is it possible, page-12

Thanks Jevalent
I am encouraged by your comments re patent protection and seeming inaction.
In some ways it’s positive and demonstrates a continuing interest.

Oral availability was thought to have been proved in an early very limited trial.

After the unexpected failure of the AOD9604 trial i am sure there was a plan to evaluate a topical cream or patch.
At that time TPM was in early development.
However, as the company announcement Dec 2010 re black market in AOD9604 stated,

‘While AOD9604 showed early promise in treating obesity in clinical trials it failed to reach the chosen efficacy end point in a large Phase II trial in February 2007. This may have been due to ineffective administration of the drug as an oral tablet formulation’.

And this from a body building site, who would have thought body builders and molecular biologist!
Daltons, frankly it’s beyond my HSC chemistry I’m still trying to work out Moles!

"AOD9604 failed as an anti-obesity drug. In a 536-patient Phase IIb randomised,
placebo-controlled trial of AOD9604, results of which were reported in February
2007, the drug:
• failed to achieve a statistically significant weight loss in any dosage group
after either 12 weeks or 24 weeks of treatment; and
• showed precious little overall weight loss - even after allowing for the formal
diet and exercise programme that had been put in place for this trial (and had
not been for previous trials) the weight-loss results were sparse, with less
than 1 kg drop across all dose groups6 at both measurement points.""


However,

AOD9604 did burn fat for at least one trial group. When AOD9604’s Phase IIb
investigators looked at females in the trial with ‘low response to the diet and
exercise before randomisation’7 the result was ‘similar effect sizes to those
reported in the previous trial’, that trial being a Phase IIb trial which had shown
good performance for low doses of the drug. It’s well known that physical
exercise results in the body producing growth hormone8, and that would
potentially explain why AOD9604, as a growth hormone derivative, failed to
produce much response across most treatment groups where exercise
compliance was better – the drug didn’t ‘synergise’ an exercise programme in
terms of overall body weight, as Metabolic had hoped prior to initiating the trial. It
did, however, burn fat9. We think this data partly confirmed what Metabolic had
observed in February 2002 when it reported results of its first Phase IIa of
AOD9604, where patients registered an increase in fat breakdown 2 hours after
AOD9604 dosing compared to placebo. Patients over 35 showing a 25% increase
in blood levels of non-esterified fatty acids (NEFA) compared to placebo, with a p
value of less than 0.01. This trial, in 23 obese subjects, saw AOD9604
administered intravenously.
In vivo data suggests that AOD9604 can burn fat when it reaches the sites
of fat storage. Two papers from scientists working with Metabolic in Frank Ng’s
lab established in vivo evidence that AOD9604 could stimulate lipolysis:
• The 2000 Hormone Research10 paper. This paper looked at oral treatment of
obese rats with AOD9604, where the drug reduced weight gain over a 19 day
period by over 50% compared to the controls. When the adipose tissues of
the rats were studied the scientists found ‘an increase in lipolytic activity’,
that is, it was fat and not some other tissue that was burned.
• The 2001 Endocrinology11 paper. This paper identified a potential mechanism
of action for AOD9604. The drug, when administered to ob/ob mice
intraperitoneally over a 14 day period, not only saw marked weight losses in
the mice, but also a noticeable increased in the level of expression of ?3
adrenergic receptors whose major function of these receptors is
enhancement of lipolysis.


Also,

AOD9604’s delivery could have been the key issue. POH’s basic thinking on
AOD9604 is that the drug failed because it was made orally available, which likely
reduced bioavailability and also potentially resulted in protein denaturisation in
the gastrointestinal tract, which would have reduced the drug’s activity.
• The molecule was too unwieldy to be a pill - At a molecular weight of 1,815
daltons, AOD9604 is a large drug, around five or six times the size of a typical
small molecule. Drugs much smaller have low oral bioavailability due to
difficulty in getting through the gut wall. For example, leuprolide is a synthetic
nine amino acid peptide with a 1,200 dalton molecular weight used in the
treatment of prostate cancer in men and endometriosis in women. That drug
has virtually no oral bioavailability and has to be delivered through injectable,
injectable depot or subcutaneous implant formats. Even if AOD9604 was
only a small peptide, it would still be susceptible to enzymatic degradation in
the gut, being derived as it is from a naturally occurring protein12.
• Some drug, but probably not enough, got through - For AOD9604, large
molecule size wouldn’t have reduced bioavailability to zero, and the use of
polyethylene glycol as an excipient may have increased bioavailability
slightly13, however there is the distinct possibility that not enough of the drug
got through the gastrointestinal tract to make a therapeutic difference.
• There is evidence that injecting the drug works better – Looking at the charts
which Ng et al. disclosed on AOD9604’s activity in WO 99/12969 (the basic
patent application for the drug), it appears that intraperitoneal injections of
the drug were more effective than oral gavage, with injections showing
weight losses, and oral gavage showing merely slowing of weight gain14.
• POH would further argue that if insulin, three times the size of AOD9604, can
be delivered transdermally via TPM, and then successful transdermal delivery of
AOD9604 is not a problem15.

As this site shows AOD9604 is $45 for 5 mg. with a dose of 500-1000mcg per day however (1 mg is equal to 1000 mcg so 5 to 10 days treatment )

http://clinicalgradepeptides.com/purepeptides/index.php?_a=product&product_id=5

If I understand correctly from what you have posted earlier the cost of manufacture may be such that simply increasing dosage may be a viable option.

There may be another option on the horizon i.e. Micro needles: a valuable physical enhancer to increase transdermal drug delivery.

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery.