Safety and Pharmacodynamics of CJC-1134-PC, a Novel GLP-1 ReceptorAgonist, in Patients with Type 2 Diabetes Mellitus

"Safety and Pharmacodynamics of CJC-1134-PC, a Novel GLP-1 Receptor
Agonist, in Patients with Type 2 Diabetes Mellitus: A Randomized,
Placebo-Controlled, Double-Blind, Dose-Escalation Study
Year: 2007
Abstract Number: 0498-P

Authors:
MAGGIE WANG, MARK KIPNES, STEPHANIE MATHESON, STELLA WEN, BETTY
LAWRENCE, KAREN THIBAUDEAU, JEAN-PAUL CASTAIGNE, THOMAS ULICH, Montreal,
PQ, Canada, San Antonio, TX

Results:
CJC-1134-PC is a modified exendin-4 analog conjugated to recombinant
human albumin to form a novel, long-acting GLP-1 receptor agonist. This
double-blind, placebo-controlled study evaluated the safety and efficacy
of escalating single doses of CJC-1134-PC in 58 patients with Type 2
diabetes mellitus. Forty-two male (n=18) and female (n=24) patients
discontinued their oral antidiabetic agents for [ge]1 week and were
randomized into 6 escalating cohorts. Within each cohort, 7 patients
received a subcutaneous injection of CJC-1134-PC (n=6) or placebo (n=1)
on Day 1 at doses of 310, 620, 1250, 2500, 3750 or 5000 [micro]g, and
remained in the CPU until Day 7. An additional group of 16 patients (9
males, 7 females) received either 3000 [micro]g of CJC-1134-PC (n=12) or
placebo (n=4), and remained in the CPU until Day 22. All patients were
evaluated weekly after discharge until Day 42. Placebo and doses of 310
to 620 [micro]g had no significant effect on mean daily or fasting
glucose levels. Doses of [ge]1250 [micro]g produced rapid and
long-lasting reductions in mean daily glucose levels, persisting for 1
to 3 weeks after the single injection. At doses [ge]1250 [micro]g,
dose-related decreases in mean daily glucose levels at the end of the
first week ranged from 11.8% to 24.2%, relative to baseline. Similarly,
the mean reduction of fasting glucose at the end of the first week
ranged from 4.1% to 11.3%, relative to baseline. A notable mean
reduction in body weight of 2.5 kg (vs. 1.2 kg for placebo) was observed
for the 3000 [micro]g group at the end of the 3-week in-clinic stay on a
controlled diet. No significant safety or tolerability issues were
reported at dose levels up to 3000 [micro]g. Two patients experienced
mild (3750 [micro]g) or moderate (5000 [micro]g) vomiting on Day 1.
There were no reports of injection site reactions. No significant
changes in clinical laboratory results, vital signs, physical
examination, or ECG were noted. The PK profile exhibited a plasma Cmax
from approximately day 2 to 7, and a prolonged exposure that supports at
least a weekly dosing interval. In summary, CJC-1134-PC is locally and
systemically well-tolerated at doses that lowered both fasting and mean
daily glucose for at least one week in patients with Type 2 diabetes
after a single injection.

Category:
Clinical Therapeutics/New Technology - Pharmacologic Treatment of
Diabetes or its Complications"

http://scientificsessions.diabetes.o...alledByID=1006
Abstract number 0498-P (enter abstract number in link below.
http://tinyurl.com/etaho

