Sunday, May 30, 2010

Validation of Mannkind's claims regarding Afrezza

Mark Twain famously said this about mining companies. He said a mine is nothing but "A Hole in the Ground with a Liar at the Top". 

Certainly lots of Biotech companies fit that description as well. Fortunately Mannkind is not one of them given the current set of facts (you are entitled to your opinions but not to your facts). The landscape of Biotech-ville is littered with corpses of dead companies that were long on promise and short on (efficacious) products. The allure of bio-tech companies is simple. The promise of untold riches. I call this the low "P/D" syndrome. The D is for dreams, you just keep dreaming big about payoffs and any price (P) is justified & worth paying. Just like airline industry, the biotech industry as a whole has failed to deliver any returns. Though the biotech shareholders as a whole have suffered, the products that successful biotech companies brought have benefited patients and the general society enormously.

For every Amgen that succeeds, there are a thousand companies that took a one way ticket to oblivion. It pays to be vigilant. The motto should be Trust but verify. As I am long Mannkind, I follow "Bruce Berkowitz" (founder of Fairholme capital management) principle. Berkowitz principle is, you try to kill your idea. I wake up every day trying to punch hole in my theory. So far I've not yet found one. If you have one, please email me or post a comment.

Mannkind certainly makes some bold claims regarding Afrezza.Let's take a critical look.

Mannkind claims Afrezza (a.k.a. Technosphere Insulin, TI, Afresa) can
  1. Reduce postprandial glucose excursions to normal levels
  2. Virtually avoid causing hypoglycemia
  3. Require no complex meal titration
  4. Reduce the need for mealtime glucose measurements – likely just to infrequent fasting glucose       measurements
  5. Cause no weight gain
  6. Eliminate prandial injections

I've three sources of information. One is from Mannkind's PR, next is the journal articles written by researchers (some of them are affiliated to Mannkind) and last is the Afrezza trial participants. I've had email conversations with one such participant named Pat. His feedback has been real useful to confirm the validity of several Mannkind's claims. He has written extensively about Afrezza in some diabetes forums. I've compiled the postings in this link. The participant is just another data point.

Claim 1: Reduce postprandial glucose excursions to normal levels

Validity: A good prandial insulin should be there when the body needs it and be out of the system when its no longer required. Lets explore how Afrezza stacks up.


a) A rapid suppression of endogenous glucose production can contribute to reduced PPG levels, and hence better control of PPG (indirectly).












b) On a head to head comparison with aspart, the PPG control was better in Afrezza


c) There has been numerous journal articles written on PPG excursions. Given the PK/PD profile, it is easy to conclude that this claim has merit.

Another measure of PPG is the AUCglucose (area under the curve). This result is from a phase 2 trial comparing Afrezza (TI -technosphere insulin) and Novolog. The table below is from Mannkind's PR.

What is interesting in the above table is, the total fluctuation is half of the industry standard RAA.


Claim 2: Virtually avoid causing hypoglycemia

Validity: Insulin and hypos go like peas and carrots. Hypos have been identified as one of the barriers of initiating insulin therapy.

a) From Mannkind's side, the best article on this is a poster titled "Reduced Incidence and Frequency of Hypoglycemia in an Integrated Analysis of Pooled Data from Clinical Trials of Subjects with Type 1 Diabetes Using Prandial Inhaled Technosphere® Insulin".

The pooled analysis shows a reduction in both mild to severe hypos compared to the RAA.

b) The best validation comes from Pat (the afrezza trial participant).

"I was in a 2-year clinical trial (Phase 3) with the Technosphere Insulin (TI) (Afresa) in the Type 1 group. I injected Lantus for my basal and bolused the TI for my meals with the Medtone Inhaler to replace the injected Humalog I was using previously. At the beginning of the trial my A1c was 6.8 and when the trial ended my A1c was 5.9. During the trial I was not carb counting, although I estimated the size of my bolus of TI based on the approximate carbs in my meals. I managed to achieve the low A1c with very infrequent incidences of hypoglycemia. There were only 2 occurrences of significant hypos in that 2 year period, although I did have other marginal low blood sugars. I attributed some of this to the rapid onset of action and the short duration of action of the TI."

So one can conclude that though hypos are not eliminated, the frequency and severity of hypos are way less compared to the RAA.

Claim 3 & 4: No complex titration, infrequent fpg measurement.

