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Afrezza Review for FDA DMEP Consideration by Martin Shkreli

CDER, DMEP and FDA should issue a CRL to MannKind for Afrezza with a request for more
clinical trials. Afrezza poses substantial public health concerns in the face no imminent medical need.
The FDAs own guidance strongly suggests the Afrezza NDA has not met the burden of proof required for
approval. Herein I will pose substantial questions regarding the adequacy and integrity of the Afrezza
data sets.
There are two smoking guns that summarize my case. These deal-breakers are
supplemented by a common-sense approach to the regulatory process and a deeply researched and
analyzed perspective of MannKinds data.
Smoking gun number 1: Every Phase III MannKind study has either failed outright (4/6: TI-014,
TI-009, TI-103, TI-030) or will be disqualified due to technical circumstances (2/6: TI-117, TI-102). This
lack of success in phase 3 precludes approval of Afrezza.
Smoking gun number 2: MannKind has proposed that the FDA approve the new Dreamboat
inhaler even though the Afrezza pivotal phase III trials were conducted using the Medtone inhaler.
The FDA should not take inhaler switches lightly; inhalers are complex devices and long-standing FDA
guidance and practice suggests clinical efficacy and safety trials are required to allow for an inhaler
switch. The trial guidance and subsequent practice stipulates the old inhaler must be compared to the
new inhaler in a clinical trial, potentially one of long duration. Because MannKind no longer produces
the older MedTone inhaler model, it will be very difficult, to conduct head-to-head trials of the two.
Because the FDA questions the clinical utility of Afrezza in the first place, it is possible MannKind will
choose the prudent course of discontinuing inhaled insulin development when faced with the request
of new clinical trials.
All details are included below and I am happy to answer questions at your convenience.
Martin Shkreli
212-983-1310
martin@msmbcapital.com
Why should the FDA refuse to approve Afrezza?
1. Every Phase III Trial Failed
2. Medical necessity given weak efficacy and uncertain safety
3. Different inhalers used in trials vs. approval request, bioequivalence failures and bioavailability
discrepancies
4. Exubera
5. Auditing/compliance questions
6. Initial rejection
7. Trust
8. Fast-acting hypothesis
9. Failure to meet exposure criteria
10. Basal insulin as a confounding factor

1 Every Phase III Trial Failed


The FDA only approves new drugs with at least two successful phase III studies. Rare exceptions
include drugs for life-threatening illnesses. MannKind noted that their NDA submission included three
Phase III trials designated as pivotal trials (TI-012, TI-009 and TI-030) (26). Of course, the submission
includes all six Phase III trials, but the Company is required to designate which they feel confirm the
safety and efficacy of the product.
Phase III trial TI-012 was conducted in Type 2 Diabetes patients and the results were published
in the prestigious Lancet medical journal (3). The FDA should decline to accept this study as pivotal
because the study compares Lantus plus Afrezza versus NovoLog Mix. Comparing A+B versus C does not
imply any information about A or B individually. While the FDA signed off on this trial as part of an SPA
agreement, it remains to be seen what the relevance is as SPAs are generally not binding and the
context of the agreement is not understood. When communicating with MannKind it is difficult to
understand if the FDA has accepted this trial as relevant. In what you will come to see is classic
MannKind doublespeak, the company CSO noted to me: Based on the feed back [sic] from the agency it
would be safe to say that there is no indication that 102 is not accepted (27). No indication that a trial is
not accepted does not prove or imply acceptance.
In a study of just A versus C, in other words Lantus versus NovoLog Mix (without any inhaled
insulin, or prandial insulin for that matter!), Lantus and NovoMix were shown to be very similar: a -1.4%
decline for NovoMix and a -1.2% decline for Lantus at 26 weeks (36). The exact difference was -0.16%
and the authors concluded these treatments are similar and statistically non-inferior. How then is TI-102
a useful study, since we know that Lantus is non-inferior to NovoMix BID? Proving Lantus plus Afrezza is
non-inferior to NovoMix BID is not valuable as we already know Lantus is non-inferior to NovoMix BID.
In the TI-102 study, Lantus plus Afrezza are again weaker than NovoMix BID: a -0.12% difference. While
it is hard to compare across trials with statistical rigor, it sure looks like Afrezza adds nothing to the
Lantus versus NovoMix BID question.
The TI-012 trial has other important issues. Basal insulin dose (Lantus) was not fixed throughout
the study (28). This renders the study meaningless. As we saw in Levemirs initial rejection (2), and
common sense dictates, comparing varying doses of A + B versus C and reaching a non-inferiority
endpoint doesnt exclude the possibility (and in this case, high likelihood) that increasing doses of A
were responsible for changes seen in the primary endpoint. No data regarding how much basal insulin
was used in TI-102 is available, either in the paper (3), web appendix (30) or editorial accompanying the
article (29). An e-mailed question to the principal investigator of TI-102 was met with a refusal to answer
the question on grounds this physician does not communicate with investment companies (31).
Especially with an open-label design, it does not take a conspiracy theorist to see strong encouragement
from MannKinds clinical team for increasing doses of Lantus and Afrezza to meet NovoMixs efficacy.
Finally, the trial shows flaws with efficacy and safety. There are broad imbalances in safety
issues with Afrezza + Lantus versus NovoMix BID, including 4 deaths vs. 1 death (deaths are atypical in a
study like this), increased infection and cough, and increased dropouts in general. Efficacy was weaker
than control, as is found in every single Afrezza study. The FDAs questions regarding clinical utility
(clinical relevance in the scope of more potent diabetes drugs) are not helped by TI-102. While the
upper limit of the CI in the comparison between groups reached 0.29%, below the 0.40% limit, the