Frank

On Jul 9, 6:42 pm, Jefferson <f...@adelphia.netxeopheno> wrote:
> "Safety and Pharmacodynamics of CJC-1134-PC, a Novel GLP-1 Receptor
> Agonist, in Patients with Type 2 Diabetes Mellitus: A Randomized,
> Placebo-Controlled, Double-Blind, Dose-Escalation Study
> Year: 2007
> Abstract Number: 0498-P
>
> Authors:
> MAGGIE WANG, MARK KIPNES, STEPHANIE MATHESON, STELLA WEN, BETTY
> LAWRENCE, KAREN THIBAUDEAU, JEAN-PAUL CASTAIGNE, THOMAS ULICH, Montreal,
> PQ, Canada, San Antonio, TX
>
> Results:
> CJC-1134-PC is a modified exendin-4 analog conjugated to recombinant
> human albumin to form a novel, long-acting GLP-1 receptor agonist. This
> double-blind, placebo-controlled study evaluated the safety and efficacy
> of escalating single doses of CJC-1134-PC in 58 patients with Type 2
> diabetes mellitus. Forty-two male (n=18) and female (n=24) patients
> discontinued their oral antidiabetic agents for [ge]1 week and were
> randomized into 6 escalating cohorts. Within each cohort, 7 patients
> received a subcutaneous injection of CJC-1134-PC (n=6) or placebo (n=1)
> on Day 1 at doses of 310, 620, 1250, 2500, 3750 or 5000 [micro]g, and
> remained in the CPU until Day 7. An additional group of 16 patients (9
> males, 7 females) received either 3000 [micro]g of CJC-1134-PC (n=12) or
> placebo (n=4), and remained in the CPU until Day 22. All patients were
> evaluated weekly after discharge until Day 42. Placebo and doses of 310
> to 620 [micro]g had no significant effect on mean daily or fasting
> glucose levels. Doses of [ge]1250 [micro]g produced rapid and
> long-lasting reductions in mean daily glucose levels, persisting for 1
> to 3 weeks after the single injection. At doses [ge]1250 [micro]g,
> dose-related decreases in mean daily glucose levels at the end of the
> first week ranged from 11.8% to 24.2%, relative to baseline. Similarly,
> the mean reduction of fasting glucose at the end of the first week
> ranged from 4.1% to 11.3%, relative to baseline. A notable mean
> reduction in body weight of 2.5 kg (vs. 1.2 kg for placebo) was observed
> for the 3000 [micro]g group at the end of the 3-week in-clinic stay on a
> controlled diet. No significant safety or tolerability issues were
> reported at dose levels up to 3000 [micro]g. Two patients experienced
> mild (3750 [micro]g) or moderate (5000 [micro]g) vomiting on Day 1.
> There were no reports of injection site reactions. No significant
> changes in clinical laboratory results, vital signs, physical
> examination, or ECG were noted. The PK profile exhibited a plasma Cmax
> from approximately day 2 to 7, and a prolonged exposure that supports at
> least a weekly dosing interval. In summary, CJC-1134-PC is locally and
> systemically well-tolerated at doses that lowered both fasting and mean
> daily glucose for at least one week in patients with Type 2 diabetes
> after a single injection.
>
> Category:
> Clinical Therapeutics/New Technology - Pharmacologic Treatment of
> Diabetes or its Complications"
>
> http://scientificsessions.diabetes.o...tion=Locator.S...
> Abstract number 0498-P (enter abstract number in link below.http://tinyurl.com/etaho
>
> Frank

Frank, is this about the trials on the once-a-week or month byetta
shots?

