchitis, bronchiolitis, emphysema and asthma

    As for the potential use of Arikace as a (permanent) maintenance therapy -

    1. the cost of using the current gold-standard inhaled aminoglycoside as a maintenance therapy is over $37,000 for six months of therapy spread over the course of a year (four weeks on - four weeks off).

    2. 250,000 in the US are estimated to have Non-CF Bronchiectasis, and a further 30,000 in the US are estimated to have Cystic Fibrosis.

    3. More from the workshop -

    "H-flu, this is a bug that is normally in us, okay? And it's probably in people with non-CF bronchiectasis to a greater proportion. It certainly causes exacerbations. But again, it's 30, 35 percent of people with non-CF bronchiectasis seem to carry it. Pseudomonas is quite common --also about a third of those types of patients."

    Bear in mind that a core of patients at a more advanced stage of disease progression might be co-infected with H-flu and pseudomonas, and that less than half of the 280,000 might actually be carrying infections Arikace should control. But the estimate of pseudomonas infection is of particular interest given that the anticipated advantage of penetration of the pseudomonas biofilm by the Arikace liposomes applies also in non-CF bronchiectasis.

    It was mentioned during the workshop that Tobi is currently being used off-label in non-CF bronchiectasis. The size of the target population bodes well for the degree of early use of Arikace under the Expanded Access Program due to be initiated in 2013.

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    • Pneumonia is most often a consequence of infection by gram-positive bacteria such as Streptococcus pneumoniae. Such infections usually respond to treatment by beta-lactam antibiotics such as penicillin. But even in countries with a high standard of healthcare, thousands of people nevertheless do die of pneumonia every year.

      The common problem here seems to be infection by bacteria which are resistant to beta-lactam antibiotics, e.g. -

      ..... strains of gram-positive bacteria such as staphylococcus aureus which have developed with resistance (MRSA)

      ..... gram-negative bacteria - protected against many antibiotics by virtue of having both a cytoplasmic membrane and an outer cell membrane

      ..... mycobacteria - protected against many antibiotics by virtue of having a cell wall thicker than in many other bacteria (hydrophobic, waxy, and rich in mycolic acids/mycolates) (thanks Wiki).

      During the workshop sponsored by the FDA earlier this year to address the development of antibacterial drugs for the treatment of Non-CF Bronchiectasis, one of the leading pulmonologists was asked if there was a noticeable correlation between the severity of disease and the types of bacteria involved. His response was that the more serious conditions usually involve infection by gram-negative bacteria such as pseudomonas aeruginosa and haemophilus influenzae (aka H-flu). But he made the point that one should expect co-infection by several types of bacteria, and that it is often difficult to be sure which bacteria is responsible for the development of the pneumonia.

      That idea was reinforced by the following observations -

      "In the unit, in the hospital, we frequently double coverage people with pseudomonal pneumonia, for example, or gram-negative pneumonia, or just empirically before we know what anything is. And a patient with a ventilator-associated pneumonia, or just a rip-roaring severe pseudomonal pneumonia, often gets two drugs of a different class"

      "There's a lot more adverse events when you use two drugs versus one. I think in the end, probably you should use two drugs if someone's really sick, because it improves the chances that you're going to actually have one of them working"

      The following extract from a presentation during ECCMID 2012 confirms that the concept of "double coverage" is not new -

      "The addition of a short-course of high-dose aminoglycoside to initial antipseudomonal improve the treatment of healthcare-associated pneumonia by shortening the length of hospital stay, researchers said here at the 22nd European Congress of Clinical Microbiology and Infectious Diseases.

      Limited treatment options and delays in empiric therapy for multidrug resistant gram-negative organisms (MDR-Gn) are said to be largely to blame for the unsettling rise in such infections, causing increased lengths of stay, costs, and mortality resulting with infections.

      Healthcare-associated pneumonia has been shown to be associated with particularly resistant pathogens, and a combination therapy in which aminoglycoside is added to antipseudomonal beta-lactam has been suggested to improve treatment and resolve symptoms faster than monotherapy.

      In testing the efficacy of the combination therapy, researchers evaluated a group of 227 geriatric patients with nursing home acquired pneumonia, in which 104 patients received a combination therapy of antipseudomonal beta-lactam plus aminoglycoside and 123 received beta-lactam therapy without an aminoglycoside between 2009 and 2010.

      The results showed that the combination aminoglycoside therapy group had a mean length of stay that was 1.83 days shorter than the non-combination therapy group, resulting in lower overall inpatient costs."

      By the middle of 2013 we should know the degree to which the Arikace inhaled liposomes deliver their aminoglycoside cargo safely and effectively - though one suspects that news from the key safety study (data analysis due to start in January) will leak out much sooner. But if there are no more surprises in store, one can't help but feel that it will be practically a no-brainer to use Arikace in place of an injected aminoglycoside as a therapy for pneumonia.

      One imagines that the higher cost of Arikace will severely restrict its use in underdeveloped countries. But the following statistics still promise massive adoption of Arikace as an emergency therapy alone -

      Deaths in the US during 2009:

      50,774 - Pneumonia

      122,448 - Bronchiectasis and other chronic lower respiratory diseases, excluding cystic fibrosis, bronchitis, bronchiolitis, emphysema and asthma

      As for the potential use of Arikace as a (permanent) maintenance therapy -

      1. the cost of using the current gold-standard inhaled aminoglycoside as a maintenance therapy is over $37,000 for six months of therapy spread over the course of a year (four weeks on - four weeks off).

      2. 250,000 in the US are estimated to have Non-CF Bronchiectasis, and a further 30,000 in the US are estimated to have Cystic Fibrosis.

      3. More from the workshop -

      "H-flu, this is a bug that is normally in us, okay? And it's probably in people with non-CF bronchiectasis to a greater proportion. It certainly causes exacerbations. But again, it's 30, 35 percent of people with non-CF bronchiectasis seem to carry it. Pseudomonas is quite common --also about a third of those types of patients."

      Bear in mind that a core of patients at a more advanced stage of disease progression might be co-infected with H-flu and pseudomonas, and that less than half of the 280,000 might actually be carrying infections Arikace should control. But the estimate of pseudomonas infection is of particular interest given that the anticipated advantage of penetration of the pseudomonas biofilm by the Arikace liposomes applies also in non-CF bronchiectasis.

      It was mentioned during the workshop that Tobi is currently being used off-label in non-CF bronchiectasis.

      • 1 Reply to eyegiggle
      • Couldn't have put it better myself :-)

        It's depressing to see the following observation this morning despite the information you've only just posted -

        "Arikace will be competing with other inhalation antibiotics to treat Pseudomonas aeruginosa in CF patients, then bronchiectasis patients, then other types of pneumonia and (hopefully) the big ticket item, NTM."

        Pseudomonas is a far bigger opportunity than NTM when one factors in the rate of infection in people with Non-CF Bronchiectasis.

        One wonders if Insmed plans to use the data from the ongoing EU pivotal study of Arikace as a therapy for pseudomonas infection in people with Cystic Fibrosis to support an application under the new legislation for FDA approval of Arikace as a therapy for ALL pulmonary pseudomonas infection.

        The NTM opportunity, however, could be helpful in developing Arikace as a therapy for TB.

 
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