Post by mannmade on Jan 3, 2015 9:57:49 GMT -5
Here they come... More FUD...
seekingalpha.com/article/2793285-one-internists-glance-at-mannkinds-afrezza?uide=2145281
One Internist's Glance At MannKind's Afrezza
I recently received a message asking for my opinion on the inhaled insulin, Afrezza, which is set to be released this year by MannKind (NASDAQ:MNKD) and Sanofi-Aventis (NYSE:SNY) for the treatment of diabetes mellitus. The drug has received a lot of attention on the Seeking Alpha pages, and I don't think I can add much insight to the discussion on its financial prospects. That said, as an internal medicine physician who, quite literally, treats diabetes mellitus every working day, I think I can speak with a minor bit of authority on the subject as to a clinical view of the drug. I'd also like to start with a quick review of the evidence for the use of the medication, its efficacy and safety profile - and, what is probably most important, in my opinion, whether I'd be inclined to offer it to my patients or not.
How I Treat Diabetes - A Very General View:
My process for starting insulin in diabetic patients is usually pretty simple, and can generally be summed up by a quick glance at the guidelines for the treatment of diabetes mellitus (quick note: talking about Type 2 diabetes here; starting insulin in Type 1 isn't optional). Generally speaking, once a patient receives a diagnosis of diabetes mellitus (henceforth, "DM2," or "DM"), physicians will stratify them by their A1C, which is a measure of glycosylated hemoglobin (that roughly corresponds to the absolute, average level of glucose in the blood over a 3-4 month period of time). Though this isn't strictly-speaking evidence-based (though there's some evidence to suggest that I'm onto something), I set an arbitrary A1C goal for my patients at their age divided by 10. For patients under 65, that means, for most of them, a goal A1C of less than 6.5%; for those over 65, their A1C target tends to go up as they get older. The overall decision-making process is intended to take into account age and comorbidities, and essentially amounts to an abbreviated risk-benefit analysis. It's a rule of thumb, and not a hard-and-fast rubric (not that anything ever is, in medicine), but I've found it useful to help me individualize decision-making for my patients, some of whom may warrant stricter glucose control because of relative youth or excellent functional status, and others for whom more liberal control is warranted, because of severe comorbidities, likely adherence with therapy, or medication intolerance.
(Source: AACE)
I bring this up because I want the reader to understand that medicine is an inherently personal experience that takes place between a patient and their physician, and that blanket statements about how patients are treated do not and simply cannot capture the nuance of patient care. To that end, simply asserting that the addressable market for Afrezza amounts to "the entire diabetic population" simply isn't true; right off the bat, I can tell you that even with all things being equal (which they're not), there will be any number of patients out there who don't get started on this insulin (or other insulins, for that matter) because of who they are, or what they want, or what their other medical illnesses are. I can say definitively that most patients won't (or shouldn't) get a medication that isn't indicated or where other, safer alternatives will suffice - but it's safe to say that for any drug, fewer people will end up on it than what the studies suggest.
The guidelines usually suggest starting insulin for DM patients with an A1C of more than 9%, or for those patients who have maximized therapy with oral hypoglycemic agents like metformin and/or sulfonylureas or incretin analogues and still aren't at goals of therapy. Most of these patients, I'll have a long discussion with them about starting insulin. The majority of them are resistant to the idea. They don't like needles, sure, but they also don't like starting yet another medication in addition to the bunches they're usually already on, and they're afraid of hypoglycemia. I usually reassure them. Insulin, I tell them, usually gives a patient and her doctor a huge amount of control over an illness that can be incredibly difficult to treat with pills alone. Using insulin pens, I can dial the dose in fairly precisely over a number of weeks, and with basal/bolus dosing (using a combination of insulin glargine and aspart, for example), I can titrate the dose to correspond with a fair degree of precision with the carbohydrate load a patient is about to ingest, their preprandial blood sugar, you name it. Insulin is remarkable because of its flexibility.
To sum this up, diabetes care (which is way more complex than this simple summary would seem to suggest - ask any doctor, they'll tell you) is a highly individualized disease that requires individualized treatment strategies, and what is wonderful and kind of liberating about insulin therapy is how flexible and precise it allows me to be with my therapy. It's a lot of work, to be sure, but it allows me to safely "dial in" on the proper dosage of medication for a patient for their goal blood glucose. Typically, once patients are dialed in and they're hitting their goal A1C, that represents hundreds of hours of effort from the patient and their doc. It's not something to be trifled with lightly. That goes for nearly any disease, really, but is especially true for DM care, and it would take a whole lot for me to switch out medications for a patient under good control (say, the risk of heart failure or bladder cancer for some of thiazolidinediones).