Jefferson wrote:
> "Safety and Pharmacodynamics of CJC-1134-PC, a Novel GLP-1 Receptor
> Agonist, in Patients with Type 2 Diabetes Mellitus: A Randomized,
> Placebo-Controlled, Double-Blind, Dose-Escalation Study
> Year: 2007
> Abstract Number: 0498-P
>
> Authors:
> MAGGIE WANG, MARK KIPNES, STEPHANIE MATHESON, STELLA WEN, BETTY
> LAWRENCE, KAREN THIBAUDEAU, JEAN-PAUL CASTAIGNE, THOMAS ULICH, Montreal,
> PQ, Canada, San Antonio, TX
>
> Results:
> CJC-1134-PC is a modified exendin-4 analog conjugated to recombinant
> human albumin to form a novel, long-acting GLP-1 receptor agonist. This
> double-blind, placebo-controlled study evaluated the safety and efficacy
> of escalating single doses of CJC-1134-PC in 58 patients with Type 2
> diabetes mellitus. Forty-two male (n=18) and female (n=24) patients
> discontinued their oral antidiabetic agents for [ge]1 week and were
> randomized into 6 escalating cohorts. Within each cohort, 7 patients
> received a subcutaneous injection of CJC-1134-PC (n=6) or placebo (n=1)
> on Day 1 at doses of 310, 620, 1250, 2500, 3750 or 5000 [micro]g, and
> remained in the CPU until Day 7. An additional group of 16 patients (9
> males, 7 females) received either 3000 [micro]g of CJC-1134-PC (n=12) or
> placebo (n=4), and remained in the CPU until Day 22. All patients were
> evaluated weekly after discharge until Day 42. Placebo and doses of 310
> to 620 [micro]g had no significant effect on mean daily or fasting
> glucose levels. Doses of [ge]1250 [micro]g produced rapid and
> long-lasting reductions in mean daily glucose levels, persisting for 1
> to 3 weeks after the single injection. At doses [ge]1250 [micro]g,
> dose-related decreases in mean daily glucose levels at the end of the
> first week ranged from 11.8% to 24.2%, relative to baseline. Similarly,
> the mean reduction of fasting glucose at the end of the first week
> ranged from 4.1% to 11.3%, relative to baseline. A notable mean
> reduction in body weight of 2.5 kg (vs. 1.2 kg for placebo) was observed
> for the 3000 [micro]g group at the end of the 3-week in-clinic stay on a
> controlled diet. No significant safety or tolerability issues were
> reported at dose levels up to 3000 [micro]g. Two patients experienced
> mild (3750 [micro]g) or moderate (5000 [micro]g) vomiting on Day 1.
> There were no reports of injection site reactions. No significant
> changes in clinical laboratory results, vital signs, physical
> examination, or ECG were noted. The PK profile exhibited a plasma Cmax
> from approximately day 2 to 7, and a prolonged exposure that supports at
> least a weekly dosing interval. In summary, CJC-1134-PC is locally and
> systemically well-tolerated at doses that lowered both fasting and mean
> daily glucose for at least one week in patients with Type 2 diabetes
> after a single injection.
>
> Category:
> Clinical Therapeutics/New Technology - Pharmacologic Treatment of
> Diabetes or its Complications"
>
> http://scientificsessions.diabetes.o...alledByID=1006
> Abstract number 0498-P (enter abstract number in link below.
> http://tinyurl.com/etaho
>

There remains a concern that GLP-1 receptor agonists may increase the
incidence of brain and GI tumors because these neoplastic cell types
have been shown to express a high number of GLP-1 receptors:

http://groups.google.com/group/sci.m...682bfd701b4a8?

This concern would be extended to medications like Byetta and Januvia.

Be hungry... be healthy... be blessed.

Prayerfully in Jesus' awesome love,

Andrew <><
--
Andrew B. Chung, MD/PhD
Cardiologist

Ricavito wrote:
> On Jul 9, 6:42 pm, Jefferson <f...@adelphia.netxeopheno> wrote:
>
>>"Safety and Pharmacodynamics of CJC-1134-PC, a Novel GLP-1 Receptor
>>Agonist, in Patients with Type 2 Diabetes Mellitus: A Randomized,
>>Placebo-Controlled, Double-Blind, Dose-Escalation Study
>>Year: 2007
>>Abstract Number: 0498-P
>>
>>http://scientificsessions.diabetes.o...tion=Locator.S...
>>Abstract number 0498-P (enter abstract number in link below.http://tinyurl.com/etaho
>
> Frank, is this about the trials on the once-a-week or month byetta
> shots?
>

Yes and no. Amylin Pharmaceuticals is the manufacturer of Byetta. Both
of the products that I am aware of use a different means of extending
the effects of exendin-4. I don't know that exenatide is different from
exendin-4. ConjuChem Biotechnologies Reports PC-DACâ„¢:Exendin-4 Albumin
Conjugate Data Presented at American Diabetes Association Annual Meeting
- http://conjuchem.hyphenhealth.com/ne...ts_June_07.pdf
CJC-1134-PC is a Exendin-4 Albumin Conjugate. Albumin has a relatively
long half-life. Human Genome Sciences transfered their rights to develop
Albugon/Syncria that involves natural GLP-1 and albumin to GSK. I liked
the fact that natural GLP-1 is the basis of this therapy even though it
is not as potent as exenatide. (The latter company terms the product as
in pre-clinical level of development -
http://www.gsk.com/investors/present..._06132006.pdf).