If you talk to any diabetic, they will consider this as the most dubious of all claims. This is based on countless feedback from insulin users. If this is even partly true, then it'll be the greatest of all selling points. This claim challenges the conventional wisdom of internists, endocrinologists & patients. Even if this claim is true, it is going to take Mannkind considerable effort to change the mind-set.

Mannkind has put in lot of effort to back this claim. Let us see what Al Mann has to say on this in one of the recent quarterly call.


"I have long argued that AFRESA does not require complex meal titration. Certainly there is no need for carb counting and so forth. The basis of my view was derived from the dose escalation study with meal challenges in which better glucose control was achieved with ever greater doses of AFRESA, yet without any hypos. 

Yet based on decades of battling these challenges of conventional insulin therapy, some physicians have questioned my suggestion. Therefore, I proposed a meal escalation study in which patients would take a fixed dose of AFRESA and then a series of meal challenges. Our clinical team designed a protocol to set a standard meal with 50 g of carbohydrates. That was the 100% challenge. This was followed by challenges at 200%, 50% and zero percent. When I heard of zero I was shocked. Surely there would be severe hypo. The remarkable thing was that with the regular prescribed dose of AFRESA regardless of carbohydrate intake between zero and 100 grams the range of excursion is only plus or minus 30-35 mg [reduction] from baseline for all of the Type II patients in the study. At the ASDA meeting I described to Dr. [Jay Skyler] the finding that in Type II diabetes with a fixed dose of AFRESA and even with no food there is excellent control without hypo risk. I asked him how that was possible. “Obvious,” he responded. He was basing his comments on our recently reported 118 trial in which we showed rapid and virtually complete sensation of [hepatic] glucose relief with AFRESA and the common inability of the remaining endogenous insulin to maintain control, as is the case for a healthy person without diabetes. 

Indeed, I mentioned this result to a number of KOL’s who agree with Jay. So I say to you that AFRESA is what no other insulin has ever done for Type II diabetes. AFRESA restores more physiologic hepatic function, takes a load off the pancreas and avoids the hyperinsulinemia resulting from resistance of other insulins. It better mimics the normal pancreas response. So what does all this mean? 

First let me say that we will need to follow these findings with much larger trials. If the results of the larger trials support the earlier findings then I state to you that AFRESA should be used very early, certainly after failure with Metformin and as a first sign therapy for a significant portion of patients who are not candidates for Metformin or who do not do well with Metformin. It should be used well before fasting glucose is out of control and as we have seen, AFRESA even leads to lower fasting levels by eliminating the excessive gluconeogenesis. Of course, we will have to repeat some of these findings with specific trials but we have already seen the possibilities for AFRESA as we evaluate the timing of hypos in our already completed trials to date. From what we have seen in our extensive clinical program, AFRESA should benefit the entire progression spectrum of Type II diabetes with a very simple therapy and the experts tell us that it could even stop the progression of the disease. "


This is what Pat had to say regarding the carb counting. The emphasis are mine. (Pat Godin | November 18th, 2009 at 2:56 pm)
-----------------------------------------------------------------------
I was in a 2-year clinical trial (Phase 3) with the Technosphere Insulin (TI) (Afresa) in the Type 1 group. I injected Lantus for my basal and bolused the TI for my meals with the Medtone Inhaler to replace the injected Humalog I was using previously. At the beginning of the trial my A1c was 6.8 and when the trial ended my A1c was 5.9. During the trial I was not carb counting, although I estimated the size of my bolus of TI based on the approximate carbs in my meals. I managed to achieve the low A1c with very infrequent incidences of hypoglycemia. There were only 2 occurrences of significant hypos in that 2 year period, although I did have other marginal low blood sugars. I attributed some of this to the rapid onset of action and the short duration of action of the TI.

So I am not surprised by the information Al Mann has revealed about Afresa. I was disappointed when the trial ended and had to return to injected Humalog. My A1c is now in the range of 6.8 again. Recently I began pumping insulin. It would certainly be interesting to incorporate inhaled Afresa with a basal insulin delivered with a pump.

