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  • Northwest Biotherapeutics: Responding To Richard Pearson's Article Alleging A Promotion Scheme [View article]
    Still here Adam! Must be up to two quarts now. Do you have a family, some other hobby, anything else? I am so thrilled you are here. Cheers.
    Jul 17 10:15 PM | 1 Like Like |Link to Comment
  • Northwest Biotherapeutics: Responding To Richard Pearson's Article Alleging A Promotion Scheme [View article]
    I am always amazed that Feuerstein weighs in on these boards with snarky comments. Does he have nothing better to do like some fundamental research. He seems so emotionally immature. Sometimes he does he good job uncovering fraud and dishonesty in the biotech field and that is an important contribution but most times he seems simply to wish to destroy and then gloat when a stock goes down. It is really a strange personality, clearly defective, and not a professional one. Sometimes I wonder if he has an alcohol problem given the style of his language and his lurking on boards like this.
    Jul 17 02:14 PM | 5 Likes Like |Link to Comment
  • Northwest Biotherapeutics Gets Called Out: Should Investors Worry? [View article]
    It is appropriate to release interim data in an open label study. Patients, doctors and hedge funds can all get this information so it is in the best interests of all to have equal access. Don't think for one second that MD Anderson docs couldn't be bribed/fooled/cajoled to release open study data to "journalists" and they wouldn't be breaking any law. The potential for abuse could be far worse if the data were not generally released.
    Jun 23 08:40 PM | 7 Likes Like |Link to Comment
  • Refuting The Latest Negative Blog On Northwest Biotherapeutics [View article]
    I thought endpoints were usually pre approved by the FDA as part of trial design. How was the phase III approved by the FDA without an endpoint agreement?
    Apr 3 04:22 PM | Likes Like |Link to Comment
  • What The FDA Document Says About Afrezza: Implications For FDA Approval [View article]
    I read the details as none being related to Afrezza
    Mar 31 01:06 AM | Likes Like |Link to Comment
  • What The FDA Document Says About Afrezza: Implications For FDA Approval [View article]
    First, thanks for providing this intelligent forum for serious discussion. I am long Mannkind. I understand your point. However, the FDA appears to be trying very hard to move the discussion away from the numbers and change the conversation in a very negative way. The fact that they are so obvious and ham-handed about it gives me hope they over played it and it will backfire. For T1 trials they want to simply say it was the increase in basal and not Afrezza so the test is no good. Their second line is to push for the statistical drop out issues. For T2 trials they would like to say that oral medicines are better than Afrezza but then they would have to say they are better than all insulins. The point is so incredibly stupid they couldn't quite get there. A professional panel that is not compromised should see through this. I am just very disappointed in the FDA document and it smells to high heaven that there is something else going on here.
    Mar 30 05:57 PM | 1 Like Like |Link to Comment
  • What The FDA Document Says About Afrezza: Implications For FDA Approval [View article]
    Thanks. I do not know what is really happening behind the scenes. Just reading what I see.
    Mar 29 05:39 PM | 1 Like Like |Link to Comment
  • What The FDA Document Says About Afrezza: Implications For FDA Approval [View article]
    I have read through the FDA document it is truly one of the stupidest things ever to come out of the agency. Where to begin?
    1. FDA reference to the Prospective Diabetes Study indicates that tight control of HbA1c is the standard. This is not what the study really said. It is far more nuanced. It actually said that blood pressure control is more important than glycemic control for cardiac and microvascular complications. It went on to say that despite statistical significance the absolute risk reduction from glycemic control is small, benefits did not accrue for several years and intensive control leads to morbidity from hypoglycemia and weight gain. As I have noted in comments before, the ACCORD study showed no benefit from tighter HbA1c control in cardiovascular outcome and the study was halted due to increased mortality in patients on tighter HbA1c control. This was further validated in two other studies completed in 2008, the ADVANCE study and the VADT study.
    2. What is completely missing from the FDA report is any mention of post prandial glucose control (PPG) which in fact has been implicated in cardiovascular disease. This is one area where Afrezza did very well.
