CRL Letters #1 and #2

[derek2]

I don't think this has ever been posted. MNKD never shared it, but it is available direct from the FDA.

It's pretty fascinating. Starts off with CRL 2 and continues with CRL 1.

www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000OtherActionLtrs.pdf


Most of this info was shared in the FDA safety meeting briefing doc, but given everybody's interest here, and given that it's a publicly available document (and legally available, as published by the FDA), you may want to read them. Your money funded them, after all.

[derek2]

Also - the main page for regulatory documents for Afrezza. The leadership review recommending approval has a lot of positive info, and the safety review is fascinating. (shows why pregnant women should not use Afrezza. I always thought it was because of the insulin. Nope. It's the FDKP.)

www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022472Orig1s000TOC.cfm

[Deleted]

derek2 I don't feel up to searching through a lengthy document to find something you claim; how about copying and posting? Cannot wait to read how an inert molecule can be harmful. But than sophie claimed nothing is inert!

[Deleted]

derek2 your silence is deafening!

[mango]

Afrezza is Pregnancy Category C which is the same as Lantus (insulin glargine). Let's compare.


• AFREZZA

8 USE IN SPECIFIC POPULATIONS



8.1 Pregnancy Teratogenic Effects: Pregnancy Category C
AFREZZA has not been studied in pregnant women.AFREZZA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major malformations were observed at up to 100 mg/kg/day (a systemic exposure 14-21 times the human systemic exposure, resulting from the maximum recommended daily dose of 99 mg AFREZZA based on AUC).

In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal effects were observed at all dose groups (at human systemic exposure following a 99 mg AFREZZA dose, based on AUC).
In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased epididymis and testes weights, however, no decrease in fertility was noted, and impaired learning were observed in pups at ≥ 30 mg/kg/day (a systemic exposure 6 times human systemic exposure at the maximum daily AFREZZA dose of 99 mg based on AUC).

8.3 Nursing Mothers
Many drugs are excreted in human milk. A study in rats indicated that the carrier is excreted in milk at approximately 10% of maternal exposure levels. It is therefore highly likely that the insulin and carrier in AFREZZA is excreted in human milk. A decision should be made whether to discontinue nursing or suspend use of the drug since AFREZZA has not been studied in lactating women.


13 NONCLINICAL TOXICOLOGY


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104 week carcinogenicity study, rats were given doses up to 46 mg/kg/day of the carrier and up to 1.23 mg/kg/day of insulin, by nose-only inhalation. No increased incidence of tumors was observed at systemic exposures equivalent to the insulin at a maximum daily AFREZZA dose of 99 mg based on a comparison of relative body surface areas across species.

In a 26 week carcinogenicity study, transgenic mice (Tg-ras-H2) given doses up to 75 mg/kg/day of carrier and up to 5 mg/kg/day of AFREZZA. No increased incidence of tumors was observed.

AFREZZA was not genotoxic in Ames bacterial mutagenicity assay and in the chromosome aberration assay, using human peripheral lymphocytes with or without metabolic activation. The carrier alone was not genotoxic in the in vivo mouse micronucleus assay.

In female rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier (vehicle without insulin) beginning 2 weeks prior to mating until gestation day 7, there were no adverse effects on male fertility at doses up to 100 mg/kg/day (a systemic exposure 14-21 times that following the maximum daily AFREZZA dose of 99 mg based on AUC). In female rats there was increased pre- and post-implantation loss at 100 mg/kg/day but not at 30 mg/kg/day (14-21 times higher systemic exposure than the maximum daily AFREZZA dose of 99 mg based on AUC).

Source
www.accessdata.fda.gov/drugsatfda_docs/label/2014/022472lbl.pdf


• Lantus

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Pregnancy Category C: Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 7 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2. In rabbits, doses of 0.072 mg/kg/day, which is approximately 2 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.

There are no well-controlled clinical studies of the use of LANTUS in pregnant women.Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients.

8.3 Nursing Mothers
It is unknown whether insulin glargine is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised when LANTUS is administered to a nursing woman. Use of LANTUS is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.