It would definitely be a great marketing point if Type 1 diabetics using Afresa did not have to develop accurate carb counting skills to avoid a lot of hypos.
----------------------------------------------------------------------- end of Pat's comment

I have also analyzed this issue a little bit. Why is carb-counting needed now? The simple reason is, in current treatment paradigm, you get hammered if you take a lot of insulin (resulting in hypos) and again if you do not take enough (hyperglycemia, higher A1C etc). The other reason is, if you know you made a mistake first, the correction becomes even more complicated. Any correction dose you take will get stacked on the existing dose (that is still in the body). The RAA's have a tail and you need to figure out accurately the correction dosage. (for folks who know math, think of superimposing one sinusoid curve with another and where the starting points are the same, it is a complex task.) Talk about adding insult to injury. In some ways, the current prandial insulin is unforgiving if correct dosage is not computed. So one has to count the carb, measure their fpg, use the sliding scale to compute the prandial insulin dose and then take the injection.

So what is the deal with Afrezza? 
a) The Tmax of peak insulin is 12-14 minutes, so any corrective dosage acts real quick
b) The bolus doesn't crash (look at the PK profile of both TI and RAA, RAA comes down very fast), it is a gentle glide down
c) The tail of Afrezza is much shorter than RAA. Like a duracell battery ad, RAA goes on and on and on even when it is not needed.
d) To the extent Afrezza shuts off hepatic glucose, the body can use it later when it really needs it (reduce hypos etc)

It appears that Afrezza is much more forgiving to the dosage miscalculations.

Let us see what "Pat" says in a different post
"A limitation for some especially insulin sensitive individuals may be the dosing for the TI insulin. Basically there are two doses to work with in various combinations. For me I found them quite easy to figure out and work with in most meal situations. I found if I overestimated the dose and my blood sugar dropped too low the fall of blood sugar in the second hour after bolusing was very gentle and never "crashed" like I became accustomed to with injected Humalog. Therefore no bad hypos."


Claim 5: Causes no weight gain

Validity: A lot of evidence has been shown by Mannkind to validate this. Some studies have shown a weight loss and some have shown weight neutral. 


Intuitively it is easy to understand. Due to the hypos or fear of hypos, the patients resort to frequent snacking. This snacking causes weight gain.

And last but not least, the claim 6 "Eliminate prandial injections" needs no validation.

Thursday, May 27, 2010

Griffin update May 3

• New safety and efficacy data lend additional support for approval of Afrezza®.
• The FDA and Mannkind will meet in June to discuss the Afrezza NDA.
• Clinical data to be presented at medical conferences in the coming months.
• Expenses remain under control; the Company prepares for a financing.
• Partnering moves to the forefront for Afrezza and oncology therapies.
• We reiterate our BUY recommendation and retain our target price of $26 per share.

Partnering discussions are heating up, as the Company intends to gain an experienced marketer(s) for a global rollout of Afrezza. The FDA meeting in June may yield the information potential partners need to enter into an agreement. Meanwhile, Mannkind is seeking collaborators for its oncology program that includes three therapeutic vaccines.

The FDA meeting should set the tone for the remainder of the year, as a constructive outcome would likely set the path to commercialization. Mannkind plans to report clinical data at scientific meetings this year that should educate physicians on Afrezza’s use. And a registration statement has been filed to help finance manufacturing scale-up. Thus, Afrezza’s launch is approaching. We are reiterating our BUY recommendation and our $26 per share price target on Mannkind stock.

Oppenheimer - May 13-2010

Analyst: John Newman UNDERPERFORM 12-18 mo. Price Target $2.00

Management comments at an investor conference yesterday indicate the FDA may have issues with the HbA1c outcome for study TI-009.

Specifically,
(1) management referred to an "A1c issue", suggesting FDA viewed study TI-009 as a failure;
(2) the TI-117 trial may be insufficient since it may have failed to reach its intended objective;
(3) the FDA and MNKD apparently disagree on which assay(s) should be used to demonstrate bioequivalence; and
(4) we continue to anticipate the FDA will request additional trials, and believe a near-term cash raise is imminent.

A1c Issue for TI-009 Trial Suggests Study Failed: Management referred to an "A1c issue" at FDA, suggesting that the FDA believes study TI-009 in Type 1 diabetes failed. We believe the FDA's analysis of the pivotal TI-009 study did not show non-inferiority for AFREZZA vs. rapid-acting insulin, suggesting an
additional study will be needed.

'117 Trial May Also be Insufficient: MNKD management also stated that the TI-117 trial did not reach its intended goal, suggesting the FDA may not view the results favorably. Specifically, patients did not reach fasting glucose levels under 120 g/dL, but reached levels only slightly better than Humalog. Also,
TI-117 was much smaller than TI-009.

