Substantial New Measures to Ensure Success - Afrezza's trials include explicit and aggressive titration protocols, an independent monitoring team to make sure protocols are followed, and patients with such high blood sugar that Afrezza's chances of success are high. "Properly managed insulin titration would alleviate the problem of skewed data. So, in some cases in the past, MannKind created titration algorithms for the basal insulins as part of the protocol of the trials. But there was another problem. Clinicians, fearful of hypoglycemia and unfamiliar with Afrezza, were not dosing patients high enough with Afrezza to combat mealtime hyperglycemia - even against the study's protocol. So, MannKind and the FDA came up with three fixes for this. The first is that the titration procedures are spelled out explicitly for both the basal insulin in Affinity 1, and Afrezza in both trials. These are both "treat to target" studies for the first time. This means proper titration is not reached until blood sugar is under control. We saw that a steady dose of Afrezza works for meals in a very reasonable range, so after a working dose is titrated, Affinity 2 should show good results without risks of skewed data from improper dosing. But there is still Affinity 1 to consider. So the second fix, remarkably, is that the FDA signed off on MannKind hiring an independent monitoring team to track all of the patient data in the Affinity 1 trial, and to contact clinicians who are not following protocol. CEO Alfred Mann on the Q3 conference call: "What is truly different in 171 is the FDA understands this and has authorized us to retain an independent monitor who sees the e-Diary data, and who is charged to contact the clinician with any noncompliance. With this tool, there's a much greater likelihood that fasting glucose for those on AFREZZA will be lowered below the target of 120 milligrams per deciliter. The only non-inferiority in this trial is required for FDA approvals, with such compliance, AFREZZA patients should perform exceptionally well in this study, reaching significantly lower A1Cs. Such improvement would be unlikely for patients on rapid-acting analogs. Let me provide an example to illustrate the significance of what this compliance and the 171 study should make possible. With basal insulin titrated for an AFREZZA patient, to yield an average fasting level of, say, 110 milligrams per deciliter and with prandial glucose likely rising an average of, say, about 40 milligrams per deciliter over 2 hours for each meal, the result in A1C at 3 months would be about 5.8%, essentially normal for a nondiabetic. That would really be outstanding. For those using current prandial insulins lowering fasting glucose significantly would not be safe, and the A1Cs would, thus, not be substantially reduced." Sr. Vice President, Clinical Sciences Robert Baughman provides color on the Q4 2012 conference call: "We have an independent titration management committee that makes those recommendations to the investigators. But we are blinded to that, and the outcome of that, we will only see when we evaluate the data… we get the comment back from the committee that the investigators are being attentive to the recommendations." http://bit.ly/12OcWwT "Yet even though the kinetic dynamic profile of AFREZZA is so much more physiologic, our early trials were not yet able to clearly validate superiority of AFREZZA for A1C. But that can be explained. Since A1C effectively reflects the average blood sugar over about 2 to 3 months, substantial lowering of A1Cs can only be realized by reducing fasting level, as well as lowering prandial rises. However, since the excessive late persistence of current prandial insulin is the primary cause of hypoglycemia, out of concern for such risk in clinical practice today, physicians typically resist increasing basal insulin to lower fasting levels. As a consequence, they are managing their diabetes patients at very high fasting glucose levels that result in higher A1Cs with increased risk of long-term diabetic complications. Since there is no excessive -- such excessive persistence with AFREZZA, fasting glucose can be much more safely lowered. At a fasting level over 100 milligrams per deciliter, it's really hard to imagine how the kinetic dynamic profile of AFREZZA could lead even to a mild hypoglycemic incident. Modular A1Cs should thus be achievable, and that would reduce the risk of long-term complications of diabetes. Since our earlier trials, basal insulins were actually not titrated, the fasting glucose for the AFREZZA patients were thus excessive. What is different in this trial is the protocol very clearly defines the proper titration of the basal insulin. As a result, the AFREZZA patients end up with much lower fasting levels, though far less change would likely be possible with the current prandial insulin because of their excessive persistence. The caveat of this is that nonphysiologic interpatient variability in glargine, the basal insulin used in Affinity 1, which can also cause -- which is really the primary cause of hypoglycemia, there will probably be some residual hypos even in the AFREZZA cohort. Past experience suggest that there should not be many of those exceptions, so we are confident of good outcomes in this -- in the trial."