Afrezza - Weighing the Clinical Evidence:
I don't work for the Cochrane Group, and since I'm not at work, I don't have ready access to online resources to review the literature up close and personal. But I did have access to ClinicalTrials.gov, and doing a quick search for "Afrezza" brought up a total of 58 clinical trials, most of which don't have any results yet or only include Exubera as a study medication (more on that in a second). Out of curiosity, I tabulated some of the raw data from these trials. I included only trials that listed change from baseline A1C as a primary or secondary outcome, and also limited myself to those studies involving Afrezza (not Exubera). Trials without available data were excluded, as were studies focusing on pharmacokinetics that did not look at A1C change. The review generated 9 studies for inclusion for analysis:
Trial Title ClinicalTrials.gov Identifier Sponsor Purpose Study Type Allocation Intervention Model Masking Experimental Arm 1 Experimental Arm 2 Control Arm DM Type A1C Inclusion Smokers FEV1 TLC or FVC DLCO Significant Exclusion Criteria A1C Outcome Other Outcome 1 Other Outcome 2 Other Outcome 3
1 Safety and Efficacy of Technosphere ® Insulin Inhalation Powder and Lantus ® compared to Humalog ® and Lantus ® over 16-weeks NCT00700622 MannKind Corporation Non-inferiority Trial for Lowering of A1C Interventional Randomized Parallel Assignment Open label TI + Insulin Glargine 0 Insulin Lispro + Glargine Type 1 > 7, < 9 No smoking within 6 months > 70% > 80% > 70% Uncontrolled DM, history of hypoglycemic episodes, history of COPD or asthma, major organ system diseases Change from Baseline A1C to Week 16 A1C
2 Clinical Trial Evaluating the Efficacy and Safety of Technosphere ® Inhalation Insulin (NYSE:TI) Inhalation Powder using the Gen2 Inhaler NCT01196104 MannKind Corporation Non-inferiority Trial for lowering of A1C in comparison with Lantus + Aspart in DM2 Interventional Randomized Parallel Assignment Open label TI + Insulin Glargine 0 Insulin Aspart + Glargine Type 2 > 6.5, < 10 No smoking within 6 months > 65% 0 0 BMI > 45, history of COPD or asthma, serious complications of diabetes, history of CHF Class III-IV Change in A1C From Baseline to Week 16 Total Number of Cough Episodes Hypoglycemic Episodes
3 Clinical Trial Evaluating Technosphere® Insulin Versus Insulin Aspart in Subjects with Type 1 Diabetes Mellitus Over a 24-week Treatment Period NCT01445951 MannKind Corporation Open-label, randomized non-inferiority study Interventional Randomized Parallel Assignment Open label TI Gen2 + Basal Insulin TI MedTone C Inhaler + Basal Insulin Insulin Aspart + Basal Type 1 > 7.5, < 10 No smoking within 6 months > 70% 0 0 BMI > 38, history of hypoglycemic episodes, severe complications of diabetes, pregnancy, clinically significant abnormalities on CXR Change from Baseline to Week 24 A1C FEV1 Change from Baseline FPG Change from Baseline
4 Comparison of Technosphere ® Insulin Versus Technosphere Powder (Placebo) in Insulin-Naïve Subjects with Type 2 Diabetes Mellitus NCT01451398 MannKind Corporation Comparison of Prandial TI vs. Technosphere powder alone, both arms in conjunction with oral hypoglycemic agents, in insulin-naïve patients Interventional Randomized Parallel Assignment Double Blind TI + Oral Hypoglycemics 0 Technosphere Powder + Oral Hypoglycemics Type 2 > 7.5, < 10 No smoking within 6 months > 70% > 80% 0 BMI > 45, history of COPD, severe complications of DM, renal or cardiovascular disease, use of amiodarone Change from Baseline to Week 24 in HBA1C Proportion of Responders achieving A1C < 7.0% Proportion of Responders achieving A1C < 6.5% FEV1 Change from Baseline to Week 24
5 An Open-Label, Multi-center, International, Three-year, Safety and Tolerability "Follow on" trial NCT00754624 MannKind Corporation Non-Inferiority Interventional Non-Randomized Single Group Assignment Open label TI Powder with MedTone Inhaler (15, 30, or 60U doses) 0 0 Type 2 0 0 0 0 0 0 Annual Rate of Change in FEV1 from Baseline to End of Study (48 months) Change in FVC Change in DLCO Change in A1C
6 Efficacy and Safety of Prandial Inhalation of Technosphere Insulin in Combination with Metformin or Technosphere insulin alone vs. 2 Oral Anti-diabetic agents in subjects with Type 2 Diabetes NCT00332488 MannKind Corporation Non-Inferiority Interventional Randomized Crossover Assignment Open Label TI 15/30U, prandial TI 15/30U + Metformin Metformin + secretagogues Type 2 > 7.4, < 11 Nonsmokers > 70% > 80% > 70% BMI > 40, SCr > 1.4 (female) or 1.5 (male), history of COPD or asthma, serious complications of diabetes Difference in change from baseline to Week 12 A1C - TI + Metformin vs. Metformin / Secretagogue A1C change, TI Alone vs. Metformin + Secretagogue Change in A1C from Baseline to Week 24
7 Efficacy and Safety of Inhaled Insulin in Type 1 Diabetes NCT00308308 MannKind Corporation Efficacy Study Interventional Randomized Parallel Assignment Open label TI Insulin 0 Active comparator Type 1 >7, < 11 No smoking within 6 months > 70% > 70% > 70% History of COPD, evidence of severe diabetic complications, ALT or AST > 3x ULN Mean change from Baseline to Week 52 A1C Change from baseline to week 52 Weight Number of subjects achieving week 52 A1C levels < 7.0%
8 Safety of Inhaled Insulin with Type 1 and Type 2 Diabetes NCT00308737 MannKind Corporation Safety Study Interventional Randomized Parallel Assignment Open label TI Inhalation Powder 0 Usual Care Type 1 and Type 2 > 6.6, < 12 Nonsmokers > 70% > 80% > 80% BMI > 42, history of COPD, renal, hepatic, or cardiac disease, or severe complications of diabetes Change in A1C baseline to 24 months