Insulin Assay for Bioequivalence Study Unclear: The FDA has apparently also raised a question about the insulin assay methodology for bioequivelance testing between Medtone and Dreamboat Inhalers, suggesting additional problems. MNKD intends to file an amended NDA with data from the new
Dreamboat inhaler, but without bioequivalence this could be difficult.

Continue to Expect Additional Studies, Cash Raise: We continue to believe the FDA will request additional studies for AFREZZA, substantially delaying progress, and requiring a significant amount of additional cash. MNKD has ~$31M in cash remaining, or less than one quarter at the 2009 burn rate
(>$200M).

JP Morgan - Still Not Breathing Any Easier

Dated 30-APR-2010 - Analyst Cory Kosimov

The key takeaway, in our view, is that the company has a meeting scheduled with the FDA in June to review the requirements of its planned NDA resubmission following the March CRL.

Management’s enthusiasm and bullish outlook remain steadfast, but we are more circumspect and await clarity following the meeting with FDA. All in, we believe the resilience of MNKD shares to date will prove unsustainable over time and continue to maintain our UW rating given the company’s ~$1B EV in the face of regulatory, labeling, strategic, and commercial uncertainty. Still, with a short interest of 21% and a high retail interest, we suspect trading could remain volatile.

Regulatory situation remains murky. The company announced today that a Type A meeting with FDA is scheduled in June and anticipates submitting an amended NDA with its next generation Dreamboat device “a few weeks later.” At this point, our overriding concern relates to the agency's language in the CRL regarding the
product’s "clinical utility." Management attempted to address this issue on today’s call by reading a direct quote from an FDA e-mail stating “we are basically asking you to clarify where Afrezza fits in the treatment armamentarium for diabetes.”

While we appreciate the company’s transparency, we don’t see how this clears the air and still view the regulatory process as high risk.

Leerink Swann - APR-30-2010

Bottom Line: Today before the market open, MNKD reported 1Q10 EPS of ($0.40) vs. our ($0.49) estimate, and gave updates on the Afrezza regulatory status. In 1Q10, the company reduced its spending to manage cash levels while working toward approval of Afrezza. Although we believe Afrezza is eventually approvable, we think that the current valuation implies aggressive revenue assumptions. Our valuation on MNKD is $5.

• Progress on Afrezza Regulatory Front: The FDA has approved the manufacturing plant that was the initial reason for the missed PDUFA date earlier this year. MNKD has a meeting with the FDA in June to discuss the complete response letter. MNKD plans to submit the Dreamboat (2nd-generation inhaler) as part of the response to the complete response letter, which will likely result in a Class 2 (6-month) review. However, there is a chance that the FDA may view the Dreamboat submission as a separate NDA and perform a 10-month review.

• Getting Help from Interested Parties: MNKD noted that it continues to have discussions with potential partners. Interestingly, at least a couple of the companies have offered to help MNKD prepare for the June FDA meeting.

• The 117 Study Adds to Afrezza Clinical Profile: MNKD conducted a study of Afrezza plus basal insulin vs. rapid acting insulin plus basal insulin in Type 1 diabetics. Results showed non-inferiority of Afrezza in terms of HbA1c and even a numerical trend toward superiority. The trial design, which included a run-in period to drive patients toward 120 g/dl fasting plasma glucose, may have helped Afrezza's post-prandial effect to be more pronounced.

• Financing Overhang to Remain for a While: The company ended the quarter with $32m in cash and a line of credit for $145m. MNKD burns about $35-40m per quarter, which puts the company at financing risk. To mitigate the risk, MNKD is looking to license out its earlier stage oncology compounds. Also, the company filed a $200m shelf filing this morning, so it can quickly raise money if its stock price reacts favorably.

• Next Up: Meeting with the FDA in June, additional data presentation of the 117 study soon.

Tuesday, May 25, 2010

An exhaustive comparison of Exubera and Afrezza.


revised on july 25th 2010 for immunogenicity


Months back I wrote an article that compared these two, this is an expanded version.


This article is written for folks who fail to distinguish between Afrezza and Exubera. Other than the fact that both are inhaled, the similarities stop right there. Afrezza has benefited in some ways due to the failure of Exubera, the Mannkind management is now better prepared to present the value proposition (both to FDA and Diabetic population). Mannkind has also paid a price (still paying) as the whole inhaled insulin sector is unfairly maligned by the Exubera’s debacle.

