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   Biotech / MedicalARADIGM CORP. ARDM


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To: tuck who wrote (195)4/30/2004 10:16:06 AM
From: rkrw
   of 255
 
Bummer. I still think ardm may have a better mousetrap than nktr. But ardm can't seem to catch a break.

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To: tuck who wrote (195)4/30/2004 11:21:31 AM
From: keokalani'nui
   of 255
 
>>during the nighttime, plasma glucose levels were lower in the AERx iDMS group compared to the subcutaneous group<<

It was probably this finding, not the post-prandial elevation, that killed the trial.

Wonder why they couldn't continue the trial for the T2 diabetics.

Antibodies also.

Just bought a couple ardm tickets at $1.2, some alth too, but no gnta.

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To: rkrw who wrote (196)4/30/2004 1:03:11 PM
From: keokalani'nui
   of 255
 
Having listened to novo's and ardm's cc:

1. Both companies believe it is not the device, nor is it membrane-permeability related.

2. The 'present consensus' is that the antibodies are not neutralizing.

3. The antibody formation is significant and it will be a primary focus of the coming analysis.

4. There is precedence in early insulin replacement studies (80s) that antibodies, though not neutralizing, can over the course of a study have a modifying effect on insulin. So they will be studing samples for the insulin profiles and whether there is progression of this unfavorable BG outcome. I believe this is the first suspect.

5. Could be that this is limited to T1, as they have susbstantially more circulating abs at baseline. However, the T2 study originally planned to start this year will be delayed until they figure this out.

6. Novo says in the August cc they ought to have an answer.

7. No one knows if exubera has the same issue, as no daytime bg data has been released.

8. This was all very unexpected. A good question is how long was the T1 P2?

EDIT: sold the hot shares for a .04 loss.

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To: keokalani'nui who wrote (198)5/2/2004 6:42:25 PM
From: tuck
   of 255
 
[Impact of particle size and aerosolization time on the metabolic effect of an inhaled insulin aerosol.]

Thanks for the CC notes, Wilder. This just out:

>>Diabetes Technol Ther. 2004 Apr;6(2):119-27.

Impact of particle size and aerosolization time on the metabolic effect of an inhaled insulin aerosol.

Kapitza C, Heise T, Fishman RS, Shapiro DA, Gopalakrishnan V, Rave K, Bott S, Perera AD, Heinemann L.

Profil Institute for Metabolic Research, Neuss, Germany.

The effects were compared of varying aerosol particle size and aerosolization time within each breath on the metabolic effect elicited by inhalation of a liquid insulin aerosol in comparison with that after subcutaneous injection (s.c.) of regular insulin. In this single-center, open-label euglycemic glucose clamp study, 13 healthy non-smoking subjects received five administrations of insulin in randomized order on separate study days, once by s.c. (0.15 U/kg of regular insulin) and four times by inhalation. Subjects inhaled 1.5 U/kg of liquid insulin aerosol administered by the Aerodose(R) Insulin Inhaler (Aerogen Inc., Mountain View, CA) configured to deliver two aerosol particle sizes - fine [F, 4.4 +/- 0.3 microm (mean +/- SD)] or very fine (VF, 3.5 +/- 0.2 microm) - and two aerosolization times (aerosol released for the first 2 or 4 s after the start of each 5-s inhalation). Glucose infusion rate (GIR) values necessary to keep blood glucose concentrations constant at 5.0 mmol/L were determined over a 6-h period following insulin administration. After inhalation of insulin, the onset of action was substantially more rapid on all four inhalation study days than after s.c. insulin, and the time to maximal action [t(GIRmax) (min)] was reached earlier: F/2 s, 127 +/- 54; F/4 s, 128 +/- 55; VF/2 s, 158 +/- 91; VF/4 s, 132 +/- 72; s.c., 175 +/- 69 (P < 0.0001). The longer aerosolization time (4 vs. 2 s) resulted in higher maximal metabolic action [GIR(max) (mg/kg/min), F/4 s 8.1 +/- 3.6, VF/4 s 8.4 +/- 2.7 vs. F/2 s 6.6 +/- 2.4, VF/2 s 7.2 +/- 2.4 (P = 0.01 for 4 s vs. 2 s, grouped data)], total metabolic activity [area under the curve of GIR 0-6 h (g/kg), F/4 s 1.97 +/- 0.92, VF/4 s 2.14 +/- 0.86 vs. F/2 s 1.56 +/- 0.68, VF/2 s 1.78 +/- 0.60 (P = 0.01)], and relative biopotency [F/4 s 10.6 +/- 4.0%, VF/4 s 11.7% +/- 4.1% vs. F/2 s 8.5 +/- 3.2%, VF/2 s 9.7 +/- 2.4% (P = 0.01)]. None of these summary measures was significantly affected by particle size. No drug- or device-related adverse events were observed. This study shows that aerosolization time, but not particle size, in the ranges studied, had an impact on the metabolic effect elicited by inhaled insulin, allowing rational selection of delivery parameters for further clinical testing. Based on the observed biopotency and the rapid onset of action, inhalation of a liquid insulin aerosol generated by the Aerodose Insulin Inhaler shows promise for covering prandial insulin requirements.<<

Don't know if it relates. Could aerosolization time be a factor in ARDM/Novo's trial? This might not be comparable; I gather these were not diabetics with abs circulating.

