Question: Type 2 approval doubts

[silentbob]

Hi guys,

If you don't mind telling me, why are so many people doubtful about Type2 approval?

- Is it because we only saw 0.4 A1C reduction?
- Is it because of the increased hypos vs placebo?
- Are there other reasons?

What are the biggest concerns you have, and why?

Thanks!

[liane]

You won't hear any doubts from me.

[rak5555]

Just playing devils advocate - I believe there is more doubt about type 2 because the range of treatment options is much broader than w/ type 1s. The FDA could challenge whether the studies performed to date are specific enough with respect to the patient segment. Remember "clinical utility of the armamentarium" from crl #1?

There are several good arguments to mitigate this concern, but the concern remains nonetheless.

[notamnkdmillionaire]

Sorry, I have no doubts. I think when you look at all available data, it points to an "overwhelming" net positive for T2 sufferers. In a world where there are more people becoming diabetics, the more solutions to help diabetics the better. Afrezza has shown to do more to help than harm those who have T2D. Approval seems to be a no brainer on all fronts. Isn't that why the FDA wanted it tested? They saw that Afrezza could be a game changer for T2.

[brentie]

Mar 26, 2014 10:01:11 GMT -5 rak5555 said:

Just playing devils advocate - I believe there is more doubt about type 2 because the range of treatment options is much broader than w/ type 1s. The FDA could challenge whether the studies performed to date are specific enough with respect to the patient segment. Remember "clinical utility of the armamentarium" from crl #1?

There are several good arguments to mitigate this concern, but the concern remains nonetheless.

This sounds like clinical utility to me...


Barriers to Initiation of Insulin Therapy


Patients

Patient resistance to insulin therapy is common, and this attitude often causes delays in initiation of the therapy.7,8 As many as one-quarter of insulin-naïve patients express unwillingness to take insulin if prescribed, and another 25% are only slightly willing to take insulin.8 Survey results of insulin-naïve patients with T2DM reveal that attitudinal reluctance to take insulin—which has been termed psychological insulin resistance—derives from multiple physical concerns, including fear of injections and worries about potential weight gain and risk of hypoglycemia (Table).8 In addition, psychosocial causes of patient resistance include a sense of personal failure and discomfort about administering insulin in public.8 Psychological insulin resistance may manifest as resistance to initiation of insulin therapy and to escalation of the insulin regimen as the disease progresses.



www.jaoa.org/content/111/7_suppl_5/S13.full

[biotec]

Many type 2's are on a pill. Not saying its better, But most new type 2's are controled via pills and diet at first.

[Chris]

Attachment Deleted

Very useful slide regarding Type 2 and the FDA's take.

I hope you all find this useful. 

[silentbob]

Mar 26, 2014 10:01:11 GMT -5 rak5555 said:

Just playing devils advocate - I believe there is more doubt about type 2 because the range of treatment options is much broader than w/ type 1s. The FDA could challenge whether the studies performed to date are specific enough with respect to the patient segment. Remember "clinical utility of the armamentarium" from crl #1?

There are several good arguments to mitigate this concern, but the concern remains nonetheless.

Hi Rak,

I think the trials done so far cover the entire spectrum of diabetes patients (with the exception of children) so we should be safe on the 'clinical utility' front, which I assume is your view as well.

Thanks for the feedback!

[ashiwi]

Al Mann has stated that it's because of the inadequacies of the current insulin therapies that result is some of the oral hypoglycemics which are worse. Has anyone looked at the side effects of Victoza?
Selected Important Safety Information (Taken from the Victoza Web Site. www.victoza.com/?campaign=000722911&wt.mc_id=victoza_patient_-_brand&adgroup=victoza_%3E_misspellings_%28exact%29&wt.srch=1&utm_source=google&utm_medium=cpc&utm_term=victoza&utm_content=search&utm_campaign=victoza%20patient%20-%20brand#isi

In animal studies, Victoza® caused thyroid tumors—including thyroid cancer—in some rats and mice. It is not known whether Victoza® causes thyroid tumors or a type of thyroid cancer called medullary thyroid cancer (MTC) in people, which may be fatal if not detected and treated early. Do not use Victoza® if you or any of your family members have a history of MTC or if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). While taking Victoza®, tell your doctor if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer.
Do not use Victoza® if you are allergic to liraglutide or any of the ingredients in Victoza®. Serious allergic reactions can happen with Victoza®. If symptoms of serious allergic reactions occur, stop taking Victoza® and seek medical attention. Pancreatitis may be severe and lead to death. Before taking Victoza®, tell your doctor if you have had pancreatitis, gallstones, a history of alcoholism, or high blood triglyceride levels since these medical conditions make you more likely to get pancreatitis.

Stop taking Victoza® and call your doctor right away if you have pain in your stomach area that is severe and will not go away, occurs with or without vomiting, or is felt going from your stomach area through to your back. These may be symptoms of pancreatitis.

Before using Victoza®, tell your doctor about all the medicines you take, especially sulfonylurea medicines or insulin, as taking them with Victoza® may affect how each medicine works. If you use Victoza® with insulin, you may give both injections in the same body area (for example, your stomach area), but not right next to each other.