Given all this contrasts, Afrezza is the only insulin in the class of “super rapid acting” insulin.



#

Category

Exubera

Afrezza

Winner
is?

1

Particle

Dry particle, recombinant regular human insulin +
Excipient

Dry particle Proprietary Technosphere particle that contains monomeric insulin (derived from recombinant DNA) that is electro statically linked.

Afrezza

2

Excipient

Mannitol, glycine
and sodium citrate

FDKP (fumaryl diketo piperazine). Proprietary
compound, inert, not metabolized and excreted.
Fumaryl diketopiperazine is not a penetration enhancer.

Draw

3

Delivery

Bong sized inhaler
Air-assisted mechanism disperses the powder from
single-dose blisters into a respirable cloud captured in a holding chamber.

This hand-held, compact, pocket-sized inhaler is easy to carry and use. The inhaler is a breath-powered, high impedance, low-flow device with a passive powder de-agglomeration mechanism.
Single-use cartridges containing TI are inserted into the dispersion chamber of the inhaler, and patients administer the insulin by taking a deep breath. Because the device is breath powered, the patient does not need to coordinate the timing of activation with inhalation.
 
Medtone inhaler C (used in trials), inhaler D (ruggedized
version). Newer one is dreamboat (see the pic at
bottom of the blog) which is the size of a whistle.
There’s also one disposable inhaler.

Afrezza

4

Pharmaco-
kinetics

Very similar to RAA in terms of PK profile,
T(max) for insulin – 45 mins
Duration of action – 6 hours
Total exposure AUC (area under curve) comparable to RAA.

Mimics first phase insulin spike
T(max) for insulin – 12-14 mins
Duration of action 2-3 hours
2/3rd of insulin action happens in first 2
hours.

Afrezza
You need prandial to better mimic natural secretion.

5

Pharmaco-
dynamics

Similar to RAA (say lispro) but
has more pronounced tail.
Exubera demonstrated a significantly faster onset of
action than both regular SC insulin and SC insulin lispro,
as indicated by the shorter mean time to half-maximal effect: 32 minutes vs 48 minutes (P < .001) and 41 minutes (P < .05),
respectively. The mean time to maximal effect of INH was comparable to that
of insulin lispro (143 minutes vs
137 minutes), but shorter than that of regular insulin (193 minutes; P <
.01). Finally, the mean duration of the metabolic activity (time to late
half-maximal effect) of INH was 387 minutes, significantly longer than that
of insulin lispro (313 minutes

The link
here compares all RAA with Afrezza and Exubera

Afrezza

6

Absorp-
tion

Following oral inhalation of a single dose of human
insulin approximately 60% of the emitted dose (about 40% of the blister
content) reaches the lung while 30% is deposited in the oropharynx and 10% in
the conducting airways. Insulin is a peptide drug with negligible
gastrointestinal absorption.
Consequently, the amount of drug deposited in the
oropharynx or swallowed is not expected to affect blood PK profiles.

Approximately 60% of the administered dose is deposited into the lungs.  Inhaled TI particles are evenly distributed throughout the deep lung. At the physiological pH of the deep lung, TI micro-particles rapidly dissolve, and insulin is absorbed across the pulmonary epithelium into the systemic circulation.
 
The FDKP molecules that reach the circulation are cleared and excreted. No metabolites of FDKP have been identified in urine or feces
Technosphere insulin did not disrupt the actin cytoskeleton of cells or increase cellular
permeability; nor did it promote cytotoxicity. In
animal models, there was no insulin accumulation in the lungs and no immunologic changes were observed

Draw

7

Company/
MGMT
behind it

Initially Aventis was a partner,
Aventis sold their rights to Pfizer later. Aventis now has 1.3 billion
reasons
to be happy.
Pfizer/Nektar therapeutics.
One important thing to note is,
Pfizer lacks expertise in Diabetes area.

Mannkind corporation/waiting for marketing partner
Al Mann was the inventor of the insulin pump. He also has
a long history in devices area.

Afrezza

8

Trials for
non-
inferiority

The clinical development program is extensive and consists
of 32 single-dose pharmacological studies, 1 multi-dose (6-month) exploratory
clinical pharmacology study (study 1026) and more than 20 Phase 2/3 studies.
Eight controlled Phase 3 studies (106, 107, 108, 109, 110, 1001, 1002 and
1009), and three controlled supportive Phase 2 studies (102, 103, 104) had
been completed at the time of the marketing authorization application and
represent the core of the INH Phase 2/3 clinical development program.
During the procedure, results on additional comparative
phase 3 studies (1022, 1027, 1029, preliminary results on studies 1028 and
1030) were submitted.
Overall, 821 subjects were exposed to INH during the 32
single-dose pharmacological studies and more than 1975 patients have received
INH for more than 6 months.