    3. Much ink is spilt for pages going on about changes to dosing proposed by Mannkind and that these are based upon pharmokinetic (measures of insulin levels) and not pharmodynamic (measures of HbA1c results). This is completely irrelevant. The FDA cannot micromanage clinical dosing which is an empirical art in diabetes management. Pharmokinetic measures can provide clinical guidelines but only clinical management can find the optimum dosing for any individual patient. Just like in any of the studies, you start low and work up to optimize pharmokinetic outcome. Incredibly stupid.
    4. The greatest and most obvious stupidity is the extended effort to separate out the effects of prandial insulin from basal insulin. The suggestion is made that benefits from Afrezza are due to higher basal insulin and that on a prandial to prandial comparison Afrezza is significantly inferior. This is the main point about Afrezza. Diabetes management is based upon the combination of drugs and Afrezza, due to its rapid acting pharmokinetics, can and should be combined with higher basal insulin since its quicker elimination reduces the risks of post prandial hypoglycemia. This is Afrezza's primary advantage and to eliminate this with an ad hoc and ridiculous standard which tries to tease apart relative contributions is absurd.
    5. Afrezza's advantage in terms of lower hypoglycemia is attributed to its less strong effect on HbA1c although it met all its endpoints. Where numbers should rule here we see just an off hand dismissal. Well, we actually have very good data on these trade-offs between HbA1c and hypoglycemia. The question should be is Afrezza above, on, or below the curve. I have to think the FDA's feigned ignorance is intentional because Afrezza is below the curve indicating a positive trade off.
    6. For the 175 study no where is it mentioned that those patients on oral meds were not losing control at all but became very well controlled with diet and perhaps additional oral medications. The FDA then sets up a red herring with a table showing how effective additional oral meds can be in controlling T2 diabetes. Well of course. Diet and oral meds should always be used first. The correct comparison is when transitioning T2 patients to insulin how does Afrezza stack up against injectables. This comparison is not done from available data because it would favor Afrezza on many different measures.
    7. A comment is made that due to drop out rates Afrezza is not preferred. This is a one sided test for God's sake. Did anyone ask those who stayed on trial whether they may have preferred Afrezza?
    8. I see no discussion as to when hypoglycemia occurred with Afrezza. I suspect it occurred more frequently before or even during the meal because it was taken too early or the meal was less than anticipated. (One of the histories talks about a patient who took Afrezza before a meal and then only had a glass of wine. He had a hypo. Well duh.) It is briefly stated that Afrezza can be taken during and after a meal based upon BG measurement. Afrezza could probably be taken during the meal safely since its action is so rapid but this is never considered. This is only something a doctor and patient could try as part of an optimization program to reduce hypoglycemia even further. If hypo events were rare in later post prandial settings then basal insulin could be further increased. My bet is that Afrezza was used sub optimally in combination with basal insulins.

    Well I could go on and on. Conclusion: Some in the FDA have been captured by big pharma to bury Afrezza either through outright rejection based on new, ad hoc, and incorrect measures or calls for additional testing which can never be conclusive (see for discussion on capture of the FDA with regard to Dendreon). Is Adcom also captured or will they make an independent analysis? That should become clear quickly. One final key is how the voting question is phrased. If the question is something like "Is Afrezza a non-inferior prandial insulin when compared to other prandial insulins based upon HbA1c reductions" the answer will be no. If the question is a correct one it will sound something like this, "Does Afrezza provide additional clinical utility in managing diabetes on a case by case basis as a meaningful addition to the array of choices available to clinicians". The answer is clearly yes.
    Mar 29 04:12 PM | 8 Likes Like |Link to Comment
  • Behind The Scenes With Proactive, Inovio And Unilife [View article]
    There is nothing wrong at all with a firm getting its message out to the public so long as everything is truthful. It's called public relations or advertising or whatever. If you have found lies then more power to you. If not, then this is a waste of time. More serious issues are caused by shorts who actually do publish lies.