9 Efficacy and Safety in Subjects with Type 2 Diabetes Receiving Subcutaneous Basal Insulin and Prandial Inhalation of Technosphere/Insulin versus Subcutaneous Premixed Insulin Therapy over a 52-week Treatment Period and 4 week Follow-up NCT00309244 MannKind Corporation Safety/Efficacy Interventional Randomized Parallel Assignment Open label TI Powder with MedTone Inhaler (15, 30, or 60U doses) 0 70/30 Aspart protamine / insulin aspart Type 2 > 7, < 11 No smoking within 6 months > 70% > 80% > 70% BMI > 40, total daily dose of insulin > 1.4 IU / kg, unstable DM control, CHF NYHA Class III-IV, SCr > 1.8 mg/dL (women), > 2.0 mg/dL (NYSE:MEN), Change in A1C to Week 52 Number of Subjects Achieving Week 52 A1C < 7.0% Total Hypoglycemia Severe Hypoglycemia
Trial results are briefly summarized below. Note that I didn't necessarily go through the methodology for each trial, but was limited only to the data on ClinicalTrials.gov. Note that I also do not differentiate between the specific Afrezza regimen or the specific control regimen; you could essentially argue that the data, in aggregate, is what you get when you compare adding Afrezza to a regimen vs. only using oral hypoglycemics (Trial 6) or using subcutaneous insulin instead. Here's what I collated:
Started Completed Not Completed Quit due to Adverse Events Lost to Followup Physician Decision Protocol Violation Withdrawal by Subject Other Age Female Male Weight BMI Starting A1C A1C Reduction
Trial 1
Exp Arm 65 52 13 4 0 2 0 4 3 38.6 25 40 74.5 25.07 7.76 -0.1
Control Arm 65 60 5 0 1 1 1 1 1 39.4 32 33 74.18 25.63 7.62 -0.03
Total / Average 130 112 18 4 1 3 1 5 4 39 57 73 74.34 25.35 7.69
Trial 2
Exp Arm 19 15 4 1 0 3 0 60.6 8 11 100.9 33.2 7.76 -1.2179
Control Arm 20 15 5 0 1 3 1 58.1 4 14 100.8 33.3 7.94 -1.2652
Total / Average 39 30 9 0 1 1 0 6 1 59.35 12 25 100.85 33.25 7.85
Trial 3
Exp Arm 1 174 130 44 16 1 3 2 21 1 37.61494253 97 77 75.7 26 7.98 -0.21
Exp Arm 2 174 138 36 9 2 1 2 16 6 40.10344828 94 80 76.8 26.2 8 -0.29
Control Arm 170 151 19 0 4 0 2 8 5 39.64705882 96 74 72.6 25.4 7.88 -0.4
518 419 99 75.03333333 25.86666667 7.953333333
Trial 4
Exp Arm 177 150 27 7 6 1 1 10 2 54.93220339 95 82 90.2 31.8 8.26 -0.82
Control Arm 176 139 37 9 4 1 6 14 3 55.3125 102 74 90.8 32.4 8.35 -0.42
Total / Average 353 289 64 16 10 2 7 24 5 55.12235169 197 156 90.5 32.1 8.305
Trial 5
Exp Arm 229 160 69 16 3 8 1 28 13 56.4 93 136 87.2 7.97 -0.048
Trial 6
Initial Treatment Phase
Exp Arm 1 183 133 50 8 1 13 3 21 4 57.3 93 84 86.1 8.9 -0.7
Control 170 152 18 2 3 2 1 10 0 57.6 88 74 84.1 8.9 -0.78
Exp Arm 2 175 119 56 6 0 10 0 20 20 56.8 101 68 83.9 9
Total / Average 528 404 124 16 4 25 4 51 24 57.23333333 282 226 84.7 8.933333333
Trial 7
Exp Arm 1 301 198 103 17 5 15 3 47 16 37.9 139 154 76.7 8.4 -0.13
Control 288 220 68 2 5 7 14 19 21 38.1 132 140 76.8 8.5 -0.37
Total / Average 589 418 171 19 10 22 17 66 37 38 271 294 76.75 8.45
Trial 8
Exp Arm 1 938 475 463 104 56 15 34 218 36 50.8 366 557 87.7 29.87 8.7 -0.42
Control 951 662 289 9 80 2 9 166 23 50.4 371 578 87.53 29.76 8.7 -0.49
Total / Average 1889 1137 752 113 136 17 43 384 59 50.6 737 1135 87.615 29.815 8.7
Trial 9
Exp Arm 1 334 216 118 29 6 5 6 50 22 55.9 160 163 88.1 8.7 -0.59
Control 343 246 97 12 22 8 3 32 20 55.9 185 146 85.7 8.7 -0.71
Total / Average 677 462 215 41 28 13 9 82 42 55.9 345 309 86.9 8.7
Because that table can be a bit much to look at, and even though this is precisely what they tell you not to do when it comes to meta-analyses (it's really not proper just to lump all these studies together like this, but it'll work for our purposes here today), here's how the studies all look in the aggregate:
Started Completed Not Completed Quit due to Adverse Events Lost to Followup Physician Decision Protocol Violation Withdrawal by Subject Other Age Weight BMI Starting A1C A1C Reduction
Experimental Arm Aggregate 2769 1786 983 216 81 73 52 438 123 49.82910798 84.66677501 29.08197156 8.493322499 -0.364760599
Control Aggregate 2183 1645 538 34 119 22 36 253 74 49.50384792 84.38480531 29.41686686 8.557993587 -0.512072377
Because medication adherence is a huge part of treating diabetes, besides looking at average A1C reduction, we can and should also look at discontinuation rates, and the reasoning thereto:
Quit Rate Adverse Event Rate Physician Decision Withdrawal By Subject
Experimental Arm Aggregate 35.50% 7.80% 2.64% 15.82%
Control Aggregate 24.64% 1.56% 1.01% 11.59%
So, just a couple comments here. The selection criteria stand out to me, first off: excluding any patient with COPD or significant respiratory disease, heart failure, or very poorly controlled DM2 alone significantly reduces the addressable population for the study medication in a way that would not necessarily apply to subcutaneous insulin. Furthermore, in the aggregate, under open-label conditions for the most part, and using a variety of treatment strategies, treatment with Afrezza was associated with a statistically significant (though perhaps clinically insignificant) lower rate of A1C reduction, when compared to either standard of care treatments or placebo. In addition, treatment with Afrezza was associated with a rate of withdrawal that was over 1,000 basis points higher than rates of discontinuation associated with control therapies. Discontinuation due to adverse events in particular stands out, as reported discontinuation due to adverse events were 5x higher with Afrezza. Furthermore, belying the argument that patients will actively flock to Afrezza because it doesn't involve needles, discontinuation rate due to subject withdrawal was over 400 basis points higher for Afrezza than for control.