Until you asked, I did not know the following article was available in full:

Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of
Exenatide on Glucose Control and Body Weight in Subjects With Type 2
Diabetes - http://care.diabetesjournals.org/cgi...full/30/6/1487

"OBJECTIVE—In patients with type 2 diabetes, exenatide reduces A1C,
postprandial and fasting glucose, and weight. In this study we
investigated the effects of continuous exenatide administration from a
long-acting release (LAR) formulation.

RESEARCH DESIGN AND METHODS—In this randomized, placebo-controlled phase
2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously
once weekly for 15 weeks to subjects with type 2 diabetes (n = 45)
suboptimally controlled with metformin (60%) and/or diet and exercise
(40%): 40% female, A1C (mean ± SD) 8.5 ± 1.2%, fasting plasma glucose
9.9 ± 2.3 mmol/l, weight 106 ± 20 kg, and diabetes duration 5 ± 4 years.

RESULTS—From baseline to week 15, exenatide LAR reduced mean ± SE A1C by
–1.4 ± 0.3% (0.8 mg) and –1.7 ± 0.3% (2.0 mg), compared with +0.4 ± 0.3%
with placebo LAR (P < 0.0001 for both). A1C of ≤7% was achieved by 36
and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR,
respectively, compared with 0% of subjects receiving placebo LAR.
Fasting plasma glucose was reduced by –2.4 ± 0.9 mmol/l (0.8 mg) and
–2.2 ± 0.5 mmol/l (2.0 mg) compared with +1.0 ± 0.7 mmol/l with placebo
LAR (P < 0.001 for both). Exenatide LAR reduced self-monitored
postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had
body weight reductions (–3.8 ± 1.4 kg) (P < 0.05), whereas body weight
was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was
the most frequent adverse event. No subjects treated with exenatide LAR
withdrew from the study.

CONCLUSIONS—Exenatide LAR offers the potential of 24-h glycemic control
and weight reduction with a novel once-weekly treatment for type 2 diabetes.

Abbreviations: BID, twice daily • GLP-1, glucagon-like peptide-1 • ITT,
intention to treat • LAR, long-acting release

Exenatide LAR consists of microspheres composed of exenatide and a
poly(lactide-coglycolide) polymeric matrix. Poly(lactide-coglycolide) is
a common biodegradable medical polymer with an extensive history of
human use in absorbable sutures and extended-release pharmaceuticals.
After injection, exenatide is slowly released from the microspheres
through diffusion and erosion. ... With once-weekly exenatide LAR
injections, mean plasma exenatide concentrations rose steadily. By week
2, treatment with 2.0 mg exenatide LAR reached 50 pg/ml, a concentration
previously shown to significantly reduce plasma glucose (Fig. 2) (28).
After ~6 weeks of treatment with 2.0 mg exenatide LAR, plasma exenatide
concentrations were maintained at concentrations similar to the maximum
concentration achieved with a single injection of 10 µg exenatide
(steady-state concentration of 232 pg/ml with 2.0 mg exenatide LAR
compared with 211 pg/ml after a single injection of 10 µg exenatide)
(16). The steady-state concentration with 0.8 mg exenatide LAR was 111
pg/ml. After completion of the treatment phase at week 15, exenatide
concentrations decreased steadily to below those considered to have a
therapeutic effect by week 21."

See parts C (A1c) and D (weight change) in Figure 3 — Glycemic and
weight parameters. The lower dose of exenatide LAR lowered A1c almost
as much as the higher dose, but did not have much impact on weight. I
would imagine that exenatide LAR is closer to FDA approval than
CJC-1134-PC since it has had a longer trial and Byetta is already a FDA
approved medication.