0.40% limit is arbitrary and the FDA may question it as their guidance document indicates limits
between 0.30% and 0.40% are relevant. With strong safety imbalances, Russian and Bulgarian problem
sites enrolled in this study (30) and an open-label nature, assigning TI-102 as a clinically relevant and
successful study is a reach.
TI-009 is the main type 1 diabetes pivotal study (11, 26). This study failed to meet its primary
endpoint of the upper CI comparing the two groups A1C change falling below the non-inferiority margin
of 0.40%. MannKind has towed the line of being close: the upper limit CI does fall at exactly 0.40%, the
95% CI for Afrezza versus NovoLog was 0.08 to 0.40 using ANCOVA (11, Table 1). Unfortunately for
MannKind, statistical literature confirms non-inferiority is only possible when the upper limit lies below
the non-inferiority margin; at or above implies failure to meet non-inferiority (37). MannKind admits the
FDA has had problems accepting TI-009. Im not surprised given the study had a documented imbalance
of Lantus use (11), likely due to weak Afrezza efficacy. There was not only a greater numerical use of
Lantus in the Afrezza group, but also a much higher standard deviation of Lantus use. A former FDA
director of 25 years has indicated to me that this is a big problem.
Table 1. TI-009 pivotal trial results (11).

Another important issue with TI-009 is the choice of non-inferiority margin. Non-inferiority is a
complex topic, but the general lay persons description is that non-inferiority margins give comfort to
patients, physicians and payers that the drug is guaranteed to perform within an error margin (noninferiority). That error margin must be useful; it must be relevant to the effect size seen in the first
place. This study showed a very small effect, with the control group reaching A1C change of -0.37%. A
non-inferiority margin, 0.40%, larger than the effect size, 0.37%, is logically unacceptable. It is
meaningless to say the error band around a comparable drug includes no effect. The FDA notes they
accept a non-inferiority margin of 0.3% to 0.4%, provided that it is a suitably conservative estimate of

the magnitude of the treatment effect of the active control (1). 0.40% fails to be a suitably
conservative estimate of the treatment effect of the active control in fact, it is more than it!
Biodel recently had a problem convincing the FDA that they met their non-inferiority margins
(22). While MannKind had previously refused to acknowledge the failure of TI-009, they now seem to
have come to terms with it. Al Mann (CEO) said on June 9th, 2010, I said the 117 trial addresses the
question of A1C and the 009 trial, which was if you look at the ANCOVA statistical model on the LOCF,
which exaggerates the negativity with that statistical analysis, were essentially at the limit of the 0.4%
tolerance they provide. If you look at the mix model, looking at just the data we are actually within the
level (12). Peter Richardson (CSO), said on June 24th, 2010, I think in one of our studies, we discussed
at length in terms of the non-inferiority margin and were at the upper end of the non-inferiority margin
there. We actually have addressed that by one of the important studies that we launched after that,
based on learnings from that study (13). The FDA guidance specifically demands ANCOVA as the
preferred statistical method, not the mixed-model method (1).
There are more discrepancies with TI-009. The following graphic is taken from the TI-009 poster
and indicates an alarming difference in data calculation on the very same poster. On the left of the
poster, MannKind claims -0.13% A1C change for Afrezza, and on the right, the sophisticated computer
technology I used determines a value of closer to -0.17%. More alarming is the comparator arm which
seems wildly different from the left side of the poster. Both columns allege ITT population analysis.
Table 2. TI-009 results discrepancy. (11).