A few points on the individual trials as well. It's notable that there were no "dummy-dummy" trials, in which patients and doctors were completely blinded to the medications used (a difficult thing to do with an inhaled versus injected insulin, to be sure, but would be doable using a dummy inhaler versus dummy syringe). One of the trials did look at Afrezza vs. Technosphere powder alone, but it would have been better for both of those arms to be compared to yet an additional control arm with a dummy inhaler without any sort of medication or carrier agent whatsoever. Finally, it's worth noting that a couple trials included in the analysis used a control arm that did not involve the use of a supplemental insulin therapy, which would be usual practice. It is likely that the observed effect of the control arm would have been greater if insulin had been used as a control; it is hardly surprising that Afrezza showed greater A1C reduction than nothing at all.
There are obvious, large caveats to this analysis. First of all, the data are heterogeneous, which is a limitation that applies to any meta-analysis. Furthermore, the reader may accuse me of selection bias, which is certainly possible: my own inclusion and exclusion criteria may have adversely affected the results of this little study, though I did my utmost to select all studies, without an eye towards outcome, that met my inclusion criteria. I should note that there may be other studies out there that are not currently posted on ClinicalTrials.gov that would sway these findings, though I don't have access to them currently (or know about them, to be honest). The aggregate numbers, though, suggest strongly that Afrezza is efficacious at lowering A1C, but may not be as efficacious as standard therapies or subcutaneous insulin, and is associated with a moderately higher incidence of adverse effects of all types and a mildly higher rate of self-discontinuation by patients. It is furthermore limited to use only in patients without respiratory disease, significant diabetic complications or very poorly controlled DM, and may be associated with further declines in lung function some years after initiation.
"What does UpToDate® Say?"
For those of you who aren't in healthcare, UpToDate is the WebMD of evidence-based medicine: readily available, comprehensive, and very dangerous in the wrong hands. It provides a number of monographs on pretty much any given topic that comes up in medicine, and is a handy go-to for me whenever I have a question that needs answering right now without having the time to do a PubMed search or consult a colleague. The site provides a quick refresher on inhaled insulins, and comes up with some interesting facts:
For one thing, most publicly available data on inhaled insulin are for Exubera, which is reflected in the efficacy data. Most trials involving inhaled insulin were, as in my analysis, open-label studies.
For type 1 diabetes, though similar A1C reductions were seen with Afrezza and control therapy, the inability to tightly control the dose remains a concern. A non-trivial increase in diabetic ketoacidosis was associated with Afrezza-treated patients, though the number reporting was small.
For Type 2 diabetes, comparisons with subcutaneous insulin or oral hypoglycemics showed greater improvements in A1C with inhaled insulin, but the doses of oral hypoglycemic agents were not adjusted to glycemic targets.
Because of the contraindications associated with a number of clinical situations (as noted above), it's estimated that inhaled insulin would be inappropriate in up to 40% of DM patients, which actually increases to up to 66% after 7 years due to progressive decline in pulmonary function.
As a result of the above, subcutaneous insulin therapy is recommended over inhaled insulin therapy for all Type 1 DM patients (a grade 1B recommendation), especially since fine-increment dosing required to avoid hypo- or hyperglycemia in brittle diabetics cannot be accommodated. The majority of DM2 patients who require insulin therapy should still be treated according to published algorithms, and where insulin is indicated, subcutaneous rapid-acting insulin is still preferred.
Patients who are started on inhaled insulin will still require routine assessment of pulmonary function on an annual basis.
Conclusion:
I make no assessments as to the ultimate financial success of Afrezza here; that's been done elsewhere and I don't think I have much to add to the discussion here on Seeking Alpha. What I do take away from this review is that there may be a subset of patients for whom Afrezza would be appropriate - Type 2 DM patients, without lung disease, without complications of their disease or significant comorbidities like heart failure, who aren't very poorly controlled and have a resistance to using insulin syringes or needles. This subset is far, far smaller than the overall diabetic population, and the threat to subcutaneous insulin remains subdued, in my mind. If other physicians are anything like me, they will be resistant to switch to a regimen with the potential for less fine-tuning and control and with generally less overall efficacy in achieving the primary endpoint of therapy (i.e., reducing A1C) - and studies suggest that discontinuation rates are higher for Afrezza anyway. For those readers who are supporters of Afrezza, I would suggest curbing your enthusiasm: a market exists, and it will make money - but probably not as much money as you think.