Say, how was that Russell Creek Chardonnay, anyhow? It must be a local exclusive; I've not seen it down here.

Cheers, Tuck

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To: tuck who wrote (199)5/2/2004 7:20:28 PM
From: keokalani'nui
   of 255
 
Ardm also found in its early studies that the aerosolized insulin was more fast acting than sc. That is why they didn’t formulate today’s newer faster acting insulin, novolog—and used instead POI (plain old insulin). What novo will look at is whether the longer period of repeated dosing somehow produces a moiety that tweaks the insulin in a way so as not to neutralize it but to cause a delay in effectiveness. If they do find it, it is a dead program, imo. I just can’t believe there is some circulating Ab in T1s only that causes this phenomena.

>>Russell Creek Chardonnay<<

It was the 2001 merlot, which took 1st overall at the tri-cities tasting. I hosted a blind tasting of nouveaux 2001 Washington reds. It won, but everyone probably wanted to brush their teeth after. My friends will drink anything anyway so I’m not sure that tells you anything. The wine could use a couple years laying down. Pretty label, cool name.

russellcreek-winery.com

No, you won’t see it down there. Just about all the Yakima/Columbia wineries worth a sh*t are direct ship small fry. If you want a couple up and comers, try the 2001 Cab from patit creek, its first ever and just released (yes, I think it is good but it's just a baby), or the 2002 Ciel (have not tasted) from JM Winery (likely to be v. good).

jmcellars.com

patitcreekcellars.com

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To: keokalani'nui who wrote (198)5/5/2004 6:36:13 PM
From: Area51
   of 255
 
<<Could be that this is limited to T1, as they have substantially more circulating abs at baseline. However, the T2 study originally planned to start this year will be delayed until they figure this out.>>

I gather this is the critical question. Since the market has cut ARDM price in half it seems to say that there is a 50% chance that the product is still marketable to type 2 diabetics (which are more than 90% of all diabetics or so I understand).

Since you sold I guess you think that there is less than a 50% chance that the product will be marketable to type 2 diabetics?

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To: Area51 who wrote (201)5/5/2004 7:52:21 PM
From: keokalani'nui
   of 255
 
I have no idea why you think I think this drug has a <50% chance of success in T2 diabetics.

I sold stock I had owned all of 30 minutes because I didn't (still don't) think there is any profit owning the stock ST/LT.

Hope I'm wrong.

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To: keokalani'nui who wrote (202)5/5/2004 8:35:28 PM
From: Area51
   of 255
 
Hi Wilder,

Sorry I wasn't trying to put words in your mouth. I was only trying to understand your perspective, as you are obviously more knowledgeable than I on the science.

My perspective (which may very well be seriously flawed) is that if the ARDM product can be marketed for type 2 diabetes, that it would still be a compelling long term investment now. So I was trying to get any insight you had on whether or not it was likely or unlikely that the product would be marketable for type 2 diabetes.

Best Regards,
Area51

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To: Area51 who wrote (203)5/5/2004 10:53:42 PM
From: keokalani'nui
   of 255
 
There is just no way of knowing. I'm convinced not even novo knows. But the lead suspect, if proven, will imo be the end of the drug.

You can be also sure that it's in trouble since only a few more months and they would have had the 24-mo safety data, but they stopped the trial anyway. Would fda require 24-month data for a T2-only NDA?

You are right about the payoff however.

I don't know so much about science, btw. Could save you or make you some money knowing that. ;-)

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To: keokalani'nui who wrote (204)5/26/2004 11:45:40 AM
From: tuck
   of 255
 
Recent freebie editorial on inhaled insulin:

bmj.bmjjournals.com

Notable for the sentence:

"Formation of anti-insulin antibodies is higher with inhaled insulin, and although this is dismissed as not affecting insulin requirement over time, older diabetologists will remember the drive to reduce insulin antibody formation, with the fears that antibodies delay and render unpredictable insulin absorption and even that antibody-antigen complexes may increase risk of microvascular disease."

I think this will torpedo Exubera, too, unless long term study data that does not reflect the Novo/Aradigm experience is also submitted. I hear that relevant study data was submitted by Pfizer to EMEA, but I thought these long term studies were still ongoing.

Cheers, Tuck

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