From clinicaltrials.gov

Phases

# patients

Other IDs

Phase II

228

MKC-TI-010

Phase II

110

MKC-TI-101

Phase II

16

MKC-TI-03B

Phase II

24

MKC-TI-016

Phase II

50

MKC-TI-112

Phase II

30

MKC-TI-118

Phase III

672

MKC-TI-126

Phase III

547

MKC-TI-103

Phase III

587

MKC-TI-009

Phase III

2343

MKC-TI-030

Phase III

676

MKC-TI-102
The AFREZZA clinical program involved 49 different studies
of AFREZZA and over 5,000 adult patients

Draw

9

Trials/
Studies for superiority

None
It is possible that Pfizer planned some as post marketing.
I’m not aware of any.

Study 117 & 142
There are also other studies being performed. I don’t have
the list currently.

Afrezza
(given the current info)

10

Dosage

1mg, 3mg blisters
1mg = 3 IU of RAA
3mg = 8 IU of RAA
The non linearity of dosage was a major pain.
Exubera lacks dose proportionality and also dose
equivalence
(Three 1mg blisters = 1.4 times one 3mg blister). This
makes the titration process more complex and unpredictable.

Cartridges come in 15, 30, 45 and 60 units.
Afrezza dosage will be Current RAA * 3 (based on Mann’s
interview)
6 TU = 1.56 U
12 TU = 3.12 U
24 TU = 6.24 U
Dosage is
linear.

Afrezza

11

Placebo formulation

Not possible

TI particle without insulin can be prepared and can be
used as placebo

Afrezza

12

Variability

The within-subject variability of glucose-lowering
activity of inhaled insulin is generally comparable to that of SC regular
insulin in subjects with Type 1 or Type 2 DM.
The inter- and intra-subject variability in PK of inhaled
insulin is generally high. From the entire NDA, the % CV, on average is
expected to be >50%. This is bad news.

In the six-period crossover isoglycemic
glucose clamp study of 13 subjects with type 2 diabetes, less within-subject variation in insulin absorption was observed. Less intra-patient variability should facilitate dose titration and minimize subsequent fluctuation in prandial glucose levels.
 
Check out the link
More details in link

Afrezza

13

Bio-
availability

5-11% for non-smokers
12-19% for smokers

25% of s.c (medtone)
Dream boat’s bioavailability could be around 30% of s.c.

Afrezza (less cost)

14

Risks: Lung function

The FDA concluded that people taking Exubera suffer a
decline in lung function – as
measured by forced expiratory volume or by diffusion capacity. However, it
was found that this decline is
not progressive and there is some evidence that it may be reversible.

Same as Exubera; articles say the declines are
statistically insignificant and are reversible
 
the newer dreamboat has less impact to lung compared to Medtone C.

Draw
(maybe Afrezza as there is no powder deposition)

15

Incidence of hypos

Similar to RAA

Way less compared to RAA

Afrezza

16

Toxicology, tumorigenic
risks

Inhalation toxicology studies in rats and monkeys for up
to 6-months there was no evidence for an accumulation of particles in the
lung.
The safety of the excipients has been demonstrated in the inhalation toxicology studies in rats at levels of
up to approximately 100-300 times the human level and in monkeys of up to approximately 10-30 times the human level. The safety is also supported by a literature review on the respiratory tract deposition and clearance of
insulin inhalation dry powder. The excipients are
therefore considered safe for the intended use
No data to suggest that insulin inhalation powder may promote pre-existing preneoplastic/neoplastic
changes in the lung.

The safety of FDKP was established in a comprehensive pharmacology/toxicology program including chronic inhalation toxicology in
rats (6 months) and dogs (9 months), , genetic toxicology, reproductive toxicology, safety pharmacology, and  Read my “All about TI” article.

Draw

17

Carcino-genicity

No carcinogenicity studies have been performed.

a 2-year inhalation carcinogenicity study in rats
a 6-month subcutaneous
carcinogenicity study in transgenic mice.