Additional disclosure: This article offers ideas and opinions, but does not constitute financial advice or medical advice for any particular person or group of people. Readers with medical concerns should consult their physician prior to making any decisions regarding their diagnosis or treatment. No offer of care or solicitation of business services is being made. You are responsible for your own financial decisions.
seekingalpha.com/article/2793285-one-internists-glance-at-mannkinds-afrezza?uide=2145281
One Internist's Glance At MannKind's Afrezza
I recently received a message asking for my opinion on the inhaled insulin, Afrezza, which is set to be released this year by MannKind (NASDAQ:MNKD) and Sanofi-Aventis (NYSE:SNY) for the treatment of diabetes mellitus. The drug has received a lot of attention on the Seeking Alpha pages, and I don't think I can add much insight to the discussion on its financial prospects. That said, as an internal medicine physician who, quite literally, treats diabetes mellitus every working day, I think I can speak with a minor bit of authority on the subject as to a clinical view of the drug. I'd also like to start with a quick review of the evidence for the use of the medication, its efficacy and safety profile - and, what is probably most important, in my opinion, whether I'd be inclined to offer it to my patients or not.
How I Treat Diabetes - A Very General View:
My process for starting insulin in diabetic patients is usually pretty simple, and can generally be summed up by a quick glance at the guidelines for the treatment of diabetes mellitus (quick note: talking about Type 2 diabetes here; starting insulin in Type 1 isn't optional). Generally speaking, once a patient receives a diagnosis of diabetes mellitus (henceforth, "DM2," or "DM"), physicians will stratify them by their A1C, which is a measure of glycosylated hemoglobin (that roughly corresponds to the absolute, average level of glucose in the blood over a 3-4 month period of time). Though this isn't strictly-speaking evidence-based (though there's some evidence to suggest that I'm onto something), I set an arbitrary A1C goal for my patients at their age divided by 10. For patients under 65, that means, for most of them, a goal A1C of less than 6.5%; for those over 65, their A1C target tends to go up as they get older. The overall decision-making process is intended to take into account age and comorbidities, and essentially amounts to an abbreviated risk-benefit analysis. It's a rule of thumb, and not a hard-and-fast rubric (not that anything ever is, in medicine), but I've found it useful to help me individualize decision-making for my patients, some of whom may warrant stricter glucose control because of relative youth or excellent functional status, and others for whom more liberal control is warranted, because of severe comorbidities, likely adherence with therapy, or medication intolerance.
(Source: AACE)
I bring this up because I want the reader to understand that medicine is an inherently personal experience that takes place between a patient and their physician, and that blanket statements about how patients are treated do not and simply cannot capture the nuance of patient care. To that end, simply asserting that the addressable market for Afrezza amounts to "the entire diabetic population" simply isn't true; right off the bat, I can tell you that even with all things being equal (which they're not), there will be any number of patients out there who don't get started on this insulin (or other insulins, for that matter) because of who they are, or what they want, or what their other medical illnesses are. I can say definitively that most patients won't (or shouldn't) get a medication that isn't indicated or where other, safer alternatives will suffice - but it's safe to say that for any drug, fewer people will end up on it than what the studies suggest.
The guidelines usually suggest starting insulin for DM patients with an A1C of more than 9%, or for those patients who have maximized therapy with oral hypoglycemic agents like metformin and/or sulfonylureas or incretin analogues and still aren't at goals of therapy. Most of these patients, I'll have a long discussion with them about starting insulin. The majority of them are resistant to the idea. They don't like needles, sure, but they also don't like starting yet another medication in addition to the bunches they're usually already on, and they're afraid of hypoglycemia. I usually reassure them. Insulin, I tell them, usually gives a patient and her doctor a huge amount of control over an illness that can be incredibly difficult to treat with pills alone. Using insulin pens, I can dial the dose in fairly precisely over a number of weeks, and with basal/bolus dosing (using a combination of insulin glargine and aspart, for example), I can titrate the dose to correspond with a fair degree of precision with the carbohydrate load a patient is about to ingest, their preprandial blood sugar, you name it. Insulin is remarkable because of its flexibility.
To sum this up, diabetes care (which is way more complex than this simple summary would seem to suggest - ask any doctor, they'll tell you) is a highly individualized disease that requires individualized treatment strategies, and what is wonderful and kind of liberating about insulin therapy is how flexible and precise it allows me to be with my therapy. It's a lot of work, to be sure, but it allows me to safely "dial in" on the proper dosage of medication for a patient for their goal blood glucose. Typically, once patients are dialed in and they're hitting their goal A1C, that represents hundreds of hours of effort from the patient and their doc. It's not something to be trifled with lightly. That goes for nearly any disease, really, but is especially true for DM care, and it would take a whole lot for me to switch out medications for a patient under good control (say, the risk of heart failure or bladder cancer for some of thiazolidinediones).