13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 10 times and for the mouse approximately 5 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2. The findings in female mice were not conclusive due to excessive mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats (statistically significant) and male mice (not statistically significant) in acid vehicle containing groups. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. The relevance of these findings to humans is unknown.

Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames- and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).

In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 7 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2, maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

Source
www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf


So while Lantus might cause Ventriculomegaly and probably a skin tumor, Afrezza might decrease your balls.

And, while Lantus killed such an excessive amount of female mice during the non-clinical carcinogenicity study—the results were rendered as "non-conclusive". Yikes! Anyways, the rats and mice in the Afrezza non-clinical carcinogenicity study lived, and NO signs of toxicity were observed.

Afrezza also underwent a long-term study that demonstrated it causes NO amyloid deposits in any portion of the respiratory tract, however, there are numerous case reports and laboratory studies published that illustrates Lantus (insulin glargine) is amyloidogenic.

If I was a pregnant woman, I'd rather chance it and let my kid have smaller balls than Down Syndrome, tumors and amyloidosis.

Not sure what you were trying to prove with the CRLs and by mentioning pregnancy, but in the end, the facts show Lantus is toxic and Afrezza is not. 

[Deleted]

mango "Not sure what you were trying to prove with the CRLs and by mentioning pregnancy, but in the end, the facts show Lantus is toxic and Afrezza is not"

Thank you for writing what I was thinking!

[sayhey24]

Mango - very interesting, similar to AspB10 development but this time Lantus killed the rats. I have been watching for long-term studies on the relationship between the increased cancer rates in PWD and the Analogs. There are a few mostly out of Europe pointing to the Analogs being the cause. It seems in the U.S. they are being suppressed or just not funded.

Based on this given metformin, afrezza or any of the analogs I would think a pregnant women should pick afrezza.

[derek2]

Apr 10, 2017 20:35:57 GMT -5 @kastanes said:

derek2 your silence is deafening!

Well, I was asleep. My wife wishes I was silent when I sleep!

Personally, as a fan of data, not supposition, I was excited to find this. The info is there, you just have to read. And hey, since the drug got approved, it's overwhelmingly positive info.

An example:

Some posters hang on Al Mann's statement that Afrezza does not need refrigeration. Others accuse management if not doing their job by running a stability trial. Well, turns out both extremes are wrong. The Chemistry Review shows that MNKD ran stability tests over a 3-year period, and it was MNKD that proposed the 18 months refrigerated and 10 days at room temperature storage, and that the FDA agreed. (Chemistry Review, P 47, Other Reviews, page 22-24)

The applicant proposed in the resubmission dated 6/28/2010 the following shelf life for
the drug product : 24 months at refrigerated conditions (2 - 8ºC or 36 - 46ºF); 10 day for
unopened foil pouches and unopened blisters strips at 25ºC (77ºF); and short term
 excursions between 15-30ºC (59-86ºF). Once a blister strip is opened, all cartridges in
that strip must be used within 72 hours.

So the reason that I find this fascinating is that it shows that all parties acted rationally and professionally and came to an agreement. No evil FDA, no stupid MNKD. Many people won't care, since the drug is approved, but it shows that those stating that Afrezza does not require refrigeration should take heed of the proof that there is degradation at room temp over longer time periods. Who showed that? MNKD. It's real-world data that can help patients get the best result.EDIT: 


EDIT: The fact that a 3-year stability study was already performed also acts as a signal that a change in storage instructions is probably not part of the requested label change. It's not like MNKD was bullied into this - they recommended it after 3 years of data collection. This gives you more information as an investor. I mean, you might still think that MNKD could have requested the storage instruction change, but you have more real-world data to base your opinion on, instead of just "it would be great if" positing. Now, what it says about how in-the-loop Al was when he was claiming "no refrigeration" since 2010 is another thing. Maybe he didn't talk to the chemists.


Re: the pregnant women warning: The Medical review shows pregnant rabbits & mice having fetal malformations at VERY HIGH concentrations of FDKP. Concentrations that would never be seen in real life, but it acted as a rational basis for MNKD and the FDA to determine toxicity baselines and set a margin of safety.

