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Insmed Incorporated Message Board

  • rehdvm2004 rehdvm2004 Feb 20, 2013 9:21 AM Flag

    All four Arikace clinical trials have the same exclusion . . .

    In the case of the CF/Pa Phase III trials:

    • History of pulmonary tuberculosis or non-tuberculous mycobacterial lung disease treated within 2 years prior to Screening or requiring treatment at the time of screening

    While the Extension Study does not actually mention pulmonary TB as exclusionary, it says that only patients enrolled from Clear-108 can be enrolled which carries a prior exclusion of TB patients.
    Or in the case of the Phase IIb NTM trial:

    6. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to screening.

    Pulmonary tuberculosis would include latent tuberculosis which means (according to the CDC recommended treatment of latent TB in the US) that any patient would have had the 9 months of isoniazid followed by 24 months of no pulmonary signs of TB.

    But lets consider INSMs options for treating TB. Why would they not take one (or more) of the first line TB drugs and put it inside the liposome and have the patients inhale that array of drugs? Why would they settle for a second line drug, or as the CDC states it :

    What are the first- and second-line drugs used to treat TB?
    When drug susceptibility test results from different specimens from one patient are not the same, a treatment regimen is chosen that is most likely to be effective on the most predominant TB bacteria.
    There are 10 drugs currently approved by the U.S. Food and Drug Administration (FDA) for treating TB. Of the approved drugs, the first-line anti-TB agents that form the core of treatment regimens include
    isoniazid (INH)
    rifampin (RIF)
    ethambutol (EMB)
    pyrazinamide (PZA)
    Second-line drugs used to treat TB include
    fluoroquinolones (levofloxacin, moxifloxacin, gatifloxacin)
    three injectable drugs (amikacin, kanamycin, or capreomycin)
    ethionamide
    cycloserine
    Second-line drugs are less effective and more toxic than first-line drugs used to treat TB.

    Please note the amikacin is injectable.

    So I think the facts and the CDC is clear. No patient with latent or active TB will be inhaling Arikace or amikacin until a full blown clinical trial of that prescriptive use has been performed and reviewed by FDA, EMEA or whatever regulatory agency receive a master file. So do not start counting on those revenues anytime soon.

    Arikace is a strong buy because it has become clear that the Lewis led INSM team is on a pathway for probably two successful clinical trials to be submitted and/or completed by the end of this year. They they have to prepare an NDA which Lewis says will go into 2014. Not before. Not to even wildly be considered for any form of TB.

    Let the insults begin.

    So INSM does not want any active TB

    Sentiment: Strong Buy

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    • 1. Lewis suggests the data will meet the endpoint of "non-inferiority" for CF/Pa and was very optimistic that the data will demonstrate superiority by virtue of superior kill of Pa.

      2. He went on to explain the importance of the 28 day on 28 day off treatment equivalency with TOBI in terms of developing mutant strains that might become resistant. He then linked this treatment regimen with two important clinical facts and alluded to two others:

      a. The once per day treatment regimen is more easily scheduled for patients than BID for TOBI, or TID for Cayston.

      b. That once patients experience the single dose regimen, they will be reluctant to switch to a different BID or TID antibiotic regimen unless their is a life threatening change.

      c. Lewis alluded to an important point that is currently not emphasized, which is the concurrent therapy with other agents would be prescriptively allowable for patients. Using certain adjunctive agents (e.g., Pulmozyme) was pretty much precluded in the Clear-108 trial. That is between the physician and the patient.

      d. He also alluded to the fact that because of antibiotic resistance and non-penetration of macrophages, other antibiotic formulations could be developed in the future.

      3. He went on to suggest that the Extension Trial could be pivotal and allow use of Arikace for much longer periods than the 6 cycles in the Clear-108 Phase III.

      4. The NTM trial was referenced well by re-iterating the "captured market" for Arikace if the bacterial kill endpoint can be achieved. Relative to this use, Lewis stated:

      a. INSM believes their endpoints are achievable and will show a statistically significant therapeutic effect.

      b. If a. is achieved they will file with the FDA for expedited review by year end.

      c. If they achieve b., they will cross file in Europe, Japan and with other regulatory agencies.

      5. The most important part of the presentation, I believe, was the understanding that INSM now has of the regulatory process on an international scale. They know there is extensive regulatory filings to be submitted in order to enter and capture market(s).

      6. Lewis said that INSM would market and not look for a partner.

      7. Lewis went on to outline the IP supporting the exclusivity of the liposome for 2029 and beyond, which is the key to future drug development. The key to this IP is the fact that the liposome composition is similar to the natural lipid coat inside the lungs.

      In all, I heard the facts stated well, a good understanding of the clinical signs and endpoints, a realistic grasp of the regulatory situation and a good understanding of the market for inhalational antibiotics. It is a vast improvement from the previous administration, regulatory approach and presentation of the clinical science. Congratulations, INSM.

      I change my outlook.

      Finally . . . some light at the end of the tunnel

      • 2 Replies to insm_truth_teller
      • 1. Lewis suggests the data will meet the endpoint of "non-inferiority" for CF/Pa and was very optimistic that the data will demonstrate superiority by virtue of superior kill of Pa.