Afrezza - Weighing the Clinical Evidence:
I don't work for the Cochrane Group, and since I'm not at work, I don't have ready access to online resources to review the literature up close and personal. But I did have access to ClinicalTrials.gov, and doing a quick search for "Afrezza" brought up a total of 58 clinical trials, most of which don't have any results yet or only include Exubera as a study medication (more on that in a second). Out of curiosity, I tabulated some of the raw data from these trials. I included only trials that listed change from baseline A1C as a primary or secondary outcome, and also limited myself to those studies involving Afrezza (not Exubera). Trials without available data were excluded, as were studies focusing on pharmacokinetics that did not look at A1C change. The review generated 9 studies for inclusion for analysis:
Trial Title ClinicalTrials.gov Identifier Sponsor Purpose Study Type Allocation Intervention Model Masking Experimental Arm 1 Experimental Arm 2 Control Arm DM Type A1C Inclusion Smokers FEV1 TLC or FVC DLCO Significant Exclusion Criteria A1C Outcome Other Outcome 1 Other Outcome 2 Other Outcome 3
1 Safety and Efficacy of Technosphere ® Insulin Inhalation Powder and Lantus ® compared to Humalog ® and Lantus ® over 16-weeks NCT00700622 MannKind Corporation Non-inferiority Trial for Lowering of A1C Interventional Randomized Parallel Assignment Open label TI + Insulin Glargine 0 Insulin Lispro + Glargine Type 1 > 7, < 9 No smoking within 6 months > 70% > 80% > 70% Uncontrolled DM, history of hypoglycemic episodes, history of COPD or asthma, major organ system diseases Change from Baseline A1C to Week 16 A1C
2 Clinical Trial Evaluating the Efficacy and Safety of Technosphere ® Inhalation Insulin (NYSE:TI) Inhalation Powder using the Gen2 Inhaler NCT01196104 MannKind Corporation Non-inferiority Trial for lowering of A1C in comparison with Lantus + Aspart in DM2 Interventional Randomized Parallel Assignment Open label TI + Insulin Glargine 0 Insulin Aspart + Glargine Type 2 > 6.5, < 10 No smoking within 6 months > 65% 0 0 BMI > 45, history of COPD or asthma, serious complications of diabetes, history of CHF Class III-IV Change in A1C From Baseline to Week 16 Total Number of Cough Episodes Hypoglycemic Episodes
3 Clinical Trial Evaluating Technosphere® Insulin Versus Insulin Aspart in Subjects with Type 1 Diabetes Mellitus Over a 24-week Treatment Period NCT01445951 MannKind Corporation Open-label, randomized non-inferiority study Interventional Randomized Parallel Assignment Open label TI Gen2 + Basal Insulin TI MedTone C Inhaler + Basal Insulin Insulin Aspart + Basal Type 1 > 7.5, < 10 No smoking within 6 months > 70% 0 0 BMI > 38, history of hypoglycemic episodes, severe complications of diabetes, pregnancy, clinically significant abnormalities on CXR Change from Baseline to Week 24 A1C FEV1 Change from Baseline FPG Change from Baseline
4 Comparison of Technosphere ® Insulin Versus Technosphere Powder (Placebo) in Insulin-Naïve Subjects with Type 2 Diabetes Mellitus NCT01451398 MannKind Corporation Comparison of Prandial TI vs. Technosphere powder alone, both arms in conjunction with oral hypoglycemic agents, in insulin-naïve patients Interventional Randomized Parallel Assignment Double Blind TI + Oral Hypoglycemics 0 Technosphere Powder + Oral Hypoglycemics Type 2 > 7.5, < 10 No smoking within 6 months > 70% > 80% 0 BMI > 45, history of COPD, severe complications of DM, renal or cardiovascular disease, use of amiodarone Change from Baseline to Week 24 in HBA1C Proportion of Responders achieving A1C < 7.0% Proportion of Responders achieving A1C < 6.5% FEV1 Change from Baseline to Week 24
5 An Open-Label, Multi-center, International, Three-year, Safety and Tolerability "Follow on" trial NCT00754624 MannKind Corporation Non-Inferiority Interventional Non-Randomized Single Group Assignment Open label TI Powder with MedTone Inhaler (15, 30, or 60U doses) 0 0 Type 2 0 0 0 0 0 0 Annual Rate of Change in FEV1 from Baseline to End of Study (48 months) Change in FVC Change in DLCO Change in A1C
6 Efficacy and Safety of Prandial Inhalation of Technosphere Insulin in Combination with Metformin or Technosphere insulin alone vs. 2 Oral Anti-diabetic agents in subjects with Type 2 Diabetes NCT00332488 MannKind Corporation Non-Inferiority Interventional Randomized Crossover Assignment Open Label TI 15/30U, prandial TI 15/30U + Metformin Metformin + secretagogues Type 2 > 7.4, < 11 Nonsmokers > 70% > 80% > 70% BMI > 40, SCr > 1.4 (female) or 1.5 (male), history of COPD or asthma, serious complications of diabetes Difference in change from baseline to Week 12 A1C - TI + Metformin vs. Metformin / Secretagogue A1C change, TI Alone vs. Metformin + Secretagogue Change in A1C from Baseline to Week 24
7 Efficacy and Safety of Inhaled Insulin in Type 1 Diabetes NCT00308308 MannKind Corporation Efficacy Study Interventional Randomized Parallel Assignment Open label TI Insulin 0 Active comparator Type 1 >7, < 11 No smoking within 6 months > 70% > 70% > 70% History of COPD, evidence of severe diabetic complications, ALT or AST > 3x ULN Mean change from Baseline to Week 52 A1C Change from baseline to week 52 Weight Number of subjects achieving week 52 A1C levels < 7.0%
8 Safety of Inhaled Insulin with Type 1 and Type 2 Diabetes NCT00308737 MannKind Corporation Safety Study Interventional Randomized Parallel Assignment Open label TI Inhalation Powder 0 Usual Care Type 1 and Type 2 > 6.6, < 12 Nonsmokers > 70% > 80% > 80% BMI > 42, history of COPD, renal, hepatic, or cardiac disease, or severe complications of diabetes Change in A1C baseline to 24 months