The rest of MannKinds Phase III trial results are less equivocal. Study TI-104 was conducted
largely in Russia; the clinicaltrials.gov listing only displays Russian study centers (24). I will show
evidence later that raises suspicion regarding the integrity of MannKinds Russian study results. It is
interesting to note this study has never been widely published. MannKind issued a pseudo-release on
the data by publishing a small extract in its annual report from 2006 (25). However at the ADA 2007

meeting, MannKind disclosed in a poster that this study actually failed to reach its primary endpoint. TI104 demonstrated that NovoLog was nearly superior to Afrezza, p=0.0564; I believe the original primary
endpoint was Afrezza superiority to NovoLog. Otherwise, MannKind would describe a non-inferiority
margin. Using a failed superiority analysis (where the control is superior to the investigational) to imply
non-inferiority is bush league.
Study TI-030 was a safety study with a safety primary endpoint. The study randomized
diabetics to taking Afrezza or continuing on their current medications without it. After 2 years, there was
no statistical difference in A1C change, p=0.30. It is shocking to me that adding a meal-time insulin did
not improve hyperglycemia for these patients. Study TI-117 was interrupted early. Studies that enroll
half of their intended sample size are not considered valid. These study results are curious to begin with,
anyway. For instance, this 16-week study defies the FDA that specifically requests 6- to 12-month
controlled trials and long-term extensions of them to ensure clinical relevance (1). The 135 that were
enrolled and the 16-week nature make it difficult to refer to this study as pivotal. Study TI-103 is
mysterious, very little is written about it, but MannKind admits on a conference call the study failed to
demonstrate statistical significance.
The most legitimate MannKind studies are TI-009 and TI-102. Both studies were available for
the FDA for their first review. The FDA refused to approve Afrezza on grounds MannKind must
demonstrate the drugs clinical utility. The only new study TI-117 should not change the FDAs mind.
In an e-mail to MannKind, I attempted to glean if TI-117 supports TI-009 as a pivotal trial, or if TI-009
supports TI-117 as a pivotal trial. It is my understanding this is the way the FDA looks at the problem.
Because TI-009 technically failed and the FDA refused approval when they had this information, and TI117 was interrupted early and had a very small sample size, I received a somewhat circular answer. Note
that two successful phase III trials is a bare minimum for approval.
2 - Different inhalers used in trials vs. approval request, bioequivalence failures and bioavailability
discrepancies
MannKind has requested approval for the Dreamboat or gen 2 inhaler, an inhaler that is
smaller than their prior MedTone inhaler. However, the Dreamboat inhaler is substantially different
from the MedTone inhaler that was used in the phase III trials submitted to the FDA for approval. It uses
a different dose of insulin. It has a different expected use life. It uses different sized cartridges. It has a
different make and appearance. It results in less cough and has other relevant differences.
When changing dry powder inhalers (DPI), the FDA has specific instructions for the
pharmaceutical industry (32). This guidance document specifically states that two new clinical trials
comparing Dreamboat to Medtone must be conducted (page 10, 32). The first study is a dose-ranging
study that compares Medtone to Dreamboat to Dreamboat with no insulin. MannKind has no study
resembling this basic requirement. The next suggested study is a clinical trial comparing Dreamboat to
Medtone in an efficacy trial. MannKind no longer manufactures the Medtone inhaler (20), making it very
challenging to conduct these FDA-required studies. The FDA should enforce their requirements and not
simply allow MannKinds bioequivalence study to serve as proof these two devices are equivalent.
While the bioequivalence study does confirm each device delivers a similar amount of insulin to
patients (and it has its own flaws in that respect), it says nothing about the longer-term safety of
Dreamboat. The ex-FDA consultant I have spoken with believes it is extremely unlikely approval will