        2. He went on to explain the importance of the 28 day on 28 day off treatment equivalency with TOBI in terms of developing mutant strains that might become resistant. He then linked this treatment regimen with two important clinical facts and alluded to two others:

        a. The once per day treatment regimen is more easily scheduled for patients than BID for TOBI, or TID for Cayston.

        b. That once patients experience the single dose regimen, they will be reluctant to switch to a different BID or TID antibiotic regimen unless their is a life threatening change.

        c. Lewis alluded to an important point that is currently not emphasized, which is the concurrent therapy with other agents would be prescriptively allowable for patients. Using certain adjunctive agents (e.g., Pulmozyme) was pretty much precluded in the Clear-108 trial. That is between the physician and the patient.

        d. He also alluded to the fact that because of antibiotic resistance and non-penetration of macrophages, other antibiotic formulations could be developed in the future.

        3. He went on to suggest that the Extension Trial could be pivotal and allow use of Arikace for much longer periods than the 6 cycles in the Clear-108 Phase III.

        4. The NTM trial was referenced well by re-iterating the "captured market" for Arikace if the bacterial kill endpoint can be achieved. Relative to this use, Lewis stated:

        a. INSM believes their endpoints are achievable and will show a statistically significant therapeutic effect.

        b. If a. is achieved they will file with the FDA for expedited review by year end.

        c. If they achieve b., they will cross file in Europe, Japan and with other regulatory agencies.

        5. The most important par

      • Post of the day ----------------- thanks

        Dog inhalation study

        by restrainedmagic•11 hours agoFlag
        .

        This is not an academic endeavor by INSM. It is a mandatory safety study required by the FDA (EMEA did not require this study) for final regulatory approval to clarify a "questionable finding that INSM reported to the FDA" following a two year rat study. If it was an academic study, they could get the results and submit an abstract to any number of scientific journels at any time. But it is a regulatory piece of evidence that must be reviewed first by the FDA under the terms of confidentiality associated with the IND to determine that it answered the FDA concerns associated with the rat study. Any prior submission to a third party would be a breach of regulatory protocol and would not be viewed favorably by the FDA. Case in point, the PJ Garvin study with JS and RW on DEHP (1975) was accepted academically by the Journal of Tox and Applied Pharm, but had to be redone at Baxter Travenol because the first group of 20 rats was injected with serum control for 28 days, the second was injected with low dose, the third with intermediate dose and the fourth with the high dose. The animals were phased this way because of the elaborate process of analyzing 20 rats in a group took While academic journels do not investigate the protocols that carefully, the FDA landed on the submission by saying the "control and treatment groups were confounded in time." That means that the first groups results are not related to the last groups results because the conditions, feed, water, environment, etc. may have varied between the groups causing different results. We had to perform this study all over again by placing 5 animals in each group on study at the same time and then repeating the testing pattern four times. There were still 20 animals in each group, but they were matched among all groups. Needless to say, the reaults were the same. DEHP did not leach out into rat plasma enough to reach the toxic threshold.

        So if INSM breaks any news on the dog study, investors can be sure that the FDA has seen the data first and concurs that there is no problem. Which has been my contention all along based on the resiliency of dog lungs and their large anatomical size. But it shows that the FDA (or any Federal regulatory agency) will exercise the "first right of refusal of data" and send a company back to perform another very expensive study or group of studies to provide an answer concerning any "questionable finding." That is the regulatory process. Remember all the preclinical safety studies have to be performed according to another regulatory standard GLP (Good Laboratory Practice). Less

        Sentiment: Strong Buy

    • Accelerated/expedited approval would be involved for:

      1. NTM if the data showed kill of NTM in a reasonable time and improved FEV-1 along with the dog study data showing the foamy macrophages were reversible (this outcome gets an NTM label copy in 2014 or thereabouts);

      2. Or in Europe if Arikace showed superiority because of the extension study by knocking out Pa and showing improved, level or minimal decrease in FEV-1 (these data would probably get the EMEA equivalent of fast track review); or

      3. If with good European date for CF/Pa, good data from NTM and the dog study completed, the FDA considers the all data and allows submission of an NDA for NTM and CF/Pa in the US. This submission would be possible even though the US study which was supposed to be compared with a parallel regimen with the liposome placebo because the NTM study has 50 patients that got placebo alone. All INSM would have to do is perform an ANOVA on unbalanced numbers in study groups and compare the 50 placebo recipients in the NTM study with the 150 patients that received Arikace in the European study and get a P =/

      Sentiment: Strong Buy

      • 1 Reply to rehdvm2004
      • One of the fastest ways to get in trouble with the Feds (in this case the FDA) is to leak data for monetary gain, or prevent loss purposes. In the case of this company, that parallels the famous "MMD failed leak to get Ipsen Roche to drop that use from the Settlement Agreement 50% royalty for co-marketing provision." The current status at CTgove is "unknown" (Clinical Trial No. NCT00577577, Coordinated by Dr. Moxley), but the strong buy pundants on this MB were saying it was all a ploy to off load Ipsen Roche. The junk information that pervades this MB just keeps "carrying over."

        If you want to do some easy DD, look up the difference between an antibiotic effect on bacteria and an anti-mycolic acids in treating TB. Then you might understand why the bogusclubfud is so totally wrong about this infectious bacteria. Antibiotics cannot get into this bacteria because of the protective outer membrane. A good place to start is Bacterial Pathogenesis - A molecular Approach by Salyers and Whitt. Chapter 26 entitled Tuberculosis.

        I am a strong buy advocate now, but came to this conclusion slowly through 7 years of baloney and non-performance. Now there is a true leader for INSM and slowly released bits of information that suggest real progress. Not simply "justification for giving bonuses and stock options" to underperforming executives.
        ) came out,

    • you mean no accelerated approval?;- ) No matter if its TB 600 or ...is has to be Evelyn (fud4) Off to Penny's _ )

 
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