9 Efficacy and Safety in Subjects with Type 2 Diabetes Receiving Subcutaneous Basal Insulin and Prandial Inhalation of Technosphere/Insulin versus Subcutaneous Premixed Insulin Therapy over a 52-week Treatment Period and 4 week Follow-up NCT00309244 MannKind Corporation Safety/Efficacy Interventional Randomized Parallel Assignment Open label TI Powder with MedTone Inhaler (15, 30, or 60U doses) 0 70/30 Aspart protamine / insulin aspart Type 2 > 7, < 11 No smoking within 6 months > 70% > 80% > 70% BMI > 40, total daily dose of insulin > 1.4 IU / kg, unstable DM control, CHF NYHA Class III-IV, SCr > 1.8 mg/dL (women), > 2.0 mg/dL (NYSE:MEN), Change in A1C to Week 52 Number of Subjects Achieving Week 52 A1C < 7.0% Total Hypoglycemia Severe Hypoglycemia
Trial results are briefly summarized below. Note that I didn't necessarily go through the methodology for each trial, but was limited only to the data on ClinicalTrials.gov. Note that I also do not differentiate between the specific Afrezza regimen or the specific control regimen; you could essentially argue that the data, in aggregate, is what you get when you compare adding Afrezza to a regimen vs. only using oral hypoglycemics (Trial 6) or using subcutaneous insulin instead. Here's what I collated:
Started Completed Not Completed Quit due to Adverse Events Lost to Followup Physician Decision Protocol Violation Withdrawal by Subject Other Age Female Male Weight BMI Starting A1C A1C Reduction
Trial 1
Exp Arm 65 52 13 4 0 2 0 4 3 38.6 25 40 74.5 25.07 7.76 -0.1
Control Arm 65 60 5 0 1 1 1 1 1 39.4 32 33 74.18 25.63 7.62 -0.03
Total / Average 130 112 18 4 1 3 1 5 4 39 57 73 74.34 25.35 7.69
Trial 2
Exp Arm 19 15 4 1 0 3 0 60.6 8 11 100.9 33.2 7.76 -1.2179
Control Arm 20 15 5 0 1 3 1 58.1 4 14 100.8 33.3 7.94 -1.2652
Total / Average 39 30 9 0 1 1 0 6 1 59.35 12 25 100.85 33.25 7.85
Trial 3
Exp Arm 1 174 130 44 16 1 3 2 21 1 37.61494253 97 77 75.7 26 7.98 -0.21
Exp Arm 2 174 138 36 9 2 1 2 16 6 40.10344828 94 80 76.8 26.2 8 -0.29
Control Arm 170 151 19 0 4 0 2 8 5 39.64705882 96 74 72.6 25.4 7.88 -0.4
518 419 99 75.03333333 25.86666667 7.953333333
Trial 4
Exp Arm 177 150 27 7 6 1 1 10 2 54.93220339 95 82 90.2 31.8 8.26 -0.82
Control Arm 176 139 37 9 4 1 6 14 3 55.3125 102 74 90.8 32.4 8.35 -0.42
Total / Average 353 289 64 16 10 2 7 24 5 55.12235169 197 156 90.5 32.1 8.305
Trial 5
Exp Arm 229 160 69 16 3 8 1 28 13 56.4 93 136 87.2 7.97 -0.048
Trial 6
Initial Treatment Phase
Exp Arm 1 183 133 50 8 1 13 3 21 4 57.3 93 84 86.1 8.9 -0.7
Control 170 152 18 2 3 2 1 10 0 57.6 88 74 84.1 8.9 -0.78
Exp Arm 2 175 119 56 6 0 10 0 20 20 56.8 101 68 83.9 9
Total / Average 528 404 124 16 4 25 4 51 24 57.23333333 282 226 84.7 8.933333333
Trial 7
Exp Arm 1 301 198 103 17 5 15 3 47 16 37.9 139 154 76.7 8.4 -0.13
Control 288 220 68 2 5 7 14 19 21 38.1 132 140 76.8 8.5 -0.37
Total / Average 589 418 171 19 10 22 17 66 37 38 271 294 76.75 8.45
Trial 8
Exp Arm 1 938 475 463 104 56 15 34 218 36 50.8 366 557 87.7 29.87 8.7 -0.42
Control 951 662 289 9 80 2 9 166 23 50.4 371 578 87.53 29.76 8.7 -0.49
Total / Average 1889 1137 752 113 136 17 43 384 59 50.6 737 1135 87.615 29.815 8.7
Trial 9
Exp Arm 1 334 216 118 29 6 5 6 50 22 55.9 160 163 88.1 8.7 -0.59
Control 343 246 97 12 22 8 3 32 20 55.9 185 146 85.7 8.7 -0.71
Total / Average 677 462 215 41 28 13 9 82 42 55.9 345 309 86.9 8.7
Because that table can be a bit much to look at, and even though this is precisely what they tell you not to do when it comes to meta-analyses (it's really not proper just to lump all these studies together like this, but it'll work for our purposes here today), here's how the studies all look in the aggregate:
Started Completed Not Completed Quit due to Adverse Events Lost to Followup Physician Decision Protocol Violation Withdrawal by Subject Other Age Weight BMI Starting A1C A1C Reduction
Experimental Arm Aggregate 2769 1786 983 216 81 73 52 438 123 49.82910798 84.66677501 29.08197156 8.493322499 -0.364760599
Control Aggregate 2183 1645 538 34 119 22 36 253 74 49.50384792 84.38480531 29.41686686 8.557993587 -0.512072377
Because medication adherence is a huge part of treating diabetes, besides looking at average A1C reduction, we can and should also look at discontinuation rates, and the reasoning thereto:
Quit Rate Adverse Event Rate Physician Decision Withdrawal By Subject
Experimental Arm Aggregate 35.50% 7.80% 2.64% 15.82%
Control Aggregate 24.64% 1.56% 1.01% 11.59%
So, just a couple comments here. The selection criteria stand out to me, first off: excluding any patient with COPD or significant respiratory disease, heart failure, or very poorly controlled DM2 alone significantly reduces the addressable population for the study medication in a way that would not necessarily apply to subcutaneous insulin. Furthermore, in the aggregate, under open-label conditions for the most part, and using a variety of treatment strategies, treatment with Afrezza was associated with a statistically significant (though perhaps clinically insignificant) lower rate of A1C reduction, when compared to either standard of care treatments or placebo. In addition, treatment with Afrezza was associated with a rate of withdrawal that was over 1,000 basis points higher than rates of discontinuation associated with control therapies. Discontinuation due to adverse events in particular stands out, as reported discontinuation due to adverse events were 5x higher with Afrezza. Furthermore, belying the argument that patients will actively flock to Afrezza because it doesn't involve needles, discontinuation rate due to subject withdrawal was over 400 basis points higher for Afrezza than for control.
