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   Biotech / MedicalARADIGM CORP. ARDM


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To: tuck who wrote (205)5/26/2004 4:14:43 PM
From: keokalani'nui
   of 255
 
Nice, very nice, work. Might see if there is a footnote to that quote.

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To: keokalani'nui who wrote (197)6/7/2004 2:56:58 PM
From: tuck
   of 255
 
INHL' studies continue to show no effect, but night time glucose levels not measured? Would the FDA ask for such data? Two year results coming soon, should be interesting . . .

Message 20200796

Cheers, Tuck

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To: tuck who wrote (207)6/7/2004 4:07:53 PM
From: keokalani'nui
   of 255
 
tuck, apparently7 exubera shared l/t safety and efficacy at ADA today. I didn't focus on it and probably won't since I got no dog in the fight.

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To: rkrw who wrote (196)6/9/2004 3:21:01 PM
From: tuck
   of 255
 
It would appear that night time glucose levels, which derailed AERx, weren't measured in Exubera long term safety studies. From this year's ADA meeting:

>>Sustained Long-Term Efficacy and Safety of Inhaled Insulin during 4 Years of Continuous Therapy

Abstract Information
Abstract Number: 486-P
Authors: JAY SKYLER, FOR THE EXUBERA® PHASE II STUDY GROUP
Institution: Miami, FL
Results: Inhaled insulin has shown encouraging efficacy and safety data in short-term clinical trials. This study examined whether these favorable results are maintained in the long term. Continued open-label inhaled insulin therapy was offered to patients with diabetes who had completed any of three 3-month, randomized, controlled clinical trials (type 1, insulin-treated type 2 or type 2 diabetes uncontrolled on oral agents [OAs]). A total of 204 patients entered the extension, with 159 electing to stay on inhaled insulin (INH) or switch from comparator treatments and 89 patients having received at least 4 years of INH therapy. A small group of patients (n=23) on OAs or subcutaneous insulin was followed for up to 2 years as well. Mean (± SD) HbAì1cí was 8.23 ± 1.21% after 4 years in INH patients compared with 8.71 ± 1.49% at the start of INH treatment. Inhaled insulin dose increased slightly from 0.15 mg/kg after 3 months of treatment to 0.18 mg/kg after 4 years. The rate of overall hypoglycemia decreased from 2.58 episodes/subject month (first 4 weeks of INH treatment) to 1.50 after 4 years (final 6 months). Annualized changes in the lung function parameters FEVì1í and DLìCOí (mean ± SE) in INH patients over 4 years were -0.057 ± 0.004 L/yr and -0.376 ± 0.067 mL/min/mmHg/yr, respectively. Corresponding declines in non-INH patients (based on 2-year data only) were -0.071 ± 0.023 L/yr and -0.673 ± 0.423 mL/min/mmHg/yr, respectively. In conclusion, glycemic control and pulmonary function are well maintained during long-term continuous inhaled insulin therapy.<<

So my question is, why has ARDM/Novo made this measurement while NKTR and partners have not? Will the FDA want this parameter? I would think that if the former thought it was appropriate to delay development while investigating this issue, that the FDA would surely want to look at it from all comers. I wonder what others are thinking. FBR downgraded NKTR today, but I can't find the rationale. The results appear pretty good, absent the above measurement.

Thanks for any thoughts from anyone on this.

Cheers, Tuck

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To: tuck who wrote (209)6/10/2004 1:24:55 PM
From: tuck
   of 255
 
Thanks to deeno for this ML report which mentions for the first time in the analytical domain (that I have seen) the ARDM/Novo experience as a potential problem for Exubera.

Message 20210503

Cheers, Tuck

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To: rkrw who wrote (196)8/10/2004 3:28:44 PM
From: tuck
   of 255
 
>>CAMBRIDGE, Mass.--(BUSINESS WIRE)--Aug. 10, 2004--Alkermes, Inc. (Nasdaq: ALKS - News) announced today that Eli Lilly and Company ("Lilly") has made a positive product decision and will proceed with significant investment for the further development of an inhaled formulation of insulin. The decision follows the successful execution of several critical steps: the completion and analysis of data from a Phase 2 study; the achievement of commercial manufacturing powder production scale-up; and the development and testing of the commercial pulmonary insulin inhaler system. Development activities will include both clinical trials and additional manufacturing activities for the inhaler system and the production facility.

A recently completed Phase 2 clinical trial for inhaled insulin using Alkermes' AIR® technology showed that patients with type 1 diabetes achieved glycemic control levels similar to injected insulin. The trial was a multi-center, cross-over design study with 120 patients with type 1 diabetes receiving an inhaled formulation of insulin using AIR technology for a three-month period. Inhaled insulin had a rapid onset of action and was well tolerated with adverse events similar in both treatment arms.