occur, and this is one of the key reasons why. Another consultant noted the proposed approval of
Dreamboat based solely on a bioequivalence study was unreal to her.
I spoke with a former employee of Aventis. Recall that Exubera was developed by Nektar
(formerly known as Inhale Therapeutics), Pfizer and Aventis (subsequently known as Sanofi-Aventis).
Nektar has said in public statements, confirmed by the former Aventis employee, that a new inhaler was
in development. The former employee stated, market research knew the first inhaler was going to be a
problem, so we considered a bioequivalence study between Exubera and our new inhaler. The FDA
advised us a new clinical program would be required. I think the evidence I have accumulated that
Dreamboat has not been sufficiently tested, and therefore approval of Afrezza is impossible, is
insurmountable.
MannKind has begun several new phase III studies with the Dreamboat (18). These studies are
expensive and likely would not have been launched unnecessarily. The FDA should be conservative and
require results from these trials before approval of the Dreamboat, assuming results are good and they
can find comfort with the rest of the content of this document. To my knowledge, there have been four
different MedTone inhalers and one Dreamboat inhaler used in the Afrezza development program.
Reconciling these data is not likely to be worth doing as new head-to-head efficacy studies will provide
more precise information.
The FDA holds a high standard for formulation changes for even simpler drugs. Recently, TEVAs
Copaxone suffered a rejection when they tried to receive approval for a lower-volume injection of the
same drug. The FDA suggested a full clinical trial to compare the two formulations (34).
There is controversy surrounding particle size with Afrezza. In one poster (10), MannKind claims
the average diameter of Technosphere (Afrezza) particles is 2-2.5uM. In another, it claims 3.88uM for
Dreamboat and 13.28uM for Medtone (35). This data not only suggests questionable data integrity, but
also supports the thesis that Dreamboat may be substantially different from Medtone in a clinical trial.
3 - Medical necessity given weak efficacy and uncertain safety
There is no pressing medical need for inhaled insulin. There are a number of insulins available on
the market: Lantus, NovoLog, Humalog, Humulin, Novolin, Apidra and Levemir, all of which have good
long-term safety profiles and have satisfied regulators. These drugs have a good convenience profile and
there is no evidence to show Afrezza will make a difference with respect to compliance. There are
multiple classes of type 2 diabetes drugs that allow for glycemic control above and beyond insulin, as
well. Therefore it behooves the FDA to carefully understand the risk-benefit trade off and err on the side
of caution.
The safety risks of approving Afrezza without long-term information on cancer and lung function
(due to the new delivery method and excipient FDKP) raise a high hurdle for the FDA. We have no
information on these topics because the trials did not interrogate these issues, and the trials used a
different inhaler that is not bioequivalent to the inhaler MannKind used in trials. The rest of this
document will substantiate safety concerns.
The FDA considers medical need carefully when approving drugs. Here is an excerpt from the
first-cycle rejection of Levemir by the FDA: insulin detemir does not offer any major advantage over
NPH Therefore, a delay in the approval of detemir will not deprive patients of the benefits of an