A few points on the individual trials as well. It's notable that there were no "dummy-dummy" trials, in which patients and doctors were completely blinded to the medications used (a difficult thing to do with an inhaled versus injected insulin, to be sure, but would be doable using a dummy inhaler versus dummy syringe). One of the trials did look at Afrezza vs. Technosphere powder alone, but it would have been better for both of those arms to be compared to yet an additional control arm with a dummy inhaler without any sort of medication or carrier agent whatsoever. Finally, it's worth noting that a couple trials included in the analysis used a control arm that did not involve the use of a supplemental insulin therapy, which would be usual practice. It is likely that the observed effect of the control arm would have been greater if insulin had been used as a control; it is hardly surprising that Afrezza showed greater A1C reduction than nothing at all.
There are obvious, large caveats to this analysis. First of all, the data are heterogeneous, which is a limitation that applies to any meta-analysis. Furthermore, the reader may accuse me of selection bias, which is certainly possible: my own inclusion and exclusion criteria may have adversely affected the results of this little study, though I did my utmost to select all studies, without an eye towards outcome, that met my inclusion criteria. I should note that there may be other studies out there that are not currently posted on ClinicalTrials.gov that would sway these findings, though I don't have access to them currently (or know about them, to be honest). The aggregate numbers, though, suggest strongly that Afrezza is efficacious at lowering A1C, but may not be as efficacious as standard therapies or subcutaneous insulin, and is associated with a moderately higher incidence of adverse effects of all types and a mildly higher rate of self-discontinuation by patients. It is furthermore limited to use only in patients without respiratory disease, significant diabetic complications or very poorly controlled DM, and may be associated with further declines in lung function some years after initiation.
"What does UpToDate® Say?"
For those of you who aren't in healthcare, UpToDate is the WebMD of evidence-based medicine: readily available, comprehensive, and very dangerous in the wrong hands. It provides a number of monographs on pretty much any given topic that comes up in medicine, and is a handy go-to for me whenever I have a question that needs answering right now without having the time to do a PubMed search or consult a colleague. The site provides a quick refresher on inhaled insulins, and comes up with some interesting facts:
For one thing, most publicly available data on inhaled insulin are for Exubera, which is reflected in the efficacy data. Most trials involving inhaled insulin were, as in my analysis, open-label studies.
For type 1 diabetes, though similar A1C reductions were seen with Afrezza and control therapy, the inability to tightly control the dose remains a concern. A non-trivial increase in diabetic ketoacidosis was associated with Afrezza-treated patients, though the number reporting was small.
For Type 2 diabetes, comparisons with subcutaneous insulin or oral hypoglycemics showed greater improvements in A1C with inhaled insulin, but the doses of oral hypoglycemic agents were not adjusted to glycemic targets.
Because of the contraindications associated with a number of clinical situations (as noted above), it's estimated that inhaled insulin would be inappropriate in up to 40% of DM patients, which actually increases to up to 66% after 7 years due to progressive decline in pulmonary function.
As a result of the above, subcutaneous insulin therapy is recommended over inhaled insulin therapy for all Type 1 DM patients (a grade 1B recommendation), especially since fine-increment dosing required to avoid hypo- or hyperglycemia in brittle diabetics cannot be accommodated. The majority of DM2 patients who require insulin therapy should still be treated according to published algorithms, and where insulin is indicated, subcutaneous rapid-acting insulin is still preferred.
Patients who are started on inhaled insulin will still require routine assessment of pulmonary function on an annual basis.
Conclusion:
I make no assessments as to the ultimate financial success of Afrezza here; that's been done elsewhere and I don't think I have much to add to the discussion here on Seeking Alpha. What I do take away from this review is that there may be a subset of patients for whom Afrezza would be appropriate - Type 2 DM patients, without lung disease, without complications of their disease or significant comorbidities like heart failure, who aren't very poorly controlled and have a resistance to using insulin syringes or needles. This subset is far, far smaller than the overall diabetic population, and the threat to subcutaneous insulin remains subdued, in my mind. If other physicians are anything like me, they will be resistant to switch to a regimen with the potential for less fine-tuning and control and with generally less overall efficacy in achieving the primary endpoint of therapy (i.e., reducing A1C) - and studies suggest that discontinuation rates are higher for Afrezza anyway. For those readers who are supporters of Afrezza, I would suggest curbing your enthusiasm: a market exists, and it will make money - but probably not as much money as you think.
Additional disclosure: This article offers ideas and opinions, but does not constitute financial advice or medical advice for any particular person or group of people. Readers with medical concerns should consult their physician prior to making any decisions regarding their diagnosis or treatment. No offer of care or solicitation of business services is being made. You are responsible for your own financial decisions.