    Mar 27 05:13 PM | 4 Likes Like |Link to Comment
  • Fear, Greed, And Prudent Risks: A Clarion Call To The Keepers Of The MannKind Flame [View article]
    Afrezza and the Accord Study

    Much has been made of Afrezza's failure to match subcutaneous injected insulin in HbA1c reductions even though the differences were generally statistically insignificant. Such judgement misses the sea change in thinking about diabetic control since the ACCORD study results published in the New England Journal of Medicine. This study of over 10,000 type 2 diabetics compared trying to achieve tight HbA1c control approaching 6% with more moderate control of less than 8%. The study set out to show that tight control would result in a statistically significant reduction in cardiac events. Instead the study was halted because the cardiac benefit was not statistically significant and the "harm associated with the increased risk of death in the intensive therapy group outweighed potential benefits." Possible reasons for the increased death rate were both the lower HbA1c levels, the speed of attainment and the increase in severe hypoglycemia! Afrezza had statistically significantly less severe hypoglycemia in almost every study while lowering HbA1c. Afrezza is a very effective and important tool that needs to be added to the array of therapies available to doctors and patients trying to control diabetes. So I repeat, it would be a tragedy to deny this therapy to diabetics and a travesty of moral and scientific perfidy for the FDA to not approve Afrezza
    Mar 27 04:39 PM | Likes Like |Link to Comment
  • Fear, Greed, And Prudent Risks: A Clarion Call To The Keepers Of The MannKind Flame [View article]
    Amazing Afrezza and the 175 Study

    Much disinformation has been posted on the 175 study. This study took 353 type 2 diabetic patients on oral medications and added either Afrezza or placebo powder. The patients were supposedly inadequately controlled on oral medications. After 12 weeks titration lead in and 12 weeks of therapy the results were as follows: HbA1c change (-.82% Afrezza and -.42% placebo), A1c target achievement of < 7% (37.7% Afrezza and 19% placebo), A1c target achievement of < 6.5% (15.9% Afrezza and 4.2% placebo), mild to moderate hypoglycemia (67.2% Afrezza and 30.1% placebo), severe hypoglycemia (5.1% Afrezza and 1.7% placebo), weight gain (.49 kg Afrezza and -1.13 kg placebo), fasting blood glucose (-11.2 mg/dl Afrezza and -3.8 mg/dl placebo).
    The essential negative case is that Afrezza failed because the decrease in HbA1c did not justify the increase in hypoglycemia (mild, moderate, and severe) or the relative weight gain of 1.62 kg. This judgement fails on multiple levels. First, it is clear that the placebo group were not losing glycemic control. This group improved their HbA1c readings by .42% and they lost 1.13 kg.! Either additional and effective oral medications were added during the treatment period or dietary counseling offered during the trial had a tremendous effect. Insulin is not added lightly to any therapeutic regimen. It should be considered only when there is a loss of glycemic control and the disease is progressing. Therefor this study was flawed from the beginning. Second, as many posters have pointed out, this trial did not compare Afrezza vs. subcutaneous insulin being added to oral medications. The conclusion that Afrezza failed and should not be added to the arsenal of available insulin medications is absurd. Third, the criticism falsely combines rates of mild hypoglycemia with severe hypoglycemia. If you ever had a heavy carb meal and felt that you needed to lie down, guess what. You just had a mild hypo event. Not so terrible unless you have thousands of them which means you are probably overweight and developing diabetes. It is the severe events that most concern doctors treating diabetic patients and the difference between Afrezza and placebo in this study was not statistically significant.