improved insulin. For these reasons, I believe that detemir should not be approved (2). Novo
conducted a dozen pivotal trials of Levemir and still saw the FDA disqualify many ostensibly successful
trials due to technicalities.
4 - Exubera
Pfizers inhaled insulin Exubera was approved in 2006 only to see Pfizer remove marketing of the
drug in 2007 due to poor sales. In 2008, a lung cancer analysis showed Exubera had several-fold more
cases of lung cancer than its control arms in trials. The FDA should question both safety and clinical
meaningfulness that Afrezza brings to the table. On the medical need front, the FDA now sees from the
non-use of Exubera that patients are not crying out for inhaled insulin therapy. Taking a high risk,
namely that Afrezza is unsafe is now not worth the very low reward, namely that very few patients will
bother taking the drug in the first place to be helped by its benefits.
Although the FDA approved Exubera, I argue that the FEV1 changes in Exubera are linearly
progressive and dangerous (page 45, 4). The FDA required significant long-term post-marketing studies
to examine these effects.
The cancer label modifications with Exubera are distressing. In a letter to Pfizer on September
29th, 2008, the FDA noted that they conducted an analysis of clinical trial data, postmarketing reports
and medical literature that showed an imbalance in lung cancer between Exubera and control groups
(14). Pfizers press release in April 2008 noted 7 cases of lung cancer versus 1 in control groups of clinical
trials (15). While these data dont prove a lung cancer link, the large amount of insulin inserted in the
lung due to low bioavailability of inhaled insulin renders a potential mechanism of action reasonable.
Without much benefit to inhaled insulin, any risk of serious adverse events must be taken seriously.
5 - Auditing/compliance
There are two documented whistleblowers (former employees) that insist MannKind has
covered up questionable data to avoid FDA scrutiny. The first is Wendell Cheatham, who was
MannKinds CMO.
In a Complaint filed on May 23rd, 2005, Cheatham accused MannKind of wrongful termination
for first trying to bring to Al Manns attention discrepancies in methods of formulation and in testing
that could potentially result in mistakes leading to injury or fatalities in the clinical trials, and then for
alerting specific quality control issues with erroneous filling of drug supply cartridges and a failure to
appropriately conduct tests of drug performance prior to packaging and shipping to clinical sites for
human testing. This failure and the subsequent analysis could have lead [sic] to the delivery of a drug to
patients at a rate of one and a half to two times that which it should have been. This resulted in an
additional amendment to the protocols, which Plaintiff was again chastised for by management (16).
Finally, Cheatham alerted the company to his finding that the company was, in his eyes, fraudulently
and illegally filing that the Afrezza Phase II and Phase III formulations were similar (16). Cheatham
settled with MannKind. This behavior seems to indicate MannKind is indeed a company that cuts
regulatory corners.
John Arditi sued MannKind on September 16th, 2010. Arditi and his colleague noticed data fraud
from certain clinical trials sites in November 2009, 6 months after MannKind filed their NDA with the
FDA (17). Specifically, Dr. Yuri G. Shvartzs clinical trial site in Russia contained fraudulent data, and

Bulgarian data had similar fraud (17). My knowledge of MannKinds clinical trials indicates that these
sites likely enrolled patients in the TI-014 study, which had largely Russian patients. This is one of the
only allegedly successful studies in the Afrezza program. Without this study, which appears to contain
invalid data, MannKind has no hope of receiving Type 2 Diabetes approval.
6 - Initial rejection
MannKind initially filed the Afrezza NDA in March 2009. On March 15th 2010, the FDA rejected
Afrezza by issuing a complete response letter. In my experience, the FDAs actions generally speak very
loudly. The rejection letter asked for information supporting the clinical utility of Afrezza, as well as
currently available clinical data that support the clinical utility of Afrezza. As MannKind puts it, The
letter did not require any additional pre-marketing clinical studies in order for the FDA to complete its
review of the NDA. This is very careful wordsmithing. MannKind seems to insist new clinical trials were
not required to approve Afrezza; however the company has conducted additional clinical trials in the
time between the prior rejection and the upcoming rejection. My experience leads me to believe
MannKind has misled investors and analysts on this topic: if no new clinical trials were required, why has
MannKind conducted so many? Even though the FDA did not require additional pre-marketing clinical
studies to complete its review, a complete review does not imply approval. Note that MannKind did not
say, the letter did not require any additional pre-marketing clinical studies in order for the FDA to
approve Afrezza.
Furthermore, the phrase clinical utility is very alarming. It should be very clear what the
clinical utility of Afrezza is: it is used as a meal-time insulin to control hyperglycemia. Why would the
FDA need for information regarding its clinical utility? The answer is because Afrezza has such weak
efficacy; it is not a useful tool for physicians and patients.
7 - Trust
Management has indicated partnership potential previously and failed to deliver. Management
has not been clear about many regulatory topics, including the FDAs first rejection of Afrezza.
Mannkinds most recent 10-K filing includes this statement: "A consistent finding was that AFREZZA
produced decreases in A1C levels that were essentially comparable to the decreases observed in the
control arm of these studies". The term essentially comparable should not be necessary, as Afrezza is
required to be comparable without qualification.
8 - Fast acting hypothesis
The ultra-fast-acting hypothesis MannKind claims gives Afrezza its differentiated clinical profile
is an about face from the convenience claim the company first trumpeted many years ago. The failure of
Exubera and the encroachment of five competing inhaled insulins (all of which were abandoned) caused
MannKind to alter their sales pitch. While Afrezza may or may not have a substantially different
physiological effect than other insulins, the applicability of ultra-fast-action is debatable. While most of
the medical community agrees that suppressing glucose excursions is a good thing, I would imagine the
FDA would want to discuss this at an advisory committee meeting or confirm the benefit with an
outcomes study. Indeed, a paper published by Currie and colleagues suggests such tight A1C control
may not be so beneficial (33). Of course, if Afrezza had such a great clinical profile, it would have
suppressed glucose at least as well as other rapid acting agents, but it failed to do so.