[derek2]

Apr 10, 2017 20:57:05 GMT -5 mango said:

Afrezza is Pregnancy Category C which is the same as Lantus (insulin glargine). Let's compare.

Wasn't trying to show anything, other than an example that the risk was assessed by both MNKD and the FDA before the label was agreed to, instead of the ridiculous "FDA forced a label on MNKD" narrative.

Not trying to scaremonger or anything. How could I? Pregnant women don't use Afrezza. If I wanted to scaremonger I'd cherry pick data about some indicated population, but I don't do that kind of crap.

I found this data - as anybody with the slightest interest could have - and shared it. Done.

[Deleted]

derek2 "the pregnant women warning: The Medical review shows pregnant rabbits & mice having fetal malformations at VERY HIGH concentrations of FDKP. Concentrations that would never be seen in real life, but it acted as a rational basis for MNKD and the FDA to determine toxicity baselines and set a margin of safety."

That is the definition of FUD: make some ludicrous remark that you claim to have found in a voluminous document and tell people go find the relevant data. Unfortunately for you mango did that and determined FDKP is NOT harmful as you claim in realistic dosages.

Water and salt taken in large quantities are harmful, should they have black box warnings???

[derek2]

Apr 11, 2017 6:46:09 GMT -5 @kastanes said:

derek2 "the pregnant women warning: The Medical review shows pregnant rabbits & mice having fetal malformations at VERY HIGH concentrations of FDKP. Concentrations that would never be seen in real life, but it acted as a rational basis for MNKD and the FDA to determine toxicity baselines and set a margin of safety."

That is the definition of FUD: make some ludicrous remark that you claim to have found in a voluminous document and tell people go find the relevant data. Unfortunately for you mango did that and determined FDKP is NOT harmful as you claim in realistic dosages.

I have no interest other than pointing to the document repository. Actually, the scientific reviews are far more interesting than the 2 CRL letters. Lots of detail showing that MNKD were not stumblebums that got hosed by the FDA. They did science with rigor and in concert with the FDA (other than ignoring the FDA regarding bioequivalency studies) Just forget I ever mentioned pregnant women. (Derek then proceeds to give more detail about pregnant women)

Page 32 of the Cross Discipline Leader Review and detailed animal studies starting on page 9 of the Pharmacology Studies (section: Margin of Safety).

I didn't see the mango stuff at first because I have him on ignore. (A great feature that people can take advantage of to mute me at any time. Hey look! No more Derek!)

Once again - there's no FUD to spread about use by pregnant women. It's already out there. They are cautioned on the label:

8.1 Pregnancy Teratogenic Effects: Pregnancy Category C

AFREZZA has not been studied in pregnant women. AFREZZA should not be used during
pregnancy unless the potential benefit justifies the potential risk to the fetus.

In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major
malformations were observed at up to 100 mg/kg/day (a systemic exposure 14-21 times the
human systemic exposure, resulting from the maximum recommended daily dose of 99 mg
AFREZZA based on AUC).

Page 12 of 22

Reference ID: 3533688

In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal
effects were observed at all dose groups (at human systemic exposure following a 99 mg
AFREZZA dose, based on AUC).


In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles
(vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased
epididymis and testes weights, however, no decrease in fertility was noted, and impaired
learning were observed in pups at ≥ 30 mg/kg/day (a systemic exposure 6 times human
systemic exposure at the maximum daily AFREZZA dose of 99 mg based on AUC).

So some adverse effects at 6X - 20X real-world human equivalent doses in rats (paragraphs 1 & 3 and in real-world human equivalent doses in rabbits (paragraph 2).

MNKD attested to this on the label. It's been available for years, out there front and center on the label. (Did I mention that it's on the label already?) 

I just stated that it was interesting to see the background and rationale as to why pregnant women are waned on the label. 

I get that I'm not your cup of tea. Discussion boards can sometimes breed division. If we met in real life, after you got over the urge to bop me in the nose, I bet we'd have a good convo over a beer or 2. Vive la difference! 