Frank

On Jul 10, 12:52 pm, Jefferson <f...@adelphia.netxeopheno> wrote:
> Ricavito wrote:
> > On Jul 9, 6:42 pm, Jefferson <f...@adelphia.netxeopheno> wrote:
>
> >>"Safety and Pharmacodynamics of CJC-1134-PC, a Novel GLP-1 Receptor
> >>Agonist, in Patients with Type 2 Diabetes Mellitus: A Randomized,
> >>Placebo-Controlled, Double-Blind, Dose-Escalation Study
> >>Year: 2007
> >>Abstract Number: 0498-P
>
> >>http://scientificsessions.diabetes.o...tion=Locator.S....
> >>Abstract number 0498-P (enter abstract number in link below.http://tinyurl.com/etaho
>
> > Frank, is this about the trials on the once-a-week or month byetta
> > shots?
>
> Yes and no. Amylin Pharmaceuticals is the manufacturer of Byetta. Both
> of the products that I am aware of use a different means of extending
> the effects of exendin-4. I don't know that exenatide is different from
> exendin-4. ConjuChem Biotechnologies Reports PC-DAC™:Exendin-4 Albumin
> Conjugate Data Presented at American Diabetes Association Annual Meeting
> -http://conjuchem.hyphenhealth.com/news/CJB_ADA_Results_June_07.pdf
> CJC-1134-PC is a Exendin-4 Albumin Conjugate. Albumin has a relatively
> long half-life. Human Genome Sciences transfered their rights to develop
> Albugon/Syncria that involves natural GLP-1 and albumin to GSK. I liked
> the fact that natural GLP-1 is the basis of this therapy even though it
> is not as potent as exenatide. (The latter company terms the product as
> in pre-clinical level of development -http://www.gsk.com/investors/presentations/2006/goldmansachs_06132006...).
>
> Until you asked, I did not know the following article was available in full:
>
> Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of
> Exenatide on Glucose Control and Body Weight in Subjects With Type 2
> Diabetes -http://care.diabetesjournals.org/cgi/content/full/30/6/1487
>
> "OBJECTIVE-In patients with type 2 diabetes, exenatide reduces A1C,
> postprandial and fasting glucose, and weight. In this study we
> investigated the effects of continuous exenatide administration from a
> long-acting release (LAR) formulation.
>
> RESEARCH DESIGN AND METHODS-In this randomized, placebo-controlled phase
> 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously
> once weekly for 15 weeks to subjects with type 2 diabetes (n = 45)
> suboptimally controlled with metformin (60%) and/or diet and exercise
> (40%): 40% female, A1C (mean ± SD) 8.5 ± 1.2%, fasting plasma glucose
> 9.9 ± 2.3 mmol/l, weight 106 ± 20 kg, and diabetes duration 5 ± 4 years.
>
> RESULTS-From baseline to week 15, exenatide LAR reduced mean ± SE A1C by
> -1.4 ± 0.3% (0.8 mg) and -1.7 ± 0.3% (2.0 mg), compared with +0.4 ±0.3%
> with placebo LAR (P < 0.0001 for both). A1C of 7% was achieved by 36
> and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR,
> respectively, compared with 0% of subjects receiving placebo LAR.
> Fasting plasma glucose was reduced by -2.4 ± 0.9 mmol/l (0.8 mg) and
> -2.2 ± 0.5 mmol/l (2.0 mg) compared with +1.0 ± 0.7 mmol/l with placebo
> LAR (P < 0.001 for both). Exenatide LAR reduced self-monitored
> postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had
> body weight reductions (-3.8 ± 1.4 kg) (P < 0.05), whereas body weight
> was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was
> the most frequent adverse event. No subjects treated with exenatide LAR
> withdrew from the study.
>
> CONCLUSIONS-Exenatide LAR offers the potential of 24-h glycemic control
> and weight reduction with a novel once-weekly treatment for type 2 diabetes.
>
> Abbreviations: BID, twice daily · GLP-1, glucagon-like peptide-1 · ITT,
> intention to treat · LAR, long-acting release
>
> Exenatide LAR consists of microspheres composed of exenatide and a
> poly(lactide-coglycolide) polymeric matrix. Poly(lactide-coglycolide) is
> a common biodegradable medical polymer with an extensive history of
> human use in absorbable sutures and extended-release pharmaceuticals.
> After injection, exenatide is slowly released from the microspheres
> through diffusion and erosion. ... With once-weekly exenatide LAR
> injections, mean plasma exenatide concentrations rose steadily. By week
> 2, treatment with 2.0 mg exenatide LAR reached 50 pg/ml, a concentration
> previously shown to significantly reduce plasma glucose (Fig. 2) (28).
> After ~6 weeks of treatment with 2.0 mg exenatide LAR, plasma exenatide
> concentrations were maintained at concentrations similar to the maximum
> concentration achieved with a single injection of 10 µg exenatide
> (steady-state concentration of 232 pg/ml with 2.0 mg exenatide LAR
> compared with 211 pg/ml after a single injection of 10 µg exenatide)
> (16). The steady-state concentration with 0.8 mg exenatide LAR was 111
> pg/ml. After completion of the treatment phase at week 15, exenatide
> concentrations decreased steadily to below those considered to have a
> therapeutic effect by week 21."
>
> See parts C (A1c) and D (weight change) in Figure 3 - Glycemic and
> weight parameters. The lower dose of exenatide LAR lowered A1c almost
> as much as the higher dose, but did not have much impact on weight. I
> would imagine that exenatide LAR is closer to FDA approval than
> CJC-1134-PC since it has had a longer trial and Byetta is already a FDA
> approved medication.
>
> Frank