9 - Failure to meet exposure criteria


The FDA clearly states in its guidance document (lines 843-855, 1) for diabetes products that
2500 subjects should have been exposed to the investigational product. I believe MannKind very
narrowly makes this estimate. The document further states at least 1,300 to 1,500 of these subjects
exposed to the investigational product for 1 year or more and at least 300 to 500 subjects exposed to
the investigational product for 18 months or more. I believe MannKind has clearly failed to establish
these criteria. MannKind has likely followed 1,100 Afrezza patents, at most, for over 1 year.
Exubera was approved on January 27th, 2006 with only 589 patients exposed to drug for more
than 1 year. The FDAs guidance document post-dates the Exubera approval and is likely a reaction to
prior lax policy that resulted in Exubera, phen-fen, Accomplia and Avandia issues, among other agents.
10 - Basal insulin as confounding factor
All but one pivotal study run by MannKind for Afrezza included other insulins. As patients titrate
their insulin to meet glycemic goals, it is impossible to know if Afrezza is a useful insulin without also
knowing what basal insulin starting and finishing doses were in clinical trials. Only one phase 3 was
published and no information is contained in this publication (3), other than titration was allowed.
It is impossible to determine the efficacy of a prandial insulin unless basal insulin dose is locked
in place. Otherwise up-titration of basal insulin will compensate for weak prandial insulin effects. This
dynamic led to the CRL received by Levemir (2).