Also tell your doctor if you have severe stomach problems such as slowed emptying of your stomach (gastroparesis) or problems with digesting food; have or have had kidney or liver problems; have any other medical conditions; or are pregnant or plan to become pregnant. Tell your doctor if you are breastfeeding or plan to breastfeed. It is unknown if Victoza® will harm your unborn baby or if Victoza® passes into your breast milk.

Your risk for getting hypoglycemia, or low blood sugar, is higher if you take Victoza® with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. The dose of your sulfonylurea medicine or insulin may need to be lowered while taking Victoza®.

Victoza® may cause nausea, vomiting, or diarrhea leading to dehydration, which may cause kidney failure. This can happen in people who have never had kidney problems before. Drinking plenty of fluids may reduce your chance of dehydration.

The most common side effects with Victoza® include headache, nausea, and diarrhea. Nausea is most common when first starting Victoza®, but decreases over time in most people. Immune system related reactions, including hives, were more common in people treated with Victoza® compared to people treated with other diabetes drugs in medical studies.

Afrezza can and will be a safer and better therapy for Type 1 and Type 2 diabetics.
How can the Ad Comm and the FDA do anything but Approval.

[silentbob]

Mar 26, 2014 14:49:05 GMT -5 biotec said:

Many type 2's are on a pill. Not saying its better, But most new type 2's are controled via pills and diet at first.

Sure, but many of those pills are rubbish and MNKD just did trials testing orals in combination with Afrezza.
It's more of a commercialization concern then an approval concern, isn't it?

Thanks for your input!

[spiro]

Let us not forget  Scripps research linking Metformin to Alzheiner's disease.

www.scripps.edu/news/press/2013/20130410polleux.html

[silentbob]

To be honest I expected more risks to be brought forward since I see so much negativity and fear among many longs. This is great though, everybody is confident of approval and nobody has a care in the world!

As for me, I expect approval yet I keep in mind the following issues:

--------- Non-trivial issues -----------

- In Type1 the fact that less diabetics on Afrezza reached <7.0 and <6.5 could make it to the label. That would be unfair since this is most likely just an artifact of the trial design and I believe Afrezza would outperform RAA in a real world setting.

- In Type2 Mannkind reported hypos in % of patients instead of an event rate like the way they reported on Type1. It could be that the event rate for severy hypos looks worse then the % because of the one patient they hinted at that had a lot of severe hypos . While they may be right to exclude such an outlier, the FDA will have the full data and I would have preferred honest disclosure as well.

This is just speculation though - for all I know the event rate is fine, but then why get cute with the data like this?

This shouldn't prevent approval though - one patient is just not significant.

- Lung testing. This will be discussed at the ADCOM. One of the questions posed to the committee might be "Should we recommend pulmonary testing prior to treatment with Afrezza". I don't believe this will become a requirement, but the briefing documents may provide insight into the FDA's thinking.

- Unknowns! Whatever is new to us will move the share price and unknown issues are the greatest risk we face.

- As for April 15, a short delay or CRL with minor issues not on our radar is always possible. Remember the packaging issue in the first CRL? Label negotiations, factory inspection timing, etc...
I'm expecting a straightforward approval but we've there before.

--------- Other issues -----------

Issues that I will look out for but don't consider serious threats:

- Antibodies. This will be discussed, but if the CRL didn't mention a concern then increased antibodies are unlikely to become a roadblock.

- The "confidence interval does not cross zero" issue. A non-issue considering we met the trial endpoint, period.

- Post approval lung trials. I think this is expected by the market, the cost will be carried by the partner, and is not a real concern.

- Upper respiratory tract infections. A past trial saw a small increase. It was not reported on in the last trials. A sore throat is a trivial issue so this should not affect approval but may be a minor mention in the label.

- Shorts and skeptics may find fodder for fear mongering in the briefing documents, even if no real new negatives surface. If that causes a drop in share price a smooth ADCOM will more then make up for it 2 days later. Lets try to cut through the noise and focus on the facts if that happens.

---------

I hope I didn't freak anybody out with this list.
Keep in mind that the safety profile is great and barring unpleasant surprises the ADCOM and PDUFA should go fine.


I will stay an unhedged long through ADCOM and approval and I expect it to be rewarded this time. On the other hand I didn't forget how painful that strategy was last time around, when I was also confident of approval.

That is why I was seeking the concerns other people have, to see if I missed something.

Thoughts?

[biotec]

silentbob, How do you know most the pills are junk? You have type 2? You on them? Im saying there is more options for type 2's not so for type 1's.Would you start insulin or take a pill? The FDA looks at all angles.JMO We all are allowed one right? And your welcome for my input, Anytime.

[alcc]

The fact there are more options for T2 should not be a factor re adcom or FDA's thought process. Efficacy and safety, yes. Limiting choice, no. FWIW, Exubera adcom vote for T2 was 9-0, whereas it was 7-2 for T1.

[mannmade]

Let's not forget this is also being presented as a first in class type of drug which can possibly prevent the progression of the disease, something pills cannot do as most T-1's become insulin dependent. And I believe the ADA has recommended insulin therapy for early T-2's.