    But wait, it turns out we do have data on other insulins being added to oral meds so we can make some comparisons. We have for instance Hsiao, Chen: “Severe Hypoglycemia in Type 2 Diabetics: A Hospital Retrospective Study” In a study of 1442 type 2 diabetics they found that adding subcutaneous insulin to oral medication increased the rate of severe hypoglycemia to 17.8%! From Gross, Kramer et. al: “Effect of Anti-hyperglycemic Agents added to Metformin….” Annals of Internal Medicine, we have a large meta study. Adding subcutaneous insulin to oral medications for type 2 patients actually losing glycemic control resulted in a 1% relative decline in HbA1c but at a cost of a statistically significant doubling of severe hypoglycemia and a 2.84 kg relative weight increase. Recall that Afrezza was compared to patients who were actually gaining glycemic control and losing weight. If the placebo group had just been stable Afrezza would have shown a .82% relative benefit with only a .42 kg gain in weight! When we add in compliance issues for transitioning type 2’s to subcutaneous insulin we see clearly that Afrezza is a very effective and important tool that needs to be added to the array of therapies available to doctors and patients trying to control diabetes. It would be a tragedy to deny this therapy to diabetics and a travesty of moral and scientific perfidy for the FDA to not approve Afrezza.
    Mar 27 03:41 PM | 2 Likes Like |Link to Comment
  • Fear, Greed, And Prudent Risks: A Clarion Call To The Keepers Of The MannKind Flame [View article]
    Dear Vertical View: It is too bad you get your understanding of Mannkind from Rapp78. His commentary is generally skewed and misleading. The Type 2 trial reported on 8/14/13 was against patients naive to insulin on oral meds only. Of course insulin will cause more hypoglycemia, especially in naive patients making this transition. The increase in severe hypoglycemia was not statistically significant anyways. The key is what insulin is better when a transition beyond oral meds is required. On this score Afrezza did better or as well on a consistent basis and a deeper understanding of the results shows Afrezza, when properly used, is far superior to subcutaneous injectables for both type 1 and type 2 diabetics.
    Going all the way back to results reported in 2009 Afrezza decreased HbA1c only .06% less in Type 2's and was essentially the same in Type 1's. Weight gain was lower and mild to moderate, severe, and total hypoglycemia was less and significantly so. Results reported in 2010 show HbA1c decreases only .02% less for Afrezza in Type 1 and 2's. Weight gain was significantly less on Afrezza as were both total and severe hypoglycemic events. In a 16 week study with results released later that year Afrezza actually did better than Lispro in reducing HbA1c. Hypoglycemic events were again lower for Afrezza. So now we get to the 171 and 175 studies with data released in August of 2013. Lets look at the Type 1 study which was against a rapid acting injectable insulin, not oral meds. HbA1c decreased less in the Afrezza group but this was not statistically significant. Total hypoglycemia was less and this was statistically significant. Afrezza users lost weight while the control group gained weight and this was also statistically significant. But this isn't even the best stuff.
    In all reported studies, Afrezza was significantly better than the control arm in Fasting Plasma Glucose (FPG) levels and Post Prandial Glucose (PPG) with much better post prandial excursion control. First of all, PPG is highly correlated with severe cardiac and microvascular disease so controlling PPG is very important. Second, FPG and PPG strongly correlate with long term HbA1c control. Studies (some referenced below) have shown that 94% of patients achieving PPG control achieve long term HbA1c below 7% and 64% if patients achieving FPG control also reach HbA1c goals. FPG becomes more important when HbA1c is poorly controlled and PPG becomes more important when HbA1c is better controlled but not at target. So why did Afrezza not perform much better on A1c and only met non-inferiority when it did so well in FPG and PPG? Clearly because basal insulin levels were not optimized for Afrezza. Afrezza users who have blogged have indicated that they were able to achieve A1c targets with experience to optimize the combination of an ultra fast insulin and basal insulin. The timing of Afrezza is also different. Things to look for in the submission documents will be the amount of basal insulin used in Afrezza vs. control and the timing of hypoglycemic events for Afrezza. Specifically, did these occur before the meal, indicating Afrezza was taken too early as habit would dictate.
    Now for your reading pleasure may I point you to something other than the blogs such as:
    Woerle, Neuman, Zschau: "Impact of fasting and post prandial glycemic control in type 2 diabetes" Diabetes Res Clin Pract 2007
    Schrot: "Targeting Plasma Glucose" Clinical Diabetes 2004
    Bonorra, Calcaterra, Lombardi: "Plasma Glucose levels throughout the day and the HbA1c relationships" Diabetes Care 2001
    Shimuzu, Uehera, Okada: "Contribution of fasting and hyperglycemia to hemoglobin A1c" Endroc J 2008.