[slapshot]

Apr 11, 2017 5:34:50 GMT -5 derek2 said:

Some posters hang on Al Mann's statement that Afrezza does not need refrigeration. Others accuse management if not doing their job by running a stability trial. Well, turns out both extremes are wrong. The Chemistry Review shows that MNKD ran stability tests over a 3-year period, and it was MNKD that proposed the 18 months refrigerated and 10 days at room temperature storage, and that the FDA agreed. (Chemistry Review, P 47, Other Reviews, page 22-24


So the reason that I find this fascinating is that it shows that all parties acted rationally and professionally and came to an agreement. No evil FDA, no stupid MNKD. Many people won't care, since the drug is approved, but it shows that those stating that Afrezza does not require refrigeration should take heed of the proof that there is degradation at room temp over longer time periods. Who showed that? MNKD. It's real-world data that can help patients get the best result.

Derek, from what I saw, you have misconstrued the data/results of the chemistry reviews.  I agree that MNKD performed stability trials that prove the shelf life stability when refrigerated over long periods of time (actually up to 4 years), but i saw no data or evidence that suggested that they performed the same tests without refrigeration nor that any such conditions showed degradation.  Thus, i believe you are jumping to (unsupported) conclusions when you say that because MNKD performed stability studies with refrigeration that proves refrigeration is required...

What logic are you using that i am missing?

[Deleted]

slapshot derek2 is using FUDSTER's logic!

[derek2]

Apr 11, 2017 7:36:14 GMT -5 slapshot said:

Apr 11, 2017 5:34:50 GMT -5 derek2 said:

Some posters hang on Al Mann's statement that Afrezza does not need refrigeration. Others accuse management if not doing their job by running a stability trial. Well, turns out both extremes are wrong. The Chemistry Review shows that MNKD ran stability tests over a 3-year period, and it was MNKD that proposed the 18 months refrigerated and 10 days at room temperature storage, and that the FDA agreed. (Chemistry Review, P 47, Other Reviews, page 22-24


So the reason that I find this fascinating is that it shows that all parties acted rationally and professionally and came to an agreement. No evil FDA, no stupid MNKD. Many people won't care, since the drug is approved, but it shows that those stating that Afrezza does not require refrigeration should take heed of the proof that there is degradation at room temp over longer time periods. Who showed that? MNKD. It's real-world data that can help patients get the best result.

Derek, from what I saw, you have misconstrued the data/results of the chemistry reviews.  I agree that MNKD performed stability trials that prove the shelf life stability when refrigerated over long periods of time (actually up to 4 years), but i saw no data or evidence that suggested that they performed the same tests without refrigeration nor that any such conditions showed degradation.  Thus, i believe you are jumping to (unsupported) conclusions when you say that because MNKD performed stability studies with refrigeration that proves refrigeration is required...

What logic are you using that i am missing?

I think you just missed 1 piece of data in the Chemistry review regarding the shorter term studies.

My logic, however, is pinned on two items:

#1 The company - who had run the stability trials - suggested both a 15 day room temperature excursion, then a 10 day time frame, know their compound.

Page 47:

The applicant proposed in the resubmission dated 6/28/2010 the following shelf life for

the drug product : 24 months at refrigerated conditions (2 - 8ºC or 36 - 46ºF); 10 day for

unopened foil pouches and unopened blisters strips at 25ºC (77ºF); and short term

excursions between 15-30ºC (59-86ºF). Once a blister strip is opened, all cartridges in

that strip must be used within 72 hours.

Page 46

#2 - they did shorter term tests at room temperature. I misconstrued nothing.

Three batches of Technosphere Insulin Inhalation Powder were filled into Gen2

cartridges (both 10 U and 20 U strengths) packaged in blisters with foil overwrap and

placed on stability. Samples have been stored at 5°C for up to 21 months to date. Samples

for the “extension” or “end use” study are obtained from the 5°C chamber and then stored

at 25°C/60% RH for up to 30 days or at 30°C/65% RH for up to 10 days.

Hopefully that clarifies it.

[mnkdfann]

Tough room!