Afrezza as more tests were done

18

Costs

For a 70kg adult, using 0.5 units/kg/day
$8-9/day
Blister packs = $3042 +
1 chamber $19 + 28 release units/year = $3145.00/year

(guess) within 10-20% the current prandial insulin costs
~$3.5 - 5/day = $1300-$1800
Compare this with s.c
injections ~ $1000/year

Afrezza

20

Antibodies

Exubera showed dramatic increase in antibodies (30 fold
increase
), no one has identified the root cause.
FDA didn’t think of this as an issue
The antibodies did not have an effect on the action of insulin.
In the "Comparative Discontinuation Phase of Study 111" it was shown that among subjects with type 1 DM,
mean insulin antibody level fell by approximately 50% within the initial 3
months after inhaled insulin discontinuation. Among subjects with type 2 DM,
mean insulin antibody level also fell after  discontinuation, but the decline was slightly less and more protracted than in type 1 patients.

Type 2: Afrezza showed <3 fold increase, control arm 2 fold increase;
Type 1: Afrezza 8-fold vs 2-fold for sc insulins.

Afrezza

21

Manu-
facturing

No details; it has been widely reported that they botched
the marketing, manufacturing etc

Mannkind acquired cheap insulin from Pfizer,
Completed state of art manufacturing plant in Danbury to produce; mgmt
claims to have enough insulin for $10 billion sales; it looks like Mannkind
is better prepared.

N/A;

22

Moolah;
not
including opportunity
costs

$2.8 billion USD

Roughly $1.5+ Billion and counting;

Meaningless

23

Benefits – liver

Avoid injections for prandial insulin
Does a poor job of shutting off hepatic glucose production
(gluconeogenesis)

Avoid injections for prandial insulin
Does a far better job in shutting off hepatic glucose
production. Refer to “C-peptide Correction Method” articles in mannkind website.

Afrezza

24

Benefits –
PPG
Post prandial glucose
excursions

Same as RAA.

The best there is, PPG excursions cause long term
complications and can even cause beta cell toxicity and death.
Afrezza controls PPG excursions better than any other
product out there.

Afrezza

25

Benefits
continued..
Patient
satisfaction
surveys

Positive (85%)

Very positive (95%)

Afrezza

26

Effective glycemic
control – reduction in HbA1c
levels

Same as RAA; demonstrates non-inferiority over RAA
Link
for Type 1

This is a controversial topic, Afrezza is in
and out very fast and when compared with RAA, Afrezza looks slightly
inferior. Due to the big tail of RAA, the physicians maintain a high level of fasting plasma glucose and the effects of Afrezza are masked. To compare apples to apples, the fpg should be brought to near normal levels. In such a comparison, the patients RAA control arm would have fallen flat (due to Hypos) and Afrezza arm will be up and running great.
Who wants to sign up for the control arm for such a trial? :)

Can we have diabetics in Hapoalim securities sign up for the control arm?

Afrezza if proper
studies are done
(based on Pk/Pd
profiles)

27

Benefits continued..
Weight gain: Insulin and
weight gain
go like peas and carrots.
One major inhibition to initiating
insulin is the weight
factor.

No significant weight gain

Weight neutral to weight loss; Afrezza doesn’t cause the
weight loss per se, but the lack of snacking in between meals results in
losing some weight that was gained already. The snacking is obviously due to
the hypos (again the tail of RAA)

Afrezza

28

Benefits continued..
Improvement in quality of life

If you live in an open culture (Netherlands
anyone), areas of California,
then there is no inhibition to use a bong device.

Dramatic improvement in quality of life as the dreamboat
inhaler can be used in any public place without attracting attention.

Afrezza (as device is discreet)

29

Cough

The % is not known, but cough is an issue for Exubera also

1% of patients quit TI due to cough

Draw



In Diabetes mine interview, this is what Al Mann has to say about Exubera


“Exubera was very inconvenient, it had absolutely no benefits clinically, and it was not as good as the other treatments on the market. Comparing Afresa to Exubera is like saying that Rezulin — a bad drug that failed — is the same as Actos — a good drug with good outcomes.

What we have is a different form of insulin (from Exubera). It’s powder so we deliver it into the lungs. But that’s an advantage because it’s delivered in the arterial blood system instead of the capillary system. We’re actually delivering insulin monomers (molecules). Nobody ever did that before.

It behaves much like normal pancreatic insulin does. Normal people don’t get hypos, and people taking Afresa don’t either, even if they dose and don’t eat.”