    Monnier, Lapinski, Collette: "Contributions of fasting and post prandial fasting glucose increments to the overall diurnal hypoglycemia of type 2 diabetic patients"
    Diabetes Care 2003
    Mar 24 11:43 PM | 4 Likes Like |Link to Comment
  • Fear, Greed, And Prudent Risks: A Clarion Call To The Keepers Of The MannKind Flame [View article]
    This article is really a waste of space. You have said nothing. SA is really digging at the bottom of the barrel. Must be a slow day for articles.
    Mar 24 04:04 PM | 4 Likes Like |Link to Comment
  • MannKind: Follow The Smart Money [View article]
    Great article George.

    I continue to see the Amarin comparison so here is my take. Much has been made of the decision by the FDA to delay any approval of Amarin's purified EPA (fish oil) for patients with triglycerides between 200 and 500 mg/dl even though the study met its primary and secondary endpoints. The reasons for this were two fold. First, the placebo was mineral oil and the study showed a strange increase in the triglycerides of the placebo group thereby putting into question the actual comparative effect of the EPA. Second, recent studies showed little clinical benefit for reducing triglycerides in terms of cardiovascular outcomes for patients whose LDL was controlled by statins. Amarin is in fact conducting a large trial that will look at clinical outcomes in just this situation and it was decided to await the results from this trial. The FDA's position seems reasonable except for the issue of whether they went off the ranch by moving the goal posts. So the question is can the FDA reasonably move the goal posts on Mannkind. My opinion is no.

    There is no issue with the alternative against which Afrezza was measured. It was not a placebo but the actual drugs currently used by diabetics. In the 175 study for Type II diabetics the alternative was metformin which is prescribed before patients move to insulin. Afrezza performed very well reducing A1c levels below both 7% and 6.5% in more patients than metformin and this was statistically significant. Afrezza also reduced post prandial glucose excursions better than metformin and this was statistically significant. Both of these are well studied clinical benefit measures about which there is no question. There was more hypoglycemia in the Afrezza but this was to be expected since the control group was not on insulin therapy. Less

    The 171 study for Type I diabetics used a control on fast acting aspart insulin, the current gold standard for post prandial insulin therapy so no placebo issue here at all. Afrezza was non inferior to aspart insulin and significantly better with regards to hypoglycemia and fasting blood glucose levels. Again these are clinical outcomes with known benefits which cannot be questioned. Note that if aspart insulin was used in the 175 study this indicates it would assuredly have caused even a worse comparison with metformin with regard to hypoglycemic events than Afrezza so Afrezza would be the superior choice of insulin when going beyond oral therapies. Also note that it was difficult in the trial to adjust the basal insulin and Afrezza doses to optimize outcomes and if this was permitted, as in a real world situation, Afrezza may well outperform aspart insulin on A1c measures as has been reported informally by study participants.
    The FDA has no ability to use any of the goal post moving measures taken in the Amarin case. The only non approval reason would have to be related to worries about cancer or heart issues and there has been no evidence at all for these risks. The incidence of cough had negligible effect on compliance and we know the cough reported reduced significantly beyond one week. Changes in forced expiratory volume was also insignificant.
    In conclusion I do not see any pathway for Adcom or FDA rejection of Afrezza which shows significant improvements in known clinical benefits and was measured against current alternative therapies and not a placebo.
    Mar 10 06:50 PM | 5 Likes Like |Link to Comment
  • NanoViricides: House Of Cards With -80% Downside, 'Strong Sell' Recommendation [View article]
    You are right on in your analysts. The product is unique because it does not interact with cellular mechanisms, the immune system or other complex chemical pathways in the body. What happens in vitro and in animals should be exactly what happens in humans. We just need to know it is safely cleared fro the body.
    Feb 15 01:24 PM | Likes Like |Link to Comment