"We're delighted that the strength of the clinical data and our achievement of commercialization milestones provided the basis of the decision by Lilly to move forward with further development for inhaled insulin," said Elliot Ehrich, M.D., Chief Medical Officer at Alkermes. "We look forward to initiating additional clinical studies that will bring us another step closer to developing an important new treatment for the growing number of people living with diabetes."

The inhaled insulin delivery system is based on Alkermes' AIR pulmonary drug delivery technology, which uses a small, easy-to-use, inhaler designed to provide drug delivery for a wide range of drug doses. Alkermes and Lilly have collaborated on the inhaled insulin program since 2001 to develop an innovative treatment option for people with diabetes.

About Diabetes

Diabetes is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. According to the American Diabetes Association ("ADA"), diabetes can be associated with serious complications and premature death, but people with diabetes can take steps to control the disease and lower the risk of complications (Source ADA). Additionally, the World Health Organization ("WHO") lists diabetes as one of the leading causes of mortality worldwide. Approximately 193 million people around the world have diabetes, and this number is expected to double to 330 million by the year 2025 (Source International Diabetes Federation). <<

There is no thread for Alkermes, according to the lame SI search engine. NKTR recently got creamed by EMEA "not licensable" letter a few days ago. Not sure what the specific concerns were, but one wonders if the antibody issue is haunting them, too. Will Lilly and Alkermes really escape? NKTR is up 10%, ALKS 20% . . . and ARDM is still in its hospital bed.

Cheers, Tuck

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To: tuck who wrote (211)8/24/2004 10:52:05 AM
From: tuck
   of 255
 
[Intrasubject variability of inhaled insulin in type 1 diabetes: a comparison with subcutaneous insulin.]

>>Diabetes Technol Ther. 2004 Aug;6(4):466-72.

Intrasubject variability of inhaled insulin in type 1 diabetes: a comparison with subcutaneous insulin.

Kapitza C, Hompesch M, Scharling B, Heise T.

Profil Institute for Metabolic Research, Neuss, Germany.

We compared intrasubject variability of insulin and glucose profiles after a standardized meal between insulin inhaled via the AERx((R)) insulin Diabetes Management System (AERx iDMS, Aradigm Corp., Hayward, CA) and given as a subcutaneous injection. In this single-center, parallel, randomized, open-labeled trial, 17 male, non-smoking patients with type 1 diabetes (mean age, 27.7 years; body mass index, 23.4 kg/m(2)) received a fixed, individualized dose of human insulin, on four treatment days followed by an individualized breakfast, administered either by inhalation via AERx iDMS (n = 9) or by subcutaneous injection. Serum insulin and serum glucose levels were determined at regular intervals for 6 h postdose. Intrasubject variability was expressed as coefficient of variation. No statistically significant differences in intrasubject variability were observed between the treatments for the areas under the insulin curves for 0-6 h [27% vs. 19% (inhaled insulin vs. subcutaneous)] and areas under the glucose curves 0-6 h (30% vs. 23%). Intrasubject variability values for insulin half-life, terminal elimination rate constant, and mean residence time were significantly less in the inhaled insulin group compared with the subcutaneous insulin group (P = 0.01-0.02). Only one potentially trial product-related adverse event (an audible wheeze) was reported, and no clinically relevant changes in pulmonary function were detected. The intrasubject variability was comparable between patients receiving inhaled insulin and subcutaneous insulin, thereby confirming the reproducibility of administering insulin via AERx iDMS. Inhaled insulin was well tolerated and is a feasible alternative to subcutaneous insulin in patients with type 1 diabetes.<<

Nothing major here . . .

Cheers, Tuck

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To: tuck who wrote (212)8/26/2004 11:54:58 AM
From: tuck
   of 255
 
Now KOSP is playing in the inhaled insulin space, too. Here's the relevant snip from a PR today:

>>The results of the phase IIa trial show that Kos' internally developed inhaled insulin formulation is comparable to the market leading injectable insulin in controlling blood glucose levels, while also reducing blood lipids such as LDL cholesterol and triglycerides. (Please note table of summary results below.) Kos' inhaled insulin formulation also demonstrated bioavailability of up to 23% in a previous phase I human study. The successful completion of these phase I and IIa studies support the safety and efficacy of Kos' patient-friendly, excipient-free formulation.