Phase
Name
n
Primary
Arms
Duration Population
Disclosure
Outcome
Notes
CT
137
Change from Visit 5 to Visit 14 in A1C
Afrezza+Lantus versus Humalog+Lantus
16 weeks T1 Diabetes 6/10/10 PR Unclear
Not Reliable NCT00700622
III Pivotal
TI-117
308
Mean change in A1C from baseline
Afrezza+Basal versus RAA+Basal
24 weeks T2 Diabetes 2006 AR
Less Efficacy All Russian Centers?
NCT00539890
III Pivotal
TI-014
565
Compare mean change from baseline to week
Afrezza+Lantus
52 in A1C versus Novolog+Lantus
52 weeks T1 Diabetes EASD 2009 Unclear
Failure
NCT00308308
III Pivotal
TI-009
547
Change in AIC from baseline at 12 weeks. Afrezza mono vs Orals vs Afrezza+metformin 24 weeks T2 Diabetes Analyst Day Monotherapy???Odd results NCT00332488
III Pivotal
TI-103
654
Mean change in A1C from baseline at 52 weeks
Afrezza+Lantus vs NPH???
52 weeks T2 Diabetes Lancet Pub, 12/18/08
Success
PR
Only PublishedNCT00309244
III Pivotal
TI-102
II/III Pivotal
TI-101
110
Change in blood glucose following meal Afrezza+Lantus vs NovoRapid+Lantus
12 weeks T1 Diabetes Unclear
Unclear
Phase 2 or 3!? NCT00539396
III Safety
TI-030
2343 Pulmonary study.
Afrezza or SOC
2 year
Diabetes
Unclear
Unclear
NCT00308737
III Safety Substudy
TI-164
200
DLCO/FEV. PFT study for -161, -162, -166 Gen2 Afrezza vs SOC
Unclear Diabetes
N/A
ENROLLING NCT01201928
III Pivotal
TI-162/AFFINITY-2
360
Non-inferiority at week 16
Gen2 TI+Lantus versus Novolog+Lantus
16 weeks T2 Diabetes N/A
ENROLLING NCT01196104
III Pivotal
TI-166
N/A
N/A
Gen2 Afrezza
N/A
N/A
N/A
N/A
Not Listed
III Pivotal
TI-161
N/A
N/A
Gen2 Afrezza
N/A
N/A
N/A
N/A
Not Listed
III Safety
TI-105
N/A
Terminated
Terminated
TerminatedAsthma
Terminated Terminated
Terminated
NCT00332826
III Safety
TI-126
672
Safety
-009, -102, -103, -030 pulmonary follow
8 weeks Diabetes
None
N/A
NCT00741429
III Safety
TI-134
510
Safety
TI vs SOC
52 weeks Asthma/COPD N/A
ENROLLING NCT00642616
II Formulation TI-142
N/A
CI between 0.8-1.25 for Medtone C/D versusAfrezza
Gen2. Primary
Gen2 versus
endpoint
Medtone
on poster
C, Afrezza
is misleading/unclear.
2x10U 3versus
days 1x20U.
Healthy
Presented at DTM
Significant
2010 red flags:
Crossover
90% of
CIhealthies
forNot
BE.Listed
- no diseased
II Formulation TI-116
28
Bioequivalence
TI A, TI B, Humalog
6 hours T1 Diabetes None
N/A
NCT00662857
II Safety
TI-005
217
MRI results
Technosphere, possible control group?
18 weeks T2 Diabetes Unclear
Unclear
NCT00511732
II Safety
TI-010
228
MRI results
Technosphere, open-label extension of -005
3 years? Diabetes
EASD 2009 Unclear
NCT00754624
II Efficacy
PDC-INS-0008
N/A
Glucose control
TI versus TI placebo
12 weeks T2 Diabetes Unclear
Unclear
NCT00511602
II Efficacy
TI-016
24
Bioavailability between smoker/non-smokerAfrezza
52 days T2 Diabetes Unclear
Unclear
NCT00934414
II Efficacy
TI-119
30
PPG excursion
TI vs Humalog
15 weeks Diabetes
N/A
RECRUITING NCT00747006
II Efficacy
TI-03B
16
Meal challenge
Afrezza
6 hours T2 Diabetes Unclear
Unclear
NCT00419302
II Efficacy
TI-118
30
EGP
Afrezza
8 hours T2 Diabetes Unclear
Unclear
NCT00570687
II PK
TI-003B2 N/A
PK
versus Insulin
TI vs Human
Insulin? the FDA considers
Unclear
Unclear
Unclear
NCT00511719
There
is substantial evidence
to suggest
typeT21Diabetes
diabetes
and type
2 diabetes
II Safety
TI-112
50
PK of FDKP
Afrezza vs SOC
4 hours Diabetes
Unclear
Unclear
NCT00642681
different
diseases,
and
therefore,
companies
wishing to receive an
approval
insulinUnclear
productGlucose
are Infusion,NCT00511979
I Efficacy
PDC-INS-0002
N/A
Dose
response effect
versus
insulin
TI
vs Human Insulin?
Unclear
Healthy for any
Unclear
1999 initiation
I QTc
T-131 required
48
QTcto
interval
TI vs moxifloxacin
days Healthy
Unclear
Unclear
NCT00721344
prove efficacy and safety
with preferably two pivotal11trials
for each disease.
Pfizer
I PK
TI-114
12
PK
TI, Albuterol, Fluticasone
6 hours Healthy
Unclear
Unclear
NCT00674050
conducted
four pivotal trials for Exubera
in each disease. Novo Nordisk
conducted
seven Levemir
phase
I PK
TI-017
36
PK
Afrezza
14 days CKD
Unclear
Unclear
NCT00626249
studies.
only one of the type I studies30was
and
could beUnclear
considered
I PK
TI-015 III 39
PK The FDA concluded thatAfrezza
days positive
COPD
Unclear
NCT01021891
I PK
TI-122 pivotal
13
PK
Afrezza
2 months Healthy
Unclear
Unclear
NCT00757367
(3).
I Safety
TI-027
N/A
N/A
N/A
N/A
Asthma
N/A
N/A
Not Listed
I PK
TI-113
24
PK
TI, Albuterol
6 hours Asthma
None
Unknown
NCT00673621

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Conflict of Interest
I am a fund manager who will benefit substantially if the FDA adopts my viewpoint. I have
substantial financial conflicts of interest. Despite these conflicts, the FDA should review my
statements with care and knowledge of my integrity. My fund brings a multi-disciplinary analysis to
the process of drug reviews and our success is aligned with making good choices for the benefit of
public health. We have reviewed hundreds of investigational drugs and generally agree with the FDAs
position. We have a vested interest in conducting a thorough and impartial analysis of a sponsors
data to handicap future use of the sponsors agent.
Martin Shkreli

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