Ah, thanks for posting this Frank. Byetta is effective I believe if
one remembers to take it or can deal with the portability issues
(work, travel, hot weather, etc.). The weekly injection would solve
this.

On Mon, 09 Jul 2007 21:42:15 -0400, Jefferson
<fwroy@adelphia.netxeopheno> wrote:

> In summary, CJC-1134-PC is locally and
>systemically well-tolerated at doses that lowered both fasting and mean
>daily glucose for at least one week in patients with Type 2 diabetes
>after a single injection.

Very cool - and at the human trial stage too! Is it still a DPP-4
inhibitor, Frank?

Nicky.
T2 dx 05/04 + underactive thyroid
D&E, 100ug thyroxine
Last A1c 5.6% BMI 25

Nicky wrote:
> On Mon, 09 Jul 2007 21:42:15 -0400, Jefferson
> <fwroy@adelphia.netxeopheno> wrote:
>
>
>>In summary, CJC-1134-PC is locally and
>>systemically well-tolerated at doses that lowered both fasting and mean
>>daily glucose for at least one week in patients with Type 2 diabetes
>>after a single injection.
>
>
> Very cool - and at the human trial stage too! Is it still a DPP-4
> inhibitor, Frank?
>
No, CJC-1134-PC is based on exendin-4, otherwise known as Exenatide or
Byetta by another manufacturer (Amylin Pharm.). The extended life
relates to it linking to albumin which has a long half-life. This might
not be the best technical explanation.

On Wed, 11 Jul 2007 15:18:56 -0400, Jefferson
<fwroy@adelphia.netxeopheno> wrote:

>> Very cool - and at the human trial stage too! Is it still a DPP-4
>> inhibitor, Frank?
>>
>No, CJC-1134-PC is based on exendin-4, otherwise known as Exenatide or
>Byetta by another manufacturer (Amylin Pharm.). The extended life
>relates to it linking to albumin which has a long half-life. This might
>not be the best technical explanation.

Oh, I thought it was another Januvia look-alike! Thanks for putting me
straight.

Nicky.
T2 dx 05/04 + underactive thyroid
D&E, 100ug thyroxine
Last A1c 5.6% BMI 25