In the head-to-head comparative study of 24 type 2 diabetic patients, insulin-naive patients were randomized to receive either Kos' inhaled insulin formulation at meals or a single evening injection of insulin glargine, a basal insulin analog marketed by Aventis Pharmaceuticals Inc. under the brand name Lantus® (and currently the most prescribed insulin in the U.S.). Following a one-month treatment period, Kos' inhaled insulin formulation demonstrated a mean reduction in blood glucose of 28%, compared with a mean reduction of 23% with insulin glargine. Kos' formulation also showed a trend toward greater improvement with respect to hemoglobin (Hb) A1c, showing a mean absolute reduction of 1.23 mg/dL, compared with a mean absolute reduction of 1.05 mg/dL with insulin glargine. The safety profiles of both treatments were comparable, with four mild to moderate hypoglycemic episodes occurring in both groups. Additionally, Kos' inhaled insulin formulation produced a 10% reduction of LDL cholesterol at day 28, compared with an increase of 1.4% with insulin glargine. Similarly, triglycerides were reduced by 36% with Kos' inhaled formulation, compared with a 12% reduction with the injectable insulin. Such results are quite important in so far as many type 2 diabetics not only require good control of blood sugar, but also require modulation of abnormal lipids, which occur in more than 60% of all diabetics.

SUMMARY DATA FROM PHASE IIa STUDY IN TYPE 2 DIABETES

Day 7 Day 28
------------------------- --------------------------
Kos Injectable Kos Injectable
Inhaled Insulin Inhaled Insulin
Insulin glargine Insulin glargine
------- -------- ------- --------
(n=12) (n=12) (n=12) (n=12)

Mean Change in
Glucose (%) -26.8 -24.8 -27.8 -23.1

Absolute Change
in Hb A1c
(mg/dL) -0.23 -0.18 -1.23 -1.05

LDL Cholesterol
(%) -5.2 1.9 -9.9 1.4

Triglycerides
(%) -40.7 -28.6 -35.8(1) -11.5

(1) Significant at p less than or equal to 0.05 vs. injectable
insulin glargine (Lantus). Given the small sample size of the study,
statistical significance was not observed with the exception of
triglycerides at day 28, however, results did show trends toward
improvement in post-prandial measures of blood glucose and blood
lipids.

"Injections have long been a hurdle in the treatment of certain patients with diabetes," said Jay Skyler, MD, Director of Endocrinology, Diabetes, and Metabolism, University of Miami. "A user-friendly inhaled insulin product will open the door for patients who have been hesitant to start therapy or comply with their current treatment."

Kos' excipient-free formulation coupled with Kos' patented compact, hand-held Breath Actuated Inhaler ("BAI") device offers a precision lung delivery platform for insulin therapy. The Kos formulation, which does not require refrigeration, contains no carriers or preservatives and incorporates a crystalline, recombinant human insulin (rh-insulin) delivered by a standard, well-tested non-CFC, environmentally-friendly propellant. In clinical testing, patients and physicians were impressed with the ease of use of the patented BAI delivery system in administering insulin therapy, potentially improving patient compliance. Both the excipient-free formulation and the BAI device were entirely developed internally by Kos. The Company is seeking a corporate partner to complete the clinical development of its innovative inhaled insulin product.

"We are extremely excited about the achievement of these important R&D milestones in both the solid dose and inhalation areas," said Adrian Adams, President and CEO, Kos Pharmaceuticals, Inc. "Kos' inhaled insulin formulation is expected to confer highly potent and patient-friendly insulin therapy that is well tolerated, possibly allaying side effects that have been observed with other preparations of inhaled insulin therapy. This formulation was designed to eliminate specific chemical additives, some of which have been associated with certain pulmonary side effects and have been cited as an issue with earlier generations of inhaled insulin. Further, this excipient-free, user-friendly technology is a product of our continued and measured investments in our inhalation platform, consisting of proprietary formulation and device technologies."<<

Cheers, Tuck

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To: tuck who wrote (213)8/26/2004 12:45:35 PM
From: rkrw
   of 255
 
KOSP program has been around a long time. Any idea why kosp is able to get such dramatic drops in ldl and triglycerides with inhalation? I wonder how it compares with exubera and aerx?

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To: rkrw who wrote (214)8/26/2004 1:12:42 PM
From: tuck
   of 255
 
No, though that struck me, too. I don't know why KOSP is targeting those parameters. If they've been measured for competing systems, I haven't been able to find any data or even mention of it. What struck me as more crucial was the "excipient-free" formulation. Wondering if AERx and Exubera use excipients that might cause those pulmonary problems. Don't think that relates directly to AERx' night time glucose level issues, though.

Cheers, Tuck

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